The receptor for activated C kinase 1 (RACK1) is a protein that plays a crucial role in various signaling pathways and is involved in the pathogenesis of Alzheimer's disease (AD), a prevalent neurodegenerative disease. RACK1 is highly expressed in neuronal cells of the central nervous system and regulates the pathogenesis of AD. Specifically, RACK1 is involved in regulation of the amyloid-β precursor protein processing through α- or β-secretase by binding to different protein kinase C isoforms. Additionally, RACK1 promotes synaptogenesis and synaptic plasticity by inhibiting N-methyl-D-aspartate receptors and activating gamma-aminobutyric acid A receptors, thereby preventing neuronal excitotoxicity. RACK1 also assembles inflammasomes that are involved in various neuroinflammatory pathways, such as nuclear factor-kappa B, tumor necrosis factor-alpha, and NOD-like receptor family pyrin domain-containing 3 pathways. The potential to design therapeutics that block amyloid-β accumulation and inflammation or precisely regulate synaptic plasticity represents an attractive therapeutic strategy, in which RACK1 is a potential target. In this review, we summarize the contribution of RACK1 to the pathogenesis of AD and its potential as a therapeutic target.
","appendixList":[],"articleBusiness":{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","articleState":"-1","articleType":"1","baiduIncludeResult":0,"baiduIncludeResultSearchNum":0,"baiduPushLastDate":1688007300000,"baiduPushNum":3,"baiduXueShuIncludeResult":0,"baiduXueShuIncludeResultSearchNum":0,"baiduXueShuPushLastDate":1688007300000,"baiduXueShuPushNum":3,"filename":"JBR-2022-0259.xml","googleIncludeResult":0,"googleIncludeResultSearchNum":0,"htmlSource":1,"htmlViewCount":264,"id":"be16093d-ec2c-4f77-84f2-935a01a873f1","isRegCstr":0,"isRegDOI":1,"pdfDownCount":35,"pdfEnFileSizeInt":0,"pdfFileName":"JBR-2022-0259.pdf","pdfFileSize":7922.7,"pdfFileSizeInt":7922,"remark":"excel","sortNum":0,"viewCount":387,"xmlDownCount":0,"xmlFileSize":148.0},"articleNo":"JBR-2022-0259","authors":[{"addressTagIds":"aff1","articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","authorNameEn":"Wenting He","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Wenting","id":"1029ebef-5e2e-46c2-abac-c35795885c2d","sortNumber":1,"surNameEn":"He"},{"addressTagIds":"aff1","articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","authorNameEn":"Xiuyu Shi","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":true,"correspinfoEn":"Xiuyu Shi and Zhifang Dong, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, 136 Zhongshan 2nd Road, Yuzhong District, Chongqing 400014, China. E-mails: ","deceased":0,"email":"zfdong@cqmu.edu.cn","givenNamesEn":"Zhifang","id":"8411720b-9de7-4ed6-89da-4f3764f5c254","sortNumber":3,"surNameEn":"Dong"}],"categoryNameEn":"Review Article","citationCn":"","citationEn":"Wenting He, Xiuyu Shi, Zhifang Dong. The roles of RACK1 in the pathogenesis of Alzheimer's disease[J]. The Journal of Biomedical Research, 2024, 38(2): 137-148. DOI: 10.7555/JBR.37.20220259","doi":"10.7555/JBR.37.20220259","figList":[{"columnNums":2,"dataId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2022-0259-1.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0259-1.jpg","id":"302e93db-1535-4594-b43f-d844e5a1dff1","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"RACK1/PKCs participate in the neurofunctional pathway of APP metabolism.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"The α-secretase cleavage of APP (non-amyloidogenic pathway on the left side with blue background) is neuroprotective and regulated by PKC isozymes in conjunction with RACK1. This results in the production of sAPPα, which has also been demonstrated to have neuroprotective properties when aided by RACK1 and PKCβⅡ. However, the β-secretase cleavage of APP (amyloidogenic pathway on the right side with orange background) generates Aβ, which is neurotoxic with the help of RACK1 on the membrane. Cell membranes are represented by a phospholipid bilayer and its upper side represents the extracellular space. Abbreviations: Aβ, amyloid-β; APP, Aβ precursor protein; sAPPα, soluble APP alpha; sAPPβ, soluble APP beta; CTF, C-terminal fragment; C83, CTF of 83 amino acids; C99, CTF of 99 amino acids; P3, peptide P3; RACK1, receptor for activated C kinase 1; PKC, protein kinase C. This figure was created with BioRender.com.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},{"columnNums":2,"dataId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2022-0259-2.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0259-2.jpg","id":"3bf8576d-5905-45dc-91c6-d6e353df5dd8","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Illustration of the interactions of RACK1 and NMDARs in different brain regions.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"A and B: In the hippocampus and dorsal striatal neurons, RACK1 binds to the NR2B subunit's tail and Fyn kinase to prevent NR2B phosphorylation (A). When RACK1 is removed from the NMDARs, Fyn can phosphorylate NR2B (B). C: In the cerebral cortex, RACK1 is linked to Fyn but not to the NMDARs. D: In the dorsolateral striatum and the nucleus accumbens, RACK1 interacts with none of the proteins mentioned above. The dark green line represents the synaptic membrane and its light green-filled inner side represents the intracellular space. Abbreviations: NMDAR, N-methyl-aspartate receptors; NR1 and NR2B, subunit 1 and subunit 2B of NMDAR; Fyn, a member of the Src family of protein tyrosine kinases; GPCR, G protein-coupled receptor; PACAP, pituitary adenylate cyclase-activating polypeptide; Gα, Gβ and Gγ, different subunits of the heterotrimeric G protein; RACK1, receptor for activated C kinase 1.","tagId":"Figure2","type":"article","typesetSecTagId":"s04"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/","firstFig":{"columnNums":2,"dataId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2022-0259-1_mini.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0259-1.jpg","id":"302e93db-1535-4594-b43f-d844e5a1dff1","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"RACK1/PKCs participate in the neurofunctional pathway of APP metabolism.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"The α-secretase cleavage of APP (non-amyloidogenic pathway on the left side with blue background) is neuroprotective and regulated by PKC isozymes in conjunction with RACK1. This results in the production of sAPPα, which has also been demonstrated to have neuroprotective properties when aided by RACK1 and PKCβⅡ. However, the β-secretase cleavage of APP (amyloidogenic pathway on the right side with orange background) generates Aβ, which is neurotoxic with the help of RACK1 on the membrane. Cell membranes are represented by a phospholipid bilayer and its upper side represents the extracellular space. Abbreviations: Aβ, amyloid-β; APP, Aβ precursor protein; sAPPα, soluble APP alpha; sAPPβ, soluble APP beta; CTF, C-terminal fragment; C83, CTF of 83 amino acids; C99, CTF of 99 amino acids; P3, peptide P3; RACK1, receptor for activated C kinase 1; PKC, protein kinase C. This figure was created with BioRender.com.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},"hasPage":true,"htmlAccess":true,"id":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","issue":"2","issueArticle":"0","keywords":[{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","id":"ea146929-9055-49ec-9c08-8aea5d6ef214","keywordEn":"RACK1","sortNum":1},{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","id":"64702e0d-964a-4ecb-81db-3bd64e3b245d","keywordEn":"Alzheimer's disease","sortNum":2},{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","id":"3af167f7-699f-4a81-9785-354e11c7361d","keywordEn":"PKC","sortNum":3},{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","id":"dccdf83c-370a-4ca3-9709-55bdc5e4e7d3","keywordEn":"amyloid-β","sortNum":4},{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","id":"dd9a39d1-4cff-4e37-8e25-61911f3c7b01","keywordEn":"synaptic plasticity","sortNum":5},{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","id":"2b3eaf1c-1a79-4589-8913-b93b5e3ac753","keywordEn":"neuroinflammation","sortNum":6}],"language":"en","page":"137-148","pdfAccess":true,"publisherId":"JBR-2022-0259","releaseProgress":{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","lastReleaseTime":"2024-05-29 18:14","maxLastReleaseTime":"2024-05-29 18:14","minLastReleaseTime":"2024-03-28 16:12","otherReleaseList":[{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2024-02-27 17:58","maxLastReleaseTime":"2024-02-27 17:58","minLastReleaseTime":"2024-02-27 17:58","otherReleaseList":[]},{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-06-29 10:51","maxLastReleaseTime":"2023-06-29 10:51","minLastReleaseTime":"2023-06-28 16:15","otherReleaseList":[]},{"articleId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","currentState":"Accepted Manuscript","currentStateEn":"Accepted Manuscript","lastReleaseTime":"2023-06-08 13:06","maxLastReleaseTime":"2023-06-08 13:06","minLastReleaseTime":"2023-06-08 13:06","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20240002000000","subTitleCn":"","subTitleEn":"","supplements":[],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"The roles of RACK1 in the pathogenesis of Alzheimer's disease","topicNameEn":"","type":"research-article","volume":"38","year":"2024","yearInt":2024},"dataId":"8ed224eb-e20f-4276-bdd4-eddf75d5c674","dataType":"Article","id":"c94b9159-aab6-4f8c-8ca5-e53f12defc62","language":"cn,en","sort":61,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"Aging is characterized by progressive degeneration of tissues and organs, and it is positively associated with an increased mortality rate. The brain, as one of the most significantly affected organs, experiences age-related changes, including abnormal neuronal activity, dysfunctional calcium homeostasis, dysregulated mitochondrial function, and increased levels of reactive oxygen species. These changes collectively contribute to cognitive deterioration. Aging is also a key risk factor for neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. For many years, neurodegenerative disease investigations have primarily focused on neurons, with less attention given to microglial cells. However, recently, microglial homeostasis has emerged as an important mediator in neurological disease pathogenesis. Here, we provide an overview of brain aging from the perspective of the microglia. In doing so, we present the current knowledge on the correlation between brain aging and the microglia, summarize recent progress of investigations about the microglia in normal aging, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and then discuss the correlation between the senescent microglia and the brain, which will culminate with a presentation of the molecular complexity involved in the microglia in brain aging with suggestions for healthy aging.
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E-mail: caizhiyou@ucas.ac.cn","deceased":0,"email":"caizhiyou@ucas.ac.cn","givenNamesEn":"Zhiyou","id":"6d7f248f-687e-4f21-ba92-8c3fc7a9b206","sortNumber":10,"surNameEn":"Cai"}],"categoryNameEn":"Review Article","citationCn":"","citationEn":"Haixia Fan, Minheng Zhang, Jie Wen, Shengyuan Wang, Minghao Yuan, Houchao Sun, Liu Shu, Xu Yang, Yinshuang Pu, Zhiyou Cai. Microglia in brain aging: An overview of recent basic science and clinical research developments[J]. The Journal of Biomedical Research, 2024, 38(2): 122-136. DOI: 10.7555/JBR.37.20220220","doi":"10.7555/JBR.37.20220220","figList":[{"columnNums":2,"dataId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2022-0220-1.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0220-1.jpg","id":"957a19d6-c56b-4ed2-a179-d23e08ec7d61","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Microglial phenotypes and functions.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"Microglia, resident immune cells in the brain, perform a wide range of functions other than immunity in both health and unhealthy aging. Microglial phenotypes are divided into five main states: 1) The primary function of microglia in their resting state (M0) is immune surveillance and homeostasis of the brain's physiological environment; 2) Classically activated microglia (M1) is neurotoxic that can secrete inflammatory cytokines; 3) Alternative activated microglia (M2a) has a role in repair and regeneration; 4) Transitional activated microglia (M2b) is associated with immune regulation, such as the recruitment of regulatory T cells and the release of the anti-inflammatory cytokine IL-10; 5) Acquired deactivated microglia (M2c) participate in neuroprotection and release some anti-inflammatory cytokines. Distinctive stimuli, phenotypic marker expression, and secreted mediators play roles in the final result of these polarization states. Abbreviations: BBB, blood-brain barrier; CD, cluster of differentiation; ARG1, arginase 1; MHC Ⅱ, major histocompatibility complex class Ⅱ; IL-10, interleukin-10.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},{"columnNums":2,"dataId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2022-0220-2.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0220-2.jpg","id":"35043509-d432-4deb-8fbe-fda272eb5854","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Microglial changes in healthy and unhealthy brain aging.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"Microglia exhibit alterations in their morphology, phenotypes, and protein markers. In healthy brain aging, the percentage of hypertrophic microglia, featured with an enlarged cell soma and the thickened length of processes, is age-dependent. Iron overload can be observed in the microglia and influence their functional phenotypes. Microglia can build up lipid droplets with age, which is identified as lipid droplet-accumulating microglia (LDAM) featuring phagocytosis defect, the increased production of reactive oxygen species, and higher secretion of inflammatory cytokines. In unhealthy brain aging, dystrophic microglia, characterized by small body and deramified processes, are more common in the aged brain with neurodegenerative disease. These cells transform into disease-associated microglia (DAM), representing a neurodegeneration-specific and transcriptionally-distinct microglial phenotype in different diseases, such as AD and PD. Both states of brain aging share similar dysfunctions, such as phagocytosis and immune regulation defects, reduced motility and migration, and chronic inflammation persistence. However, the effect of these dysfunctions may be more pronounced in unhealthy brain aging. Notably, unhealthy brain aging is associated with shorter lifespans, reduced cognition, and a lower quality of life. Abbreviations: AD, Alzheimer's disease; PD, Parkinson's disease; ALS, amyotrophic lateral sclerosis; P2Y12, purinergic receptor P2Y, G-protein coupled, 12; CD, cluster of differentiation; CX3CR1, C-X3-C motif chemokine receptor 1; IBA1, ionized calcium binding adapter molecule 1; MHC Ⅱ, major histocompatibility complex Ⅱ.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2022-0220-3.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0220-3.jpg","id":"39b4de2d-69f4-4702-b9ca-c1759b31dd99","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"Microglial signaling pathways activated in different neurodegenerative diseases.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"The CNS microglia contribute to neuronal death in diseases like AD, PD, ALS, and HD. MAPK/AP-1, NF-κB, and other related pathways are associated with AD; TLR2/4/5/TNF-α, NLRP3/ NF-κB, TNF-α/STAT1, and PKB are involved in PD; PI3K/ PKB, and NF-κB are involved with ALS; MMP3, NF-κB, TNF-α, and MAPK are main active molecules. Microglial activation is a hallmark of most brain diseases mentioned above, triggering inflammation signaling pathways. Thus, anti-inflammatory strategies that repress microglial activation and exert neuroprotective effects are important in neurodegenerative diseases. Abbreviations: AD, Alzheimer's disease; PD, Parkinson's disease; ALS, amyotrophic lateral sclerosis; HD, Huntington's disease; CNS, central nervous system; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; IL-10, interleukin-10; MAPK, mitogen-activated protein kinase; AP-1, activating protein-1; PKB, protein kinase B; NF-κb, nuclear factor-kappa B; STAT1, signal transducer and activator of transcription 1; TLR, Toll-like receptors; NLRP3, NOD-like receptor thermal protein domain associated protein 3; PI3K, phosphatidylinositol 3 kinase.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/","firstFig":{"columnNums":2,"dataId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2022-0220-1_mini.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0220-1.jpg","id":"957a19d6-c56b-4ed2-a179-d23e08ec7d61","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Microglial phenotypes and functions.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"Microglia, resident immune cells in the brain, perform a wide range of functions other than immunity in both health and unhealthy aging. Microglial phenotypes are divided into five main states: 1) The primary function of microglia in their resting state (M0) is immune surveillance and homeostasis of the brain's physiological environment; 2) Classically activated microglia (M1) is neurotoxic that can secrete inflammatory cytokines; 3) Alternative activated microglia (M2a) has a role in repair and regeneration; 4) Transitional activated microglia (M2b) is associated with immune regulation, such as the recruitment of regulatory T cells and the release of the anti-inflammatory cytokine IL-10; 5) Acquired deactivated microglia (M2c) participate in neuroprotection and release some anti-inflammatory cytokines. Distinctive stimuli, phenotypic marker expression, and secreted mediators play roles in the final result of these polarization states. Abbreviations: BBB, blood-brain barrier; CD, cluster of differentiation; ARG1, arginase 1; MHC Ⅱ, major histocompatibility complex class Ⅱ; IL-10, interleukin-10.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},"hasPage":true,"htmlAccess":true,"id":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","issue":"2","issueArticle":"0","keywords":[{"articleId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","id":"307f5c02-970f-4944-9933-7df55c948268","keywordEn":"microglia","sortNum":1},{"articleId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","id":"78d10ae3-7157-4f1c-9ee3-c3230882297e","keywordEn":"brain aging","sortNum":2},{"articleId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","id":"4ce5d097-6ad4-46f4-85a8-b4379fa632d8","keywordEn":"Alzheimer's disease","sortNum":3},{"articleId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","id":"d6f7390c-7d37-4fe6-a7c5-745fcea937dc","keywordEn":"Parkinson's disease","sortNum":4},{"articleId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","id":"a995b3e8-d82e-4cec-8f1b-d2eb13c5f486","keywordEn":"Huntington's disease","sortNum":5}],"language":"en","page":"122-136","pdfAccess":true,"publisherId":"JBR-2022-0220","releaseProgress":{"articleId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","lastReleaseTime":"2024-05-29 18:14","maxLastReleaseTime":"2024-05-29 18:14","minLastReleaseTime":"2024-03-28 16:12","otherReleaseList":[{"articleId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2024-01-31 09:16","maxLastReleaseTime":"2024-01-31 09:16","minLastReleaseTime":"2023-11-23 09:49","otherReleaseList":[]},{"articleId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","currentState":"Accepted Manuscript","currentStateEn":"Accepted Manuscript","lastReleaseTime":"2023-06-08 13:06","maxLastReleaseTime":"2023-06-08 13:06","minLastReleaseTime":"2023-06-08 13:06","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20240002000000","subTitleCn":"","subTitleEn":"","supplements":[],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Microglia in brain aging: An overview of recent basic science and clinical research developments","topicNameEn":"","type":"research-article","volume":"38","year":"2024","yearInt":2024},"dataId":"3cdead58-d431-41cb-8fc8-af5e3bc4bfd7","dataType":"Article","id":"6bec80b7-7c68-4927-8dfc-4fa497753f2a","language":"cn,en","sort":71,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"One of the quintessential challenges in cancer treatment is drug resistance. Several mechanisms of drug resistance have been described to date, and new modes of drug resistance continue to be discovered. The phenomenon of cancer drug resistance is now widespread, with approximately 90% of cancer-related deaths associated with drug resistance. Despite significant advances in the drug discovery process, the emergence of innate and acquired mechanisms of drug resistance has impeded the progress in cancer therapy. Therefore, understanding the mechanisms of drug resistance and the various pathways involved is integral to treatment modalities. In the present review, I discuss the different mechanisms of drug resistance in cancer cells, including DNA damage repair, epithelial to mesenchymal transition, inhibition of cell death, alteration of drug targets, inactivation of drugs, deregulation of cellular energetics, immune evasion, tumor-promoting inflammation, genome instability, and other contributing epigenetic factors. Furthermore, I highlight available treatment options and conclude with future directions.
","appendixList":[],"articleBusiness":{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","articleState":"-1","articleType":"1","baiduIncludeResult":0,"baiduIncludeResultSearchNum":0,"baiduPushLastDate":1702098600000,"baiduPushNum":1,"baiduXueShuIncludeResult":0,"baiduXueShuIncludeResultSearchNum":0,"baiduXueShuPushLastDate":1702098600000,"baiduXueShuPushNum":1,"filename":"JBR-2023-0248.xml","googleIncludeResult":0,"googleIncludeResultSearchNum":0,"htmlSource":1,"htmlViewCount":37,"id":"6ce746bc-575a-4084-8710-96f42a16c616","isRegCstr":0,"isRegDOI":1,"pdfDownCount":14,"pdfEnFileSizeInt":0,"pdfFileName":"JBR-2023-0248.pdf","pdfFileSize":3175.01,"pdfFileSizeInt":3175,"remark":"excel","sortNum":0,"viewCount":57,"xmlDownCount":0,"xmlFileSize":28.0},"articleNo":"JBR-2023-0248","authors":[{"addressTagIds":"aff1","articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","authorNameEn":"Pavan Kumar Dhanyamraju","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":true,"correspinfoEn":"Pavan Kumar Dhanyamraju, Fels Cancer Institute of Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA. E-mail: panbio77@gmail.com","deceased":0,"email":"panbio77@gmail.com","givenNamesEn":"Pavan Kumar","id":"bfcdf345-108c-41e9-97ac-a0d58556f7b6","sortNumber":1,"surNameEn":"Dhanyamraju"}],"categoryNameEn":"Review Article","citationCn":"","citationEn":"Pavan Kumar Dhanyamraju. Drug resistance mechanisms in cancers: Execution of pro-survival strategies[J]. The Journal of Biomedical Research, 2024, 38(2): 95-121. DOI: 10.7555/JBR.37.20230248","doi":"10.7555/JBR.37.20230248","figList":[{"columnNums":2,"dataId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2023-0248-1.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0248-1.jpg","id":"c27676e8-a5bb-4403-bf5b-5424ab286d1a","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Modes of drug resistance.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A graphical representation of the two main types of drug resistance observed in cancer cells. Intrinsic resistance and acquired resistance. Intrinsic, innate, or primary resistance is the kind of resistance present in cancer cells even before treatment with chemotherapeutic drugs, whereas extrinsic, acquired, or secondary resistance is the kind of resistance that develops after an initial period of sensitivity to the drug, but later develops resistance against the chemotherapeutic drugs.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},{"columnNums":2,"dataId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2023-0248-2.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0248-2.jpg","id":"503dbd13-6220-44ab-bc76-ebf98a975e93","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"A graphical illustration of drug resistance mechanisms in cancer cells.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"The basic modes through which cancer cells may resist chemotherapeutic drugs and radiotherapy are depicted. These mechanisms of drug resistance may function independently or synergistically.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2023-0248-3.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0248-3.jpg","id":"44c6f85a-c140-4b2e-abb6-08fd8cbbf7f0","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"A graphical illustration of signaling pathways involved in drug resistance in cancer cells.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"Some of the most commonly deregulated signaling pathways that contribute to drug resistance in cancer cells are depicted here. Abbreviations: PI3K/AKT/mTOR, phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin; TGF-β, transforming growth factor beta; Hh, Hedgehog; JAK/STAT, Janus kinase/signal transducers and activators of transcription; EGFR, epidermal growth factor receptor; Wnt, wingless-related integration site; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells. Note: Not all the pathways contributing to cancer cell drug resistance are depicted here.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2023-0248-4.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0248-4.jpg","id":"9be7742c-6c44-4659-8649-f70af0dff306","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Graphical illustration of \"revised\" hallmarks of cancer.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"Various aspects of cancer cells have been depicted in this figure. Acquisition of one or more feature/s by a normal cell would lead to cancer. The figure has been adapted and modified from the specified references[4–5].","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2023-0248-5.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0248-5.jpg","id":"b18e4578-997d-46e3-a51f-0b3dee6eb03f","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Graphical representation of microRNAs in cancer drug resistance.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"Deregulated expression of various microRNAs plays a significant role in cancer drug resistance. The resistance can be against radiotherapy and/or chemotherapy. Note: not all microRNAs involved in drug resistance are depicted here.","tagId":"Figure5","type":"article","typesetSecTagId":"s04"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/","firstFig":{"columnNums":2,"dataId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/2/JBR-2023-0248-1_mini.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0248-1.jpg","id":"c27676e8-a5bb-4403-bf5b-5424ab286d1a","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Modes of drug resistance.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A graphical representation of the two main types of drug resistance observed in cancer cells. Intrinsic resistance and acquired resistance. Intrinsic, innate, or primary resistance is the kind of resistance present in cancer cells even before treatment with chemotherapeutic drugs, whereas extrinsic, acquired, or secondary resistance is the kind of resistance that develops after an initial period of sensitivity to the drug, but later develops resistance against the chemotherapeutic drugs.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},"hasPage":true,"htmlAccess":true,"id":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","issue":"2","issueArticle":"0","keywords":[{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","id":"57eecf26-7863-462d-b210-90840e2a6039","keywordEn":"cancer","sortNum":1},{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","id":"878ba8d5-3b6c-449b-a397-5f49da9970f2","keywordEn":"drug resistance","sortNum":2},{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","id":"95de3666-f6c4-4369-b47b-2d4cbc627edf","keywordEn":"mechanisms","sortNum":3},{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","id":"45dcae71-3dc5-4872-88af-f20c56105086","keywordEn":"microRNAs","sortNum":4},{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","id":"976d6d14-dca1-42ee-91e8-c73e81b2273c","keywordEn":"treatment strategies","sortNum":5}],"language":"en","page":"95-121","pdfAccess":true,"publisherId":"JBR-2023-0248","releaseProgress":{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","lastReleaseTime":"2024-05-29 18:14","maxLastReleaseTime":"2024-05-29 18:14","minLastReleaseTime":"2024-03-28 16:12","otherReleaseList":[{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2024-03-07 17:30","maxLastReleaseTime":"2024-03-07 17:30","minLastReleaseTime":"2024-02-28 08:53","otherReleaseList":[]},{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2024-01-22 19:30","maxLastReleaseTime":"2024-01-22 19:30","minLastReleaseTime":"2024-01-22 18:05","otherReleaseList":[]},{"articleId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","currentState":"Accepted Manuscript","currentStateEn":"Accepted Manuscript","lastReleaseTime":"2023-12-09 13:07","maxLastReleaseTime":"2023-12-09 13:07","minLastReleaseTime":"2023-12-09 13:07","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20240002000000","subTitleCn":"","subTitleEn":"","supplements":[],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Drug resistance mechanisms in cancers: Execution of pro-survival strategies","topicNameEn":"","type":"research-article","volume":"38","year":"2024","yearInt":2024},"dataId":"e55de6a8-6aed-4fcb-a4a1-b5c10ffa2dcd","dataType":"Article","id":"34eeec59-1e5b-4d87-b949-987d05387ee6","language":"cn,en","sort":81,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis, but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking. To address this gap, we conducted a study aiming to investigate this association and identify relevant biomarkers. We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment, biological activity, and the immune microenvironment. Additionally, we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies (GWASs) involving both East Asian (7062 cases and 195745 controls) and European (24476 cases and 23073 controls) populations. We employed mediation analysis to infer the causal pathway, and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells. Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1 (FEN1) gene were significantly enriched in colorectal tumor tissues, compared with normal tissues. Moreover, a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer (odds ratio = 0.94, 95% confidence interval: 0.90–0.97, Pmeta = 4.70 × 10−9). Importantly, we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors, and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication. In conclusion, this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity, expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.
