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  • ISSN 1674-8301
  • CN 32-1810/R
Articles in press have been peer-reviewed and accepted, which are not yet assigned to volumes /issues, but are citable by Digital Object Identifier (DOI).
Islet beta cells (β-cells) produce insulin in response to high blood glucose levels, which is essential for preserving glucose homeostasis. Voltage-gated ion channels in β-cells, including Na+, K+, and Ca2+ channels, aid in the release of insulin. Epithelial sodium channel alpha subunit (α-ENaC), a voltage-independent sodium ion channel, is also expressed in human pancreatic endocrine cells. However, there has not been much study done on ENaC's function in β-cells. In the current work, we found that human pancreatic glandule and pancreatic islet β-cells expressed α-ENaC. In the pancreas of db/db mice, high-fat diet-induced obesity, and in mouse islet β-cells (Min6 cells) treated with palmitate, α-ENaC expression was increased. When α-ENaC was overexpressed in Min6 cells, insulin content and glucose-induced insulin secretion were markedly reduced. On the other hand, palmitate injured islet β-cells, suppressed insulin synthesis and secretion, and increased α-ENaC expression in Min6 cells. However, α-ENaC knockout (Scnn1a−/−) in Min6 cells attenuated β-cells disorder induced by palmitate. Furthermore, we revealed that α-ENaC regulated the ubiquitylation and degradation of Sirtuin 2 in β-cells. α-ENaC also modulated β-cell function related to inositol-requiring enzyme 1alpha/X-box-binding protein-1 (IRE1α/XBP1) and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein (PERK/CHOP) endoplasmic reticulum stress pathways. These results suggest that α-ENaC plays a novel role in insulin synthesis and secretion in β-cells. Upregulation of α-ENaC promotes islet β-cell dysfunction. As a result, α-ENaC is a key regulator involved in islet β-cell damage and a potential therapeutic target for type 2 diabetes mellitus.
The present study aimed to dynamically observe the segmental and global myocardial movements of the left ventricle during coronary artery bypass grafting using transesophageal speckle-tracking echocardiography, and to assess the impact of sevoflurane on cardiac function. Sixty-four patients scheduled for the off-pump coronary artery bypass grafting were randomly divided into a sevoflurane-based anesthesia (AS) group and a propofol-based total intravenous anesthesia (AA) group. The AS group demonstrated a higher absolute value of left ventricular global longitudinal strain than the AA group at both T1 (after harvesting all grafts and before coronary anastomosis) and T2 (30 min after completing all coronary anastomoses) (P < 0.05). Moreover, strain improvement in the segment with the highest preoperative strain was significantly reduced in the AS group, compared with the AA group at both T1 and T2 (P < 0.01). The flow of the left internal mammary artery-left anterior descending artery graft was superior, and the postoperative concentration of troponin T decreased rapidly in the AS group, compared with the AA group (P < 0.05). Compared with total intravenous anesthesia, sevoflurane resulted in a significantly higher global longitudinal strain, stroke volume, and cardiac output. Sevoflurane also led to an amelioration in the condition of the arterial graft. Furthermore, sevoflurane significantly reduced strain improvement in the segmental myocardium with a high preoperative strain value. The findings need to be replicated in large studies.
Aging is characterized by the progressive degeneration of tissues and organs, which is positively correlated with an increased mortality rate. The brain is one of the most affected organs. Age-related brain changes include abnormal neuronal activity, dysfunctional calcium homeostasis, dysregulated mitochondrial function, and increased reactive oxygen species (ROS), all contributing to cognitive deterioration. Aging is also a key risk factor for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). For many years, neurodegenerative disease research has been concentrated primarily on neurons, with less attention given to microglia 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 microglia's perspective. In doing so, we present the current knowledge on the relationship between brain aging and the microglia, summarize recent progress of research about the microglia in normal aging, AD, PD, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), and then discuss the relationship between the senescent microglia and the brain. This will culminate with an understanding of the molecular complexity involved in the microglia in brain aging with suggestions for healthy aging.
