Gastric cancer (GC), a malignant tumor of the gastric mucosa, is the second leading cause of cancer deaths worldwide. Although the incidence and mortality of gastric cancer have been reduced in the US Show more
Gastric cancer (GC), a malignant tumor of the gastric mucosa, is the second leading cause of cancer deaths worldwide. Although the incidence and mortality of gastric cancer have been reduced in the US and elsewhere, it is still a major public health concern. In this study, we attempted to investigate the function of tripartite motif-containing protein 37 (TRIM37) in GC cell lines in order to propose a new therapy for GC. The expression of TRIM37 in GC patients and cell lines was detected by immunohistochemistry, real-time PCR and Western blotting analysis. After TRIM37 knockdown or overexpression, the cell cycle, proliferation and apoptosis, as well as the expression of related proteins, were detected. In addition, in vivo experiments on nude mice were performed. We found that TRIM37 expression was significantly elevated in tumor tissues of GC patients and GC cell lines, and patients with high expression of TRIM37 had a poor prognosis. Knockdown of TRIM37 in GC cells significantly inhibited cell proliferation and cell cycle progression, promoted apoptosis, increased cleaved caspase 3 and decreased c-myc and phosphorylation of protein kinase 1/2 (p-ERK1/2). Effects of TRIM37 overexpression were opposite to that of TRIM37 knockdown and were potently attenuated by an ERK1/2 inhibitor. In addition, an ERK1/2 agonist increased TRIM37 and p-ERK1/2 in a dose-dependent manner, and TRIM37 knockdown potently attenuated EGF-induced cell proliferation and expression of TRIM37 and p-ERK1/2. Interestingly, we found that TRIM37 overexpression did not affect the mRNA level of dual-specificity phosphatase 6 (DUSP6), but reduced its protein level in GC cells. Co-immunoprecipitation (Co-IP) analyses revealed that TRIM37 interacted with DUSP6, and TRIM37 overexpression enhanced DUSP6 ubiquitination in GC cells. In vivo experiments on nude mice showed the inhibitory effect of TRIM37 knockdown on tumor growth. These findings suggest that TRIM37 may act as an oncogene in the growth of GC cells and illustrate its potential function as a target in the treatment of GC. Show less
The metastasis of cervical cancer has always been a clinical challenge. We investigated the effects of low-dose naltrexone (LDN) on the epithelial mesenchymal transition of cervical cancer cells in vi Show more
The metastasis of cervical cancer has always been a clinical challenge. We investigated the effects of low-dose naltrexone (LDN) on the epithelial mesenchymal transition of cervical cancer cells in vitro as well as its influence on macrophage polarization and associated cytokines in vivo. The results suggested that LDN supressed the proliferation, migration and invasion abilities and promote their apoptosis in Hela cells, whereas the opioid growth factor receptor (OGFr) silenced significantly reversed these effects in vitro. Knockdown the expression of OGFr, the inhibitory of LDN on EMT was weakened. LDN could inhibit cervical cancer progression in nude mice. In additon, LDN indirectly reduced the number of tumor-associated macrophages (TAMs), mainly M2 macrophages, and decreased expression of anti-inflammatory factor IL-10 in the serum of nude mice. These findings demonstrate that LDN could be a potential treatment for cervical cancer. Show less
SULT2B1b (SULT2B) is a prostate-expressed hydroxysteroid sulfotransferase, which may regulate intracrine androgen homeostasis by mediating 3β-sulfation of dehydroepiandrosterone (DHEA), the precursor Show more
SULT2B1b (SULT2B) is a prostate-expressed hydroxysteroid sulfotransferase, which may regulate intracrine androgen homeostasis by mediating 3β-sulfation of dehydroepiandrosterone (DHEA), the precursor for 5α-dihydrotestosterone (DHT) biosynthesis. The aldo-keto reductase (AKR)1C3 regulates androgen receptor (AR) activity in castration-resistant prostate cancer (CRPC) by promoting tumor tissue androgen biosynthesis from adrenal DHEA and also by functioning as an AR-selective coactivator. Herein we report that SULT2B-depleted CRPC cells, arising from stable RNA interference or gene knockout (KO), are markedly upregulated for AKR1C3, activated for ERK1/2 survival signal, and induced for epithelial-to-mesenchymal (EMT)-like changes. EMT was evident from increased mesenchymal proteins and elevated EMT-inducing transcription factors SNAI1 and TWIST1 in immunoblot and single-cell mass cytometry analyses. SULT2B KO cells showed greater motility