","appendixList":[],"articleBusiness":{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","articleState":"-1","articleType":"1","baiduIncludeResult":0,"baiduIncludeResultSearchNum":0,"baiduPushLastDate":1702946700000,"baiduPushNum":3,"baiduXueShuIncludeResult":0,"baiduXueShuIncludeResultSearchNum":0,"baiduXueShuPushLastDate":1702946700000,"baiduXueShuPushNum":3,"filename":"JBR-2023-0081.xml","googleIncludeResult":0,"googleIncludeResultSearchNum":0,"htmlSource":1,"htmlViewCount":310,"id":"d7ed90b6-afce-4f72-83dd-72a7ebd9463a","isRegCstr":0,"isRegDOI":1,"pdfDownCount":20,"pdfEnFileSizeInt":0,"pdfFileName":"JBR-2023-0081.pdf","pdfFileSize":6619.45,"pdfFileSizeInt":6619,"remark":"excel","sortNum":0,"viewCount":453,"xmlDownCount":0,"xmlFileSize":110.0},"articleNo":"JBR-2023-0081","authors":[{"addressTagIds":"aff1","articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","authorNameEn":"Sumeng Wang","authorNotesEn":"△The authors contributed equally.","authorRoleType":"author","authorTagVal":"1, △","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Sumeng","id":"53ff055f-161b-4f1d-9817-41690df87beb","sortNumber":1,"surNameEn":"Wang"},{"addressTagIds":"aff2, aff3","articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","authorNameEn":"Silu Chen","authorNotesEn":"△The authors contributed equally.","authorRoleType":"author","authorTagVal":"2, 3, △","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Silu","id":"7f4d8d4c-bfcf-4725-97a1-c41aff855d74","sortNumber":2,"surNameEn":"Chen"},{"addressTagIds":"aff4","articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","authorNameEn":"Huiqin Li","authorRoleType":"author","authorTagVal":"4","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Huiqin","id":"2a2b26ed-2d99-42b3-90e5-096be09ea03f","sortNumber":3,"surNameEn":"Li"},{"addressTagIds":"aff2, aff3","articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","authorNameEn":"Shuai Ben","authorRoleType":"author","authorTagVal":"2, 3","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Shuai","id":"74f2c0c3-afc4-41c4-9c1b-f7a607b2a682","sortNumber":4,"surNameEn":"Ben"},{"addressTagIds":"aff1","articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","authorNameEn":"Tingyu Zhao","authorRoleType":"author","authorTagVal":"1","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Tingyu","id":"450b4f4a-2c50-4d25-8573-4c06ec328216","sortNumber":5,"surNameEn":"Zhao"},{"addressTagIds":"aff2, aff3","articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","authorNameEn":"Rui Zheng","authorRoleType":"author","authorTagVal":"2, 3","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Rui","id":"19b284c3-b130-42d5-8a0e-c84db53aa832","sortNumber":6,"surNameEn":"Zheng"},{"addressTagIds":"aff2, aff3","articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","authorNameEn":"Meilin Wang","authorRoleType":"author","authorTagVal":"2, 3","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Meilin","id":"cb246409-1f4d-4843-880e-7e3cf4325e4a","sortNumber":7,"surNameEn":"Wang"},{"addressTagIds":"aff5","articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","authorNameEn":"Dongying Gu","authorRoleType":"author","authorTagVal":"5","authorType":"org","corresper":true,"correspinfoEn":"Dongying Gu, Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, China. E-mail: dygu@njmu.edu.cn","deceased":0,"email":"dygu@njmu.edu.cn","givenNamesEn":"Dongying","id":"3a582f30-af4f-48b1-ae6b-46f0aa7b76b1","sortNumber":8,"surNameEn":"Gu"},{"addressTagIds":"aff1","articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","authorNameEn":"Lingxiang Liu","authorRoleType":"author","authorTagVal":"1","authorType":"org","corresper":true,"correspinfoEn":"Lingxiang Liu, Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China. E-mail: llxlau@163.com","deceased":0,"email":"llxlau@163.com","givenNamesEn":"Lingxiang","id":"c8f21024-1bb5-4896-9d23-5d7db67dd459","sortNumber":9,"surNameEn":"Liu"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Sumeng Wang, Silu Chen, Huiqin Li, Shuai Ben, Tingyu Zhao, Rui Zheng, Meilin Wang, Dongying Gu, Lingxiang Liu. Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS[J]. The Journal of Biomedical Research, 2024, 38(1): 37-50. DOI: 10.7555/JBR.37.20230081","doi":"10.7555/JBR.37.20230081","figList":[{"columnNums":2,"dataId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0081-1.jpg","fileSize":"628KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0081-1.jpg","id":"a72b608b-2280-4b9d-9702-b83f525fa9dc","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Flow chart of the study design.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"Omics data and methods used in the current study are shown in cylinders and orange boxes, respectively. The key results of the study are displayed in red boxes. Four distinct pathways were derived by intersecting the results obtained from GSEA and GSVA using transcriptomic level and proteomic level datasets. Subsequently, MAGMA analysis was employed with genome-wide summary statistics to identify pathways that exhibited statistical significance. Additionally, a specific gene of interest, FEN1, and its corresponding SNP (rs4246215) were identified. Notably, the tumor immune microenvironment was also depicted, providing valuable insights into the interplay between genetic factors and the immune response within the context of tumorigenesis. To further explore causal associations, mediation analysis, and multiplex immunofluorescence were conducted, enabling a comprehensive understanding of the underlying mechanisms. Abbreviations: BBJ, Biobank Japan; GECCO, Genetics and Epidemiology of Colorectal Cancer Consortium; GEO, Gene Expression Omnibus; TCGA, The Cancer Genome Atlas; GSEA, gene set enrichment analysis; MAGMA, Multi-marker Analysis of GenoMic Annotation; SNPs, single nucleotide polymorphisms.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0081-2.jpg","fileSize":"1504KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0081-2.jpg","id":"dd406208-3bee-4208-a580-3703dad8be0f","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Pathway enrichment analysis and activity estimation at both the RNA and protein levels.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"A: Significant pathways underlying the GSEA algorithm across five datasets at the RNA level. B: Significant pathways underlying the GSVA algorithm across five datasets at the RNA level. C: Four significant pathways were yielded from intersections between GSEA and GSVA analyses across five datasets. D: Differential activity of four representative pathways between colorectal tumors and normal tissues of the Nanjing cohort at the RNA level (top) and the protein level (bottom). Abbreviations: GSEA, gene set enrichment analysis; GSVA, gene set variation analysis; TCGA, The Cancer Genome Atlas.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0081-3.jpg","fileSize":"2835KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0081-3.jpg","id":"b7d08232-fa26-4918-8067-5dd99c24ad03","imgWidth":"15.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"Genetic effects on colorectal cancer susceptibility and expression pattern of FEN1 and DNA replication activity.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"A: Manhattan plot of the genetic effect at the gene level via MAGMA. The red dotted line shows the significance threshold of Bonferroni-adjusted P < 0.05. B: Regional plot for the association of rs4246215 and colorectal cancer risk derived from BBJ, GECCO, and GWAS meta-analyses. Each unique locus was defined as ± 100 kilobases (kb) on either side of rs4246215. C: Expression pattern of FEN1 and DNA replication activity of the Nanjing cohort at the RNA (top) and protein (bottom) levels. ****P < 0.0001. D: Representative multiple immunofluorescence images of FEN1 in colorectal tumors and normal tissues. Scale bar: 100 μm (upper) and 25 μm (lower), respectively. E: The average intensity of FEN1 in colorectal tumors and normal tissues. The P-value was calculated by Wilcoxon test. **P < 0.01. Abbreviation: SNPs, single nucleotide polymorphisms.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0081-4.jpg","fileSize":"2521KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0081-4.jpg","id":"c7e56a1b-1561-45b0-b770-0827a12ec5e3","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Differentially infiltrating immune cells and their correlations with FEN1 and DNA replication.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"A: Differentially infiltrating immune cells between colorectal tumors and normal tissues underlying the CIBERSORT (top) and xCell (bottom) algorithms across five datasets. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. B: Correlations of FEN1 expression (top) and DNA replication activity (bottom) with infiltrating immune cells. The meta value was derived by combining the results from the five datasets using a random effect model. The x-axis represents Spearman's rank correlation coefficient. Abbreviations: CLP, common lymphoid progenitors; CMP, common myeloid progenitors; DC, dendritic cells; MEP, megakaryocyte-erythroid progenitors; pDC, plasmacytoid dendritic cells.","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0081-5.jpg","fileSize":"5446KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0081-5.jpg","id":"ce23e4bc-36b1-40ae-9ca6-805a057a914a","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Genetic effect of rs4246215 and multiplex immunofluorescence evaluation.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"A: The opposite genetic effect of rs4246215 on FEN1 in colorectal tumors (left) and normal tissues (right), TCGA dataset. Gene expression data were log2 transformed. B: Genetic effect of rs4246215 on DNA replication activity in colorectal tumors (left) and normal tissues (right), TCGA dataset. C: Genetic effect of rs4246215 on immunity (TCGA dataset). The P-value was calculated by linear regression. D: Representative multiple immunofluorescence images of CD3, CD22 and CD45 in colorectal tumors and normal tissues. Scale bar: 100 μm for the first and third rows and 25 μm for the second and forth rows, respectively. E: The average intensity of CD3, CD22 and CD45 in colorectal tumors and normal tissues. The P-value was calculated by the Wilcoxon test. *P < 0.05 and **P < 0.01. Abbreviations: TCGA, The Cancer Genome Atlas; Tem, effector memory T cells.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0081-6.jpg","fileSize":"1301KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0081-6.jpg","id":"3d5788d7-fb23-4315-b6cb-19f1c6f0182f","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"6","nameEn":"Causal mediation analysis between rs4246215 and immune cells mediated by FEN1 and DNA replication.","referSecTagIds":"","sort":5,"supplementRemarkCn":"","supplementRemarkEn":"A: A schematic diagram of mediation analysis. B–F: Detailed results for mediation analysis. Abbreviations: IE, indirect effect; TE, total effect; Tem, effector memory T cells.","tagId":"Figure6","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/","firstFig":{"columnNums":2,"dataId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0081-1_mini.jpg","fileSize":"628KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0081-1.jpg","id":"a72b608b-2280-4b9d-9702-b83f525fa9dc","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Flow chart of the study design.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"Omics data and methods used in the current study are shown in cylinders and orange boxes, respectively. The key results of the study are displayed in red boxes. Four distinct pathways were derived by intersecting the results obtained from GSEA and GSVA using transcriptomic level and proteomic level datasets. Subsequently, MAGMA analysis was employed with genome-wide summary statistics to identify pathways that exhibited statistical significance. Additionally, a specific gene of interest, FEN1, and its corresponding SNP (rs4246215) were identified. Notably, the tumor immune microenvironment was also depicted, providing valuable insights into the interplay between genetic factors and the immune response within the context of tumorigenesis. To further explore causal associations, mediation analysis, and multiplex immunofluorescence were conducted, enabling a comprehensive understanding of the underlying mechanisms. Abbreviations: BBJ, Biobank Japan; GECCO, Genetics and Epidemiology of Colorectal Cancer Consortium; GEO, Gene Expression Omnibus; TCGA, The Cancer Genome Atlas; GSEA, gene set enrichment analysis; MAGMA, Multi-marker Analysis of GenoMic Annotation; SNPs, single nucleotide polymorphisms.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},"hasPage":true,"htmlAccess":true,"id":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","issue":"1","issueArticle":"0","keywords":[{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","id":"4187253b-e988-405d-8263-c6a2bcbaad98","keywordEn":"trans-omics","sortNum":1},{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","id":"f73ea038-febd-47cb-8ec3-6a885a59520d","keywordEn":"DNA replication","sortNum":2},{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","id":"f7df725d-6c7a-40fe-bac4-6130696bae04","keywordEn":"tumor immune microenvironment","sortNum":3},{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","id":"da1ff125-bea2-4595-93fe-8cc13af5c76d","keywordEn":"causal mediation","sortNum":4},{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","id":"b5fcf824-f299-4f76-8f1c-8c3a6e4ef483","keywordEn":"colorectal tumorigenesis","sortNum":5}],"language":"en","page":"37-50","pdfAccess":true,"publisherId":"JBR-2023-0081","releaseProgress":{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","lastReleaseTime":"2024-01-26 09:25","maxLastReleaseTime":"2024-01-26 09:25","minLastReleaseTime":"2024-01-26 09:20","otherReleaseList":[{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-12-19 08:42","maxLastReleaseTime":"2023-12-19 08:42","minLastReleaseTime":"2023-12-19 08:42","otherReleaseList":[]},{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-06-12 13:14","maxLastReleaseTime":"2023-06-12 13:14","minLastReleaseTime":"2023-06-12 13:14","otherReleaseList":[]},{"articleId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","currentState":"Accepted Manuscript","currentStateEn":"Accepted Manuscript","lastReleaseTime":"2023-06-03 13:13","maxLastReleaseTime":"2023-06-03 13:13","minLastReleaseTime":"2023-06-03 13:13","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20240001000000","subTitleCn":"","subTitleEn":"","supplements":[{"dataId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","downloadNum":6,"fileLastName":"pdf","fileName":"JBR-2023-0081-Supplementary.pdf","filePath":"/fileSWYXYJZZYWB/journal/article/file/d7765cf0-a0d9-4d38-9d16-1329e947aeab.pdf","fileSize":"29462KB","fileType":"file","id":"acea5ee3-7b9a-4a74-a354-a73b373e624a","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","nameCn":"JBR-2023-0081-Supplementary","nameEn":"JBR-2023-0081-Supplementary","type":"article"}],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS","topicNameEn":"","type":"research-article","volume":"38","year":"2024","yearInt":2024},"dataId":"26b73a14-5477-429d-bb78-fd4f0bfd8fc7","dataType":"Article","id":"1f10d399-d243-4b0f-adc7-3a1741126ea3","language":"cn,en","sort":91,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"Peroxisomes are organelles enclosed by a single membrane and are present in various species. The abruption of peroxisomes is correlated with peroxisome biogenesis disorders and single peroxisomal enzyme deficiencies that induce diverse diseases in different organs. However, little is known about the protein compositions and corresponding roles of heterogeneous peroxisomes in various organs. Through transcriptomic and proteomic analyses, we observed heterogenous peroxisomal components among different organs, as well as between testicular somatic cells and different developmental stages of germ cells. As Pex3 is expressed in both germ cells and Sertoli cells, we generated Pex3 germ cell- and Sertoli cell-specific knockout mice. While Pex3 deletion in Sertoli cells did not affect spermatogenesis, the deletion in germ cells resulted in male sterility, manifested as the destruction of intercellular bridges between spermatids and the formation of multinucleated giant cells. Proteomic analysis of the Pex3-deleted spermatids revealed defective expressions of peroxisomal proteins and spermiogenesis-related proteins. These findings provide new insights that PEX3-dependent peroxisomes are essential for germ cells undergoing spermiogenesis, but not for Sertoli cells.
