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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).
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.
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.
In the present study, we introduced the H2O2-sensitive thiazolidinone moiety at the 4th amino group of gemcitabine (GEM) to synthesize a new target compound named GEM-ZZQ, and then we confirmed its chemical structure by nuclear magnetic resonance spectroscopy. We further confirmed that GEM-ZZQ had a good chemical stability in different pH solutions in vitro and that it could be activated by H2O2 to release GEM. Pharmacodynamic studies revealed that the growth inhibition of human normal epithelial cells was weaker by GEM-ZZQ than by GEM treatment and that the inhibition of various lung cancer cell lines by GEM-ZZQ was similar to that of GEM. For the lung cancer cell lines that are resistant to the epidermal growth factor receptor (EGFR)-targeting inhibitor osimertinib, GEM-ZZQ showed less growth inhibition than GEM; however, GEM-ZZQ in combination with cisplatin showed better synergistic effects than GEM in the low-dose groups. In summary, we provided a new anti-cancer compound GEM-ZZQ for treating lung cancer by modifying the GEM structure.
Scapular surgery has mainly been studied in the setting of fractures; regional anesthesia can be utilized as part of a multimodal analgesia regimen for postoperative pain relief. Previous studies are limited to scapular fracture pain. The available literature supports the use of various types of nerve blocks and even combinations of different blocks, of which the paravertebral nerve block is one such block that has been effective. We present a case of a patient undergoing excision of a scapular osteochondroma who received a single-shot paravertebral nerve block after surgery with an effective analgesia.
Long noncoding RNA (lncRNA) IDH1 antisense RNA 1(IDH1-AS1) is involved in the progression of multiple tumors, but its role in epithelial ovarian cancer (EOC) is unknown. Therefore, we investigated the expression level 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 dual-luciferase reporter, qPCR, rescure experiments, and Western blotting. We found that the expression level of IDH1-AS1 was 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 favorable prognosis, because IDH1-AS1 inhibited cells proliferation and xenograft tumor growth of EOC. It is likely that IDH1-AS1 may sponge miR-518c-5p whose overexpression promoted EOC cells 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 cells proliferation, and that RBM47 overexpressing plasmid counteracted the proliferation promoting effect caused by IDH1-AS1 knockdown. Taken together, IDH1-AS1 may suppress EOC cell proliferation and tumor growth via the miR-518c-5p/RBM47 axis.
Ionizing radiation is a popular and effective treatment option for glioblastoma (GBM). However, resistance to radiation therapy inevitably occurs during treatment. It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity. Here, we found that heat shock protein 90 beta family member 1 (HSP90B1) was significantly upregulated in radioresistant GBM cells. More importantly, HSP90B1 promoted the localization of glucose transporter type 1 (GLUT1) on plasma membrane, which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells. These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients, bringing a new dawn to the treatment of glioblastoma.
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.
ELABELA (ELA), an endogenous ligand of apelin receptor (also known as apelin peptide jejunum), has been observed 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. We then 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 high glucose cultured HK-2 cells. Furthermore, the autophagy markers, the 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). It is likely that ELA protected against renal damage in db/db mice and injury in high glucose-induced HK-2 cells through the activation of renal tubular autophagy. In conclusion, ELA may effectively protect against DKD by activating high glucose-inhibited renal tubular autophagy.
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.
The current study aims to ascertain the anatomical feasibility of transferring the contralateral S1 ventral root (VR) to the ipsilateral L5 VR for treating unilateral spastic lower limb paralysis. Six formalin-fixed (three males and three females) cadavers were used. The VR of the contralateral S1 was transferred to the VR of the ipsilateral L5. The sural nerve was selected as a bridge between the donor and recipient nerve. The number of axons, the cross-sectional areas and the pertinent distances between the donor and recipient nerves were measured. The extradural S1 VR and L5 VR could be separated based on anatomical markers of the dorsal root ganglion. The gross distance between S1 nerve root and L5 nerve root was (31.31 ± 3.23) mm, while that on the diffusion tensor imaging was (47.51 ± 3.23) mm. The numbers of axons in the S1 VRs and L5 VRs were 13 414.20 ± 2 890.30 and 10 613.20 ± 2 135.58, respectively. The cross-sectional areas of S1 VR and L5 VR were (1.68 ± 0.26) mm2 and (1.08 ± 0.26) mm2, respectively. In conclusion, transfer of the contralateral S1 VR to the ipsilateral L5 VR may be an anatomically feasible treatment option for unilateral spastic lower limb paralysis.
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.