and invasion in vitro; growth escalation in xenograft study; and enhanced metastatic potential predicted on the basis of decreased cell stiffness and adhesion revealed from atomic force microscopy analysis. While AR and androgen levels were unchanged, AR activity was elevated, since PSA and FKBP5 mRNA induction by DHT-activated AR was several-fold higher in SULT2B-silenced cells. AKR1C3 silencing prevented ERK1/2 activation and SNAI1 induction in SULT2B-depleted cells. SULT2B was undetectable in nearly all CRPC metastases from 50 autopsy cases. Primary tumors showed variable and Gleason score (GS)-independent SULT2B levels. CRPC metastases lacking SULT2B expressed AKR1C3. Since AKR1C3 is frequently elevated in advanced prostate cancer, the inhibitory influence of SULT2B on AKR1C3 upregulation, ERK1/2 activation, EMT-like induction, and on cell motility and invasiveness may be clinically significant. Pathways regulating the inhibitory SULT2B-AKR1C3 axis may inform new avenue(s) for targeting SULT2B-deficient prostate cancer. Show less
Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in Show more
Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered. We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci ( In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels. Show less
Tumour cells interfere with normal immune functions by affecting the expression of some immune-related genes, which play roles in the prognosis of cancer patients. In recent years, immunotherapy for t Show more
Tumour cells interfere with normal immune functions by affecting the expression of some immune-related genes, which play roles in the prognosis of cancer patients. In recent years, immunotherapy for tumours has been widely studied, but a practical prognostic model based on immune-related genes in lung adenocarcinoma comparable to existing model has not been established and reported. We first obtained publicly accessible lung adenocarcinoma RNA expression data from The Cancer Genome Atlas (TCGA) for differential gene expression analysis and then filtered immune-related genes based on the ImmPort database. By using the lasso algorithm and multivariate Cox Proportional-Hazards (CoxPH) regression analysis, we identified candidate genes for model development and validation. The robustness of the model was further examined by comparing the model with three established gene models. Gene expression data from a total of 524 lung adenocarcinoma patients from TCGA were used for model development. We identified four biomarkers (MAP3K8, CCL20, VEGFC, and ANGPTL4) that could predict overall survival in lung adenocarcinoma (HR = 1.98, 95% CI 1.48 to 2.64, P = 4.19e-06) and this model could be used as a classifier for the evaluation of low-risk and high-risk groups. This model was validated with independent microarray data and was highly comparable with previously reported gene expression signatures for lung adenocarcinoma prognosis. In this study, we identified a practical and robust four-gene prognostic model based on an immune gene dataset with cross-platform compatibility. This model has potential value in improving TNM staging for survival predictions in patients with lung adenocarcinoma. The study provides a method of immune relevant gene prognosis model and the identification of immune gene classifier for the prediction of lung adenocarcinoma prognosis with RNA sequencing and microarray compatibility. Show less
Hepatocellular carcinoma is one of the most common cancer types worldwide. In cases of advanced-stage disease, sorafenib is considered the treatment of choice. However, resistance to sorafenib remains Show more
Hepatocellular carcinoma is one of the most common cancer types worldwide. In cases of advanced-stage disease, sorafenib is considered the treatment of choice. However, resistance to sorafenib remains a major obstacle for effective clinical application. Based on integrated phosphoproteomic and The Cancer Genome Atlas (TCGA) data, we identified a transcription factor, Y-box binding protein-1 (YB-1), with elevated phosphorylation of Ser102 in sorafenib-resistant HuH-7 Show less
Homozygous and compound heterozygous mutations in the vacuolar protein sorting 13C (VPS13C) gene can cause autosomal recessive parkinsonism via mitochondrial pathway. The present study aimed to screen Show more