Long noncoding RNA (lncRNA) IDH1 antisense RNA 1 (IDH1-AS1) is involved in the progression of multiple cancers, but its role in epithelial ovarian cancer (EOC) is unknown. Therefore, we investigated the expression levels of IDH1-AS1 in EOC cells and normal ovarian epithelial cells by quantitative real-time PCR (qPCR). We first evaluated the effects of IDH1-AS1 on the proliferation, migration, and invasion of EOC cells through cell counting kit-8, colony formation, EdU, transwell, wound-healing, and xenograft assays. We then explored the downstream targets of IDH1-AS1 and verified the results by a dual-luciferase reporter, qPCR, rescue experiments, and Western blotting. We found that the expression levels of IDH1-AS1 were lower in EOC cells than in normal ovarian epithelial cells. High IDH1-AS1 expression of EOC patients from the Gene Expression Profiling Interactive Analysis database indicated a favorable prognosis, because IDH1-AS1 inhibited cell proliferation and xenograft tumor growth of EOC. IDH1-AS1 sponged miR-518c-5p whose overexpression promoted EOC cell proliferation. The miR-518c-5p mimic also reversed the proliferation-inhibiting effect induced by IDH1-AS1 overexpression. Furthermore, we found that RNA binding motif protein 47 (RBM47) was the downstream target of miR-518c-5p, that upregulation of RBM47 inhibited EOC cell proliferation, and that RBM47 overexpressing plasmid counteracted the proliferation-promoting effect caused by the IDH1-AS1 knockdown. Taken together, IDH1-AS1 may suppress EOC cell proliferation and tumor growth via the miR-518c-5p/RBM47 axis.
The current study aimed to compare the effects between remimazolam and propofol on hemodynamic stability during the induction of general anesthesia in elderly patients. We used propofol at a rate of 60 mg/(kg·h) in the propofol group (group P) or remimazolam at a rate of 6 mg/(kg·h) in the remimazolam group (group R) for the induction. A processed electroencephalogram was used to determine whether the induction was successful and when to stop the infusion of the study drug. We measured when patients entered the operating room (T0), when the induction was successful (T1), and when before (T2) and 5 min after successful endotracheal intubation (T3). We found that mean arterial pressure (MAP) was lower at T1–3, compared with T0 in both groups, but higher at T2 in the group R, while ΔMAPT0–T2 and ΔMAPmax were smaller in the group R (ΔMAPT0–T2: the difference between MAP at time point T0 and T2, ΔMAPmax: the difference between MAP at time point T0 and the lowest value from T0 to T3). Cardiac index and stroke volume index did not differ between groups, whereas systemic vascular resistance index was higher at T1–3 in the group R. These findings show that remimazolam, compared with propofol, better maintains hemodynamic stability during the induction, which may be attributed to its ability to better maintain systemic vascular resistance levels.
Immune-related adverse events (irAEs) represent an increasingly concerned challenge in the assessment of biopharmaceutical products. In contrast to the historically rare allergic incidence of small chemical drugs, contemporary biotherapeutics exhibit a significantly higher morbidity of irAEs due to their complex structure and comprehensive mechanisms of action. While the immunogenicity of protein-based compounds is associated to the induction of anti-drug antibody (ADA), the pathogenesis of irAEs in advanced biologics, such as cell and gene therapy, remains to be further delineated. Herein, in the current study, we present an updated profile regarding untoward immune effects of medications covering various material categories systematically, with the underlying mechanisms to inspire risk mitigation in biopharmaceutical development and application.
Nocardiosis manifests as an opportunistic infection, primarily affecting individuals who are immunocompromised and susceptible to the infection. We present a case study of one patient with nephrotic syndrome and membranous nephropathy, who underwent treatment with prednisone and cyclosporine in 2016. In early 2017, the patient was diagnosed with a "fungal infection" and discontinued the use of cyclosporine. After anti-infection therapy for one month, a cranial magnetic resonance imaging scan showed multiple abscesses in the right temporal region. The diagnosis of nocardiosis was confirmed based on the presence of metastatic abscess masses, multiple lung and brain lesions, and a positive culture of Nocardia in the drainage. We changed the anti-infection therapy to a combination of trimethoprim-sulfamethoxazole (TMP-SMX), minocycline, and voriconazole. However, the patient experienced sudden cardiac arrest and subsequently recovered after cardiopulmonary resuscitation. During the five-month follow-up period following the discharge, the patient displayed an enhanced nutritional status and stable renal function. The focal infection ultimately resolved during the subsequent three years. Neuro-infection caused by Nocardia should be considered in immunocompromised patients, and TMP-SMX is the preferred initial therapy; however, given the high mortality rate, long-term combination therapy with imipenem, cefotaxime, amikacin and TMP-SMX is suggested.