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E-mail: shajh@njmu.edu.cn","deceased":0,"email":"shajh@njmu.edu.cn","givenNamesEn":"Jiahao","id":"492e62ec-5a57-4e2f-a2f4-0dd394be7e6b","sortNumber":11,"surNameEn":"Sha"},{"addressTagIds":"aff1","articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","authorNameEn":"Xuejiang Guo","authorRoleType":"author","authorTagVal":"1","authorType":"org","corresper":true,"correspinfoEn":"Xuejiang Guo, State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu 211166, China. E-mail: guo_xuejiang@njmu.edu.cn","deceased":0,"email":"guo_xuejiang@njmu.edu.cn","givenNamesEn":"Xuejiang","id":"9d0f239e-56b1-475b-8b6d-dd636f4dc0a8","sortNumber":12,"surNameEn":"Guo"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Yejin Yao, Baolu Shi, Xiangzheng Zhang, Xin Wang, Shuangyue Li, Ying Yao, Yueshuai Guo, Dingdong Chen, Bing Wang, Yan Yuan, Jiahao Sha, Xuejiang Guo. Germ cell-specific deletion of Pex3 reveals essential roles of PEX3-dependent peroxisomes in spermiogenesis[J]. The Journal of Biomedical Research, 2024, 38(1): 24-36. DOI: 10.7555/JBR.37.20230055","doi":"10.7555/JBR.37.20230055","figList":[{"columnNums":2,"dataId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0055-1.jpg","fileSize":"4427KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0055-1.jpg","id":"a50195fa-0d71-4a4c-a739-8d074e450cde","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Heterogeneity of peroxisomes in organs and testicular cells.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: Heatmap visualizing the scaled, normalized expression of the peroxisomal genes in the mouse organs. Columns represent different organs. Rows represent clustered peroxisomal genes. B: Heatmap of scaled, normalized expression of the peroxisomal proteins in different stages of spermatogenic cells and somatic cells during spermatogenesis. The experiments were independently two biological replicates, each biological replicate was two technical replicates. n = 4. C: Western blotting of peroxisomal proteins PEX3 and PEX16 in germ and somatic cells as in panel B. MRPS22 served as an internal control. n = 3. D: Immunofluorescence staining of typical PMPs from 8-week wild-type testes. Colors of immunofluorescent markers were indicated (green, peroxisomal proteins; red, PNA-marker of acrosome, and PLZF-marker of spermatogonia). Scale bars, 100 μm. The magnified images are in the upper right area. The red dotted line represents the basement membrane of the seminiferous tubules. Scale bars, 20 μm. E: Real-time PCR for Pex3 from 8-week-old WT organs. 18S rRNA served as a control. n = 3. F: Venn diagram of peroxisomal genes, the gene that ended up intersecting was Pex3. Data are presented as mean ± standard error of the mean. Abbreviations: SG, spermatogonia; PS, pachytene spermatocyte; RS, round spermatid; ES, elongated spermatid; SC, Sertoli cell; IC, interstitial cell.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0055-2.jpg","fileSize":"2091KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0055-2.jpg","id":"460656ba-01c0-4450-939f-226fa89a143b","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Specific deletion of Pex3 in germ cells triggered spermatogenic failure.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"A: Expression of Pex3 in haploid cell (N), tetraploid cell (4N), and Sertoli cell (SC). n = 3. B: Schematic of the Pex3tm1a(EUCOMM)Wtsi floxed allele from Wellcome Trust Sanger Institute (top allele). Cassette represents recombinase-mediated cassette exchange of gene editing. Stra8-Cre;Pex3fl/fl (Pex3sko) or Amh-Cre;Pex3fl/fl (Pex3ako) (bottom allele) were generated by crossing the Pex3fl/fl mice (middle allele) with the Stra8-Cre or Amh-Cre transgenic mice, respectively. C: Testes of 8-week-old Pex3ako, Pex3sko , and wild-type (WT) mice. Scale bar, 0.5 cm. D: Histological analysis of testes (upper panel) and epididymis cauda (bottom panel) from WT, 10-week-old Pex3ako and Pex3sko mice. Arrows indicate MGCs. Upper scale bars, 50 μm; bottom scale bars, 20 μm. E: Sperm counts of WT and Pex3ako males. n = 3. F: Sperm counts of WT and Pex3sko males. n = 3. G: Quantification of the number of MGCs and MGCs positive (MGC+) tubules in testis cross-sections between control and Pex3sko mice. n = 3. Data are presented as mean ± standard error of the mean. Two-tailed unpaired Student's t-test was applied for two-group comparisons. ***P < 0.001. Abbreviations: ns, not significant; MGCs, multinucleated giant cells.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0055-3.jpg","fileSize":"3851KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0055-3.jpg","id":"f1178ab7-7dcb-4b92-a1da-14b4e46fff7a","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"MGCs occur when spermatids develop.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"A: Real-time PCR for Pex3 from 0 to 8-week-old wild-type (WT) testes. 18s served as a control. n = 3. B: Scanned images of 3-week-old WT and Pex3sko testes. Images are magnified on the right. P-pachytene spermatocytes. Z-zygotene spermatocytes. D-diplotene spermatocytes. RS-round spermatids. Scale bars, 500 μm. The magnified images were in the right area. Scale bars, 20 μm. C: Scanned images of 4-week-old WT and Pex3sko testes. Images are magnified on the right. Scale bars, 500 μm. The magnified images were in the right area. Scale bars, 20 μm. D and E: Distribution plot of haploid (N), diploid (2N) and tetraploid (4N) cells isolated from 3-week-old and 4-week-old WT and Pex3sko testes through fluorescence-activated cell sorting with Hoechst staining. F and G: Counts of haploid cells in 3-week-old and 4-week-old WT and Pex3sko testes. n = 3. H: Electron microscope images of ICBs from 4-week-old control and Pex3sko testes. Arrowheads represent normal ICBs structures, and arrows represent destroyed ICBs lack of partial dense materials. Upper scale bars, 2 μm; bottom scale bars, 1 μm. I: Immunofluorescence staining of ICBs by marker TEX14 in 4- and 8-week-old control, Pex3sko and Pex3ako testes. Arrows highlight the lengthening of round spermatid ICBs. Scale bars, 20 μm. J: Cell apoptosis detection assay revealed apoptosis in WT and Pex3sko testes. Green, apoptosis cells. Blue, Hoechst. Upper scale bars, 50 μm; bottom scale bars, 20 μm. K: Apoptosis cells in WT and Pex3sko testes. n = 3. Data are presented as mean ± standard error of the mean. Two-tailed unpaired Student's t-test was applied for comparisons of adjacent time points (A) or the two-groups (F, G and K). *P < 0.05, **P < 0.01, and ***P < 0.001. Abbreviations: MGCs, multinucleated giant cells; ns, not significant; P, pachytene spermatocyte; RS, round spermatid. ES, elongated spermatid; V, vacuole.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0055-4.jpg","fileSize":"3199KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0055-4.jpg","id":"51cb9158-3605-4729-b0c9-88515598cc92","imgWidth":"15.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Deletion of Pex3 triggers differentially regulated proteins involved in spermatids.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"A: Proteomic workflow for identifying differential proteins between 4-week-old wild-type (WT) and Pex3sko spermatids. B: Heatmap of the differential proteins between 4-week-old control and Pex3sko spermatids. C: Gene Ontology enrichment analysis of downregulated proteins. D: The network of the linkages of genes and biological events of downregulated proteins in (C). E: Volcano plot comparison revealed the patterns of all differential proteins between control and Pex3sko spermatids. Highlighted proteins were peroxisomal proteins by 1.6-fold change. F: Western blotting (WB) analysis of PEX16, PEX14, GNPAT, AGPS and HSD17B4 in 4-week-old WT and Pex3sko testes. β-Actin was served as an internal control. n = 3. G: Relative protein expression of PEX16, PEX14, GNPAT, AGPS and HSD17B4 in 4-week-old WT and Pex3sko testes. n = 3. H: Venn diagram of peroxins enriched in spermatids, and up-regulated and down-regulated peroxins in Pex3sko spermatids. Data are presented as mean ± standard erron of the mean. Two-tailed unpaired Student's t-test was applied for two-group comparisons. *P < 0.05, **P < 0.01, and ***P < 0.001. Abbreviations: FC, fold change; AGPS, alkylglycerone phosphate synthase; HSD17B4, hydroxysteroid 17-beta dehydrogenase 4; GNPAT, glycerophosphate O-acyltransferase; peroxins: peroxisomal proteins.","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0055-5.jpg","fileSize":"3300KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0055-5.jpg","id":"76afd3ba-ef62-4daa-9b07-ad5ae1bd9b58","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Deficiency of PEX3-dependent peroxisomes leads to the increased oxidative stress in the testes.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"A: Identification of expression of three peroxisomal proteins (PEX16, ABCD1, and ABCD3) between wild-type (WT) and Pex3sko testes. Green, peroxisomal proteins. Red, PNA-marker of acrosome; PLZF-marker of spermatogonia. Gray, Hoechst-marker of the nucleus. Arrows represent ABCD3-positive spermatogonia. The magnified images are in the upper right area. Scale bars, 20 μm. B and C: DHE staining of ROS production in 4- and 8-week-old WT, Pex3sko and Pex3ako testes. Scale bars, 50 μm. D: Quantification of CAT activities of 4- and 8-week-old WT and Pex3sko testes. n = 6. E: Quantification of MDA level related to the degree of membrane lipid peroxidation in 4- and 8-week-old WT and Pex3sko testes. n = 3. Data are presented as mean ± standard error of the mean. Two-tailed unpaired Student's t-test was applied for two-group comparisons. *P < 0.05 and **P < 0.01. Abbreviations: ABCD1, ATP binding cassette subfamily D member 1; DHE, dihydroethidium; CAT, catalase; MDA, malondialdehyde.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/","firstFig":{"columnNums":2,"dataId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0055-1_mini.jpg","fileSize":"4427KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0055-1.jpg","id":"a50195fa-0d71-4a4c-a739-8d074e450cde","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Heterogeneity of peroxisomes in organs and testicular cells.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: Heatmap visualizing the scaled, normalized expression of the peroxisomal genes in the mouse organs. Columns represent different organs. Rows represent clustered peroxisomal genes. B: Heatmap of scaled, normalized expression of the peroxisomal proteins in different stages of spermatogenic cells and somatic cells during spermatogenesis. The experiments were independently two biological replicates, each biological replicate was two technical replicates. n = 4. C: Western blotting of peroxisomal proteins PEX3 and PEX16 in germ and somatic cells as in panel B. MRPS22 served as an internal control. n = 3. D: Immunofluorescence staining of typical PMPs from 8-week wild-type testes. Colors of immunofluorescent markers were indicated (green, peroxisomal proteins; red, PNA-marker of acrosome, and PLZF-marker of spermatogonia). Scale bars, 100 μm. The magnified images are in the upper right area. The red dotted line represents the basement membrane of the seminiferous tubules. Scale bars, 20 μm. E: Real-time PCR for Pex3 from 8-week-old WT organs. 18S rRNA served as a control. n = 3. F: Venn diagram of peroxisomal genes, the gene that ended up intersecting was Pex3. Data are presented as mean ± standard error of the mean. Abbreviations: SG, spermatogonia; PS, pachytene spermatocyte; RS, round spermatid; ES, elongated spermatid; SC, Sertoli cell; IC, interstitial cell.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},"hasPage":true,"htmlAccess":true,"id":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","issue":"1","issueArticle":"0","keywords":[{"articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","id":"5a1a2e54-2ffb-4fc4-9447-42c0d292784e","keywordEn":"male infertility","sortNum":1},{"articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","id":"a3e693b2-01e2-468b-b515-4cc3240211e8","keywordEn":"spermiogenesis","sortNum":2},{"articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","id":"bc5c324e-2a3b-4608-91dd-76d70a740610","keywordEn":"peroxisome","sortNum":3},{"articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","id":"8d7b578a-7bcd-4b85-abf6-267f893574c9","keywordEn":"oxidative stress","sortNum":4},{"articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","id":"5e682c74-03ee-460b-84d3-7bbaa22a46b2","keywordEn":"PEX3","sortNum":5}],"language":"en","page":"24-36","pdfAccess":true,"publisherId":"JBR-2023-0055","releaseProgress":{"articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","lastReleaseTime":"2024-03-25 16:46","maxLastReleaseTime":"2024-03-25 16:46","minLastReleaseTime":"2024-01-26 09:19","otherReleaseList":[{"articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-12-08 10:14","maxLastReleaseTime":"2023-12-08 10:14","minLastReleaseTime":"2023-12-08 10:14","otherReleaseList":[]},{"articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-06-16 17:28","maxLastReleaseTime":"2023-06-16 17:28","minLastReleaseTime":"2023-06-16 17:28","otherReleaseList":[]},{"articleId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","currentState":"Accepted Manuscript","currentStateEn":"Accepted Manuscript","lastReleaseTime":"2023-06-03 13:13","maxLastReleaseTime":"2023-06-03 13:13","minLastReleaseTime":"2023-06-03 13:13","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20240001000000","subTitleCn":"","subTitleEn":"","supplements":[{"dataId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","downloadNum":4,"fileLastName":"pdf","fileName":"JBR-2023-0055-Supplementary.pdf","filePath":"/fileSWYXYJZZYWB/journal/article/file/70565b8b-06da-4e13-8c93-4151e51c7c87.pdf","fileSize":"2801KB","fileType":"file","id":"27f7dc90-1a46-4768-8c2c-7cfd8ada6cef","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","nameCn":"JBR-2023-0055-Supplementary","nameEn":"JBR-2023-0055-Supplementary","type":"article"}],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Germ cell-specific deletion of Pex3 reveals essential roles of PEX3-dependent peroxisomes in spermiogenesis","topicNameEn":"","type":"research-article","volume":"38","year":"2024","yearInt":2024},"dataId":"35aaa439-43ed-4067-b2b2-4af3e3aa6614","dataType":"Article","id":"0d03e9bd-09f3-4d75-8126-f8d99d8e6e4e","language":"cn,en","sort":92,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"Immune-related adverse events (irAEs) represent an increasingly concerning challenge in the assessment of biopharmaceutical products. In contrast to historically rare allergic reactions associated with small chemical drugs, contemporary biotherapeutics exhibit a significantly higher morbidity of irAEs, because of their complex structure and comprehensive mechanisms of action. While the immunogenicity of protein-based compounds is associated with the induction of anti-drug antibodies, the pathogenesis of irAEs in advanced biologics, such as cell and gene therapy, remains to be further delineated. In the current study, I present an updated profile regarding the untoward immune effects of medications, covering various material categories systematically, with the underlying mechanisms to inspire risk mitigation in biopharmaceutical development and application.
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E-mail: daohong@hotmail.com","deceased":0,"email":"daohong@hotmail.com","givenNamesEn":"Daohong","id":"e2ce0aec-ddcf-4c52-9de9-492470e2306c","sortNumber":1,"surNameEn":"Chen"}],"categoryNameEn":"Review Article","citationCn":"","citationEn":"Daohong Chen. Untoward immune effects of modern medication[J]. The Journal of Biomedical Research, 2024, 38(1): 17-23. DOI: 10.7555/JBR.37.20230071","doi":"10.7555/JBR.37.20230071","figList":[{"columnNums":2,"dataId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0071-1.jpg","fileSize":"293KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0071-1.jpg","id":"a9c01c47-9b19-4939-9011-1eb47d797123","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"A machanism summary for irAEs of medication.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"Given that large molecular drugs contain antigen epitopes potentially to initiate the canonical immune processing network, small chemical compounds may act as haptens to be antigenic upon binding with certain serum proteins. 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Abbreviations: irAEs, immune-related adverse events; APC, antigen presenting cell; CD, cluster of differentiation; PF, platelet factor; CAR-T, chimeric antigen receptor T cell.","tagId":"Figure1","type":"article","typesetSecTagId":"s01"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/","firstFig":{"columnNums":2,"dataId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0071-1_mini.jpg","fileSize":"293KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0071-1.jpg","id":"a9c01c47-9b19-4939-9011-1eb47d797123","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"A machanism summary for irAEs of medication.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"Given that large molecular drugs contain antigen epitopes potentially to initiate the canonical immune processing network, small chemical compounds may act as haptens to be antigenic upon binding with certain serum proteins. 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Abbreviations: irAEs, immune-related adverse events; APC, antigen presenting cell; CD, cluster of differentiation; PF, platelet factor; CAR-T, chimeric antigen receptor T cell.","tagId":"Figure1","type":"article","typesetSecTagId":"s01"},"hasPage":true,"htmlAccess":true,"id":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","issue":"1","issueArticle":"0","keywords":[{"articleId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","id":"34c3bb73-239d-4580-b62c-c295b6cf7318","keywordEn":"immunotoxicology","sortNum":1},{"articleId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","id":"a75f265f-db61-4fa0-a97b-be84f623142a","keywordEn":"immune-related adverse events","sortNum":2},{"articleId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","id":"cc3bbf4b-9da5-48a6-a60a-871ec3110be6","keywordEn":"anti-drug antibody","sortNum":3}],"language":"en","page":"17-23","pdfAccess":true,"publisherId":"JBR-2023-0071","releaseProgress":{"articleId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","lastReleaseTime":"2024-01-26 09:25","maxLastReleaseTime":"2024-01-26 09:25","minLastReleaseTime":"2024-01-26 09:19","otherReleaseList":[{"articleId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-12-18 14:53","maxLastReleaseTime":"2023-12-18 14:53","minLastReleaseTime":"2023-12-18 14:53","otherReleaseList":[]},{"articleId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-10-31 08:40","maxLastReleaseTime":"2023-10-31 08:40","minLastReleaseTime":"2023-10-31 08:40","otherReleaseList":[]},{"articleId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","currentState":"Accepted Manuscript","currentStateEn":"Accepted Manuscript","lastReleaseTime":"2023-06-08 13:06","maxLastReleaseTime":"2023-06-08 13:06","minLastReleaseTime":"2023-06-08 13:06","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20240001000000","subTitleCn":"","subTitleEn":"","supplements":[],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Untoward immune effects of modern medication","topicNameEn":"","type":"research-article","volume":"38","year":"2024","yearInt":2024},"dataId":"734b91d3-7d76-4840-9b9c-47cccf9fd05e","dataType":"Article","id":"e140634f-8201-45cb-9d56-d849676ce333","language":"cn,en","sort":93,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"In mammals, the timing of physiological, biochemical and behavioral processes over a 24-h period is controlled by circadian rhythms. To entrain the master clock located in the suprachiasmatic nucleus of the hypothalamus to a precise 24-h rhythm, environmental zeitgebers are used by the circadian system. This is done primarily by signals from the retina via the retinohypothalamic tract, but other cues like exercise, feeding, temperature, anxiety, and social events have also been shown to act as non-photic zeitgebers. The recently identified myokine irisin is proposed to serve as an entraining non-photic signal of exercise. Irisin is a product of cleavage and modification from its precursor membrane fibronectin type Ⅲ domain-containing protein 5 (FNDC5) in response to exercise. Apart from well-known peripheral effects, such as inducing the \"browning\" of white adipocytes, irisin can penetrate the blood-brain barrier and display the effects on the brain. Experimental data suggest that FNDC5/irisin mediates the positive effects of physical activity on brain functions. In several brain areas, irisin induces the production of brain-derived neurotrophic factor (BDNF). In the master clock, a significant role in gating photic stimuli in the retinohypothalamic synapse for BDNF is suggested. However, the brain receptor for irisin remains unknown. In the current review, the interactions of physical activity and the irisin/BDNF axis with the circadian system are reconceptualized.
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Inyushkin","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":true,"correspinfoEn":"Alexey N. Inyushkin, Department of Human & Animal Physiology, Samara National Research University, 1 Acad. Pavlova Str., Samara 443011, Russia. E-mail: ainyushkin@mail.ru","deceased":0,"email":"ainyushkin@mail.ru","givenNamesEn":"Alexey N.","id":"c4aaf73a-77c8-4e56-b78e-6cf53c448e51","sortNumber":1,"surNameEn":"Inyushkin"},{"addressTagIds":"aff1","articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","authorNameEn":"Vitalii S. Poletaev","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Vitalii S.","id":"b3359270-e4f3-40af-92e5-cfce79789b94","sortNumber":2,"surNameEn":"Poletaev"},{"addressTagIds":"aff1","articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","authorNameEn":"Elena M. 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Kalberdin, Andrey A. Inyushkin. Irisin/BDNF signaling in the muscle-brain axis and circadian system: A review[J]. The Journal of Biomedical Research, 2024, 38(1): 1-16. DOI: 10.7555/JBR.37.20230133","doi":"10.7555/JBR.37.20230133","figList":[{"columnNums":1,"dataId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0133-1.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0133-1.jpg","id":"c2377f11-518c-48eb-8bd3-8c2bace7fd37","imgWidth":"8.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"A simplified molecular model of the mammalian circadian oscillator.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"Connecting lines ending with arrows and bars represent activation and repression, respectively. The two core circadian clock genes, Bmal1 and Clock, and their corresponding proteins are at the center of the two coupled feedback loops of the clock gene expression. The BMAL1 and CLOCK proteins translocate to the nucleus and form a heterodimeric transcriptional activator complex, BMAL1:CLOCK, thereby activating their target genes Per and Cry (the first feedback loop) and Rev-Erbα (the second feedback loop). Once the concentration of heterodimeric complexes PER:CRY has reached a threshold, they repress BMAL1:CLOCK, so Per and Cry mRNAs and their corresponding proteins are no longer produced until the activity of BMAL1 and CLOCK is no longer inhibited by PER:CRY repressor complexes. Then, a new 24-h PER and CRY production cycle is initiated. In the second feedback loop, BMAL1:CLOCK activates the circadian transcription of the genes encoding REV-ERBα, responsible for the rhythmic repression of the Bmal1 and Clock genes. Additionally, BMAL1:CLOCK complexes activate thousands of clock-controlled genes (CCGs), using the rhythmic output of the circadian oscillator for numerous physiological, hormonal, and behavioral rhythms.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},{"columnNums":2,"dataId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0133-2.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0133-2.jpg","id":"29e3f663-94ef-4806-8d4e-5bfc821ac185","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Cleavage of irisin from FNDC5, stimulation of BDNF expression by irisin, and irisin/BDNF signaling.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"A: A schematic representation of FNDC5 containing irisin, as part of the fibronectin Ⅲ domain. Irisin is cleaved from FNDC5 and released into the extracellular medium. The cleavage of irisin is encouraged by PGC-1α. In turn, irisin regulates the expression of BDNF. B: Signaling pathways activated by irisin and BDNF in neurons. Signaling pathways involved in the proposed irisin-integrin αVβ5 interaction and BDNF-TrkB interaction include: (1) cAMP signaling: cAMP activates PKA, which induces the phosphorylation of CREB; (2) Ras-MAP/ERK signaling: the phosphorylation of integrin and Trk receptors provides a site for binding the PTB domain of the adaptor protein Shc, which recruits the adaptor protein Grb2, and complexes with SOS, an exchange factor for Ras. Ras activates signaling via downstream pathways, ERK 1/2, p38 MAPK, and Raf; (3) PI-3 kinase signaling: phosphatidylinositides, generated by PI3-kinase, activate phosphatidylinositide-dependent protein kinase (PDK-1), which in turn activates the protein kinase Akt (also known as PKB). Akt then phosphorylates downstream proteins; and (4) PLC-γ signaling: the phosphorylated TrkB receptors bind to PLC-γ. The activated PLC-γ hydrolyzes phosphatidylinositol to generate IP3 and DAG. IP3 induces the release of Ca2+ from internal stores. DAG activates DAG-regulated PKC. Boxes indicate intracellular mediators activated (↑) or inhibited (↓) by irisin and BDNF. In the boxes marked with a red background are mediators for which the involvement in the SCN clock entrainment is proven[22,125–126,134–138]. For the remaining mediators, the involvement in the SCN clock entrainment is hypothetical. Abbreviations: SS, signal sequence; FN Ⅲ, fibronectin Ⅲ domain; MD, membrane domain; CD, cytosolic domain; TrkB, tropomyosin receptor kinase B; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP response element-binding protein; Shc, Src homology 2 domain-containing transforming protein 1; Grb2, growth factor receptor-bound protein 2; Ras, Ras protein; ERK 1/2, extracellular signal-regulated kinase 1/2; p38 MAPK, p38 mitogen-activated protein kinase; Raf, proto-oncogene serine/threonine-protein kinase; PI-3K, phosphatidylinositol-3 kinase; AKT/PKB, protein kinase B; IKK, inhibitory kappa B kinase; Bcl-2, B-cell lymphoma-2 protein; Bcl-XL, B-cell lymphoma extra-large protein; BAD, Bcl-2 associated agonist of cell death; FOXO, forkhead box O protein; BAX, Bcl-2 associated X protein; YAP, Yes-associated protein; PLC-γ, phospholipase C gamma; IP3, inositol trisphosphate; DAG, diacylglycerol; PKC, protein kinase C.","tagId":"Figure2","type":"article","typesetSecTagId":"s04"},{"columnNums":1,"dataId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0133-3.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0133-3.jpg","id":"d3319900-bee3-46e7-9445-470db89274cf","imgWidth":"8.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"A schematic outline of irisin's action on the SCN master clock.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"\"Peripheral\" irisin is released from contracting skeletal muscles during exercise. Irisin penetrates the BBB, entering the hypothalamus and entraining the SCN circadian clock. \"Central\" irisin is produced in several regions of the brain, such as the hippocampus, midbrain, cerebellum, hypothalamus, cortex, and medulla oblongata. It enters the SCN, entraining the circadian clock. In the SCN, irisin is hypothesized to induce BDNF expression and release. BDNF is able to gate the input light signal entering the SCN from ipRGCs via RHT. The SCN, in turn, orchestrates physiological, biochemical, and behavioral rhythms via neurohumoral, hormonal, temperature, and other indirect signals (not shown). Abbreviations: BDNF, brain-derived neurotrophic factor; SCN, suprachiasmatic nucleus; ipRGCs, intrinsically photosensitive retinal ganglion cells; RHT, retinohypothalamic tract; BBB, blood-brain barrier.","tagId":"Figure3","type":"article","typesetSecTagId":"s07"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/","firstFig":{"columnNums":1,"dataId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2024/1/JBR-2023-0133-1_mini.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0133-1.jpg","id":"c2377f11-518c-48eb-8bd3-8c2bace7fd37","imgWidth":"8.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"A simplified molecular model of the mammalian circadian oscillator.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"Connecting lines ending with arrows and bars represent activation and repression, respectively. The two core circadian clock genes, Bmal1 and Clock, and their corresponding proteins are at the center of the two coupled feedback loops of the clock gene expression. The BMAL1 and CLOCK proteins translocate to the nucleus and form a heterodimeric transcriptional activator complex, BMAL1:CLOCK, thereby activating their target genes Per and Cry (the first feedback loop) and Rev-Erbα (the second feedback loop). Once the concentration of heterodimeric complexes PER:CRY has reached a threshold, they repress BMAL1:CLOCK, so Per and Cry mRNAs and their corresponding proteins are no longer produced until the activity of BMAL1 and CLOCK is no longer inhibited by PER:CRY repressor complexes. Then, a new 24-h PER and CRY production cycle is initiated. In the second feedback loop, BMAL1:CLOCK activates the circadian transcription of the genes encoding REV-ERBα, responsible for the rhythmic repression of the Bmal1 and Clock genes. Additionally, BMAL1:CLOCK complexes activate thousands of clock-controlled genes (CCGs), using the rhythmic output of the circadian oscillator for numerous physiological, hormonal, and behavioral rhythms.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},"hasPage":true,"htmlAccess":true,"id":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","issue":"1","issueArticle":"0","keywords":[{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","id":"a7f3e278-1003-4ac7-92c8-8a62bb40c9d1","keywordEn":"irisin","sortNum":1},{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","id":"e8c5e650-afd9-4d8e-a7ca-e670591735c1","keywordEn":"brain-derived neurotrophic factor","sortNum":2},{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","id":"fc166c70-90d6-46bf-98a3-06ba9bd6745d","keywordEn":"peroxisome proliferator-activated receptor γ coactivator 1α","sortNum":3},{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","id":"30c697e8-41a8-47ec-8b4f-c1b6f15d0606","keywordEn":"circadian rhythm","sortNum":4},{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","id":"cdb9ee23-0e9f-40ff-a33a-2b75d0260081","keywordEn":"circadian system","sortNum":5},{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","id":"42f5c507-c307-49a7-a348-8ab3916dd32b","keywordEn":"muscle-brain axis","sortNum":6}],"language":"en","page":"1-16","pdfAccess":true,"publisherId":"JBR-2023-0133","releaseProgress":{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","lastReleaseTime":"2024-06-28 11:28","maxLastReleaseTime":"2024-06-28 11:28","minLastReleaseTime":"2024-01-26 09:19","otherReleaseList":[{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2024-01-03 14:50","maxLastReleaseTime":"2024-01-03 14:50","minLastReleaseTime":"2024-01-03 14:50","otherReleaseList":[]},{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-10-18 09:08","maxLastReleaseTime":"2023-10-18 09:08","minLastReleaseTime":"2023-10-18 09:08","otherReleaseList":[]},{"articleId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","currentState":"Accepted Manuscript","currentStateEn":"Accepted Manuscript","lastReleaseTime":"2023-09-28 13:43","maxLastReleaseTime":"2023-09-28 13:43","minLastReleaseTime":"2023-09-28 13:43","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20240001000000","subTitleCn":"","subTitleEn":"","supplements":[],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Irisin/BDNF signaling in the muscle-brain axis and circadian system: A review","topicNameEn":"","type":"research-article","volume":"38","year":"2024","yearInt":2024},"dataId":"c26e63b6-bdc2-4c9c-91a4-d59329ad3158","dataType":"Article","id":"d44f64d0-64ff-44dc-8c9e-6c34741d22d0","language":"cn,en","sort":94,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy and lacks effective treatment. Bulk-sequencing of different gene transcripts by comparing HCC tissues and adjacent normal tissues provides some clues for investigating the mechanisms or identifying potential targets for tumor progression. However, genes that are exclusively expressed in a subpopulation of HCC may not be enriched or detected through such a screening. In the current study, we performed a single cell-clone-based screening and identified galectin-14 as an essential molecule in the regulation of tumor growth. The aberrant expression of galectin-14 was significantly associated with a poor overall survival of liver cancer patients with database analysis. Knocking down galectin-14 inhibited the proliferation of tumor growth, whereas overexpressing galectin-14 promoted tumor growth in vivo. Non-targeted metabolomics analysis indicated that knocking down galectin-14 decreased glycometabolism; specifically that glycoside synthesis was significantly changed. Further study found that galectin-14 promoted the expression of cell surface heparan sulfate proteoglycans (HSPGs) that functioned as co-receptors, thereby increasing the responsiveness of HCC cells to growth factors, such as epidermal growth factor and transforming growth factor-alpha. In conclusion, the current study identifies a novel HCC-specific molecule galectin-14, which increases the expression of cell surface HSPGs and the uptake of growth factors to promote HCC cell proliferation.