Homozygous and compound heterozygous mutations in the vacuolar protein sorting 13C (VPS13C) gene can cause autosomal recessive parkinsonism via mitochondrial pathway. The present study aimed to screen the mutations of VPS13C in a cohort of Chinese patients with early-onset Parkinson's disease (EOPD) and further explore its pathogenicity via burden analysis. A total of 669 patients with EOPD were sequenced with whole-exome sequencing and analyzed homozygous or compound heterozygous mutations in VPS13C. Moreover, rare variants with minor allele frequency <0.1% were included in the burden analysis. In total, 7 (1.05%) patients with EOPD carried compound heterozygous mutations in VPS13C, including 3 patients with novel compound heterozygous missense mutations and 4 patients with at least 1 nonsense or splicing-site mutations. Furthermore, burden analysis indicated that patients with EOPD had an enrichment of rare variants in VPS13C. In conclusion, our findings of compound missense mutations expanded the mutation spectrum of VPS13C in EOPD. Burden analysis further elucidated the importance of VPS13C in the pathogenesis of PD. Show less
It is widely accepted that the oxygen level in tumor tissue is significantly lower than the adjacent normal tissue, thus termed hypoxia. Intratumoral hypoxia represents a major driving force in cancer Show more
It is widely accepted that the oxygen level in tumor tissue is significantly lower than the adjacent normal tissue, thus termed hypoxia. Intratumoral hypoxia represents a major driving force in cancer progression, recurrence, metastasis, and decreased survival. Though multiple gene signatures reflect the complex cellular response to hypoxia have been established in several cancer types such as head and neck, breast, and lung cancers, the hypoxic panorama in colorectal cancer (CRC) remains poorly understood. A hypoxic signature constituted by a total of 356 genes, including canonical hypoxia-responsive ADM, ANGPTL4, CA9, and VEGFA, was established based on systemic literature search. A total of 1,730 CRC samples across four independent cohorts were used for CRCs mainly fell into two subgroups, one indicated as hypoxia and the other one designated as normoxia. Hypoxia was correlated with poor outcomes in CRC and will increase the risk of a subset of stage II patients to the level of normoxic stage III. Additionally, hypoxia was closely associated with activation of RAS signaling pathway independent of These findings will facilitate the development of a hypoxia-oriented therapy strategy to enhance the treatment effect in the near future. Show less
The aims of the NYU Children's Health and Environment Study (CHES) are to evaluate influences of prenatal non-persistent chemical exposures on fetal and postnatal growth and pool our data with the US Show more
The aims of the NYU Children's Health and Environment Study (CHES) are to evaluate influences of prenatal non-persistent chemical exposures on fetal and postnatal growth and pool our data with the US National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program to answer collaborative research questions on the impact of the preconceptual, prenatal, and postnatal environment on childhood obesity, neurodevelopment, pre/peri/postnatal outcomes, upper and lower airway outcomes, and positive health. Eligible women were ≥ 18 years old, < 18 weeks pregnant, had a pregnancy that is not medically threatened, and planned to deliver at NYU Langone Hospital-Manhattan, Bellevue Hospital, or NYU Langone Hospital-Brooklyn. Between March 22, 2016 and April 15, 2019, we recruited 2469 pregnant women, from whom 2193 completed an initial questionnaire and continued into NYU CHES. Of the 2193, 88 miscarried, 28 terminated, and 20 experienced stillbirth, while 57 were lost to follow up. We report here demographic and other characteristics of the 2000 live deliveries (2037 children), from whom 1624 (80%) consented to postnatal follow-up. Data collection in pregnancy was nested in clinical care, with questionnaire and specimen collection conducted during routine prenatal visits at < 18, 18-25, and > 25 weeks gestation. These have been followed by questionnaire and specimen collection at birth and regular postpartum intervals. Show less
Pathogen-host cell interactions play an important role in many human infectious and inflammatory diseases. Several pathogens, including Escherichia coli (E. coli), Mycobacterium tuberculosis (M. tb), Show more