The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2 (MDM2, also termed HDM2 in humans) through a feedback mechanism. At the same time, TP53 is the most frequently mutated gene in human cancers. Mutant p53 proteins lose wild-type p53 tumor suppression functions and acquire new oncogenic properties among which are deregulated cell proliferation, increased chemoresistance, disruption of tissue architecture, promotion of migration, invasion and metastasis, and several other pro-oncogenic activities. The oncogenic p53 mutation Y220C, which accounts for over 100 000 cancer cases per year, creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation. This cavity can accommodate stabilizing small molecules that have therapeutic value. The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein. In this review, we summarize approaches that target p53-Y220C, including reactivating this mutation with small molecules that bind Y220C hydrophobic pocket and developing immunotherapies as the goal of near future, which could target tumor cells that express the p53-Y220C neoantigen.
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 be 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 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 is unknown yet. In the current review, the interactions of physical activity and the irisin/BDNF axis with the circadian system are reconceptualized.
We have developed a protein array system, named “Phospho-Totum”, which reproduces the phosphorylation state of a sample on the array. The protein array contains 1 471 proteins from 173 known signaling pathways. According to the activation degrees of tyrosine kinases in the sample, the corresponding groups of substrate proteins on the array are phosphorylated under the same conditions. In addition to the measured phosphorylation levels of the 1 471 substrates, we developed and performed the AI-assisted tools to further characterize the phosphorylation state and estimate pathway activation, tyrosine kinase activation, and a list of kinase inhibitors that produce phosphorylation states similar to that of the sample. The Phospho-Totum system, which seamlessly links and interrogates the measurements and analyses, has the potential to not only elucidate pathophysiological mechanisms in diseases, by reproducing the phosphorylation state of samples, but also be useful for drug discovery, particularly for screening targeted kinases for potential drug kinase inhibitors.
Deterministic compartment models (CMs) and stochastic models, including stochastic CMs and agent-based models (ABMs), are widely utilized in epidemic modeling. However, the relationship between CMs and their corresponding stochastic models is not well understood. The present study aimed to address this gap by conducting a comparative study using SEIR and its extended CMs from the coronavirus disease 2019 modeling literature. We demonstrated the equivalence of the numerical solution of CMs using the Euler scheme and their stochastic counterparts through theoretical analysis and simulations. Based on this equivalence, we proposed an efficient model calibration method that can replicate the exact solution of CMs in the corresponding stochastic models through parameter adjustment. The advancement in calibration techniques enhanced the accuracy of stochastic modeling in capturing the dynamics of epidemics. However, it should be noted that discrete-time stochastic models cannot perfectly reproduce the exact solution of continuous-time CMs. Additionally, we proposed a new stochastic compartment and agent mixed model as an alternative to ABMs for large-scale population simulations with a limited number of agents. This model offered a balance between computational efficiency and accuracy. The results of this research contributed to the comparison and unification of deterministic CMs and stochastic models in epidemic modeling. Furthermore, the results had implications for the development of hybrid models that integrated the strengths of both frameworks. Overall, the present study has provided valuable epidemic modeling techniques and their practical applications for understanding and controlling the spread of infectious diseases.
Renal transplant patients receive several immunosuppressive drug regimens that are potentially nephrotoxic for treatment. Serum creatinine is the standard for monitoring kidney functions; however, cystatin C (Cys C) and kidney injury molecule-1 (KIM-1) have been found to indicate kidney injury earlier than serum creatinine and reflect the kidney functions much better. Here, we assessed Cys C and KIM-1 serum levels in renal transplant patients receiving mycophenolate mofetil, tacrolimus, sirolimus, everolimus, or cyclosporine for evaluating the kidney function. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation, which is based on creatinine, Cys C and combined creatinine with Cys C, was used to estimate glomerular filtration rate (GFR). Then we assessed association between serum KIM-1 and GFR < 90 mL/(min·1.73 m2). We observed significantly higher serum Cys C levels in patients with the elevated serum creatinine, compared to those with normal serum creatinine. The estimated GFRs based on creatinine were significantly greater than the other equations, while a significant positive correlation was observed among all equations. Serum KIM-1 levels were negatively correlated with the estimated GFRs by the CKD-EPI Cys C and combined creatinine with Cys C equations. Serum KIM-1 above 0.71 ng/mL is likely to indicate GFR < 90 mL/(min·1.73 m2). We observed a significant correlation between serum creatinine and Cys C in our renal transplant patients. Therefore, serum KIM-1 may be used for monitoring renal function with potential nephrotoxic drug use in renal transplants.