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy and lacks of effective treatment. The bulk-sequencing of different gene expression by comparing HCC and adjacent tissue provides certain clues on the mechanism investigation or target identification of tumor progression, but those essential genes only expressed in a sub-population of HCC might not be enriched and founded by such screening. In the current study, we performed a single cell-clone based screening and identified galectin-14 as an essential molecule in regulating tumor growth. The aberrant expression of galectin-14 was significantly associated with poor overall survival of liver cancer patients according to the database analysis. Knocking down galectin-14 inhibited the proliferation of tumor growth, whereas overexpression of galectin-14 promoted tumor growth in vivo. Non-targeted metabolomics analysis indicated that knocking-down galectin-14 decreased the glycol-metabolism, especially the glycoside synthesis was significantly changed. Further study found that galectin-14 could promote the expression of cell surface heparan sulfate proteoglycans (HSPGs), which functioned as co-receptors, to increase the sensitivities of HCC cells responding to growth factor treatments including EGF and TGF-α. Taken together, our study identified a novel HCC-specific molecule galectin-14, which increased the cell surface HSPGs and the uptake of growth factors to promote HCC proliferation.
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 process of aging is characterized by progressive tissue and organ degeneration, which is positively correlated with a higher 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 reactive oxygen species (ROS), all contributing to cognitive deterioration. Aging is therefore also one of the key risk factors in the development of 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 microglia cells receiving significantly less attention. 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.
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 could be covalently modified to lysine residues of histones and other proteins, which is called lactylation. Our results showed that the higher level of lactate and LDHA enhanced the H3K18lac in ectopic endometrial (EC) tissues and ectopic endometrial stromal cells (eESCs) than that in normal tissues and normal endometrial stromal cells (nESCs). Lactate could promote cell proliferation, migration, and invasion in endometriosis. Mechanistically, lactate induced H3K18lac promotes the expression of 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, we showed that lactate could induce histone lactylation to promote endometriosis progression by upregulating the expression of HMGB1, which could provide a novel target for the prevention and treatment of endometriosis.
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.
Immune-related adverse events (irAEs) represent an increasingly concerned challenge in assessment of bio-pharmaceutical products. In contrast to rare allergic incidence of small chemical drugs historically, contemporary bio-therapeutics come up with substantially higher morbidity of irAEs due to their complex structure and comprehensive mechanisms of action. Whereas immunogenicity of protein-based compounds is evidently linked to induction of anti-drug antibody (ADA), the irAE pathogenesis of advanced biologics, such as cell and gene therapy, is yet to be further delineated. Herein, this article thus presents an updated profile regarding untoward immune effects of medications covering various material categories systematically, with the underlying mechanisms to inspire the risk mitigation in bio-pharmaceutic development and application.
The process of aging is characterized by the progressive degeneration of tissues and organs, resulting in a higher mortality rate. The brain is one of the most affected organs. Age-related brain changes include the abnormal neuronal activity, calcium homeostasis dysfunction, dysregulation of mitochondrial function, and reactive oxygen species (ROS), finally all contributing to cognitive deterioration. Aging is also one of the main risk factors for the development of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, etc. For many years, neurodegenerative disease research was concentrated primarily on neurons, with microglia receiving significantly less attention. Recently, microglial homeostasis has emerged as an important mediator in the pathogenesis of neurological diseases. To facilitate an overview of the current knowledge, here we look at brain aging from the microglia’s perspective, present the current state of knowledge on the relationship of brain aging and the microglia. We summarize the recent progress of research about microglia in normal aging, Alzheimer's disease(AD), Parkinson's disease(PD), Huntington's disease(HD), and amyotrophic lateral sclerosis(ALS), then discuss the relationship between senescent microglia and brain aging. Understanding the molecular complexity of the microglia in brain aging will suggest new avenues for healthy aging.
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.
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 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 cisplatin sensitivity to HepG2 cells. Furthermore, we found that FAK and CaMKⅡ were upregulated in hepatoblastoma. The group with high expression of FAK and CaMKⅡ exhibited significantly lower ImmunoScore as well as CD8+ T and NK cells. CaMKⅡ was positively correlated with PDCD1 and LAG3. Correspondingly, FAK was negatively correlated with 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.