Pathogen-host cell interactions play an important role in many human infectious and inflammatory diseases. Several pathogens, including Escherichia coli (E. coli), Mycobacterium tuberculosis (M. tb), and even the recent 2019 novel coronavirus (2019-nCoV), can cause serious breathing and brain disorders, tissue injury and inflammation, leading to high rates of mortality and resulting in great loss to human physical and mental health as well as the global economy. These infectious diseases exploit the microbial and host factors to induce serious inflammatory and immunological symptoms. Thus the development of anti-inflammatory drugs targeting bacterial/viral infection is an urgent need. In previous studies, YojI-IFNAR2, YojI-IL10RA, YojI-NRP1,YojI-SIGLEC7, and YojI-MC4R membrane-protein interactions were found to mediate E. coli invasion of the blood-brain barrier (BBB), which activated the downstream anti-inflammatory proteins NACHT, LRR and PYD domains-containing protein 2(NLRP2), using a proteomic chip conjugated with cell immunofluorescence labeling. However, the studies of pathogen (bacteria/virus)-host cell interactions mediated by membrane protein interactions did not extend their principles to broad biomedical applications such as 2019-nCoV infectious disease therapy. The first part of this feature article presents in-depth analysis of the cross-talk of cellular anti-inflammatory transduction signaling among interferon membrane protein receptor II (IFNAR2), interleukin-10 receptor subunit alpha (IL-10RA), NLRP2 and [Ca Show less
Prostate cancer (PCa) is the second leading cause of cancer-associated mortality in men. Speckle-type pox virus and zinc finger protein (SPOP), the most frequently mutated gene in PCa, functions as a Show more
Prostate cancer (PCa) is the second leading cause of cancer-associated mortality in men. Speckle-type pox virus and zinc finger protein (SPOP), the most frequently mutated gene in PCa, functions as a tumor suppressor via degradation of cancer-promoting substrates. However, its upstream regulation in PCa metastasis remains poorly determined. Here, in a Snail-induced metastatic PCa model, we observed an accelerated degradation of SPOP protein in cells, which is crucial for the PCa migration and activation of the AKT signaling pathway. Mechanistically, we demonstrated that binding to Snail promoted SPOP ubiquitination and degradation. Moreover, the bric-a-brac/tramtrack/broad complex (BTB) domain of SPOP is turned out to be essential for Snail-mediated SPOP degradation. Thus, our findings reveal a post-translational level regulation of SPOP expression that facilitates the metastasis of PCa cells. Show less
Benzo [a]pyrene (BaP) is a well-known endocrine disruptor. Exposure to BaP is known to impair embryo implantation. The corpus luteum (CL), the primary source of progesterone during early pregnancy, pl Show more
Benzo [a]pyrene (BaP) is a well-known endocrine disruptor. Exposure to BaP is known to impair embryo implantation. The corpus luteum (CL), the primary source of progesterone during early pregnancy, plays a pivotal role in embryo implantation and pregnancy maintenance. The inappropriate luteal function may result in implantation failure and spontaneous abortions. However, the effect of BaP on CL remains unknown. This study investigated the deleterious effects of BaP on the structure and function of CL during early pregnancy. Pregnant rats were dosed with BaP at 0.2 mg.kg-1. d from day 1 (D1) to day 9 (D9) of gestation. We found that BaP reduced the number of CLs, disturbed the secretion of steroid and impacted the luteal vascular networks. BaP significantly decreased the angiogenesis factor (VEGFR, Ang-1 and Tie2) and increased the anti-angiogenic factor THBS1. Inhibited THBS1 function by LSKL partially rescued the angiogenesis defect caused by BaP. In vitro, BaP metabolite BPDE also interfered the expression levels of angiogenesis-related factors in HUVECs and impaired the angiogenesis, whereas supplemented with rAng-1 can alleviate the anti-angiogenic effect of BPDE. Furthermore, Notch signaling molecules, including Notch1, Dll4, Jag1 and Hey2, which are essential for the establishment and maturation of vascular networks, were affected by BaP exposure. Collectively, BaP broke the molecular regulatory balance between luteal angiogenesis and vascular maturation, impaired the construction of luteal vascular networks, and further affected luteal formation and endocrine function during early pregnancy. Our findings might provide new insight into the relationship between BaP and luteal insufficiency in early pregnancy. These data also give a new line of evidence for curtailing BaP emissions and protecting the women of childbearing age from occupational exposure. Show less
The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF s Show more
The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development. Show less
Studies have increasingly shown that carbamoyl phosphate synthetase 1 ( Several biological databases including UALCAN, GEPIA and Oncomine were used to analyze the expression of The Oncomine platform, Show more