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 (CNS) and regulates the pathogenesis of AD. Specifically, RACK1 is involved in the regulation of amyloid-β (Aβ) precursor protein (APP) processing through α- or β-secretase by binding to different PKC isoforms. Additionally, RACK1 promotes synaptogenesis and synaptic plasticity by inhibiting N-methyl-aspartate receptors (NMDARs) and activating GABAA receptors (GABAARs), thereby preventing neuronal excitotoxicity. RACK1 also assembles inflammasomes, which is involved in various neuroinflammatory pathways, such as nuclear factor-kappaB (NF-κB), Tumour Necrosis Factor alpha (TNF-α), and NOD-like receptor family pyrin domain-containing 3 (NLRP3) pathways. The potential to design therapeutics that block Aβ accumulation and inflammation or precisely regulate synaptic plasticity represents an attractive therapeutic strategy, of which RACK1 is a potential target. In this review, we summarize the contribution of RACK1 to the different pathogenesis of AD and its potential as a therapeutic target.
Retinal neurodegenerative disease is the leading cause of blindness among the elderly in developed countries, including glaucoma, diabetes retinopathy, traumatic optic neuropathy and optic neuritis, etc. The current clinical treatment is not very effective. Indirubin is one of the main bioactive components of the traditional Chinese medicine Danggui Huilong Pill. In the current study, we investigated the role of indirubin in retinal neurodegeneration. Indirubin had no detectable tissue toxicity in vivo and cytotoxicity in vitro. Indirubin could improve visual function and ameliorate retinal neurodegeneration in mice after optic nerve crush injury in vivo. Indirubin could reduce the apoptosis of retinal ganglion cells induced by oxidative stress in vitro. In addition, the indirubin could significantly suppress the increased intracellular ROS production and decrease SOD activity induced by oxidative stress. Mechanically, indirubin played the neuroprotective role through the regulation of the PI3K/Akt/Bad/Bcl-2 signaling. Collectively, indirubin protected retinal ganglion cells from oxidative damage and alleviated retinal neurodegeneration induced by optic nerve crush injury. The current study provides a potential therapeutic medicine for retinal neurodegenerative diseases.
Peroxisomes are organelles enclosed by a single membrane and present in various species. Abruption of peroxisomes is associated with peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme deficiencies (PEDs) 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 proteomics 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, germ cell deletion resulted in male sterility, manifested as destruction of intercellular bridges (ICBs) between spermatids and the formation of multinucleated giant cells (MGCs). Proteomic analysis of Pex3-deleted spermatids revealed defective expression of peroxisomal proteins and spermiogenesis-related proteins. These findings provide new sights that PEX3-dependent peroxisomes are essential for germ cells undergoing spermiogenesis, but not for Sertoli cells.
Genetic variants in super-enhancers (SEs) are increasingly implicated as a disease risk-driving mechanism. Previous studies have reported the associations between benzo[a]pyrene (BaP) exposure and some malignant tumor incidences. Currently, it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk, as well as the related intrinsic molecular mechanisms. In the current study, logistic regression was used to determine that rs5057581 in 22q-SE significantly increased prostate cancer risk (odds ratio = 1.26, P = 7.61×10−5). The rs6001092, in high linkage disequilibrium with rs5057581 (r2 = 0.98), is located in a regulatory AhR motif and could interact with the FAM227A promoter via bioinformatics analysis. A series of functional experiments and BaP acute exposure were performed to assess the biological function of the genetic variant and the target gene. Biologically, the rs6001092-G allele strengthened the transcription factor binding affinity of AhR, thereby upregulating FAM227A, especially upon exposure to BaP, which induced the malignant phenotypes of prostate cancer. The current study highlights that AhR acts as an environmental sensor of BaP and is involved in SE-mediated prostate cancer risk, providing new insights into the aetiology of prostate cancer associated with inherited SE variants under environmental carcinogen stressors.