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Tel/Fax: +86-519-81087722/+86-519-81087711, E-mail: hj042153@hotmail.com","deceased":0,"email":"hj042153@hotmail.com","givenNamesEn":"Jin","id":"e183ce50-d072-4c05-8d20-633abb3ded36","sortNumber":7,"surNameEn":"Huang"},{"addressTagIds":"aff1, aff3","articleId":"4f793e0c-853c-4999-a023-3024ff002641","authorNameEn":"Wei Gao","authorRoleType":"author","authorTagVal":"1, 3","authorType":"org","corresper":true,"correspinfoEn":"Wei Gao, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu 211166, China. Tel/Fax: +86-25-86869471/+86-25-86869471, E-mail: gao@njmu.edu.cn","deceased":0,"email":"gao@njmu.edu.cn","givenNamesEn":"Wei","id":"d7f64dae-0e8a-4c62-9653-aeab388e77e3","sortNumber":8,"surNameEn":"Gao"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Liming Gou, Gang Yang, Sujuan Ma, Tong Ding, Luan Sun, Fang Liu, Jin Huang, Wei Gao. Galectin-14 promotes hepatocellular carcinoma tumor growth via enhancing heparan sulfate proteoglycan modification[J]. The Journal of Biomedical Research, 2023, 37(6): 418-430. DOI: 10.7555/JBR.37.20230085","doi":"10.7555/JBR.37.20230085","figList":[{"columnNums":2,"dataId":"4f793e0c-853c-4999-a023-3024ff002641","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0085-1.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0085-1.jpg","id":"693b3838-d7f6-43a8-a2a8-fbfe75630bdb","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Galectin-14 was to be downregulated by single cell clone-based RNA-seq screening.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: A schematic graph to show the working flow of single cell clone-based RNA-seq screening. B: Comparison of 3D sphere-forming ability of Huh-7 and sc22 cells. Scale bar: 200 μm. C: Comparison of the subcutaneously xenografted tumor of Huh-7 and sc22 cells in BALB/c nude mice. All the xenograft tumors of each group (n = 10) were collected at the end time point (day 21). D: RNA-seq analysis to determine the differentially expressed genes (DEGs) in Huh-7 and sc22 xenografted tumors. Left: volcano plot of all the DEGs. Right: top 10 up-regulated genes and top 10 down-regulated genes. E: Quantitative RT-PCR assay to validate the up-regulated (left) and down-regulated (right) DEGs of interest in Huh-7 (control) and sc22 cells. F: Western blotting to detect the galectin-14 (GAL-14) expression in different single cell clones (sc1, sc13 and sc22) of Huh-7 cells. Values are presented as mean ± standard deviation (n = 3). Statistical analyses were performed by Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"4f793e0c-853c-4999-a023-3024ff002641","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0085-2.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0085-2.jpg","id":"c7c6cc90-0caa-4d3f-92bc-0d71dd227f8e","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Clinical relevance analysis of galectin-14 and tumors.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"A: Normal tissue cDNA array to detect galectin-14 mRNA expression in human normal tissues. B: Quantitative RT-PCR assay to detect galectin-14 mRNA expression in tumor samples collected from 94 hepatocellular carcinoma patients. C: The cBioportal database analysis of galectin-14 coding gene genomic alterations. D: Analysis of the cBioportal database for correlation of galecin-14 coding gene (LGALS14) genomic alterations with overall survival in patients with pan-cancer. Abbreviation: HCC, hepatocellular carcinom.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"4f793e0c-853c-4999-a023-3024ff002641","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0085-3.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0085-3.jpg","id":"16fe62cd-eb0e-452a-8beb-fa49e724a341","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"Galectin-14 promoted the proliferation of tumor cells in vitro and in vivo.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"A: Western blotting assay to determine the knockdown or overexpressing efficiency of galectin-14 (GAL-14) in Huh-7, sc1, and sc22 cells. B: CCK-8 assay to detect cell proliferation after galectin-14 knockdown in Huh-7 cells (n = 3). C: Xenograft tumor growth of wild type and galectin-14 knockdown sc1 cells in mice (n = 10 for each group). D: Xenograft tumor growth of wild type and galectin-14 overexpressed sc22 cells in mice (n = 10 for the mock group; n = 9 for the GAL-14 overexpressed group). Values are presented as mean ± standard deviation (B) or mean ± standard error of the mean (C and D). Statistical analyses were performed by two-way ANOVA. *P < 0.05, **P < 0.01, and ****P < 0.0001. Abbreviations: WT, LV-control; KD, LV-shGal-14; Mock, LV-mock; GAL-14, LV-Gal-14.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"4f793e0c-853c-4999-a023-3024ff002641","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0085-4.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0085-4.jpg","id":"c337db4f-1596-4533-b5ed-73e183757472","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Galectin-14 affected the expression of HSPGs in HCC.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"A: The heatmap of the top 15 metabolites with the most significant changes in positive and negative modes determined by untargeted metabolomics analysis in wild-type and galectin-14 knockdown Huh-7 cells. Red fonts indicate the metabolites correlated with glycolytic metabolism. B: CCK-8 assay to detect the proliferation ability of wild-type and galectin-14 knockdown Huh-7 cells treated with or without 5 mmol/L 2-DG for 6 days. C: Flow cytometry to detect the expression of heparan sulfate proteoglycans (HSPGs) in wild-type and galectin-14 knockdown Huh-7 cells. The bar chart shows the geometric mean of the flow peak chart. D: Flow cytometry to detect the expression of HSPGs in wild type and galectin-14 knockdown Huh-7 cells treated with or without 5 mmol/L 2-DG. The bar chart shows the geometric mean of the flow peak chart. E: Flow cytometry to detect HSPG expression after knockdown of EXT1 in wild-type and galectin-14 knockdown Huh-7 cells. The bar chart shows the geometric mean of the flow peak chart. F: CCK-8 assay to detect cell proliferation after knockdown of EXT1 in wild-type and galectin-14 knockdown Huh-7 cells after 72-h of culture. All the experiments were repeated three times. Values are presented as mean ± standard deviation. Statistical analyses were performed by two-way ANOVA (B) or Student's t-test (C–F). *P < 0.05, **P < 0.01, and ***P < 0.001. Abbreviations: ns, not significant; WT, LV-control; KD, LV-shGal-14.","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"4f793e0c-853c-4999-a023-3024ff002641","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0085-5.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0085-5.jpg","id":"fa1c2bed-3065-439b-af03-d8ddfa67b2a0","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Galectin-14 sensitized the tumor cells responding to growth factor treatment.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"A and B: CCK-8 assay to detect the proliferation of wild type and galectin-14 knockdown Huh-7 cells treated with 5 ng/mL EGF (A) or 5 ng/mL TGF-α (B) for 4 days. C: Quantitative RT-PCR assay to detect the expression levels of receptors of EGF and TGF-α in wild-type and galectin-14 knockdown Huh-7 cells. All the experiments were repeated three times. Values are presented as mean ± standard deviation. Statistical analyses were performed by two-way ANOVA (A and B) or Student's t-test (C). ****P < 0.0001. Abbreviations: ns, not significant; WT, LV-control; KD, LV-shGal-14; TPM, transcripts per kilobase million.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"4f793e0c-853c-4999-a023-3024ff002641","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0085-6.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0085-6.jpg","id":"2d30002f-a973-4e1f-be3b-33dafb8f4d7d","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"6","nameEn":"A schematic representation of how galectin-14 regulates hepatocellular carcinoma cells proliferation.","referSecTagIds":"","sort":5,"supplementRemarkCn":"","supplementRemarkEn":"Active expression of galectin-14 in hepatocellular carcinoma (HCC) cells promotes HCC tumor growth by up-regulating HSPG expression on cell surface, and thus increasing the response of tumor cells to growth factors. Abbreviation: HSPGs, heparan sulfate proteoglycans.","tagId":"Figure6","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/","firstFig":{"columnNums":2,"dataId":"4f793e0c-853c-4999-a023-3024ff002641","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0085-1_mini.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0085-1.jpg","id":"693b3838-d7f6-43a8-a2a8-fbfe75630bdb","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Galectin-14 was to be downregulated by single cell clone-based RNA-seq screening.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: A schematic graph to show the working flow of single cell clone-based RNA-seq screening. B: Comparison of 3D sphere-forming ability of Huh-7 and sc22 cells. Scale bar: 200 μm. C: Comparison of the subcutaneously xenografted tumor of Huh-7 and sc22 cells in BALB/c nude mice. All the xenograft tumors of each group (n = 10) were collected at the end time point (day 21). D: RNA-seq analysis to determine the differentially expressed genes (DEGs) in Huh-7 and sc22 xenografted tumors. Left: volcano plot of all the DEGs. Right: top 10 up-regulated genes and top 10 down-regulated genes. E: Quantitative RT-PCR assay to validate the up-regulated (left) and down-regulated (right) DEGs of interest in Huh-7 (control) and sc22 cells. F: Western blotting to detect the galectin-14 (GAL-14) expression in different single cell clones (sc1, sc13 and sc22) of Huh-7 cells. Values are presented as mean ± standard deviation (n = 3). Statistical analyses were performed by Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},"hasPage":true,"htmlAccess":true,"id":"4f793e0c-853c-4999-a023-3024ff002641","issue":"6","issueArticle":"0","keywords":[{"articleId":"4f793e0c-853c-4999-a023-3024ff002641","id":"4defa6d8-9496-4652-8234-067c72e64fb6","keywordEn":"hepatocellular carcinoma","sortNum":1},{"articleId":"4f793e0c-853c-4999-a023-3024ff002641","id":"7d2d8d31-b6c7-472e-be65-a54e526fd888","keywordEn":"galectin-14","sortNum":2},{"articleId":"4f793e0c-853c-4999-a023-3024ff002641","id":"066fe0e5-dfb0-491f-9ce5-3d4d78505909","keywordEn":"heparan sulfate proteoglycans","sortNum":3},{"articleId":"4f793e0c-853c-4999-a023-3024ff002641","id":"a0565ad1-f48c-4851-9ab1-4bfa9aedaa96","keywordEn":"co-receptor","sortNum":4}],"language":"en","page":"418-430","pdfAccess":true,"publisherId":"JBR-2023-0085","releaseProgress":{"articleId":"4f793e0c-853c-4999-a023-3024ff002641","lastReleaseTime":"2024-03-27 09:03","maxLastReleaseTime":"2024-03-27 09:03","minLastReleaseTime":"2023-11-22 09:35","otherReleaseList":[{"articleId":"4f793e0c-853c-4999-a023-3024ff002641","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-11-17 08:40","maxLastReleaseTime":"2023-11-17 08:40","minLastReleaseTime":"2023-11-17 08:40","otherReleaseList":[]},{"articleId":"4f793e0c-853c-4999-a023-3024ff002641","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-06-14 14:01","maxLastReleaseTime":"2023-06-14 14:01","minLastReleaseTime":"2023-06-14 14:01","otherReleaseList":[]},{"articleId":"4f793e0c-853c-4999-a023-3024ff002641","currentState":"Accepted Manuscript","currentStateEn":"Accepted Manuscript","lastReleaseTime":"2023-06-03 13:13","maxLastReleaseTime":"2023-06-03 13:13","minLastReleaseTime":"2023-06-03 13:13","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20230006000000","subTitleCn":"","subTitleEn":"","supplements":[{"dataId":"4f793e0c-853c-4999-a023-3024ff002641","downloadNum":2,"fileLastName":"pdf","fileName":"JBR-2023-0085-Supplementary.pdf","filePath":"/fileSWYXYJZZYWB/journal/article/file/fbd2006e-514b-4ebd-bab6-cf710f1d0ffa.pdf","fileSize":"991KB","fileType":"file","id":"aa36d4cf-ea10-4eeb-9940-062906932e85","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","nameCn":"JBR-2023-0085-Supplementary","nameEn":"JBR-2023-0085-Supplementary","type":"article"}],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Galectin-14 promotes hepatocellular carcinoma tumor growth via enhancing heparan sulfate proteoglycan modification","topicNameEn":"","type":"research-article","volume":"37","year":"2023","yearInt":2023},"dataId":"4f793e0c-853c-4999-a023-3024ff002641","dataType":"Article","id":"8a8ef9e6-9679-4ed5-a439-c67e1ed77e58","language":"cn,en","sort":95,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"cis-Diamminedichloroplatinum (CDDP) is widely used for the treatment of various solid cancers. Here we reported that CDDP increased the expression and enzymatic activities of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2), along with the upregulation of pregnane X receptor (PXR) and the downregulation of differentiated embryonic chondrocyte-expressed gene 1 (DEC1) in human hepatoma cells, primary mouse hepatocytes, mouse liver and intestine. The overexpression or knockdown of PXR alone upregulated or downregulated the CES1 and CES2 expression, respectively. The increases in CES1 and CES2 expression levels induced by CDDP abolished or enhanced by PXR knockdown or overexpression, implying that CDDP induces carboxylesterases through the activation of PXR. Likewise, the overexpression or knockdown of DEC1 alone significantly decreased or increased PXR and its targets. Moreover, the increases of PXR and its targets induced by CDDP were abolished or alleviated by the overexpression or knockdown of DEC1. The overexpression or knockdown of DEC1 affected the response of PXR to CDDP, but not vice versa, suggesting that CDDP increases carboxylesterases by upregulating PXR mediated by the decrease of DEC1. In addition, CDDP did not increase DEC1 mRNA degradation but suppressed DEC1 promoter reporter activity, indicating that it suppresses DEC1 transcriptionally. The combined use of CDDP and irinotecan had a synergistic effect on two cell lines, especially when CDDP was used first.
","appendixList":[],"articleBusiness":{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","articleState":"-1","articleType":"1","baiduIncludeResult":0,"baiduIncludeResultSearchNum":0,"baiduPushLastDate":1701239700000,"baiduPushNum":4,"baiduXueShuIncludeResult":0,"baiduXueShuIncludeResultSearchNum":0,"baiduXueShuPushLastDate":1701239700000,"baiduXueShuPushNum":5,"filename":"JBR-2023-0047.xml","googleIncludeResult":0,"googleIncludeResultSearchNum":0,"htmlSource":1,"htmlViewCount":381,"id":"906bbb15-b4e7-43b9-839e-1475473c1dad","isRegCstr":0,"isRegDOI":1,"pdfDownCount":16,"pdfEnFileSizeInt":0,"pdfFileName":"JBR-2023-0047.pdf","pdfFileSize":6725.18,"pdfFileSizeInt":6725,"remark":"XML","viewCount":668,"xmlDownCount":0,"xmlFileSize":105.0},"articleNo":"JBR-2023-0047","authors":[{"addressTagIds":"aff1","articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","authorNameEn":"Minqin Xu","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Minqin","id":"4164379c-9853-4d9b-b0e8-533e74668903","sortNumber":1,"surNameEn":"Xu"},{"addressTagIds":"aff1","articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","authorNameEn":"Lihua Zhang","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Lihua","id":"e82a0099-665f-4099-9c7d-204f9335ba96","sortNumber":2,"surNameEn":"Zhang"},{"addressTagIds":"aff1","articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","authorNameEn":"Lan Lin","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Lan","id":"3650bf94-76a8-421c-9c73-8e14b2914b77","sortNumber":3,"surNameEn":"Lin"},{"addressTagIds":"aff1","articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","authorNameEn":"Zhiyi Qiang","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Zhiyi","id":"4deb8bac-91bd-49f9-9e31-baf6b048b897","sortNumber":4,"surNameEn":"Qiang"},{"addressTagIds":"aff1","articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","authorNameEn":"Wei Liu","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Wei","id":"e4c3cd01-08cf-4f3f-b02f-8b4753011f93","sortNumber":5,"surNameEn":"Liu"},{"addressTagIds":"aff1","articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","authorNameEn":"Jian Yang","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":true,"correspinfoEn":"Jian Yang, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 211166, China. Tel: +86-25-86869408, E-mail: jianyang@njmu.edu.cn","deceased":0,"email":"jianyang@njmu.edu.cn","givenNamesEn":"Jian","id":"ae7a14f9-f854-48bf-950c-0925fffa423e","sortNumber":6,"surNameEn":"Yang"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Minqin Xu, Lihua Zhang, Lan Lin, Zhiyi Qiang, Wei Liu, Jian Yang. Cisplatin increases carboxylesterases through increasing PXR mediated by the decrease of DEC1[J]. The Journal of Biomedical Research, 2023, 37(6): 431-447. DOI: 10.7555/JBR.37.20230047","doi":"10.7555/JBR.37.20230047","figList":[{"columnNums":2,"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0047-1.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0047-1.jpg","id":"d8642cac-e164-40fd-bef8-32cfc499a7a4","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Induction of CES1 and CES2 expression as well as their activities in HepG2 cells.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A–F: HepG2 cells were treated with various concentrations (0, 1.25, 2.5, 5, and 10 μmol/L) of CDDP or RIF (10 μmol/L, as a positive control) for 24 h or with the same concentration (5 μmol/L) of CDDP for 0, 3, 6, 12, and 24 h. mRNA and protein levels of CES1, CES2, and CYP3A4 were detected by qRT-PCR (A and B) and Western blotting (C and D), respectively. Gapdh was used as a reference gene for qRT-PCR and β-actin was used as a loading control for Western blotting. The overall hydrolysis activities of cell lysates were determined with standard substrate PNPA (E and F). G: HepG2 cells were pretreated with or without CDDP (5 μmol/L) for 12 h and then treated with oseltamivir, clopidogrel, or CPT11 for another 24 h. Cell viability was determined by MTT assay. H: Morphological analysis of the HepG2 cells treated with oseltamivir (100 μmol/L), clopidogrel (100 μmol/L), or CPT11 (80 μmol/L) for 48 h with or without CDDP (5 μmol/L) pretreatment. Scale bar: 50 μm. The data are expressed as mean ± standard deviation (n = 3). The significance was determined by one-way analysis of variance, followed by Tukey's post hoc test and the paired comparisons were analyzed by Student's t-test. *P < 0.05, **P< 0.01, ***P <0.001, and ****P < 0.0001 vs. the control group (0 μmol/L or 0 h) or comparisons shown in the figure. Abbreviations: CDDP, cis-diamminedichloroplatinum; RIF, rifampicin; CES1, carboxylesterase 1; CES2, carboxylesterase 2; CYP3A4, cytochrome P450 3A4; PNPA, p-nitrophenylacetic acid; CPT11, irinotecan.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0047-2.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0047-2.jpg","id":"fcadb723-b844-45d8-815c-28ae1a71dbce","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Inverse regulation of PXR and DEC1 expression by CDDP in HepG2 cells.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"HepG2 cells were treated with various concentrations (0, 1.25, 2.5, 5, and 10 μmol/L) of CDDP or RIF (10 μmol/L, as a positive control) for 24 h or with the same concentration (5 μmol/L) of CDDP for 0, 3, 6, 12, and 24 h. Relative mRNA and protein levels of DEC1 and PXR were detected by qRT-PCR (A and B) and Western blotting (C and D), respectively. Gapdh was used as a reference gene for qRT-PCR and β-actin was used as a loading control for Western blotting. The data are expressed as mean ± standard deviation (n = 3). The significance determined by one-way analysis of variance, followed by Tukey's post hoc test and the paired comparisons were analyzed by Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 vs. the control group (PBS or 0 h). Abbreviations: CDDP, cis-diamminedichloroplatinum; DEC1, differentiated embryonic chondrocyte-expressed gene 1; PXR, pregnane X receptor; RIF, rifampicin.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0047-3.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0047-3.jpg","id":"4e15bcbd-a369-45eb-8c26-7f90a35a6288","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"CDDP increased carboxylesterases expression and their activities along with increased PXR and decreased STRA13 in the liver and intestine of mice.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"Mice were intraperitoneally injected with CDDP [0, 2.5, or 5 mg/(kg·day)] for 3 days (n = 5 per group). Mice in the control group received the same volume of normal saline. A–D: STRA13, mouse PXR (mPXR), CES1D, CES1E, and CYP3A11 protein levels in the liver (A and B) and intestine (C and D) of mice were detected by Western blotting. β-Actin was used as a loading control. E and F: S9 fractions of the mice's liver and intestine were prepared and analyzed for overall hydrolysis activity with standard substrate PNPA. The data are expressed as mean ± standard deviation (n = 6). The significance was determined by one-way analysis of variance, followed by Tukey's post hoc test and the paired comparisons were analyzed by Student's t-test. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. the control group (0 mg/kg or 0 h). Abbreviations: CDDP, cis-diamminedichloroplatinum; STRA13 (DEC1), stimulated with retinoic acid 13; mPXR, mouse pregnane X receptor; CES1D, carboxylesterase 1d; CES1E, carboxylesterase 1e; CYP3A11, cytochrome P450 3A11; PNPA, p-nitrophenylaceticacid.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0047-4.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0047-4.jpg","id":"d245432c-96ba-41ad-b6a8-ab67ee3d963a","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Involvement of PXR in the increase of carboxylesterases induced by CDDP in HepG2 cells.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"A and B: HepG2 cells were transfected with si-PXR construct or an equal amount of corresponding vector, cultured for 48 h, and then treated with CDDP (5 μmol/L) or DMSO (0.1%, v/v) for 24 h. Protein levels of DEC1, CES1, CES2, and CYP3A4, as well as the knockdown efficiency of PXR, were detected by Western blotting. C and D: HepG2 cells were transfected with OE-PXR construct or an equal amount of the corresponding vector, cultured for 24 h, and received the treatment as mentioned above. Protein levels of DEC1, CES1, CES2, and CYP3A4, as well as the overexpression efficiency of PXR, were detected by Western blotting. β-Actin was used as a loading control. The data are expressed as mean ± standard deviation (n = 3). The significance was determined by two-way analysis of variance, followed by Tukey's post hoc test and the paired comparisons were analyzed by Student's t-test. *P < 0.05 and **P < 0.01, #P < 0.05, ##P < 0.01, and nsP > 0.05, as comparisons shown in the figures. Abbreviations: CDDP, cis-diamminedichloroplatinum; DEC1, differentiated embryonic chondrocyte-expressed gene 1; PXR, pregnane X receptor; CES1, carboxylesterase 1; CES2, carboxylesterase 2; CYP3A4, cytochrome P450 3A4.","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0047-5.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0047-5.jpg","id":"caa8b91e-6e1a-4501-80b5-b3ec8dece450","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Involvement of DEC1 in the induction of PXR and its targets by CDDP in HepG2 cells.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"A and B: HepG2 cells were transfected with OE-DEC1 construct or an equal amount of corresponding vector, cultured for 24 h, and then treated with CDDP (5 μmol/L) or DMSO (0.1%, v/v) for 24 h. Protein levels of PXR, CES1, CES2, and CYP3A4, as well as the overexpression efficiency of DEC1, were detected by Western blotting. C and D: HepG2 cells were infected with lentivirus (LV-shDEC1 or LV-Con) and screened with a medium containing puromycin. Purified DEC1 knockdown cells were treated as mentioned above. β-Actin was used as a loading control. Protein levels of PXR, CES1, CES2, and CYP3A4, as well as the knockdown efficiency of DEC1, were detected by Western blotting. The data are expressed as mean ± standard deviation (n = 3). The significance was performed by two-way analysis of variance, followed by Tukey's post hoc test, and the paired comparisons were analyzed by Student's t-test. *P < 0.05 and **P < 0.01, #P < 0.05, ##P < 0.01, and nsP > 0.05, as comparisons shown in the figures. Abbreviations: CDDP, cis-diamminedichloroplatinum; DEC1, differentiated embryonic chondrocyte-expressed gene 1; PXR, pregnane X receptor; CES1, carboxylesterase 1; CES2, carboxylesterase 2; CYP3A4, cytochrome P450 3A4.