Studies have increasingly shown that carbamoyl phosphate synthetase 1 ( Several biological databases including UALCAN, GEPIA and Oncomine were used to analyze the expression of The Oncomine platform, UALCAN and gene expression profiling interactive analysis (GEPIA) were used and revealed that the expression levels of Our work indicated that Show less
Obesity is influenced by genetic and environmental factors. Despite the success of human genome-wide association studies, the specific genes that confer obesity remain largely unknown. The objective o Show more
Obesity is influenced by genetic and environmental factors. Despite the success of human genome-wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits. This study measured obesity-relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome-wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers. This study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and there was extensive pleiotropy at individual loci. This study demonstrates the utility of HS rats for investigating the genetics of obesity-related traits across institutions and identify several candidate genes for future functional testing. Show less
Emerging evidence is revealing that microRNAs (miRNAs) play essential roles in mechanosensing for regulating osteogenesis. However, no mechanoresponsive miRNAs have been identified in human bone speci Show more
Emerging evidence is revealing that microRNAs (miRNAs) play essential roles in mechanosensing for regulating osteogenesis. However, no mechanoresponsive miRNAs have been identified in human bone specimens. Show less
Numb is a conserved protein plays important roles in the development of cancer. Two Numb isoforms have been found produced by alternative splicing and play contrast roles in regulating cellular functi Show more
Numb is a conserved protein plays important roles in the development of cancer. Two Numb isoforms have been found produced by alternative splicing and play contrast roles in regulating cellular functions. It is reported that the expression of Numb long isoform (Numb-L) was increased in various kinds of cancers, but in endometrial cancer, the condition is still unknown. The level of two Numb transcripts and protein isoforms were detected by semiquantitative polymerase chain reaction and immunoblotting in 47 paired endometrial tumor and adjacent non-tumor control tissues. The level of three alternative splicing related proteins: RBM5, RBM6, and RBM10 was determined by immunoblotting. MiRNAs targeting RBM10 were predicted by bioinformatics tools and their interaction with RBM10 was confirmed by luciferase assay and immunoblotting. The function of miR-335 in endometrial cancer was examined in xenograft mouse model. Numb-L level was increased in tumors and negatively correlated with RBM10 protein level. RBM10 mRNA level was not significantly altered in endometrial tumors suggesting its expression may regulated by post transcriptional regulators such as miRNAs. We identified miR-133a, miR-133b, and miR-335 directly target RBM10, but only miR-335 level increased in tumors and negatively correlated with RBM10 protein level. miR-335 overexpression promoted tumor growth by downregulating RBM10 and upregulating Numb-L level in xenograft mouse model. miR-335 overexpression promoted Numb-L expression via targeting RBM10 in endometrial cancer, which may provide new biomarkers for EC diagnosis. Show less
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases in the world. Nowadays, the percentage of non-obese or lean patients with NAFLD is increasing. NAFLD in non-obese po Show more
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases in the world. Nowadays, the percentage of non-obese or lean patients with NAFLD is increasing. NAFLD in non-obese populations, especially the lean subgroup with a normal waist circumference (WC), might lead to more problems than obese individuals, as these individuals may not visit clinics for NAFLD diagnosis or ignore the diagnosis of NAFLD. If the precise characteristics of these populations, especially the lean subgroup, are identified, the clinicians would be able to provide more appropriate advice and treatment to these populations. To investigate the prevalence, clinical characteristics, risk factors, and possible indicators for NAFLD in lean Chinese adults with a normal WC. People without diabetes mellitus or significant alcohol consumption who underwent routine health examinations were included. Their fatty liver index (FLI), abdominal