Aberrant alternative polyadenylation (APA) events played an important role in cancers, but little is known about whether APA related genetic variants contribute to the susceptibility of bladder cancer. Previously the genome-wide association study identified 17,955 single nucleotide polymorphisms (SNPs) located at alternative polyadenylation quantitative trait loci (apaQTL) in bladder cancer. We found that gene symbols of APA affected by apaQTL-SNPs were closely related to cancer signaling pathways, high mutational burden, and immune infiltration. Association analysis showed that apaQTL-SNP rs34402449 C>A, rs2683524 C>T and rs11540872 C>G significantly associated with susceptibility to bladder cancer (rs34402449: OR = 1.355, 95% 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 effects 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, which had the most significant effect on cell proliferation in bladder cancer cell lines, was higher expressed in bladder cancer tissues than in adjacent tissues. Moreover, rs2683524 T allele was related to a shorter 3′ untranslated regions (3′UTR) of PRR13 and could increase PRR13 expression levels, exhibiting the apaQTL and expression quantitative trait loci (eQTL) effects. Collectively, our findings provided informative apaQTL resources and insights into the regulatory mechanisms linking variants to bladder cancer risk.
cis-Diamminedichloroplatinum (CDDP) is widely used for the treatment of various solid cancers. Here we report CDDP increases carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) expression and enzymatic activities along with the increase of pregnane X receptor (PXR) and decrease of DEC1 in human hepatoma cells, primary mouse hepatocytes, mouse liver and intestine. The overexpression or knockdown of PXR alone can increase or decrease the CES1 and CES2 expression. The increases of CES1 and CES2 expression induced by CDDP can be abolished or enhanced by the knockdown or overexpression of PXR, implying CDDP induces carboxylesterases through the activation of PXR. Likewise, the overexpression or knockdown of DEC1 alone can significantly decrease or increase PXR and its targets. Moreover, the increase of PXR and its targets induced by CDDP can be abolished or alleviated by the overexpression or knockdown of differentiated embryonic chondrocyte-expressed gene 1 (DEC1). The overexpression or knockdown of DEC1 can affect the response of PXR to CDDP, but not vice versa, which suggests CDDP increases carboxylesterases through increasing PXR mediated by the decrease of DEC1. In addition, CDDP does not increase DEC1 mRNA degradation but suppresses DEC1 promoter reporter activity, suggesting it suppresses DEC1 transcriptionally. The combined use of CDDP and irinotecan has a synergistic effect on two cell lines, especially, on the use of CDDP first.
Nonalcoholic fatty liver disease (NAFLD) is considered as 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 describe a novel Long noncoding RNA, lnc_217, which is liver enriched and upregulated in high-fat diet fed mice and genetic animal model of NAFLD. Liver specific knockdown of lnc_217 is resistant to high-fat diet induced hepatic lipid accumulation and decreases serum lipid in mice. Mechanistically, knockdown of lnc_217 not only decreases de novo lipogenesis by inhibiting sterol regulatory element binding protein 1-c cleavage, but also increases fatty acids β-oxidation through activation of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1 α. Taken together, we conclude that lnc_217 is a novel regulator of hepatic lipid metabolism and a potential therapeutic target for the treatment of hepatic steatosis and NAFLD-related metabolic disorders.
Previous studies on the relationship between hypertensive disorders in pregnancy (HDP) and the neurodevelopment of infants are inconsistent. Based on the Jiangsu Birth Cohort, a prospective cohort study, we included 2576 singleton pregnancies and 261 twin pregnancies in the present study. Infant neurodevelopment assessment was performed using the Bayley Scales of Infant and Toddler Development Screening Test, Third Edition at 1 year of age. General linear regression models and Poisson regression models were performed to estimate the relationships between maternal HDP and infant neurodevelopment at 1 year old. Among singleton pregnancies, compared with those mothers of non-HDP exposure, infants born to mothers with chronic hypertension had a lower score (β, −0.67; 95% confidence interval [CI], −1.19–−0.15) and at a higher risk of "non-optimal" development in gross motor (RR, 2.21; 95% CI: 1.02–4.79). Among twin pregnancies, infants born to mothers with HDP had 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 higher risk of "non-optimal" development in gross motor (RR, 2.12; 95% CI, 1.16–3.88). Our study suggested that infants born to mothers with HDP had poorer neurodevelopment outcomes at 1 year old.