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0047-6.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0047-6.jpg","id":"1e6bf7b7-d163-4433-9a72-18ed768aad0d","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"6","nameEn":"Dec1 deficiency showed an increase of PXR and its targets in the liver and intestine of mice.","referSecTagIds":"","sort":5,"supplementRemarkCn":"","supplementRemarkEn":"A–F: The mRNA and protein levels of mouse PXR (mPXR) and its targets, such as CES1D, CES1E, and CYP3A11 in the liver and intestine of Dec1+/+ and Dec1−/− mice were detected by qRT-PCR (A and B) and Western blotting (C–F), respectively. Gapdh was used as a reference gene for qRT-PCR and β-actin was used as a loading control for Western blotting. G and H: The overall hydrolysis activities of the liver and intestine S9 fraction obtained from the above mice were determined with standard substrate PNPA. The data are expressed as mean ± standard deviation (n = 6). The significance was performed by one-way analysis of variance, followed by Tukey's post hoc test, and the paired comparisons were analyzed by Student's t-test. *P < 0.05, **P < 0.01, and ***P < 0.001, compared with the Dec1+/+ group. Abbreviations: Dec1, differentiated embryonic chondrocyte-expressed gene 1; mPXR, mouse pregnane X receptor; Ces1d, carboxylesterase 1d; Ces1e, carboxylesterase 1e; CYP3A11, Cytochrome P450 3A11.","tagId":"Figure6","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0047-7.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0047-7.jpg","id":"eb1ab45c-750b-45d6-94ec-9894623c51fa","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"7","nameEn":"CDDP suppressed DEC1 transcriptionally.","referSecTagIds":"","sort":6,"supplementRemarkCn":"","supplementRemarkEn":"A: HepG2 cells were treated with CDDP (5 μmol/L) alone or together with transcription inhibitor Act D (2 μmol/L) for 0, 20, 40, 60, 80, 100, and 120 min. The total RNA was isolated and analyzed for the DEC1 mRNA level by qRT-PCR. GAPDH was used as a reference gene. B: HepG2 cells were transfected with a promoter reporter construct pGL3-DEC1-1.3kb-Luc or pGL3-DEC1-1.1kb-Luc) and Renilla plasmid and treated with CDDP or PBS for 48 h. Cells were lysed and the luciferase activities were determined. The data are expressed as mean ± standard deviation (n = 3). The significance was determined by one-way analysis of variance, followed by Tukey's post hoc test and the paired comparisons were analyzed by Student's t-test. ***P < 0.001. Abbreviations: CDDP, cis-diamminedichloroplatinum; Act D, actinomycin D; DEC1, differentiated embryonic chondrocyte-expressed gene 1.","tagId":"Figure7","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0047-8.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0047-8.jpg","id":"e297dcf3-644b-4207-9760-5ed1c5ad9896","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"8","nameEn":"Enhanced effect of CPT11 by CDDP through increasing PXR expression mediated by inhibiting DEC1 expression in HepG2 cells.","referSecTagIds":"","sort":7,"supplementRemarkCn":"","supplementRemarkEn":"A: HepG2 cells were seeded into 96-well plates at a density of 5000 cells per well overnight. The cells were subsequently treated with the indicated concentrations of CPT11 alone or together with CDDP (5 μmol/L) for 24 h, or the cells were treated with CDDP (5 μmol/L) for 2 h first, and then treated with the indicated concentrations of CPT11 (including CDDP) for another 22 h. B–D: HepG2 cells with DEC1 knockdown or overexpression (transfected with vector, sh-DEC1, or OE-DEC1) (B), PXR knockdown or overexpression (transfected with vector, si-PXR, or OE-PXR) (C), PXR knockdown plus DEC1 overexpression or DEC1 knockdown plus PXR overexpression (transfected with vector, OE-DEC1 + si-PXR, or sh-DEC1 + OE-PXR) (D) were seeded into 96-well plates at a density of 5000 cells per well overnight. The cells were subsequently treated with CDDP (5 μmol/L) for 2 h, followed by treatment with the indicated concentrations of CPT11 (including CDDP) for another 22 h. Cell viability (relative to the control group) was determined by the MTT assay, and the IC50 of CPT11 was calculated. The data are expressed as mean ± standard deviation (n = 3). The significance was determined by one-way (A) or two-way (B–D) analysis of variance, followed by Tukey's post hoc test and the paired comparisons were analyzed by Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Abbreviations: CDDP, cis-diamminedichloroplatinum; CPT11, irinotecan; DEC1, differentiated embryonic chondrocyte-expressed gene 1; PXR, pregnane X receptor.","tagId":"Figure8","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/","firstFig":{"columnNums":2,"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0047-1_mini.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0047-1.jpg","id":"d8642cac-e164-40fd-bef8-32cfc499a7a4","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Induction of CES1 and CES2 expression as well as their activities in HepG2 cells.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A–F: HepG2 cells were treated with various concentrations (0, 1.25, 2.5, 5, and 10 μmol/L) of CDDP or RIF (10 μmol/L, as a positive control) for 24 h or with the same concentration (5 μmol/L) of CDDP for 0, 3, 6, 12, and 24 h. mRNA and protein levels of CES1, CES2, and CYP3A4 were detected by qRT-PCR (A and B) and Western blotting (C and D), respectively. Gapdh was used as a reference gene for qRT-PCR and β-actin was used as a loading control for Western blotting. The overall hydrolysis activities of cell lysates were determined with standard substrate PNPA (E and F). G: HepG2 cells were pretreated with or without CDDP (5 μmol/L) for 12 h and then treated with oseltamivir, clopidogrel, or CPT11 for another 24 h. Cell viability was determined by MTT assay. H: Morphological analysis of the HepG2 cells treated with oseltamivir (100 μmol/L), clopidogrel (100 μmol/L), or CPT11 (80 μmol/L) for 48 h with or without CDDP (5 μmol/L) pretreatment. Scale bar: 50 μm. The data are expressed as mean ± standard deviation (n = 3). The significance was determined by one-way analysis of variance, followed by Tukey's post hoc test and the paired comparisons were analyzed by Student's t-test. *P < 0.05, **P< 0.01, ***P <0.001, and ****P < 0.0001 vs. the control group (0 μmol/L or 0 h) or comparisons shown in the figure. Abbreviations: CDDP, cis-diamminedichloroplatinum; RIF, rifampicin; CES1, carboxylesterase 1; CES2, carboxylesterase 2; CYP3A4, cytochrome P450 3A4; PNPA, p-nitrophenylacetic acid; CPT11, irinotecan.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},"hasPage":true,"htmlAccess":true,"id":"aedc8662-a085-49b5-a6c3-76abf6448abe","issue":"6","issueArticle":"0","keywords":[{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","id":"d07c6532-d8b1-4c8a-8c04-fee05da9b373","keywordEn":"cis-diamminedichloroplatinum","sortNum":1},{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","id":"230172c0-52bd-4faa-8a36-0d15fc39a465","keywordEn":"pregnane X receptor","sortNum":2},{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","id":"c494efef-8a38-4de8-877a-b7e650f7aad3","keywordEn":"differentiated embryonic chondrocyte-expressed gene 1","sortNum":3},{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","id":"7c91089c-8c82-4b2e-b9f3-5dc313767dda","keywordEn":"carboxylesterase 1","sortNum":4},{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","id":"7c976ea2-8308-462c-8ec5-449f4dce9552","keywordEn":"carboxylesterase 2","sortNum":5},{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","id":"bb7de971-0b1a-450b-b789-c2e7b5dc33d5","keywordEn":"irinotecan","sortNum":6}],"language":"en","page":"431-447","pdfAccess":true,"publisherId":"JBR-2023-0047","releaseProgress":{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","lastReleaseTime":"2024-03-27 09:03","maxLastReleaseTime":"2024-03-27 09:03","minLastReleaseTime":"2023-11-22 09:36","otherReleaseList":[{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-06-03 15:38","maxLastReleaseTime":"2023-06-03 15:38","minLastReleaseTime":"2023-06-03 15:38","otherReleaseList":[]},{"articleId":"aedc8662-a085-49b5-a6c3-76abf6448abe","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-06-03 14:57","maxLastReleaseTime":"2023-06-03 14:57","minLastReleaseTime":"2023-06-03 14:55","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20230006000000","subTitleCn":"","subTitleEn":"","supplements":[{"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","downloadNum":1,"fileLastName":"pdf","fileName":"JBR-2023-0047-supplementary.pdf","filePath":"/fileSWYXYJZZYWB/journal/article/file/179020a9-6ec6-490b-a89c-c3d733efb580.pdf","fileSize":"7104KB","fileType":"file","id":"02c2b4dc-022a-4f65-8eff-71d9302aa195","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","nameCn":"JBR-2023-0047-supplementary","nameEn":"JBR-2023-0047-supplementary","type":"article"}],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Cisplatin increases carboxylesterases through increasing PXR mediated by the decrease of DEC1","topicNameEn":"","type":"research-article","volume":"37","year":"2023","yearInt":2023},"dataId":"aedc8662-a085-49b5-a6c3-76abf6448abe","dataType":"Article","id":"0802243b-20c5-4237-bc01-8691e487c22b","language":"cn,en","sort":96,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"Aberrant alternative polyadenylation (APA) events play an important role in cancers, but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer. Previous genome-wide association study performed APA quantitative trait loci (apaQTL) analyses in bladder cancer, and identified 17 955 single nucleotide polymorphisms (SNPs). We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways, high mutational burden, and immune infiltration. Association analysis showed that apaQTL-associated SNPs rs34402449 C>A, rs2683524 C>T, and rs11540872 C>G were significantly associated with susceptibility to bladder cancer (rs34402449: OR = 1.355, 95% confidence interval [CI]: 1.159–1.583, P = 1.33 × 10−4; rs2683524: OR = 1.378, 95% CI: 1.164–1.632, P = 2.03 × 10−4; rs11540872: OR = 1.472, 95% CI: 1.193–1.815, P = 3.06 × 10−4). Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer (Ptrend = 2.87 × 10−12). We found that PRR13, being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines, was more highly expressed in bladder cancer tissues than in adjacent normal tissues. Moreover, the rs2683524 T allele was correlated with shorter 3′ untranslated regions of PRR13 and increased PRR13 expression levels. Collectively, our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.
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Tels: +86-25-8686-8423/+86-25-8686-8499. E-mails: hantingliu@njmu.edu.cn (Liu) and drzdzhang@njmu.edu.cn (Zhang)","deceased":0,"email":"hantingliu@njmu.edu.cn","givenNamesEn":"Hanting","id":"2b468afd-a646-41cb-a267-9710ac134447","sortNumber":10,"surNameEn":"Liu"},{"addressTagIds":"aff1, aff2","articleId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","authorNameEn":"Zhengdong Zhang","authorRoleType":"author","authorTagVal":"1, 2","authorType":"org","corresper":true,"correspinfoEn":"","deceased":0,"email":"drzdzhang@njmu.edu.cn","givenNamesEn":"Zhengdong","id":"2413a9ad-5a8f-4d6e-a4ee-ad0d7345562a","sortNumber":11,"surNameEn":"Zhang"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Ting Liu, Jingjing Gu, Chuning Li, Mengfan Guo, Lin Yuan, Qiang Lv, Chao Qin, Mulong Du, Haiyan Chu, Hanting Liu, Zhengdong Zhang. Alternative polyadenylation-related genetic variants contribute to bladder cancer risk[J]. The Journal of Biomedical Research, 2023, 37(6): 405-417. DOI: 10.7555/JBR.37.20230063","doi":"10.7555/JBR.37.20230063","figList":[{"columnNums":2,"dataId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0063-1.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0063-1.jpg","id":"b4f0f6e4-36f2-49bb-9edf-70e2ee2d060a","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Identification and characterization of apaQTL-SNPs in bladder cancer.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: Flowchart of the current study. First, we obtained apaQTL-SNPs and apaQTL-genes from the SNP2APA database and further screened them in combination with TCGA differential expression analysis. Subsequently, we integrated apaQTL-SNPs and our GWAS data of bladder cancer (580 cases and 1101 controls). Furthermore, we prioritized the most significant risk loci (r2 > 0.8), and after FDR correction, three candidate apaQTL-SNPs were obtained. DepMap was used to identify the essential gene, and a series of analyses were conducted to investigate the association between candidate apaQTL-SNP variant rs2683524 and bladder cancer risk. B: Manhattan plot of 17995 apaQTL-SNPs correlated with bladder cancer downloaded from SNP2APA database. The vertical coordinate used the P-value of apaQTL, calculated by Matrix eQTL. C and D: Pie charts indicating proportions of SNPs annotated with each functional category (upstream gene, downstream gene, regulatory region, TF binding site, non-coding transcript, 3′ UTR, intergenic, intron, and other). Abbreviations: PAS, polyadenylation signal; TCGA, the Cancer Genome Atlas; SNP, single nucleotide polymorphism; BLCA, bladder cancer; GWAS, genome-wide association study; MAF, minor allele frequency; HWE, Hardy-Weinberg equilibrium; LD, linkage disequilibrium; FDR, false discovery rate; APA, alternative polyadenylation; UTR, untranslated region; TF, transcript factor.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},{"columnNums":2,"dataId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0063-2.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0063-2.jpg","id":"a19768ec-fa6b-4453-bd96-2bda50f8daa2","imgWidth":"17.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Genes affected by apaQTL-SNPs play crucial roles in cancer development.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"A: KEGG pathway analysis demonstrated that apaQTL-genes were enriched in multiple cancer pathways. B: GISTIC analysis indicated that apaQTL-genes frequently occurred focal amplification (top/red) and deletion (bottom/blue) SCNAs along the genome in bladder cancer tumor samples from TCGA. C: Somatic mutational landscape of bladder cancer tumor samples. The top 10 somatic mutations of apaQTL-genes were shown, and mutation subtypes were denoted by color (bottom). D: Copy number alternations landscape of bladder cancer tumor samples. The top 10 copy number alterations of apaQTL-genes were shown and amplification and deep deletion were denoted by color (bottom). E: The association between the expression of apaQTL-genes and infiltration proportion of immune cells, which was estimated by the CIBERSORT algorithm using gene expression profile from TCGA tumor samples. F: Bubble diagram depicting the correlation between apaQTL-genes and individual immune cell types in bladder cancer tumor. The value displayed is the Spearman correlation of immune cell fractions (rows) with apaQTL-genes expression (columns). Red indicates a positive correlation (increasing proportion of indicated cell type with increasing gene expression), and blue indicates a negative correlation, respectively. The size of the bubble indicates the significance of correlation. Abbreviation: TMB, tumor mutational burden.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0063-3.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0063-3.jpg","id":"84a7ffe5-dd9d-4777-ad6d-b5ab850ac490","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"SNP selection and association with bladder cancer risk.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"A: A volcano plot displaying differential expressed genes of 288 apaQTL-genes, including 138 up-regulated genes (red) and 23 down-regulated genes (blue). B: Manhattan plot for associations between apaQTL-SNPs and bladder cancer risk based on GWAS data of 580 cases and 1 101 controls. Abbreviations: SNP, single nucleotide polymorphism; GWAS, genome-wide association study.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0063-4.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0063-4.jpg","id":"07e2e2c1-c5fd-4bac-869b-a0b61e0d10dc","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Expression level of PRR13 in bladder cancer tissues and normal tissues.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"A: Heatmap clustering showed three apaQTL-genes effects (rows) based on twenty-eight cell lines of bladder cancer of CRISPR data from DepMap. The color changes from red to blue, indicated that the effect of inhibiting cell viability was better. B–D: Student's t-test of paired and unpaired to analyze the differences in the gene. The mRNA expression level of PRR13 were evaluated based on the TCGA database (B and C) and GEO database GSE38264 (D). E: The distribution of PRR13 in bladder cancer immune subtypes derived from TCGA dataset downloaded from TISIDB website. The P-value was calculated by the Kruskal-Wallis test. The immune subtypes were C1 (wound healing), C2 (IFN-gamma dominant), C3 (inflammatory), C4 (lymphocyte depleted), C5 (immunologically quiet), and C6 (TGF-β dominant).","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0063-5.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0063-5.jpg","id":"ca6df5a0-980b-45b6-8929-69c009344129","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"The role of rs2683524 in APA and PRR13 expression.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"A: RNA secondary structure diagram and minimum free energy (MFE) of rs2683524 for wild-type and mutant. Images and data were obtained from the RNAfold website. B: Boxplots represent the alternative polyadenylation levels in individuals carrying homozygote CC, heterozygous CT, and homozygote TT, respectively. C: 3′ UTR schematic of PRR13 as depicted in the image. The functional polyA sites estimated from PolyA_DB and PolyASite were highlighted in red and green respectively. D: The mechanistic map shows that rs2683524 regulates alternative polyadenylation, affects PRR13 translation efficiency, and increases bladder cancer risk. Abbreviations: MFE, minimum free energy; PDUI, percentage of distal polyA site usage index; PAS, polyadenylation site.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/","firstFig":{"columnNums":2,"dataId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0063-1_mini.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0063-1.jpg","id":"b4f0f6e4-36f2-49bb-9edf-70e2ee2d060a","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Identification and characterization of apaQTL-SNPs in bladder cancer.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: Flowchart of the current study. First, we obtained apaQTL-SNPs and apaQTL-genes from the SNP2APA database and further screened them in combination with TCGA differential expression analysis. Subsequently, we integrated apaQTL-SNPs and our GWAS data of bladder cancer (580 cases and 1101 controls). Furthermore, we prioritized the most significant risk loci (r2 > 0.8), and after FDR correction, three candidate apaQTL-SNPs were obtained. DepMap was used to identify the essential gene, and a series of analyses were conducted to investigate the association between candidate apaQTL-SNP variant rs2683524 and bladder cancer risk. B: Manhattan plot of 17995 apaQTL-SNPs correlated with bladder cancer downloaded from SNP2APA database. The vertical coordinate used the P-value of apaQTL, calculated by Matrix eQTL. C and D: Pie charts indicating proportions of SNPs annotated with each functional category (upstream gene, downstream gene, regulatory region, TF binding site, non-coding transcript, 3′ UTR, intergenic, intron, and other). Abbreviations: PAS, polyadenylation signal; TCGA, the Cancer Genome Atlas; SNP, single nucleotide polymorphism; BLCA, bladder cancer; GWAS, genome-wide association study; MAF, minor allele frequency; HWE, Hardy-Weinberg equilibrium; LD, linkage disequilibrium; FDR, false discovery rate; APA, alternative polyadenylation; UTR, untranslated region; TF, transcript factor.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},"hasPage":true,"htmlAccess":true,"id":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","issue":"6","issueArticle":"0","keywords":[{"articleId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","id":"ef74aed7-611e-41a9-8d82-b3aa2abefef7","keywordEn":"alternative polyadenylation","sortNum":1},{"articleId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","id":"aec29e13-c1ac-4452-ae16-73c24ba9aa8f","keywordEn":"genetic variant","sortNum":2},{"articleId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","id":"ccf8ad71-a6a1-45e7-afb2-98a1ac7f4ec8","keywordEn":"bladder cancer","sortNum":3},{"articleId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","id":"a85f23d3-84d6-4f59-ba7d-3a50ec9641d3","keywordEn":"PRR13","sortNum":4},{"articleId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","id":"24c66039-e4e5-400e-8d90-f1652e6c6008","keywordEn":"apaQTL","sortNum":5}],"language":"en","page":"405-417","pdfAccess":true,"publisherId":"JBR-2023-0063","releaseProgress":{"articleId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","lastReleaseTime":"2024-03-27 09:03","maxLastReleaseTime":"2024-03-27 09:03","minLastReleaseTime":"2023-11-22 09:35","otherReleaseList":[{"articleId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-11-17 08:40","maxLastReleaseTime":"2023-11-17 08:40","minLastReleaseTime":"2023-11-09 08:43","otherReleaseList":[]},{"articleId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-06-03 17:06","maxLastReleaseTime":"2023-06-03 17:06","minLastReleaseTime":"2023-06-03 17:06","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20230006000000","subTitleCn":"","subTitleEn":"","supplements":[{"abstractCn":"","abstractEn":"","contentCn":"","contentEn":"","createTime":1728969680000,"dataId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","doi":"","downloadNum":2,"fileLastName":"pdf","fileName":"","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/7884d5fc-abca-436a-a942-2c63340a3c19.pdf","fileSize":"10536KB","fileType":"file","id":"a2c4accf-e862-47e8-a9cb-0df2cadeb61d","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","link":"","nameCn":"JBR-2023-0063-Supplementary","nameEn":"JBR-2023-0063-Supplementary","openTarget":"","remarkCn":"","remarkEn":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"","type":"article"}],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Alternative polyadenylation-related genetic variants contribute to bladder cancer risk","topicNameEn":"","type":"research-article","volume":"37","year":"2023","yearInt":2023},"dataId":"bb8a0380-b2ae-4336-a35f-2e4b17dea920","dataType":"Article","id":"796d2dbb-ed3a-4e8b-a44c-b51ca9a4a528","language":"cn,en","sort":97,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"The endosomal trafficking of signaling membrane proteins, such as receptors, transporters and channels, is mediated by the retromer-mediated sorting machinery, composed of a cargo-selective vacuolar protein sorting trimer and a membrane-deforming subunit of sorting nexin proteins. Recent studies have shown that the isoforms, sorting nexin 5 (SNX5) and SNX6, have played distinctive regulatory roles in retrograde membrane trafficking. However, the molecular insight determined functional differences within the proteins remains unclear. We reported that SNX5 and SNX6 had distinct binding affinity to the cargo protein vesicular monoamine transporter 2 (VMAT2). SNX5, but not SNX6, specifically interacted with VMAT2 through the Phox domain, which contains an alpha-helix binding motif. Using chimeric mutagenesis, we identified that several key residues within this domain were unique in SNX5, but not SNX6, and played an auxiliary role in its binding to VMAT2. Importantly, we generated a set of mutant SNX6, in which the corresponding key residues were mutated to those in SNX5. In addition to the gain in binding affinity to VMAT2, their overexpression functionally rescued the altered retrograde trafficking of VMAT2 induced by siRNA-mediated depletion of SNX5. These data strongly suggest that SNX5 and SNX6 have different functions in retrograde membrane trafficking, which is determined by the different structural elements within the Phox domain of two proteins. Our work provides a new information on the role of SNX5 and SNX6 in the molecular regulation of retrograde membrane trafficking and vesicular membrane targeting in monoamine neurotransmission and neurological diseases.