ultrasonography results, and controlled attenuation parameter were all assessed. Genotyping for single-nucleotide polymorphisms associated with NAFLD was performed in another small group consisting of biopsy-proven NAFLD subjects and healthy controls. A total of 2715 subjects who underwent routine health examinations were included in the study. Among 810 lean participants with a normal WC, 142 (17.5%) fulfilled the diagnostic criteria for NAFLD. Waist-height ratio, hemoglobin, platelets, and triglycerides were significant factors associated with the presence of NAFLD in these participants. The appropriate cut-off value of the FLI score in screening for NAFLD in the lean subjects with a normal WC was 25.15, which had a 77.8% sensitivity and 75.9% specificity. There was no significant difference in the single-nucleotide polymorphisms in the NAFLD is not uncommon in lean Chinese adults even with a normal WC. Metabolic factors, rather than genetic factors, may play important roles in the development of NAFLD in this population. A lower cut-off value of the FLI score in screening for NAFLD should be used for lean Chinese adults with a normal WC. Show less
Aberrant activation of ERK signaling is a hallmark of lung cancer. Although constitutively activating mutations of EGFR and KRAS contribute to the hyperactivation of ERK1/2, other mechanisms remain el Show more
Aberrant activation of ERK signaling is a hallmark of lung cancer. Although constitutively activating mutations of EGFR and KRAS contribute to the hyperactivation of ERK1/2, other mechanisms remain elusive. In this study, the zinc finger protein ZNF251 was found to be upregulated in clinical lung cancer samples, and it promoted the growth of lung cancer cells and the growth of primary lung KPC cells from mouse models (Ad-Cre, Kras Show less
Aim of this study was to identify biomarkers between different grades of bladder cancer (BLCA) and its prognostic value. mRNA expression data from GSE32549 and GSE71576 were extracted for further anal Show more
Aim of this study was to identify biomarkers between different grades of bladder cancer (BLCA) and its prognostic value. mRNA expression data from GSE32549 and GSE71576 were extracted for further analysis. Differentially expressed genes (DEGs) were identified using GEO2R web tool. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and protein-protein interaction (PPI) network were conducted to explore the function and relationship of DEGs. The Cancer Genome Atlas (TCGA) database was used for external validation and Gene set enrichment analysis (GSEA) analysis was used to further identify FADS1 pathways. Bladder cancer cells and patient specimens were used to further demonstrate the function of FADS1. Datasets from GEO identified a panel of DEGs. Functional enrichment analysis highlighted that DEGs were associated with nuclear division, spindle, cell cycle and p53 signaling pathway. External validation from TCGA demonstrated that FADS1 was an independent prognostic marker in BLCA patients. In cell lines and tumor specimen analysis, FADS1 was overexpressed in the tumor specimen, compared with adjacent tissues, and positively correlated with tumor grade of BLCA. Moreover, FADS1 could enhance the proliferation ability and influence cell cycle of bladder cancer cells. FADS1 was an independent prognostic biomarker for BLCA and could confer the bladder cancer cells increased proliferation ability. Show less
Long noncoding RNAs (lncRNAs) are currently considered to have a vital and wide range of biological functions, but the molecular mechanism underlying triglycerides metabolism remains poorly understood Show more
Long noncoding RNAs (lncRNAs) are currently considered to have a vital and wide range of biological functions, but the molecular mechanism underlying triglycerides metabolism remains poorly understood. This study aims to identify novel lncRNAs differentially expressed in rat livers with hypertriglyceridemia and elucidated the function role in TG metabolism. Differentially expressions of lncRNAs in rat livers with hypertriglyceridemia were identified by transcriptome sequencing and validated by real-time PCR. The role of lnc19959.2 in triglyceride metabolism was assessed both in vitro and in vivo. RNA pulldown and RIP assays were conducted to evaluate the interactions between lnc19959.2 and its target proteins. ChIP and Dual report assays were performed to detect the interactions between transcription factors and promoters of its target genes. We identified a novel lncRNA, and lnc19959.2 was upregulated in rat livers with hypertriglyceridemia. The