The interplay between DNA replication stress and immune microenvironment alterations plays a crucial role in colorectal tumorigenesis. However, a comprehensive understanding of their relationship and relevant biomarkers involved in colorectal tumorigenesis is lacking. To address this gap, we conducted a study aiming to investigate this relationship 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 study (GWAS) involving both East Asian (7062 cases and 195745 controls) and European (24476 cases and 23073 controls) populations. Mediation analysis was employed to infer the causal pathway, and multiplex immunofluorescence was applied to visualize colocalized biomarkers in colorectal tumors and immune cells. Our findings revealed that DNA replication activity and 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, which exhibited significantly decreased infiltration in colorectal tumors, were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication. In conclusion, this trans-omics incorporating GWAS study provides insights into a plausible pathway connecting DNA replication and immunity, expanding the biological knowledge of colorectal tumorigenesis and therapeutic targets.
Renal transplant patients receive several immunosuppressive drug regimens. Serum creatinine has been the standard of monitoring kidney functions. Cystatin C (Cys C) and Kidney Injury Molecule-1 (KIM-1) have been shown to indicate injury to kidney earlier than serum creatinine. We evaluated the serum concentrations of Cys C and KIM-1 in our renal transplant patients receiving mycophenolate mofetil, tacrolimus, sirolimus, everolimus, or cyclosporine were recruited. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation based on creatinine, Cys C, and combined creatinine with Cys C was used for estimating glomerular filtration rate (GFR). Association of serum KIM-1 for those with GFR < 90 ml/min/1.73 m2 was evaluated. A significant correlation was observed between serum creatinine and Cys C concentrations. As expected, significantly higher Cys C concentrations were observed in patients with elevated serum creatinine compared to those with normal. The estimated GFRs based on CKD-EPI creatinine equation was significantly greater than the other equations but a significant correlation was observed between all the equations. Serum KIM-1 levels were negatively correlated with GFR estimated using CKD-EPI Cys C and combined creatinine and Cys C based equations. Serum KIM-1 above 0.71 ng/ml is likely to indicate GFR < 90 ml/min/1.73 m2. We observed a significant correlation between serum creatinine and Cys C in our renal transplant patients.
The Journal of Biomedical Research--2023, 37(6)
Original Article
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.
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.
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.
Nonalcoholic fatty liver disease (NAFLD) is considered a major health epidemic with an estimated 32.4% worldwide prevalence. No drugs have yet been approved and therapeutic nodes remain a major unmet need. Long noncoding RNAs are emerging as an important class of novel regulators influencing multiple biological processes and the pathogenesis of NAFLD. Herein, we described a novel long noncoding RNA, lnc_217, which was liver enriched and upregulated in high-fat diet-fed mice, and a genetic animal model of NAFLD. We found that liver specific knockdown of lnc_217 was resistant to high-fat diet-induced hepatic lipid accumulation and decreased serum lipid in mice. Mechanistically, we demonstrated that knockdown of lnc_217 not only decreased de novo lipogenesis by inhibiting sterol regulatory element binding protein-1c cleavage but also increased fatty acid β-oxidation through activation of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1α. Taken together, we conclude that lnc_217 may be a novel regulator of hepatic lipid metabolism and a potential therapeutic target for the treatment of hepatic steatosis and NAFLD-related metabolic disorders.
ELABELA (ELA), an endogenous ligand of the apelin receptor (also known as apelin peptide jejunum [APJ]), has been shown to decrease in the plasma of patients with diabetic kidney disease (DKD). In the current study, we explored the potential function as well as the underlying mechanisms of ELA in DKD. We first found that the ELA levels were decreased in the kidneys of DKD mice. Then, we found that ELA administration mitigated renal damage and downregulated the expression of fibronectin, collagen Ⅳ, and transforming growth factor-β1 in the db/db mice and the high glucose cultured HK-2 cells. Furthermore, the autophagy markers, Beclin-1 and LC3-Ⅱ/LC3-Ⅰ ratio, were significantly impaired in DKD, but the ELA treatment reversed these alterations. Mechanistically, the inhibitory effects of ELA on the secretion of fibrosis-associated proteins in high glucose conditions were blocked by pretreatment with 3-methyladenine (an autophagy inhibitor). In summary, these in vivo and in vitro results demonstrate that ELA effectively protects against DKD by activating high glucose-inhibited renal tubular autophagy, potentially serving as a novel therapeutic candidate for DKD.