","appendixList":[],"articleBusiness":{"articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","articleState":"-1","articleType":"1","baiduIncludeResult":0,"baiduIncludeResultSearchNum":0,"baiduPushLastDate":1701228300000,"baiduPushNum":3,"baiduXueShuIncludeResult":0,"baiduXueShuIncludeResultSearchNum":0,"baiduXueShuPushLastDate":1701240000000,"baiduXueShuPushNum":4,"filename":"JBR-2023-0112.xml","googleIncludeResult":0,"googleIncludeResultSearchNum":0,"htmlSource":1,"htmlViewCount":369,"id":"62ce28b1-8553-4236-bce7-5f4bb1d8cada","isRegCstr":0,"isRegDOI":1,"pdfDownCount":25,"pdfEnFileSizeInt":0,"pdfFileName":"JBR-2023-0112.pdf","pdfFileSize":6209.81,"pdfFileSizeInt":6209,"remark":"XML","viewCount":638,"xmlDownCount":0,"xmlFileSize":89.0},"articleNo":"JBR-2023-0112","authors":[{"addressTagIds":"aff1","articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","authorNameEn":"Qing Chen","authorNotesEn":"△These authors contributed equally to this work.","authorRoleType":"author","authorTagVal":"1, △","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Qing","id":"85a347c2-0be1-4fda-a6e0-1f0b18159d28","sortNumber":1,"surNameEn":"Chen"},{"addressTagIds":"aff1","articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","authorNameEn":"Meiheng Sun","authorNotesEn":"△These authors contributed equally to this work.","authorRoleType":"author","authorTagVal":"1, △","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Meiheng","id":"360de5c5-72c5-46dd-ac1f-9bfc0a3608d3","sortNumber":2,"surNameEn":"Sun"},{"addressTagIds":"aff1","articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","authorNameEn":"Xu Han","authorRoleType":"author","authorTagVal":"1","authorType":"org","corresper":false,"deceased":0,"givenNamesEn":"Xu","id":"c74232cf-ebe8-44a7-9f1e-8ba3d75c0450","sortNumber":3,"surNameEn":"Han"},{"addressTagIds":"aff1","articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","authorNameEn":"Hongfei Xu","authorRoleType":"author","authorTagVal":"1","authorType":"org","corresper":true,"correspinfoEn":"Yongjian Liu and Hongfei Xu, Jiangsu Key Laboratory of Xenotransplantation, Department of Medical Genetics, Nanjing Medical University, Nanjing, Jiangsu 211166, China. Tel: +86-25-86869442, E-mails: young.liu78@gmail.com/yjliu@pitt.edu (Liu) and hongfei.xu@ucsf.edu (Xu). Current address of Hongfei Xu: Department of Physiology and Neurology, UCSF School of Medicine, San Francisco, CA 94158, USA","deceased":0,"email":"hongfei.xu@ucsf.edu","givenNamesEn":"Hongfei","id":"73680eb8-b1b6-4733-9495-712d7387f3c1","sortNumber":4,"surNameEn":"Xu"},{"addressTagIds":"aff1, aff2","articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","authorNameEn":"Yongjian Liu","authorRoleType":"author","authorTagVal":"1, 2","authorType":"org","corresper":true,"correspinfoEn":"","deceased":0,"email":"yjliu@pitt.edu","givenNamesEn":"Yongjian","id":"427c0338-5de8-4d1e-b573-7cd17915bbfa","sortNumber":5,"surNameEn":"Liu"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Qing Chen, Meiheng Sun, Xu Han, Hongfei Xu, Yongjian Liu. Structural determinants specific for retromer protein sorting nexin 5 in regulating subcellular retrograde membrane trafficking[J]. The Journal of Biomedical Research, 2023, 37(6): 492-506. DOI: 10.7555/JBR.37.20230112","doi":"10.7555/JBR.37.20230112","figList":[{"columnNums":2,"dataId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0112-1.jpg","fileSize":"2994KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0112-1.jpg","id":"206b97b2-1527-405b-abbb-b11f83d7a207","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"SNX5, but not SNX6, specifically interacted with VMAT2 and regulated the subcellular localization of VMAT2.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: Extracts from HeLa cells co-transfected with either 3Flag-SNX5 or 3Flag-SNX6 with 3HA-Tac-MPR were immunoprecipitated to determine the interaction between SNX5 or SNX6 and MPR. B and C: Extracts from HeLa cells co-transfected with either 3HA-SNX5 or 3HA-SNX6 and 3Flag-TacM were immunoprecipitated to determine the interaction between SNX5 or SNX6 and VMAT2. D: HeLa cells were co-transfected with CI-MPR and siRNA for control, SNX5 or SNX6, and immunostained for CI-MPR (red) and TGN46 (green). Scale bar: 10 μm (left), 2 μm (right). E: HeLa cells were co-transfected with 3HA-VMAT2 and siRNA for control, SNX5 or SNX6, and immunostained for HA (red) and TGN46 (green). Scale bar: 10 μm (left), 2 μm (right). Bar graphs indicate mean ± standard error of the mean of the band intensities normalized to maximum co-IP (A–C) and the Manders' overlapping coefficient between CI-MPR or VMAT2 and TGN46 (D and E) for each experiment (n = 3). ns: not significant; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by one-way ANOVA with Tukey's multiple comparisons test (A–E). Abbreviations: SNX5, sorting nexin 5; SNX6, sorting nexin 6; CI-MPR, cation-independent mannose 6-phosphate receptor; VMAT2, vesicular monoamine transporter 2; TGN46, trans-Golgi network protein 46.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0112-2.jpg","fileSize":"2125KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0112-2.jpg","id":"f03013a4-0815-4aca-bc22-160407fe5aac","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"The Phox (PX) domain is required for the interaction of SNX5 and VMAT2.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"A: Diagram of SNX5/6 protein showing the PX and BAR domains. B: Extracts from COS-7 cells transiently transfected with 3Flag-TacM were incubated with bacterially expressed 6His-SNX5PX or 6His-SNX6PX and detected with anti-Flag antibody by immunoblotting. Coomassie bright blue staining shows the same amount of bacterially expressed proteins used for pull down. C: HeLa cells transfected with GFP-VMAT2 and SNX5WT or SNX5PX or transfected with GFP-VMAT2 and SNX6WT or SNX6PX were immunostained for TGN46 (red). Scale bar, 10 μm. Bar graphs indicate mean ± standard error of the mean of the band intensities normalized to maximum co-IP for each experiment (n = 3). ns: not significant; **P < 0.01 and ***P < 0.001 by one-way ANOVA with Tukey's multiple comparisons test (B) and two-tailed Student's t-test (C). Abbreviations: FL, full length; PX, phox homology; BAR, Bin/amphiphysin/Rvs; SNX5, sorting nexin 5; SNX6, sorting nexin 6; GFP, green fluorescent protein; VMAT2, vesicular monoamine transporter 2; TGN46, trans-Golgi network protein 46.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0112-3.jpg","fileSize":"1764KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0112-3.jpg","id":"c5f8c3ea-d2a8-4469-a798-9721cb4b5241","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"The PX domains of SNX5 and SNX6 contain distinct residues for protein binding.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"A: Diagram of chimeric constructs between SNX5 and SNX6 (Top). The PX domain of SNX5 (1–181) was divided into three parts: A (1–90), B (91–140), and C (141–181). The amino acids from three parts were replaced with the corresponding parts of SNX6 to construct the chimeras: SNX65A, SNX65B, and SNX65C. Extracts from COS-7 cells co-transfected with Flag-TacM and HA-SNX5, SNX6, or three chimeras were immunoprecipitated for Flag, and the precipitates were immunoblotted for HA (bottom). B: Diagram of SNX6 and its truncated constructs. Extracts from COS-7 cells co-transfected with Flag-TacM and HA-SNX5, SNX6, or three truncated constructs (HA-SNX6A+BAR, HA-SNX6B+BAR, HA-SNX6C+BAR) were subjected to immunoprecipitation with Flag and immunoblotted for HA. C: Flag-TacM was transiently transfected in HeLa cells for 48 h, followed by cell lysates incubated with Ni-NTA Agarose immobilized 6His-SNX5PX, 6His-SNX6PX or A/B/C part of SNX5/6 PX domain. The association of Flag-TacM with His-fusion proteins was detected with Flag antibody by immunoblotting. D: Extracts from COS-7 cells transiently co-transfected with Flag-TacM and HA-SNX5, SNX6, truncated proteins HA-SNX5B+BAR, HA-SNX6B+BAR, or SNX5 point mutants (Y132D and F136D) were immunoprecipitated for Flag and immunoblotted for HA. Bar graphs indicate mean ± standard error of the mean of the band intensities normalized to maximum co-IP for each experiment (n = 3). ns: not significant; *P < 0.05, **P < 0.01, and ***P < 0.001 by one-way ANOVA with Tukey's multiple comparisons test (A–D). Abbreviations: PX, phox homology; BAR, Bin/amphiphysin/Rvs; SNX5, sorting nexin 5; SNX6, sorting nexin 6.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0112-4.jpg","fileSize":"3889KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0112-4.jpg","id":"bd8635f1-9723-4ac1-93e2-179caab0b924","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Identification of key residues in SNX6 required for inhibiting its interaction with VMAT2.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"A: The A and C parts of the SNX5 PX domain were further divided into five parts (A1: 1–35, A2: 36–57, A3: 58–90, C1: 141–160, C2: 161–180), followed by replacing the amino acids of the five parts with the corresponding positions of SNX6, named as SNX65A1, SNX65A2, SNX65A3, SNX65C1, and SNX65C2. B: Extracts from COS-7 cells co-transfected with 3Flag-TacM and 3HA-SNX5, SNX6, or the five chimeric proteins were immunoprecipitated for Flag and immunoblotted for HA. C: Sequence alignment of the PX domain of SNX5 and SNX6. D: Extracts from COS-7 cells co-transfected with 3Flag-TacM and 3HA-SNX5, SNX6, or point mutants on the A part [3HA-SNX6(A30P)PX, SNX6(S37P)PX, and SNX6(N62P)PX] were immunoprecipitated for Flag and immunoblotted for HA. E: Extracts from HeLa cells co-transfected with 3Flag-TacM and 3HA-SNX5, SNX6, or point mutants on the C part [3HA- SNX6(M143S)PX, SNX6(C149Q)PX, SNX6(R158S)PX, SNX6(L161R)PX] were immunoprecipitated for Flag and immunoblotted for HA. Bar graphs indicate mean ± standard error of the mean of the band intensities normalized to maximum co-IP for each experiment (n = 3). ns: not significant; *P < 0.05, **P < 0.01, and ****P < 0.0001 by one-way ANOVA with Tukey's multiple comparisons test (B, D, and E). Abbreviations: SNX5, sorting nexin 5; SNX6, sorting nexin 6; VMAT2, vesicular monoamine transporter 2.","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0112-5.jpg","fileSize":"1906KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0112-5.jpg","id":"ced72da1-ca74-4676-b63e-6a592a52f7c9","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Overexpression of SNX6tetra-Mut restored its regulatory function in TGN targeting of VMAT2.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"A: Sequence alignment of SNX5, SNX6 and SNX6tetra-Mut within the Phox domain to indicate four residues for mutagenesis. B: Extracts from HeLa cells transfected with 3Flag-TacM and 3HA-SNX5, 3HA-SNX6 or 3HA-SNX6tetra-Mut were immunoprecipitated for Flag and the precipitates were immunoblotted for HA. C: HeLa cells transfected with 3HA-SNX6 or 3HA-SNX5 with and without siRNA for SXN5. Western blotting shows that siRNA of SNX5 does not alter the expression of SNX6. D: HeLa cells co-transfected with 3Flag-VMAT2 and control siRNA, SNX5 siRNA or SNX5 siRNA with 3HA-SNX6tetra-Mut were immunostained for TGN46 (green) and Flag (red). Scale bar: 10 μm (left), 2 μm (right). The localization of VMAT2 with TGN was quantified by the Manders' colocalization coefficient. Bar graphs indicate mean ± standard error of the mean of the band intensities normalized to maximum co-IP (B and C) and Mander's coefficient (D) for each experiment (n = 3). ns: not significant; *P < 0.05, **P < 0.01, and ***P < 0.001 by one-way ANOVA with Tukey's multiple comparisons test. Abbreviations: SNX5, sorting nexin 5; SNX6, sorting nexin 6; VMAT2, vesicular monoamine transporter 2.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0112-6.jpg","fileSize":"2235KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0112-6.jpg","id":"6ec9ea4b-54e1-4c3a-a528-630140407fd1","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"6","nameEn":"Overexpression of SNX6tetra-Mut restored the LDCVs targeting and function of VMAT2 in PC12 cells.","referSecTagIds":"","sort":5,"supplementRemarkCn":"","supplementRemarkEn":"A: PC12 cells stably expressing 3Flag-VMAT2 transfected with control siRNA, Snx5 siRNA, Snx6 siRNA, or Snx5 siRNA with 3HA-SNX6tetra-Mut were immunostained for Flag (green) and SgⅡ (red). Scale bar, 10 μm. B: PC12 cells transfected with control siRNA, Snx5 siRNA, Snx6 siRNA, or Snx5 siRNA with 3HA-SNX6tetra-Mut were loaded with 3H-NE and incubated in Tyrode's solution containing 2.5 or 90 mmol/L K+. C: Equilibrium sucrose density gradient fractionation of PC12 cells stably expressing 3Flag-VMAT2 shows that Snx5 knockdown (KD) redistributed VMAT2, but not SgⅡ or synaptophysin, to light fractions. SNX6tetra-Mut rescued the DCVs targeting in Snx5 KD condition. The gradient fractions were loaded onto two gels (separated here by vertical lines) and then transferred to one membrane for detection by ECL. Bar graphs indicate mean ± standard error of the mean of the band intensities normalized to the maximum co-IP for each experiment (n = 3). ns: not significant; ***P < 0.001 and ****P < 0.0001 by one-way ANOVA with Tukey's multiple comparisons test. Abbreviations: LDCVs, large dense core vesicles; SLMVs, synaptic-like microvesicles; Snx5, sorting nexin 5; Snx6, sorting nexin 6; GFP, green fluorescent protein; VMAT2, vesicular monoamine transporter 2; SgⅡ, secretogranin Ⅱ.","tagId":"Figure6","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/","firstFig":{"columnNums":2,"dataId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/6/JBR-2023-0112-1_mini.jpg","fileSize":"2994KB","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0112-1.jpg","id":"206b97b2-1527-405b-abbb-b11f83d7a207","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"SNX5, but not SNX6, specifically interacted with VMAT2 and regulated the subcellular localization of VMAT2.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: Extracts from HeLa cells co-transfected with either 3Flag-SNX5 or 3Flag-SNX6 with 3HA-Tac-MPR were immunoprecipitated to determine the interaction between SNX5 or SNX6 and MPR. B and C: Extracts from HeLa cells co-transfected with either 3HA-SNX5 or 3HA-SNX6 and 3Flag-TacM were immunoprecipitated to determine the interaction between SNX5 or SNX6 and VMAT2. D: HeLa cells were co-transfected with CI-MPR and siRNA for control, SNX5 or SNX6, and immunostained for CI-MPR (red) and TGN46 (green). Scale bar: 10 μm (left), 2 μm (right). E: HeLa cells were co-transfected with 3HA-VMAT2 and siRNA for control, SNX5 or SNX6, and immunostained for HA (red) and TGN46 (green). Scale bar: 10 μm (left), 2 μm (right). Bar graphs indicate mean ± standard error of the mean of the band intensities normalized to maximum co-IP (A–C) and the Manders' overlapping coefficient between CI-MPR or VMAT2 and TGN46 (D and E) for each experiment (n = 3). ns: not significant; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by one-way ANOVA with Tukey's multiple comparisons test (A–E). Abbreviations: SNX5, sorting nexin 5; SNX6, sorting nexin 6; CI-MPR, cation-independent mannose 6-phosphate receptor; VMAT2, vesicular monoamine transporter 2; TGN46, trans-Golgi network protein 46.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},"hasPage":true,"htmlAccess":true,"id":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","issue":"6","issueArticle":"0","keywords":[{"articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","id":"436279a8-5fc6-4493-8864-84bdb753538a","keywordEn":"vesicular monoamine transporter 2","sortNum":1},{"articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","id":"5ce199b3-ec54-4a74-9d9a-2d4561482916","keywordEn":"SNX5","sortNum":2},{"articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","id":"92af6328-2388-4ba2-9116-d6d5ca62aedd","keywordEn":"SNX6","sortNum":3},{"articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","id":"66cb9d2d-1dbc-468a-a6d9-02540f3486d6","keywordEn":"retromer","sortNum":4},{"articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","id":"8c79bfec-493c-46c6-ba6c-94df04a3d64f","keywordEn":"retrograde trafficking","sortNum":5}],"language":"en","page":"492-506","pdfAccess":true,"publisherId":"JBR-2023-0112","releaseProgress":{"articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","lastReleaseTime":"2024-03-27 09:05","maxLastReleaseTime":"2024-03-27 09:05","minLastReleaseTime":"2023-11-22 09:39","otherReleaseList":[{"articleId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-11-15 16:27","maxLastReleaseTime":"2023-11-15 16:27","minLastReleaseTime":"2023-11-15 16:27","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20230006000000","subTitleCn":"","subTitleEn":"","supplements":[],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Structural determinants specific for retromer protein sorting nexin 5 in regulating subcellular retrograde membrane trafficking","topicNameEn":"","type":"research-article","volume":"37","year":"2023","yearInt":2023},"dataId":"7dd2783f-3aab-42e5-a394-b90e8d67e7ad","dataType":"Article","id":"bee0fda4-9ee9-41db-b34a-7f230ba91d69","language":"cn,en","sort":98,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"Age-related macular degeneration (AMD) causes irreversible blindness in people aged over 50 worldwide. The dysfunction of the retinal pigment epithelium is the primary cause of atrophic AMD. In the current study, we used the ComBat and Training Distribution Matching method to integrate data obtained from the Gene Expression Omnibus database. We analyzed the integrated sequencing data by the Gene Set Enrichment Analysis. Peroxisome and tumor necrosis factor-α (TNF-α) signaling and nuclear factor kappa B (NF-κB) were among the top 10 pathways, and thus we selected them to construct AMD cell models to identify differentially expressed circular RNAs (circRNAs). We then constructed a competing endogenous RNA network, which is related to differentially expressed circRNAs. This network included seven circRNAs, 15 microRNAs, and 82 mRNAs. The Kyoto Encyclopedia of Genes and Genomes analysis of mRNAs in this network showed that the hypoxia-inducible factor-1 (HIF-1) signaling pathway was a common downstream event. The results of the current study may provide insights into the pathological processes of atrophic AMD.
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Tel/Fax: +86-25-68303110 and +86-25-68303160, E-mails: yuansongtao@vip.sina.com and liuqh@njmu.edu.cn","deceased":0,"email":"yuansongtao@vip.sina.com","givenNamesEn":"Songtao","id":"69ef3945-bf07-4410-a41b-486a52dd1b8a","sortNumber":9,"surNameEn":"Yuan"},{"addressTagIds":"aff1","articleId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","authorNameEn":"Qinghuai Liu","authorRoleType":"author","authorTagVal":"","authorType":"org","corresper":true,"correspinfoEn":"","deceased":0,"email":"liuqh@njmu.edu.cn","givenNamesEn":"Qinghuai","id":"2851aaaf-a41f-4d4d-ace5-65134c9d9ab6","sortNumber":10,"surNameEn":"Liu"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Ruxu Sun, Hongjing Zhu, Ying Wang, Jianan Wang, Chao Jiang, Qiuchen Cao, Yeran Zhang, Yichen Zhang, Songtao Yuan, Qinghuai Liu. Circular RNA expression and the competitive endogenous RNA network in pathological, age-related macular degeneration events: A cross-platform normalization study[J]. The Journal of Biomedical Research, 2023, 37(5): 367-381. DOI: 10.7555/JBR.37.20230010","doi":"10.7555/JBR.37.20230010","figList":[{"columnNums":2,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0010-1.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0010-1.jpg","id":"e8e766b2-ba02-43f4-8015-0cbc3fd4aaf3","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"The flowchart of cross-platform integration and circRNA-miRNA-mRNA network construction.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"Abbreviations: circRNA, circular RNA; miRNA, microRNA; GSEA, Gene Set Enrichment Analysis; GO, Gene Expression Omnibus; KEGG, Kyoto Encyclopedia of Genes and Genomes; FC, fold change; TDM, Training Distribution Matching.","tagId":"Figure1","type":"article","typesetSecTagId":"s02"},{"columnNums":2,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0010-2.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0010-2.jpg","id":"dc7fd195-ea0a-43ae-9d0d-fc2c973a5dc1","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Cross-platform integration of Gene Expression Omnibus datasets and bioinformatic analysis.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"A: The principal component analysis (PCA) plot of samples from GSE135092, GSE50195, and GSE29801 before normalization. B: The PCA plot of samples from GSE50195 and GSE29801 after Combat integration. C: The PCA plot of samples from GSE135092, GSE50195, and GSE29801 after TDM integration. D–F: Gene Set Enrichment Analysis revealed that the activity of peroxisome (Hallmark_Peroxisome, D), inflammation (Hallmark_Inflammation response, E), and TNF-α signaling via NF-κB (Hallmark_TNF-α signaling via NF-κB, F) were upregulated. Abbreviations: TNF-α, tumor necrosis factor-α; NF-κB, nuclear factor kappa B; TDM, Training Distribution Matching.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":1,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0010-3.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0010-3.jpg","id":"16e0ecee-c68c-4454-b363-3dce58a5dffc","imgWidth":"8.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"Protein-protein interaction analysis of differentially expressed genes in integrated sequencing data of AMD.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"Targeted genes with over five nodes were labeled with gene symbols. Abbreviations: THBS2, thrombospondin 2; LUM, lumican; NR1H4, nuclear receptor subfamily 1 group Hmember 4.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0010-4.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0010-4.jpg","id":"bd955c3a-137d-40b6-81db-461d5c0142bc","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Construction of inflammation and oxidative stress cell models.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"A: Mitochondrial ROS was elevated in ARPE-19 cells treated with H2O2 (200 μmol/L) for 24 h. B: Total ROS in the cytoplasm was accumulated in ARPE-19 cells treated with H2O2 (200 μmol/L) for 24 h. C: NF-κB p65 translocated to the nucleus after 48 h treatment with TNF-α (100 ng/mL). D and E: Immunoblotting of ZO-1 and β-catenin in ARPE-19 cells treated with H2O2 (D) and TNF-α (E). F: Immunofluorescence of ZO-1 in ARPE-19 cells treated with H2O2 or TNF-α. G: Immunofluorescence of β-catenin in ARPE-19 cells treated with H2O2 or TNF-α. Experiments were repeated three times. The data are presented as means with standard errors of the mean. Student's t-test was applied for comparisons between two groups. *P < 0.05; **P < 0.01; ***P < 0.001. Scale bar: 50 μm.","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0010-5.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0010-5.jpg","id":"2e0ca465-4a63-4e7e-9d26-f869424f36d7","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Characterization of identified circRNAs.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"A: The number of circRNAs in chromosomes. B: Length distribution of circRNAs. C: Classification of circRNAs.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0010-6.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0010-6.jpg","id":"7c2a0895-f608-4fe0-b86c-24d9a3e08f0d","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"6","nameEn":"An overview of the expression profiling of RNAs in oxidative stress and inflammation cell models.","referSecTagIds":"","sort":5,"supplementRemarkCn":"","supplementRemarkEn":"A: Volcano plots of gene expression profiles of circRNAs, miRNAs, and mRNAs in the two cell models. B: Venn diagrams of overlapped differentially expressed circRNAs in the two cell models. Eight circRNAs were co-downregulated, and six circRNAs were co-upregulated. Abbreviation: FC, fold change.","tagId":"Figure6","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0010-7.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0010-7.jpg","id":"82e2f6a5-b880-4011-be2b-b2eedd4f7ce6","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"7","nameEn":"Differentially expressed circRNAs mediated competitive endogenous RNA network.","referSecTagIds":"","sort":6,"supplementRemarkCn":"","supplementRemarkEn":"Circular RNA: red circle; microRNA: pink circle; mRNA: orange circle.","tagId":"Figure7","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0010-8.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0010-8.jpg","id":"4056f6d9-859f-45eb-9bea-927730513402","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"8","nameEn":"GO and KEGG enrichment of differentially expressed mRNAs in the competitive endogenous RNA network.","referSecTagIds":"","sort":7,"supplementRemarkCn":"","supplementRemarkEn":"The top 10 clusters of BP (A), CC (B), MF (C), and KEGG pathways (D) for mRNAs. Abbreviations: GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; BP, biological process; CC, cell component; MF, molecular function.","tagId":"Figure8","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0010-9.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0010-9.jpg","id":"c9175856-fcc6-461d-b72c-a214db5035dc","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"9","nameEn":"Validation of co-regulated circRNAs and mRNAs in the competitive endogenous RNA network.","referSecTagIds":"","sort":8,"supplementRemarkCn":"","supplementRemarkEn":"A and B: The expression of randomly chosen circRNAs in H2O2 (A) and TNF-α (B) treated ARPE-19 cells. C and D: The expression of randomly chosen mRNAs (ALDOA, TMEM98, and SLC4A2) in H2O2 (C) and TNF-α (D) treated ARPE-19 cells. Experiments were repeated three times. The data are presented as means with standard errors of the mean. Student's t-test was applied for comparisons between two different groups. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.","tagId":"Figure9","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/","firstFig":{"abstractCn":"","abstractEn":"","contentCn":"","contentEn":"","createTime":1727591117000,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","doi":"","fileLastName":"jpg","fileName":"","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/0832877f-68fe-4034-8e3c-4832f72b6d3d.jpg","fileSize":"476KB","fileType":"firstFig","id":"22fb2de2-1a8a-4719-b031-eebdbc2ccfd5","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","link":"","nameCn":"JBR-2023-0010-1","nameEn":"","openTarget":"","remarkCn":"","remarkEn":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"","type":"article"},"hasPage":true,"htmlAccess":true,"id":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","issue":"5","issueArticle":"0","keywords":[{"articleId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","id":"77ef6901-e878-4942-be0c-c6bfebc60b11","keywordEn":"age-related macular degeneration","sortNum":1},{"articleId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","id":"de92f4ba-10ab-4c08-8125-811c06c5cbaa","keywordEn":"retinal pigment epithelium","sortNum":2},{"articleId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","id":"68b5956c-9fb5-4dc6-b454-0253caa9c1e9","keywordEn":"circular RNA","sortNum":3},{"articleId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","id":"37781d88-89ff-409d-a04c-ae5d0f8e22b9","keywordEn":"bioinformatics analysis","sortNum":4},{"articleId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","id":"2c510eca-634b-482b-9870-624fc0387f12","keywordEn":"competing endogenous RNA","sortNum":5}],"language":"en","page":"367-381","pdfAccess":true,"publisherId":"JBR-2023-0010","releaseProgress":{"articleId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","lastReleaseTime":"2024-03-27 09:09","maxLastReleaseTime":"2024-03-27 09:09","minLastReleaseTime":"2023-09-28 09:56","otherReleaseList":[{"articleId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-09-15 14:59","maxLastReleaseTime":"2023-09-15 14:59","minLastReleaseTime":"2023-05-04 15:28","otherReleaseList":[]},{"articleId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-05-04 15:29","maxLastReleaseTime":"2023-05-04 15:29","minLastReleaseTime":"2023-05-04 15:29","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20230005000000","subTitleCn":"","subTitleEn":"","supplements":[{"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","downloadNum":7,"fileLastName":"pdf","fileName":"JBR-2023-0010-supplementary.pdf","filePath":"/fileSWYXYJZZYWB/journal/article/file/18af28d7-ebfc-49b4-9c1c-f8515f1a70e8.pdf","fileSize":"2774KB","fileType":"file","id":"6036aed7-58ea-4af7-9987-cd36fc31c316","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","nameCn":"JBR-2023-0010-supplementary","nameEn":"JBR-2023-0010-supplementary","type":"article"},{"abstractCn":"","abstractEn":"","contentCn":"","contentEn":"","createTime":1727591117000,"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","doi":"","fileLastName":"jpg","fileName":"","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/0832877f-68fe-4034-8e3c-4832f72b6d3d.jpg","fileSize":"476KB","fileType":"firstFig","id":"22fb2de2-1a8a-4719-b031-eebdbc2ccfd5","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","link":"","nameCn":"JBR-2023-0010-1","nameEn":"","openTarget":"","remarkCn":"","remarkEn":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"","type":"article"}],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Circular RNA expression and the competitive endogenous RNA network in pathological, age-related macular degeneration events: A cross-platform normalization study","topicNameEn":"","type":"research-article","volume":"37","year":"2023","yearInt":2023},"dataId":"65ac4ac5-1d36-4356-9e6b-b25df42d2935","dataType":"Article","id":"5d100775-c12b-4e50-b32f-29e60333ce9c","language":"cn,en","sort":99,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"Hepatoblastoma is the most frequent liver malignancy in children. HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture. Intriguingly, we observed that the addition of calcium ions reduced cell clumping and disassociated HepG2 cells. The calcium signal is in connection with a series of processes critical in the tumorigenesis. Here, we demonstrated that extracellular calcium ions induced morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells. Mechanistically, calcium ions promoted HepG2 proliferation and migration by up-regulating the phosphorylation levels of focal adhesion kinase (FAK), protein kinase B, and p38 mitogen-activated protein kinase. The inhibitor of FAK or Ca2+/calmodulin-dependent kinase Ⅱ (CaMKⅡ) reversed the Ca2+-induced effects on HepG2 cells, including cell proliferation and migration, epithelial-mesenchymal transition protein expression levels, and phosphorylation levels of FAK and protein kinase B. Moreover, calcium ions decreased HepG2 cells' sensitivity to cisplatin. Furthermore, we found that the expression levels of FAK and CaMKⅡ were increased in hepatoblastoma. The group with high expression levels of FAK and CaMKⅡ exhibited significantly lower ImmunoScore as well as CD8+ T and NK cells. The expression of CaMKⅡ was positively correlated with that of PDCD1 and LAG3. Correspondingly, the expression of FAK was negatively correlated with that of TNFSF9, TNFRSF4, and TNFRSF18. Collectively, extracellular calcium accelerates HepG2 cell proliferation and migration via FAK and CaMKⅡ and enhances cisplatin resistance. FAK and CaMKⅡ shape immune cell infiltration and responses in tumor microenvironments, thereby serving as potential targets for hepatoblastoma.