knockdown of lnc19959.2 has profound TG lowering effects in vitro and in vivo. Subsequently, the genome-wide analysis identified that the knockdown of lnc19959.2 caused the deregulation of many genes during TG homeostasis. Further mechanism studies revealed that lnc19959.2 upregulated ApoA4 expression via ubiquitinated transcription inhibitor factor Purb, while it specifically interacted with hnRNPA2B1 to downregulate the expression of Cpt1a, Tm7sf2, and Gpam, respectively. In the upstream pathway, palmitate acid upregulated CCAAT/Enhancer-Binding Protein Beta (Cebpb) and facilitated its binding to the promoter of lnc19959.2, which resulted in significant promotion of lnc19959.2 transcriptional activity. Our findings provide novel insights into a new layer regulatory complexity of an lncRNA modulating triglyceride homeostasis by a novel lncRNA lnc19959.2. Show less
Rong Jiang, Qianqian Gao, Mingxia Chen+1 more · 2020 · Laboratory investigation; a journal of technical methods and pathology · Nature · added 2026-04-24
The epithelial-mesenchymal transition (EMT) process is a key priming activity of fibroblasts in pulmonary fibrosis during silicosis. Ets-like protein-1 (Elk-1) is a critical modulator that promotes fu Show more
The epithelial-mesenchymal transition (EMT) process is a key priming activity of fibroblasts in pulmonary fibrosis during silicosis. Ets-like protein-1 (Elk-1) is a critical modulator that promotes functional changes in cells, and the effects are mediated by oxidative stress (OS). However, whether ELK-1 is involved in EMT of silicosis remains unclear. In addition, researchers have found that Elk-1 is involved in the expression of the gene zc3h12a, which encodes the protein MCPIP1, and MCPIP1 is a member of the zinc finger Cys-Cys-Cys-His (CCCH)-type protein family. A previous study from our lab showed that ZC3H4, which is also a member of the CCCH-type protein family, critically affected the regulation of EMT during silicosis. However, it has not yet been elucidated if ELK-1 acts at the promoter for zc3h4 to increase its expression in a mechanism that is similar to that of the zc3h12a gene and whether such regulation ultimately controls EMT. Therefore, we explored the correlation between ELK-1 and ZC3H4 expression and tested the underlying mechanisms affecting ELK-1 activation induced by silica. Our study identifies that SiO Show less
It is critical to identify patients with stage II and III colorectal cancer (CRC) who will benefit from adjuvant chemotherapy (ACT) after curative surgery, while the only use of clinical factors is in Show more
It is critical to identify patients with stage II and III colorectal cancer (CRC) who will benefit from adjuvant chemotherapy (ACT) after curative surgery, while the only use of clinical factors is insufficient to predict this beneficial effect. In this study, we performed genetic algorithm (GA) to select ACT candidate genes, and built a predictive model of support vector machine (SVM) using gene expression profiles from the Gene Expression Omnibus database. The model contained four ACT candidate genes (EDEM1, MVD, SEMA5B, and WWP2) and TNM stage (stage II or III). After using Subpopulation Treatment Effect Pattern Plot to determine the optimal cutoff value of predictive scores, the validated patients from The Cancer Genome Atlas database can be divided into the predictive ACT-benefit/-futile groups. Patients in the predictive ACT-benefit group with 5-fluorouracil (5-Fu)-based ACT had significantly longer relapse-free survival (RFS) compared to those without ACT (P = .015); However, the difference in RFS in the predictive ACT-futile group was insignificant (P = .596). The multivariable analysis found that the predictive groups were significantly associated with the effect of ACT (P Show less
Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 w Show more
Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate LPL. In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-C and blocked LPL-facilitated hepatocyte VLDL-C uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome. Show less
Insults to the axons in the optic nerve head are the primary cause of loss of retinal ganglion cells (RGCs) in traumatic, ischemic nerve injury or degenerative ocular diseases. The central nervous sys Show more