Inflammatory jaw bone diseases are common in stomatology, including periodontitis, peri-implantitis, medication-related osteonecrosis of the jaw, radiation osteomyelitis of the jaw, age-related osteoporosis, and other specific infections. These diseases may lead to tooth loss and maxillofacial deformities, severely affecting patients' quality of life. Over the years, the reconstruction of jaw bone deficiency caused by inflammatory diseases has emerged as a medical and socioeconomic challenge. Therefore, exploring the pathogenesis of inflammatory diseases associated with jaw bones is crucial for improving prognosis and developing new targeted therapies. Accumulating evidence indicates that the integrated bone formation and dysfunction arise from complex interactions among a network of multiple cell types, including osteoblast-associated cells, immune cells, blood vessels, and lymphatic vessels. However, the role of these different cells in the inflammatory process and the 'rules' with which they interact are still not fully understood. Although many investigations have focused on specific pathological processes and molecular events in inflammatory jaw diseases, few articles offer a perspective of integration. Here, we review the changes and mechanisms of various cell types in inflammatory jaw diseases, with the hope of providing insights to drive further research in this field.
Anti-cancer therapy often causes premature ovarian insufficiency and infertility as the ovarian follicle reserve is extremely sensitive to chemotherapy drugs, such as cisplatin. Various fertility preservation methods have been explored for women, especially prepubertal girls undergoing radiotherapy and chemotherapy due to cancer. In recent years, mesenchymal stem cell-derived exosomes (MSC-exos) have been reported to play an important role in tissue repair and the treatment of various diseases. In the current study, we observed that human umbilical cord-derived MSC-exos (hucMSC-exos) after short-term culture improved follicular survival and development while receiving cisplatin treatment. Moreover, intravenous injection of hucMSC-exos improved ovarian function and ameliorated inflammatory environment within the ovary. The underlying mechanism of hucMSC-exos on fertility preservation was associated with the down-regulation of p53-related apoptosis and their anti-inflammatory function. Based on these findings, we propose that hucMSC-exos may be a potential approach to improve fertility in women diagnosed with cancer.
The Journal of Biomedical Research--2023, 37(4)
Editorial Commentary
Review Article
The acute myocardial infarction (AMI) and sudden cardiac death (SCD), both associated with acute cardiac ischemia, are one of the leading causes of adult death in economically developed countries. The development of new approaches for the treatment and prevention of AMI and SCD remains the highest priority for medicine. A study on the cardiovascular effects of chronic hypoxia (CH) may contribute to the development of these methods. Chronic hypoxia exerts both positive and adverse effects. The positive effects are the infarct-reducing, vasoprotective, and antiarrhythmic effects, which can lead to the improvement of cardiac contractility in reperfusion. The adverse effects are pulmonary hypertension and right ventricular hypertrophy. This review presents a comprehensive overview of how CH enhances cardiac tolerance to ischemia/reperfusion. It is an in-depth analysis of the published data on the underlying mechanisms, which can lead to future development of the cardioprotective effect of CH. A better understanding of the CH-activated protective signaling pathways may contribute to new therapeutic approaches in an increase of cardiac tolerance to ischemia/reperfusion.
The role of reactive oxygen species (ROS) in ischemic and reperfusion (I/R) injury of the heart has been discussed for more than 40 years. It has been demonstrated that reperfusion triggers a multiple increase in free radical generation in the isolated heart. Antioxidants were found to have the ability to mitigate I/R injury of the heart. However, it is unclear whether their cardioprotective effect truly depends on the decrease of ROS levels in myocardial tissues. Since high doses and high concentrations of antioxidants were experimentally used, it is highly likely that the cardioprotective effect of antioxidants depends on their interaction not only with free radicals but also with other molecules. It has been demonstrated that the antioxidant N-2-mercaptopropionyl glycine or NDPH oxidase knockout abolished the cardioprotective effect of ischemic preconditioning. Consequently, there is evidence that ROS protect the heart against the I/R injury.
The analysis of experimental data demonstrates that platelets and neutrophils are involved in the no-reflow phenomenon, also known as microvascular obstruction (MVO). However, studies performed in the isolated perfused hearts subjected to ischemia/reperfusion (I/R) do not suggest the involvement of microembolization and microthrombi in this phenomenon. The intracoronary administration of alteplase has been found to have no effect on the occurrence of MVO in patients with acute myocardial infarction. Consequently, the major events preceding the appearance of MVO in coronary arteries are independent of microthrombi, platelets, and neutrophils. Endothelial cells appear to be the target where ischemia can disrupt the endothelium-dependent vasodilation of coronary arteries. However, reperfusion triggers more pronounced damage, possibly mediated by pyroptosis. MVO and intra-myocardial hemorrhage contribute to the adverse post-infarction myocardial remodeling. Therefore, pharmacological agents used to treat MVO should prevent endothelial injury and induce relaxation of smooth muscles. Ischemic conditioning protocols have been shown to prevent MVO, with L-type Ca2+ channel blockers appearing the most effective in treating MVO.
Original Article
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.
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.
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