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Tel: +86-25-68303236, E-mail: suzhping@163.com","deceased":0,"email":"suzhping@163.com","givenNamesEn":"Zhongping","id":"862af2ee-9e8f-47ef-938f-f2c8727a39fa","sortNumber":8,"surNameEn":"Su"},{"addressTagIds":"aff1, aff2","articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","authorNameEn":"Qiang You","authorRoleType":"author","authorTagVal":"1, 2","authorType":"org","corresper":true,"correspinfoEn":"Qiang You, Department of Biotherapy, the Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjiayuan Road, Gulou District, Nanjing, Jiangsu 210011, China. Tel: +86-25-58509620, E-mail: qiang.you@njmu.edu.cn","deceased":0,"email":"qiang.you@njmu.edu.cn","givenNamesEn":"Qiang","id":"d8338a5b-9ef5-4136-b7d0-81c27bf8a6a3","sortNumber":9,"surNameEn":"You"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Haozhe Xu, Yiming Zhou, Jing Guo, Tao Ling, Yujie Xu, Ting Zhao, Chuanxin Shi, Zhongping Su, Qiang You. Elevated extracellular calcium ions accelerate the proliferation and migration of HepG2 cells and decrease cisplatin sensitivity[J]. The Journal of Biomedical Research, 2023, 37(5): 340-354. DOI: 10.7555/JBR.37.20230067","doi":"10.7555/JBR.37.20230067","figList":[{"columnNums":2,"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0067-1.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0067-1.jpg","id":"2864f2d0-478e-483a-abc7-de9ecd2239ac","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Calcium ions induced the morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: HepG2 cells were treated with indicated concentrations of CaCl2 for different times. Representative images of HepG2 cells were observed by optical microscope (Scale bar, 200 μm). B: Percentage of cell area at different times after treatment with or without calcium. **P < 0.01 and ***P < 0.001, compared with 3 h treatment in each treated calcium concentration; #P < 0.05, ##P < 0.01, and ###P < 0.001, compared with control group in each treatment time. C: HepG2 cells were treated with or without 6.25 mmol/L CaCl2 or MgCl2 or KCl (6.25 and 12.5 mmol/L) for 24 h. The group of ± CaCl2 represents HepG2 cells treated with 6.25 mmol/L CaCl2 for 24 h and then cultured without additional CaCl2 in the regular medium for another 24 h. Representative images of HepG2 cells were observed by optical microscope (Scale bar, 200 μm). D: Quantitative real-time PCR for various adhesion-related molecules in HepG2 cells treated with or without CaCl2 at 6 h. E and F: The expression of epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin) , and Twist on CaCl2-treated (6.25 mmol/L) HepG2 cells was detected by Western blotting analysis. Data are presented as mean ± standard deviation from three independent experiments. ***P < 0.001 vs. the 0 h group. G: MCF-7, Caco-2, and HUVEC cell lines were treated with or without 6.25 and 12.5 mmol/L CaCl2 for 24 h. Representative images of the cells were observed by optical microscope (Scale bar, 200 μm). H and I: EMT markers on CaCl2-treated MCF-7, Caco-2, and HUVEC cells were analyzed by Western blotting. Cells in the Ctrl group were treated with ddH2O, compared with the cells with CaCl2 , MgCl2 or KCl treatment. Data are presented as mean ± standard deviation from three independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. the control (Ctrl) group.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0067-2.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0067-2.jpg","id":"43cd011a-7090-4eed-8742-ac52402638b8","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Calcium ions promoted HepG2 cell proliferation and migration and changed the phosphorylation levels of multiple proteins.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"A: HepG2 cells were treated with indicated concentrations of CaCl2 for 24 h. Cell proliferation was assessed using the CCK8 assay. B: HepG2 cells were treated with 6.25 mmol/L CaCl2 for 12, 24, and 48 h. Cell proliferation was assessed using the CCK8 assay. C: HepG2 cells were treated with CaCl2 for 24 h. Cell proliferation was assessed using EdU proliferation assay. Scale bar, 200 μm. D and E: Wound healing assays were used to detect cell migration. Scale bar, 400 μm. F and G: Total protein was extracted, the phosphorylation of FAK, AKT, p38, p65, ERK, and STAT3 were detected using Western blotting. Cells in the Ctrl group were treated with ddH2O, compared with the cells with CaCl2 treatment. Data are presented as mean ± standard deviation from three independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. the control (Ctrl) group.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0067-3.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0067-3.jpg","id":"4a964c1b-a09c-4c29-a742-2f19f73393ef","imgWidth":"15.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"Calcium ions promoted HepG2 cell proliferation and migration by enhancing the activation of FAK-AKT signaling pathways.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"A: HepG2 cells were pretreated with six different compounds (final concentration, 10 μmol/L) for 1 h, cells in the Ctrl group were treated with 0.1% DMSO for 1 h, and then stimulated with or without CaCl2 for 12 h, the morphology of cells was observed using the optical microscope (Scale bar, 400 μm). B: Different doses (5 and 10 μmol/L) of PF573228 were used to pretreat HepG2 cells, cells in the Ctrl group were treated with 0.1% DMSO, and the morphology of cells was observed using the optical microscope (Scale bar, 200 μm). C–E: HepG2 cells were pretreated with or without 5 μmol/L PF573228 (or 0.1% DMSO in the Ctrl group) for 1 h and then treated with CaCl2 for 12 or 48 h, the proliferation abilities were detected using CCK8 (C) and EdU assays (D), cell migration was detected using the wound healing assay (E–F). Scale bar, 200 μm (D) and 400 μm (E). G–J: Western blotting analyzed the expression of E-cadherin, N-cadherin, and vimentin (G and H), and phosphorylation levels of FAK and AKT (I and J). Data are presented as mean ± standard deviation from three independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0067-4.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0067-4.jpg","id":"82a08bb5-585b-4100-8a38-a9e6d6c9b29e","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Calcium ions promoted HepG2 cell proliferation and migration via CaMKⅡ-FAK-AKT signaling pathway.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"A: HepG2 cells were pretreated with different concentrations of KN93 (5 and 10 μmol/L) for 1 h, cells in the Ctrl group were treated with 0.1% DMSO for 1 h, and then stimulated with or without CaCl2 for 12 h, the morphology of cells was observed using the optical microscope (Scale bar, 200 μm). B–D: HepG2 cells were pretreated with or without KN93 (or 0.1% DMSO in the Ctrl group) for 1 h and then treated with CaCl2 for 12 or 48 h, the proliferation abilities were detected using CCK8 (B) and EdU assays (C), cell migration was detected using the wound healing assay (D and E). Scale bar, 200 μm (C) and 400 μm (D). F–I: The expression of EMT markers (F) and phosphorylation of FAK and AKT (H) were detected using Western blotting. Data are presented as mean ± standard deviation from three independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. the control (Ctrl) group.","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0067-5.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0067-5.jpg","id":"2e69cf5d-b3a9-4cfb-b5c9-f63ffc07fa88","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Calcium ions decreased the cisplatin sensitivity of HepG2 cells.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"HepG2 cells were pretreated with CaCl2 (or ddH2O in the Ctrl group) for 24 h, and then stimulated with or without 5 μmol/L cisplatin (or 0.1% DMSO in the Ctrl group) for 24 h. A: The morphology of cells was observed using the optical microscope. Scale bar, 200 μm. B and C: Cell viability and survival cells were detected using CCK8 assay (B) and hemocytometer (C). Inhibition rate of the Ctrl group = [(Aa − Ab) / Aa] × 100%; inhibition rate of the CaCl2-pretreatment group = [(Ac − Ad) / Ac] × 100% (Aa: cell viability or survival cells of the Ctrl group; Ab: cell viability or survival cells of the cisplatin group; Ac: cell viability or survival cells of the CaCl2 group; Ad: cell viability or survival cells of the CaCl2 + cisplatin group). Data are presented as mean ± standard deviation from three independent experiments. *P < 0.05, ***P < 0.001.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0067-6.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0067-6.jpg","id":"05fd9e53-cb00-4f3f-95a3-406349225559","imgWidth":"17cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"6","nameEn":"Characterization of FAK and CaMKⅡ expression in hepatoblastoma.","referSecTagIds":"","sort":5,"supplementRemarkCn":"","supplementRemarkEn":"A: Relative expression of FAK and CaMKⅡ in hepatoblastoma tissue and adjacent normal tissue in GSE104766, GSE131329, GSE133039, and GSE151347 datasets. Data are presented as median and interquartile. B: CaMKⅡand FAK expression levels in the different Children's Hepatic Tumor International Collaboration (CHIC) Risk Stratification groups from GSE133039. Data are presented as median and interquartile. C: Combined expression of CaMKⅡ and FAK was categorized as low and high. GSEA enrichment analysis of hallmark gene sets and KEGG pathway in high expression group. D: Heatmaps of differentially expressed genes in three GEO datasets. E: The intersection of differential genes in three GEO datasets was identified as differentially expressed genes (DEGs) and the enriched KEGG pathways of the 186 DEGs. F: The protein-protein interaction network analysis of the 186 DEGs was drawn using the Cytoscape software. G: The relation expression of FAK in PBS or cisplatin-treated HepG2 cell line from GSE38122. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, and nsP > 0.05.","tagId":"Figure6","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0067-7.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0067-7.jpg","id":"e4a789e6-6d4a-4ae4-9c9e-a73ab8e86324","imgWidth":"17cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"7","nameEn":"FAK and CaMKⅡ shaped immune cell infiltration and immune responses in hepatoblastoma.","referSecTagIds":"","sort":6,"supplementRemarkCn":"","supplementRemarkEn":"A: Violin plot of immunity score, stroma score, and microenvironment score between the low and high CaMKⅡ + FAK expression groups. Data are presented as median and interquartile. B: Boxplots of the immune cell infiltration levels in the low and high CaMKⅡ + FAK expression groups used the MCP-counter algorithm. Data are presented as mean ± standard deviation. C: The heatmap of immune cells was estimated by the CIBERSORT algorithm. D: The composite thermogram shows the frequency of TME infiltrating cells among the different groups estimated by the Xcell algorithm. E and F: Scatter plot of expression correlation between CaMKⅡ or FAK with BTM3A1, CD70, LAG3, and PDCD1. G and H: The correlation between CaMKⅡ or FAK expression with inhibitory immune checkpoints (G) and immune stimulatory checkpoints (H). I: HepG2 cells were treated with or without CaCl2 for 12 h, the mRNA expression of PD-L1 and FGL1 were detected by quantitative real-time PCR. J: Flow cytometry analyzed the expression of PD-L1 on HepG2 cells treated with or without CaCl2 for 24 h. Data are presented as mean ± standard deviation (I and J). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, and nsP > 0.05.","tagId":"Figure7","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/","firstFig":{"columnNums":2,"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/5/JBR-2023-0067-1_mini.jpg","fileType":"fulltextFig","fileXMLPath":"JBR-2023-0067-1.jpg","id":"2864f2d0-478e-483a-abc7-de9ecd2239ac","imgWidth":"16.0cm","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Calcium ions induced the morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: HepG2 cells were treated with indicated concentrations of CaCl2 for different times. Representative images of HepG2 cells were observed by optical microscope (Scale bar, 200 μm). B: Percentage of cell area at different times after treatment with or without calcium. **P < 0.01 and ***P < 0.001, compared with 3 h treatment in each treated calcium concentration; #P < 0.05, ##P < 0.01, and ###P < 0.001, compared with control group in each treatment time. C: HepG2 cells were treated with or without 6.25 mmol/L CaCl2 or MgCl2 or KCl (6.25 and 12.5 mmol/L) for 24 h. The group of ± CaCl2 represents HepG2 cells treated with 6.25 mmol/L CaCl2 for 24 h and then cultured without additional CaCl2 in the regular medium for another 24 h. Representative images of HepG2 cells were observed by optical microscope (Scale bar, 200 μm). D: Quantitative real-time PCR for various adhesion-related molecules in HepG2 cells treated with or without CaCl2 at 6 h. E and F: The expression of epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin) , and Twist on CaCl2-treated (6.25 mmol/L) HepG2 cells was detected by Western blotting analysis. Data are presented as mean ± standard deviation from three independent experiments. ***P < 0.001 vs. the 0 h group. G: MCF-7, Caco-2, and HUVEC cell lines were treated with or without 6.25 and 12.5 mmol/L CaCl2 for 24 h. Representative images of the cells were observed by optical microscope (Scale bar, 200 μm). H and I: EMT markers on CaCl2-treated MCF-7, Caco-2, and HUVEC cells were analyzed by Western blotting. Cells in the Ctrl group were treated with ddH2O, compared with the cells with CaCl2 , MgCl2 or KCl treatment. Data are presented as mean ± standard deviation from three independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. the control (Ctrl) group.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},"hasPage":true,"htmlAccess":true,"id":"6d1e9bff-111e-40e6-9765-18104a17e2c0","issue":"5","issueArticle":"0","keywords":[{"articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","id":"9f69f58a-9ebd-4ac1-9400-37e4d26460f7","keywordEn":"HepG2","sortNum":1},{"articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","id":"8b77cc53-9222-49ab-9749-14f503e19867","keywordEn":"hepatoblastoma","sortNum":2},{"articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","id":"9628808a-d3a8-48dc-bce3-37f1e8154363","keywordEn":"calcium ion","sortNum":3},{"articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","id":"007e8d5f-c622-4997-84b5-b7ace2ad9cfa","keywordEn":"FAK","sortNum":4},{"articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","id":"c417445c-f317-4461-9e45-16a13307f867","keywordEn":"CaMKⅡ","sortNum":5},{"articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","id":"f0d17ebd-5994-4578-af63-53849bbd6bfd","keywordEn":"cisplatin resistance","sortNum":6}],"language":"en","page":"340-354","pdfAccess":true,"publisherId":"JBR-2023-0067","releaseProgress":{"articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","lastReleaseTime":"2024-03-27 09:07","maxLastReleaseTime":"2024-03-27 09:07","minLastReleaseTime":"2023-09-28 09:55","otherReleaseList":[{"articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-09-26 09:06","maxLastReleaseTime":"2023-09-26 09:06","minLastReleaseTime":"2023-06-06 13:03","otherReleaseList":[]},{"articleId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","currentState":"Unproofed Manuscript","currentStateEn":"Unproofed Manuscript","lastReleaseTime":"2023-09-26 09:02","maxLastReleaseTime":"2023-09-26 09:02","minLastReleaseTime":"2023-05-23 18:07","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20230005000000","subTitleCn":"","subTitleEn":"","supplements":[{"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","fileLastName":"pdf","fileName":"JBR-2023-0067-Supplementary.pdf","filePath":"/fileSWYXYJZZYWB/journal/article/file/c7fba562-9ada-4374-a818-29d9c344b556.pdf","fileSize":"5478KB","fileType":"file","id":"33a61f81-25f8-456a-a10e-fea239b7d41d","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","nameCn":"JBR-2023-0067-Supplementary","nameEn":"JBR-2023-0067-Supplementary","type":"article"}],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Elevated extracellular calcium ions accelerate the proliferation and migration of HepG2 cells and decrease cisplatin sensitivity","topicNameEn":"","type":"research-article","volume":"37","year":"2023","yearInt":2023},"dataId":"6d1e9bff-111e-40e6-9765-18104a17e2c0","dataType":"Article","id":"8f52ffc3-b457-4918-bacc-37119a7c603d","language":"cn,en","sort":100,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending (LAD) coronary artery, we first randomly divided 16 male Bama pigs into a sham group and a model group. After anesthesia, we separated the arteries and veins. Subsequently, we rapidly located the LAD coronary artery at the beginning of its first diagonal branch through a mid-chest incision. Then, we loosened and released the ligation line after five minutes of pre-occlusion. Finally, we ligated the LAD coronary artery in situ two minutes later and loosened the ligature 60 min after ischemia. Compared with the sham group, electrocardiogram showed multiple continuous lead ST-segment elevations, and ultrasound cardiogram showed significantly lower ejection fraction and left ventricular fractional shortening at one hour and seven days post-operation in the model group. Twenty-four hours after the operation, cardiac troponin T and creatine kinase-MB isoenzyme levels significantly increased in the model group, compared with the sham group. Hematoxylin and eosin staining showed the presence of many inflammatory cells infiltrating the interstitium of the myocardium in the model group but not in the sham group. Masson staining revealed a significant increase in infarct size in the ischemia/reperfusion group. All eight pigs in the model group recovered with normal sinus heart rates, and the survival rate was 100%. In conclusion, the method can provide an accurate and stable large animal model for preclinical research on ischemia/reperfusion with a high success rate and homogeneity of the myocardial infarction area.","appendixList":[],"articleBusiness":{"articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","articleState":"-1","articleType":"1","baiduIncludeResult":0,"baiduIncludeResultSearchNum":0,"baiduPushLastDate":1690521600000,"baiduPushNum":3,"baiduXueShuIncludeResult":0,"baiduXueShuIncludeResultSearchNum":0,"baiduXueShuPushLastDate":1690521600000,"baiduXueShuPushNum":3,"filename":"JBR-2022-0189.xml","googleIncludeResult":0,"googleIncludeResultSearchNum":0,"htmlSource":1,"htmlViewCount":879,"id":"fcfe98db-2954-4cc4-8857-75639b2d212e","isRegCstr":0,"isRegDOI":1,"pdfDownCount":65,"pdfEnFileSizeInt":0,"pdfFileName":"JBR-2022-0189.pdf","pdfFileSize":4651.05,"pdfFileSizeInt":4651,"remark":"XML","viewCount":1570,"xmlDownCount":0,"xmlFileSize":85.0},"articleNo":"JBR-2022-0189","authors":[{"addressTagIds":"aff1","articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","authorNameCn":"","authorNameEn":"Liuhua Zhou","authorNotesEn":"△These authors contributed equally to this work.","authorTagVal":"1, 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Lu","authorTagVal":"2","authorType":"author","corresper":false,"givenNamesEn":"Xiaohu","id":"97253e77-3a05-4d50-8433-eb33bd8b8df5","sortNumber":13,"surNameEn":"Lu"},{"addressTagIds":"aff2","articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","authorNameCn":"","authorNameEn":"Haoliang Sun","authorTagVal":"2","authorType":"author","corresper":false,"givenNamesEn":"Haoliang","id":"b8179b67-864e-4725-b8d8-94695e177924","sortNumber":14,"surNameEn":"Sun"},{"addressTagIds":"aff3","articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","authorNameCn":"","authorNameEn":"Meng Lv","authorTagVal":"3","authorType":"author","corresper":false,"givenNamesEn":"Meng","id":"549ef017-037d-4e7b-a8ed-c0e3f0bfa1a1","sortNumber":15,"surNameEn":"Lv"},{"addressTagIds":"aff1","articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","authorNameCn":"","authorNameEn":"Di Yang","authorTagVal":"1","authorType":"author","corresper":true,"correspinfoEn":"Liansheng Wang and Di Yang, Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China. Tels: +86-25-83724440 and +86-25-68136721, E-mails: drlswang@njmu.edu.cn and diyang@njmu.edu.cn","email":"diyang@njmu.edu.cn","givenNamesEn":"Di","id":"7f5bc197-ceb4-4cd4-a07f-95ee10703ca1","sortNumber":16,"surNameEn":"Yang"},{"addressTagIds":"aff1","articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","authorNameCn":"","authorNameEn":"Liansheng Wang","authorTagVal":"1","authorType":"author","corresper":true,"correspinfoEn":"","email":"drlswang@njmu.edu.cn","givenNamesEn":"Liansheng","id":"1c5f405d-de5a-477f-969f-1c9c25afaa9f","sortNumber":17,"surNameEn":"Wang"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Liuhua Zhou, Jiateng Sun, Tongtong Yang, Sibo Wang, Tiankai Shan, Lingfeng Gu, Jiawen Chen, Tianwen Wei, Di Zhao, Chong Du, Yulin Bao, Hao Wang, Xiaohu Lu, Haoliang Sun, Meng Lv, Di Yang, Liansheng Wang. Improved methodology for efficient establishment of the myocardial ischemia-reperfusion model in pigs through the median thoracic incision[J]. The Journal of Biomedical Research, 2023, 37(4): 302-312. DOI: 10.7555/JBR.36.20220189","doi":"10.7555/JBR.36.20220189","figList":[{"columnNums":2,"dataId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0189-1.jpg","fileSize":"1483KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0189-1.jpg","id":"87df655c-1ee4-4a8e-9924-337e9cf9628b","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Construction of the Bama pig ischemia-reperfusion model.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: Flowchart of construction and evaluation in different methodologies for the Bama pig sham and I/R groups. B: Schematic diagram of specific methods for constructing an I/R model in Bama pigs. C: Observation of thoracotomy ligation in the sham group (left) and model group (right) during the operation. n = 8 for each group. I/R: ischemia/reperfusion; ECG: electrocardiogram; UCG: ultrasound cardiogram; H&E: hematoxylin and eosin.