Insults to the axons in the optic nerve head are the primary cause of loss of retinal ganglion cells (RGCs) in traumatic, ischemic nerve injury or degenerative ocular diseases. The central nervous system-specific leucine-rich repeat protein, LINGO-1, negatively regulates axon regeneration and neuronal survival after injury. However, the upstream molecular mechanisms that regulate LINGO-1 signaling and contribute to LINGO-1-mediated death of RGCs are unclear. The expression of SP1 was profiled in optic nerve crush (ONC)-injured RGCs. LINGO-1 level was examined after SP1 overexpression by qRT-PCR. Luciferase assay was used to examine the binding of SP1 to the promoter regions of LINGO-1. Primary RGCs from rat retina were isolated by immunopanning and RGCs apoptosis were determined by Tunnel. SP1 and LINGO-1 expression was investigated using immunohistochemistry and Western bolting. Neuroprotection was assessed by RGC counts, RNFL thickness, and VEP tests after inhibition of SP1 shRNA. We demonstrate that SP1 was upregulated in ONC-injured RGCs. SP1 was bound to the LINGO-1 promoter, which led to increased expression of LINGO-1. Treatment with recombinant Nogo-66 or LINGO-1 promoted apoptosis of RGCs cultured under serum-deprivation conditions, while silencing of SP1 promoted the survival of RGCs. SP1 and LINGO-1 colocalized and were upregulated in ONC-injured retinas. Silencing of SP1 in vivo reduced LINGO-1 expression and protected the structure of RGCs from ONC-induced injury, but there was no sign of recovery in VEP. Our findings imply that SP1 regulates LINGO-1 expression in RGCs in the injured retina and provide insight into mechanisms underlying LINGO-1-mediated RGC death in optic nerve injury. Show less
Numerous researches supported that non-alcoholic fatty liver disease (NAFLD) was an emerging problem associated with increased visceral adiposity (obesity), diabetes and related metabolic disorders. H Show more
Numerous researches supported that non-alcoholic fatty liver disease (NAFLD) was an emerging problem associated with increased visceral adiposity (obesity), diabetes and related metabolic disorders. Huang-Qi San (HQS) is composed of three traditional Chinese medicines (Astragali Radix, Pueraria Radix and Cortex Mori Radicis) with a weight ratio of 1:2:1. HQS has been reported to be effective in improving glucose-lipid metabolism, but its underlying mechanism on NAFLD has not been fully understood. The purpose of the present study was to assess the protective effects of HQS on obesity-induced hepatic steatosis in rats fed with high fat diet (HFD). Our data revealed that administration of HQS (1.2 and 2.4 g/kg body weight) resulted in significant reduction in body weight (BW) and organs coefficients of visceral fat. The full-Body CT scan demonstrated that HQS reduced liver fat ratio, visceral and subcutaneous fat mass in a dose-dependent manner. Additionally, HQS decreased plasma TC, TG, FFA and FABP4 levels, normalized glucose and insulin levels, and improved the glucose tolerance. Pathological examination showed that HQS alleviated hepatic steatosis and reduced the cell size of epididymal visceral adipose tissue. Hepatic lipid accumulation was also reduced by HQS treatment compared with HFD fed rats. RNA-Seq analysis combining with qPCR demonstrated that the mRNA expression of some important glucose and lipid metabolism-related genes including Acat2, Apoc4, Bhmt, Cyp3a62, Cyp51, Egln3 (Phd3), Fads1, Fads2, Gnmt, Hmgcs1 and Pemt, were significantly changed by HQS treatment. Taken together, these results suggested that HQS had beneficial effects on glucose-lipid metabolism and hepatic steatosis, and its mechanism might be related to the functions of the genes in regulating glucose and lipid metabolism. Show less
Podocyte injury plays a vital role in proteinuria and nephrotic syndrome. Calcineurin (CaN) inhibitors are effective in reducing proteinuria. However, their molecular mechanism is still not fully unde Show more
The aim of this study was to explore the functions and associated mechanisms of long noncoding RNA The relative expression levels of Our results confirm that long noncoding RNA
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in regulating glucose and lipid metabolism. GIP receptor (GIPR) antagonism is believed to offer therapeutic potential Show more
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in regulating glucose and lipid metabolism. GIP receptor (GIPR) antagonism is believed to offer therapeutic potential for various metabolic diseases. Pharmacological intervention of GIPR, however, has limited success due to lack of effective antagonistic reagents. Previously we reported the discovery of two mouse anti-murine GIPR monoclonal antibodies (mAbs) with distinctive properties in rodent models. Here, we report the detailed structural and biochemical characterization of these two antibodies, mAb1 and mAb2. Show less