Endometriosis is defined as a condition with endometrium-like tissues migrating outside of the pelvic cavity. However, the mechanism of endometriosis is still unclear. Lactate can be covalently modified to lysine residues of histones and other proteins, which is called lactylation. The results showed that the higher level of lactate and lactate dehydrogenase A enhanced the histone H3 lysine 18 lactylation (H3K18lac) in ectopic endometrial tissues and ectopic endometrial stromal cells than that in normal endometrial tissues and normal endometrial stromal cells. Lactate promoted cell proliferation, migration, and invasion in endometriosis. Mechanistically, lactate induced H3K18lac to promote the expression of high-mobility group box 1 (HMGB1) in endometriosis, and HMGB1 knockdown significantly reduced the cell proliferation, migration, and invasion of the lactate-treated cells through the phosphorylation of AKT. In conclusion, lactate could induce histone lactylation to promote endometriosis progression by upregulating the expression of HMGB1, which may provide a novel target for the prevention and treatment of endometriosis.
Inconsistent findings have been reported regarding the associations between hypertensive disorders in pregnancy (HDP) and infant neurodevelopment. Leveraging data from the Jiangsu Birth Cohort, in the present study, we re-visited such associations in one-year-old infants from 2576 singleton pregnancies and 261 twin pregnancies. We first assessed infant neurodevelopment by the Bayley Scales of Infant and Toddler Development Screening Test (the Third Edition), and then estimated its association with maternal HDP using general linear regression models and Poisson regression models. In singleton pregnancies, compared with mothers unexposed to HDP, infants born to mothers with chronic hypertension exhibited a lower score ( β, −0.67; 95% confidence interval [CI], −1.19–−0.15) and a higher risk of "non-optimal" gross motor development (risk ratio [RR], 2.21; 95% CI, 1.02–4.79); in twin pregnancies, infants born to mothers with HDP exhibited lower scores in cognition ( β, −0.49; 95% CI, −0.96–−0.01), receptive communication ( β, −0.55; 95% CI, −1.03–−0.06), and gross motor ( β, −0.44; 95% CI, −0.86–−0.03), and at a higher risk of "non-optimal" gross motor development (RR, 2.12; 95% CI, 1.16–3.88). These findings indicate that infants born to mothers with HDP may have inferior neurodevelopment outcomes at the age of one year.
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.
Myocardin in biology and disease
Joseph M. Miano
2015, 29(1): 3-19.   doi: 10.7555/JBR. 29.20140151
+Abstract PDF 5076KB
Immune checkpoint inhibitors in cancer therapy
Eika S. Webb, Peng Liu, Renato Baleeiro, Nicholas R. Lemoine, Ming Yuan, Yaohe Wang
2018, 32(5): 317-326.   doi: 10.7555/JBR.31.20160168
+Abstract PDF 275KB
Exosomes and their role in the micro-/macro-environment: a comprehensive review
Naureen Javeed, Debabrata Mukhopadhyay
2017, 31(5): 386-394.   doi: 10.7555/JBR.30.20150162
+Abstract PDF 185KB
GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis in rats
Guoliang Meng, Jing Wang, Yujiao Xiao, Wenli Bai, Liping Xie, Liyang Shan, Philip K Moore, Yong Ji
2015, 29(3): 203-213.   doi: 10.7555/JBR.28.20140037
+Abstract PDF 2347KB
Platelets in hemostasis and thrombosis: Novel mechanisms of fibrinogen-independent platelet aggregation and fibronectinmediated protein wave of hemostasis