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0189-2.jpg","fileSize":"1470KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0189-2.jpg","id":"9af7f185-5066-4705-a202-6a3a3f4a5f5b","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Changes of ECG in the model and sham groups before, during, and after operation.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"ECG of the sham group (A–C) and I/R group (D–F) before, during, and after the operation. n = 8 for each group. ECG: electrocardiogram; I/R: ischemia/reperfusion.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0189-3.jpg","fileSize":"1906KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0189-3.jpg","id":"1ce69602-cb7e-4226-97e9-3367bb92242b","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"Changes of UCG in the model and sham groups 3 days before, 1 hour during, and 7 days after the operation.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"A: Representative heart images of UCG in the I/R and sham groups at 3 days before, 1 hour during, and 7 days after the operation. B–D. EF and FS of pigs in the I/R and sham groups at 3 days before, 1 hour during, and 7 days after the operation. n = 8 for each group. The data are presented as mean ± SD. ***P < 0.001 by unpaired Student's t-tests. ns: not significant. UCG: ultrasonic cardiogram; I/R: ischemia/reperfusion; EF: ejection fraction; FS: fractional shortening.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0189-4.jpg","fileSize":"425KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0189-4.jpg","id":"8db5af6c-9f30-4a67-bd77-f39560eaefe0","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Plasma levels of myocardial injury markers in the sham and model groups.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"A and B: Expression of myocardial injury markers (cTNT and CK-MB) in plasma of pigs in the I/R and sham groups at 24 h before and 24 h after the operation (baseline, 24 h after I/R) were detected by enzyme-linked immunosorbent assay. n = 8 in each group. The data are presented as mean ± SD. ***P < 0.001 by unpaired Student's t-tests. I/R: ischemia/reperfusion; cTnT: cardiac troponin T; CK-MB: creatine kinase-MB isoenzyme.","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":1,"dataId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0189-5.jpg","fileSize":"2513KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0189-5.jpg","id":"976e6ca3-f6dd-406d-87a6-3843cf185abe","imgWidth":"8.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Pathological morphology of heart tissues in the sham and model groups.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"The pathological morphology of porcine heart tissue sections was observed in the sham and model groups by HE and Masson staining. A: Comparison of pathological change by HE staining between the sham and model groups at 28 days after operation. B: Comparison of scar size by Masson staining between the sham and model groups at 28 days after operation. C: Quantification of fibrosis area of the I/R and sham groups in heart section at 28 days after operation. n = 8 in each group (A–C). The data are presented as mean ± SD. ***P < 0.001 by unpaired Student's t-tests. I/R: ischemia/reperfusion; HE: hematoxylin and eosin.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0189-6.jpg","fileSize":"1232KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0189-6.jpg","id":"62bed039-4162-4ce5-a0d4-5a387a481238","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"6","nameEn":"Emergency flow chart of treating ventricular fibrillation during ischemia-reperfusion operation.","referSecTagIds":"","sort":5,"supplementRemarkCn":"","supplementRemarkEn":"Pattern diagram of cardioversion sinus heart rate in the model group pigs with ventricular fibrillation by specific treatment.","tagId":"Figure6","type":"article","typesetSecTagId":"s03"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/","firstFig":{"columnNums":2,"dataId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0189-1_mini.jpg","fileSize":"1483KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0189-1.jpg","id":"87df655c-1ee4-4a8e-9924-337e9cf9628b","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"Construction of the Bama pig ischemia-reperfusion model.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: Flowchart of construction and evaluation in different methodologies for the Bama pig sham and I/R groups. B: Schematic diagram of specific methods for constructing an I/R model in Bama pigs. C: Observation of thoracotomy ligation in the sham group (left) and model group (right) during the operation. n = 8 for each group. I/R: ischemia/reperfusion; ECG: electrocardiogram; UCG: ultrasound cardiogram; H&E: hematoxylin and eosin.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},"hasPage":true,"htmlAccess":true,"id":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","issue":"4","issueArticle":"0","keywords":[{"articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","id":"1d272691-804e-4ab2-96c4-40c2339436db","keywordEn":"coronary artery ligation","sortNum":1},{"articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","id":"5d6da656-0d00-4d1c-a6e8-9783600d4e74","keywordEn":"myocardial ischemia-reperfusion injury","sortNum":2},{"articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","id":"8dc90980-79b1-4ea0-94e5-39b3704b03e6","keywordEn":"Bama pig","sortNum":3},{"articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","id":"a5c036fc-72a7-4f9b-81a3-4321743a22cc","keywordEn":"animal model","sortNum":4}],"language":"en","page":"302-312","pdfAccess":true,"publisherId":"JBR-2022-0189","releaseProgress":{"articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","lastReleaseTime":"2023-07-28 13:15","maxLastReleaseTime":"2023-07-28 13:15","minLastReleaseTime":"2023-07-28 13:15","otherReleaseList":[{"articleId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","currentState":"Online publication","currentStateEn":"Online publication","lastReleaseTime":"2023-06-02 14:14","maxLastReleaseTime":"2023-06-02 14:14","minLastReleaseTime":"2023-01-18 17:37","otherReleaseList":[]}]},"releaseState":1,"searchSort":"20230004000000","subTitleCn":"","subTitleEn":"","supplements":[],"tableList":[],"tags":[{"data":"{\"publisherId\":\"\",\"journalName\":\"\",\"remark\":\"\",\"createDate\":\"\",\"createUser\":\"\",\"status\":\"1\"}","id":"0","journalId":"ff007540-a7c7-4752-b593-efa08309babb","level":1,"nameCn":"轮播推荐","nameEn":"轮播推荐","outputName":"0","tags":[],"type":"recommend"}],"titleCn":"","titleEn":"Improved methodology for efficient establishment of the myocardial ischemia-reperfusion model in pigs through the median thoracic incision","type":"research-article","volume":"37","year":"2023","yearInt":2023},"dataId":"31a08661-1c9d-4b1b-adc4-d475d9bf8ddf","dataType":"Article","id":"37ac270a-1e0d-46d5-a9ed-344dbb72a471","language":"cn,en","sort":101,"tagId":"0"},{"data":{"abstractAccess":true,"abstractinfoCn":"","abstractinfoEn":"Sepsis-induced myocardial dysfunction is primarily accompanied by severe sepsis, which is associated with high morbidity and mortality. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), encoded by Hsd11b1, is a reductase that can convert inactive cortisone into metabolically active cortisol, but the role of 11β-HSD1 in sepsis-induced myocardial dysfunction remains poorly understood. The current study aimed to investigate the effects of 11β-HSD1 on a lipopolysaccharide (LPS)-induced mouse model, in which LPS (10 mg/kg) was administered to wild-type C57BL/6J mice and 11β-HSD1 global knockout mice. We asscessed cardiac function by echocardiography, performed transmission electron microscopy and immunohistochemical staining to analyze myocardial mitochondrial injury and histological changes, and determined the levels of reactive oxygen species and biomarkers of oxidative stress. We also employed polymerase chain reaction analysis, Western blotting, and immunofluorescent staining to determine the expression of related genes and proteins. To investigate the role of 11β-HSD1 in sepsis-induced myocardial dysfunction, we used LPS to induce lentivirus-infected neonatal rat ventricular cardiomyocytes. We found that knockdown of 11β-HSD1 alleviated LPS-induced myocardial mitochondrial injury, oxidative stress, and inflammation, along with an improved myocardial function; furthermore, the depletion of 11β-HSD1 promoted the phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), and silent information regulator 1 (SIRT1) protein levels both in vivo and in vitro. Therefore, the suppression of 11β-HSD1 may be a viable strategy to improve cardiac function against endotoxemia challenges.","appendixList":[],"articleBusiness":{"articleId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","articleState":"-1","articleType":"1","baiduIncludeResult":0,"baiduIncludeResultSearchNum":0,"baiduPushLastDate":1690521300000,"baiduPushNum":4,"baiduXueShuIncludeResult":0,"baiduXueShuIncludeResultSearchNum":0,"baiduXueShuPushLastDate":1690521301000,"baiduXueShuPushNum":4,"filename":"JBR-2022-0212.xml","googleIncludeResult":0,"googleIncludeResultSearchNum":0,"htmlSource":1,"htmlViewCount":919,"id":"92feccf5-c70c-4c09-b67e-e42e9af3a84e","isRegCstr":0,"isRegDOI":1,"pdfDownCount":121,"pdfEnFileSizeInt":0,"pdfFileName":"JBR-2022-0212.pdf","pdfFileSize":14403.21,"pdfFileSizeInt":14403,"remark":"XML","viewCount":1586,"xmlDownCount":0,"xmlFileSize":70.0},"articleNo":"JBR-2022-0212","authors":[{"addressTagIds":"aff1","articleId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","authorNameCn":"","authorNameEn":"Dongmei Zhu","authorTagVal":"","authorType":"author","corresper":false,"givenNamesEn":"Dongmei","id":"e9815f8d-2a73-4dec-aa2f-7275d29bbfba","sortNumber":1,"surNameEn":"Zhu"},{"addressTagIds":"aff1","articleId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","authorNameCn":"","authorNameEn":"Lingli Luo","authorTagVal":"","authorType":"author","corresper":false,"givenNamesEn":"Lingli","id":"bb069589-918e-4aae-8fd0-914b32a14161","sortNumber":2,"surNameEn":"Luo"},{"addressTagIds":"aff1","articleId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","authorNameCn":"","authorNameEn":"Hanjie Zeng","authorTagVal":"","authorType":"author","corresper":false,"givenNamesEn":"Hanjie","id":"8a684ddb-3177-4e1e-b551-ac7ce46908a6","sortNumber":3,"surNameEn":"Zeng"},{"addressTagIds":"aff1","articleId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","authorNameCn":"","authorNameEn":"Zheng Zhang","authorTagVal":"","authorType":"author","corresper":false,"givenNamesEn":"Zheng","id":"2a3cd449-ce97-4aeb-aaa8-31bcecbcb081","sortNumber":4,"surNameEn":"Zhang"},{"addressTagIds":"aff1","articleId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","authorNameCn":"","authorNameEn":"Min Huang","authorTagVal":"","authorType":"author","corresper":true,"correspinfoEn":"Min Huang and Suming Zhou, Department of Geriatrics Intensive Care Unit, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China. Tels: +86-25-68305051 and +86-25-68305053, E-mails: hmdoctor@163.com and zhousmco@aliyun.com","email":"hmdoctor@163.com","givenNamesEn":"Min","id":"4fa5ed68-5662-4e0d-8785-ee950c6c2596","sortNumber":5,"surNameEn":"Huang"},{"addressTagIds":"aff1","articleId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","authorNameCn":"","authorNameEn":"Suming Zhou","authorTagVal":"","authorType":"author","corresper":true,"correspinfoEn":"","email":"zhousmco@aliyun.com","givenNamesEn":"Suming","id":"38723f9a-4dc0-4978-9160-3fe4c11a74c9","sortNumber":6,"surNameEn":"Zhou"}],"categoryNameEn":"Original Article","citationCn":"","citationEn":"Dongmei Zhu, Lingli Luo, Hanjie Zeng, Zheng Zhang, Min Huang, Suming Zhou. Knockdown of 11β-hydroxysteroid dehydrogenase type 1 alleviates LPS-induced myocardial dysfunction through the AMPK/SIRT1/PGC-1α pathway[J]. The Journal of Biomedical Research, 2023, 37(4): 290-301. DOI: 10.7555/JBR.36.20220212","doi":"10.7555/JBR.36.20220212","figList":[{"columnNums":2,"dataId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0212-1.jpg","fileSize":"2040KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0212-1.jpg","id":"f27cddf1-b0a8-475f-aecd-8a1327cee6f8","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"11β-HSD1 deficiency attenuated myocardial dysfunction and inflammation in LPS-induced mice.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: WT mice were administered with LPS (10 mg/kg) or sterile saline (n = 6 per group) for 6 h. Western blotting and quantitative real-time PCR (qRT- PCR) were performed to detect the protein and mRNA levels of 11β-HSD1 in myocardial tissues, respectively. B: Protein and mRNA levels of 11β-HSD1 in myocardial tissues of WT and 11β-HSD1−/− mice (n = 6 per group) were detected by Western blotting and qRT-PCR. Protein expression levels were quantified relative to the loading control (α-tubulin), while mRNA levels were quantified relative to the internal control (Gapdh). C–F: WT and 11β-HSD1−/− mice (n = 6 per group) were administered with LPS (10 mg/kg) or sterile saline for 6 h. Representative M-mode echocardiograms of mice from each group were obtained (C). EF and FS were assessed by echocardiography (D). Protein levels of CK, CK-MB, and LDH in serum derived from mice in each group were determined by biochemical analysis (E). Cardiac tissue sections were immunostained for IL-6 and IL-1β, and the numbers of IL-6-positive and IL-1β-positive cardiomyocytes were quantified (F). Scale bars: 20 μm. Data are presented as mean ± SD. P-values were determined by Student's t-test (A and B) and one-way ANOVA followed by Tukey's test (D–F). *P < 0.05; **P < 0.01. WT: wild-type; LPS: lipopolysaccharide; 11β-HSD1: 11β-hydroxysteroid dehydrogenase-1; EF: ejection fraction; FS: fractional shortening; CK: creatine kinase; CK-MB: creatine kinase-MB; LDH: lactate dehydrogenase; IL-1β: interleukin-1β; IL-6: interleukin-6.","tagId":"Figure1","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0212-2.jpg","fileSize":"2007KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0212-2.jpg","id":"ab5ed9e5-1fe3-437d-924b-0dcbe45ce32e","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"2","nameEn":"Knockdown of 11β-HSD1 ameliorates mitochondrial injury and oxidative stress.","referSecTagIds":"","sort":1,"supplementRemarkCn":"","supplementRemarkEn":"WT and 11β-HSD1−/− mice were administered with LPS (10 mg/kg) or sterile saline for 6 h (n = 6 per group). A: Transmission electron microscopy analysis was performed to visualize the morphology of mitochondria. M: myocardial mitochondria; Z: Z lines; H: H-band (H); LD: lipid droplets; ASS: autophagic lysosome. Scale bars: 2 μm. B and C: ROS staining and quantitative calculation in myocardial tissues. Scale bars: 100 μm. D and E: MDA (D) and SOD (E) levels in myocardial tissues. Data are presented as mean ± SD. P-values were determined by one-way ANOVA followed by Tukey's test, and *P < 0.05; **P < 0.01. WT: wild-type; LPS: lipopolysaccharide; 11β-HSD1: 11β-hydroxysteroid dehydrogenase-1; ROS: reactive oxygen species; MDA: malondialdehyde; SOD: superoxide dismutase.","tagId":"Figure2","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0212-3.jpg","fileSize":"1520KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0212-3.jpg","id":"729e8891-b314-4a16-8a0f-6053b9c62e74","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"3","nameEn":"Knockdown of 11β-HSD1 attenuated oxidative stress in LPS-induced cardiomyocytes.","referSecTagIds":"","sort":2,"supplementRemarkCn":"","supplementRemarkEn":"NRCMs were transfected with lentiviruses carrying 11β-HSD1 knockdown vector (sh-HSD1) or corresponding empty vector (sh-NC) for 24 h, followed by the treatment of LPS (100 ng/mL) or sterile saline. A: The knockout efficiency of lentivirus vectors was determined by Western blotting. α-Tubulin was used as the loading control. B: ROS staining and quantitative calculation in NRCMs. Scale bars: 200 μm. C: MDA levels in NRCMs were measured. Data are expressed as the mean ± SD. P-values were determined by one-way ANOVA followed by Tukey's test. *P < 0.05 (n = 3). NRCMs: neonatal rat ventricular cardiomyocytes; ROS: reactive oxygen species; MDA: malondialdehyde.","tagId":"Figure3","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0212-4.jpg","fileSize":"1131KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0212-4.jpg","id":"379992f6-71d3-4e09-944e-519317640479","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"4","nameEn":"Immunofluorescence staining of myocardial tissues.","referSecTagIds":"","sort":3,"supplementRemarkCn":"","supplementRemarkEn":"WT and 11β-HSD1−/− mice were administered with LPS (10 mg/kg) or sterile saline for 6 h. Triple immunofluorescence staining for SIRT1 (green), PGC-1α (pink), and p-AMPK (red) was performed. Scale bars: 20 μm. WT: wild-type; LPS: lipopolysaccharide; 11β-HSD1: 11β-hydroxysteroid dehydrogenase-1; SIRT1: silent information regulator 1; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1α; p-AMPK: phosphorylated adenosine 5′-monophosphate-activated protein kinase; DAPI: 4′,6-diamidino-2-phenylindole.","tagId":"Figure4","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0212-5.jpg","fileSize":"2666KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0212-5.jpg","id":"ef31183b-6437-4427-9ecb-fc77a37ff6f0","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"5","nameEn":"Knockdown of 11β-HSD1 activated the AMPK/SIRT1/PGC-1α signaling pathway.","referSecTagIds":"","sort":4,"supplementRemarkCn":"","supplementRemarkEn":"A: WT and 11β-HSD1−/− mice were administered with LPS (10 mg/kg) or sterile saline for 6 h. p-AMPK, t-AMPK, SIRT1, and PGC-1α expressions in myocardial tissue of mice (n = 3 per group) were detected by Western blotting. B: NRCMs were exposed to LPS (100 ng/mL) for 0, 3, 6, 12, and 24 h, and p-AMPK, t-AMPK, SIRT1, and PGC-1α expressions were detected by Western blotting. C: NRCMs were transfected with lentiviruses carrying 11β-HSD1 knockdown vector (sh-HSD1) or corresponding empty vector (sh-NC), followed by treatment of LPS (100 ng/mL) or saline. p-AMPK, t-AMPK, and SIRT1 expressions were detected by Western blotting. GAPDH (A) or α-tubulin was used as the loading control (B and C). Representative Western blots were shown. Protein expression levels relative to the loading control and p-AMPK/t-AMPK ratios were determined by densitometric analysis. Data are presented as mean ± SD. P-values were determined by one-way ANOVA followed by Tukey's test, and *P < 0.05; **P < 0.01. WT: wild-type; LPS: lipopolysaccharide; 11β-HSD1: 11β-hydroxysteroid dehydrogenase-1; NRCMs: neonatal rat ventricular cardiomyocytes; SIRT1: silent information regulator 1; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1α; p-AMPK: phosphorylated adenosine 5′-monophosphate-activated protein kinase; t-AMPK: total AMPK; GAPDH: glyceraldehyde-3-phosphate dehydrogenase.","tagId":"Figure5","type":"article","typesetSecTagId":"s03"},{"columnNums":2,"dataId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0212-6.jpg","fileSize":"1115KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0212-6.jpg","id":"da81090d-9830-46ed-8cd5-1b060011bd2e","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"6","nameEn":"Knockdown of 11β-HSD1 alleviated LPS-induced myocardial dysfunction by attenuating inflammation and oxidative stress via the AMPK/SIRT1/PGC-1α pathway.","referSecTagIds":"","sort":5,"supplementRemarkCn":"","supplementRemarkEn":"The release of inflammatory cytokines and oxidative stress induced by LPS leads to myocardial mitochondrial dysfunction, which in turn leads to myocardial dysfunction. Knockdown of 11β-HSD1 ameliorates myocardial inflammation and oxidative stress by activating the AMPK/SIRT1/PGC-1α pathway, thereby improving LPS-induced myocardial dysfunction. LPS: lipopolysaccharide; 11β-HSD1: 11β-hydroxysteroid dehydrogenase-1; 11β-HSD1−/−: 11β- HSD1 global knockout mice; NRCMs: neonatal rat ventricular cardiomyocytes; sh-11β-HSD1: NRCMs transfected with LV-HSD1 shRNA; P: phosphorylation; AMPK: adenosine 5′-monophosphate-activated protein kinase; SIRT1: silent information regulator 1; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1α; ROS: reactive oxygen species; SOD: superoxide dismutase; MDA: malondialdehyde.","tagId":"Figure6","type":"article","typesetSecTagId":"s04"}],"filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/","firstFig":{"columnNums":2,"dataId":"c86bb238-218a-4ad3-97e5-e5c0ae29d8b9","fileFrom":"xml","fileLastName":"jpg","filePath":"/fileSWYXYJZZYWB/journal/article/swyxyjzzywb/2023/4/JBR-2022-0212-1_mini.jpg","fileSize":"2040KB","fileType":"fulltextFig","fileXMLPath":"JBR-2022-0212-1.jpg","id":"f27cddf1-b0a8-475f-aecd-8a1327cee6f8","imgWidth":"16.0cm","isFirstImg":"0","isUpdate":"1","journalId":"ff007540-a7c7-4752-b593-efa08309babb","labelText":"1","nameEn":"11β-HSD1 deficiency attenuated myocardial dysfunction and inflammation in LPS-induced mice.","referSecTagIds":"","sort":0,"supplementRemarkCn":"","supplementRemarkEn":"A: WT mice were administered with LPS (10 mg/kg) or sterile saline (n = 6 per group) for 6 h. Western blotting and quantitative real-time PCR (qRT- PCR) were performed to detect the protein and mRNA levels of 11β-HSD1 in myocardial tissues, respectively. B: Protein and mRNA levels of 11β-HSD1 in myocardial tissues of WT and 11β-HSD1−/− mice (n = 6 per group) were detected by Western blotting and qRT-PCR. Protein expression levels were quantified relative to the loading control (α-tubulin), while mRNA levels were quantified relative to the internal control (Gapdh). C–F: WT and 11β-HSD1−/− mice (n = 6 per group) were administered with LPS (10 mg/kg) or sterile saline for 6 h. Representative M-mode echocardiograms of mice from each group were obtained (C). EF and FS were assessed by echocardiography (D). Protein levels of CK, CK-MB, and LDH in serum derived from mice in each group were determined by biochemical analysis (E). Cardiac tissue sections were immunostained for IL-6 and IL-1β, and the numbers of IL-6-positive and IL-1β-positive cardiomyocytes were quantified (F). Scale bars: 20 μm. Data are presented as mean ± SD. P-values were determined by Student's t-test (A and B) and one-way ANOVA followed by Tukey's test (D–F). *P < 0.05; **P < 0.01. 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