Yan Hou, Naadiya Carrim, Yiming Wang, Reid C. Gallant, Alexandra Marshall, Heyu Ni
2015, 29(6): 437-444.   doi: 10.7555/JBR.29.20150121
+Abstract PDF 610KB
Statistical analysis for genome-wide association study
Ping Zeng, Yang Zhao, Cheng Qian, Liwei Zhang, Ruyang Zhang, Jianwei Gou, Jin Liu, Liya Liu, Feng Chen
2015, 29(4): 285-297.   doi: 10.7555/JBR.29.20140007
+Abstract PDF 3937KB
Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo
Matthew G.K. Benesch, Xiaoyun Tang, Ganesh Venkatraman, Raie T. Bekele, David N. Brindley
2016, 30(4): 272-284.   doi: 10.7555/JBR.30.20150058
+Abstract PDF 462KB
Autoantibodies in Alzheimer's disease: potential biomarkers, pathogenic roles, and therapeutic implications
Jianming Wu, Ling Li
2016, 30(5): 361-372.   doi: 10.7555/JBR.30.20150131
+Abstract PDF 426KB
Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies
Rampes Sanketh, Ma Daqing
2019, 33(4): 221-234.   doi: 10.7555/JBR.32.20180087
+Abstract + HTML PDF 1187KB
Translating transitions - how to decipher peripheral human B cell development
Mats Bemark
2015, 29(4): 264-284.   doi: 10.7555/JBR.29.20150035
+Abstract PDF 858KB
Class A scavenger receptor activation inhibits endoplasmic reticulum stress-induced autophagy in macrophage
Hanpeng Huang, Xiaoyu Li, Yan Zhuang, Nan Li, Xudong Zhu, Jin Hu, Jingjing Ben, Qing Yang, Hui Bai, Qi Chen
2014, 28(3): 213-221.   doi: 10.7555/JBR.28.20130105
+Abstract [PDF 11939KB](1121)
Dual therapy of rosiglitazone/pioglitazone with glimepiride on diabetic nephropathy in experimentally induced type 2 diabetes rats
Ravi Prakash Rao, Ansima Singh, Arun K Jain, Bhartu Parsharthi Srinivasan
2011, 25(6): 411-417.   doi: 10.1016/S1674-8301(11)60054-7
+Abstract [PDF 1947KB](1051)
A clinical perspective on mucoadhesive buccal drug delivery systems
Ritu MGilhotra, Mohd Ikram, Sunny Srivastava, Neeraj Gilhotra
2014, 28(2): 81-97.   doi: 10.7555/JBR.27.20120136
+Abstract [PDF 2323KB](1288)
AEG-1 expression correlates with CD133 and PPP6c levels in human glioma tissues
Jia Guo, Xin Chen, Ruxing Xi, Yuwei Chang, Xuanwei Zhang, Xiaozhi Zhang
2014, 28(5): 388-395.   doi: 10.7555/JBR.28.20140015
+Abstract [PDF 14254KB](1109)
Lipoprotein metabolism in nonalcoholic fatty liver disease
Zhenghui Gordon Jiang, Simon C. Robson, Zemin Yao
2013, 27(1): 1-13.   doi: 10.7555/JBR.27.20120077
+Abstract [PDF 1247KB](1659)
Development of Leishmania vaccines: predicting the future from past and present experience
Joshua Muli Mutiso, John Chege Macharia, Maria Ndunge Kiio, James Maina Ichagichu, Hitler Rikoi, Michael Muita Gicheru
2013, 27(2): 85-102.   doi: 10.7555/JBR.27.20120064
+Abstract [PDF 4KB](1494)
ApoB/apoA1 is an effective predictor of coronary heart disease risk in overweight and obesity
Min Lu, Qun Lu, Yong Zhang, Gang Tian
2011, 25(4): 266-273.   doi: 10.1016/S1674-8301(11)60036-5
+Abstract [PDF 4KB](1028)
Atrial fibrillation
Thomas M. Munger, Li-Qun Wu, Win K. Shen
2014, 28(1): 1-17.   doi: 10.7555/JBR.28.20130191
+Abstract [PDF 5352KB](2382)
Fracture resistance of posterior teeth restored with modern restorative materials
Ibrahim M. Hamouda, Salah H. Shehata
2011, 25(6): 418-424.   doi: 10.1016/S1674-8301(11)60055-9
+Abstract [PDF 763KB](976)
Maternal risk factors for low birth weight for term births in a developed region in China: a hospital-based study of 55,633 pregnancies
Yihua Bian, Zhan Zhang, Qiao Liu, Di Wu, Shoulin Wang
2013, 27(1): 14-22.   doi: 10.7555/JBR.27.20120046
+Abstract [PDF 4KB](1193)