👤 W Zeng

Ovarian cancer (OC) is the most lethal gynaecological tumor. Changes in glycolysis have been proven to play an important role in OC progression. We aimed to identify a novel glycolysis-related gene signature to better predict the prognosis of patients with OC. mRNA and clinical data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Genotype Tissue Expression (GTEx) database. The "limma" R package was used to identify glycolysis-related differentially expressed genes (DEGs). Then, a multivariate Cox proportional regression model and survival analysis were used to develop a glycolysis-related gene signature. Furthermore, the TCGA training set was divided into two internal test sets for validation, while the ICGC dataset was used as an external test set. A nomogram was constructed in the training set, and the relative proportions of 22 types of tumor-infiltrating immune cells were evaluated using the "CIBERSORT" R package. The enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were determined by single-sample gene set enrichment analysis (ssGSEA) with the "GSVA" R package. Finally, the expression and function of the unreported signature genes ISG20 and SEH1L were explored using immunohistochemistry, western blotting, qRT-PCR, proliferation, migration, invasion and xenograft tumor assays. A five-gene signature comprising ANGPTL4, PYGB, ISG20, SEH1L and IRS2 was constructed. This signature could predict prognosis independent of clinical factors. A nomogram incorporating the signature and three clinical features was constructed, and the calibration plot suggested that the nomogram could accurately predict the survival rate. According to ssGSEA, the signature was associated with KEGG pathways related to axon guidance, mTOR signalling, tight junctions, etc. The proportions of tumor-infiltrating immune cells differed significantly between the high-risk group and the low-risk group. The expression levels of ISG20 and SEH1L were lower in tumor tissues than in normal tissues. Overexpression of ISG20 or SEH1L suppressed the proliferation, migration and invasion of Caov3 cells in vitro and the growth of xenograft tumors in vivo. Five glycolysis-related genes were identified and incorporated into a novel risk signature that can effectively assess the prognosis and guide the treatment of OC patients. Show less

Non-alcoholic steatohepatitis (NASH) is a common liver disease in the western world. The mechanisms behind NASH formation are poorly understood, but there may be multiple targets considering the disease's multifactorial nature. To explore the genes related to the pathogenesis of NASH, we downloaded clinical data and gene expression of NASH patients from the Gene Expression Omnibus database (GEO). We identified 281 genes with a common expression in two NASH-related datasets (GSE89632 and GSE83452), suggesting that they may be related to NASH. Further study showed that Show less

Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that plays an important role in endothelial injury and the inflammatory response. Experimental models have implicated ANGPTL4 in acute respiratory distress syndrome (ARDS), but its impact on the progression of ARDS is unclear. Paired bronchoalveolar lavage fluid (BALF) and serum samples were obtained from patients with ARDS (n = 56) within 24 h of diagnosis and from control subjects (n = 32). ANGPTL4, angiopoietin-2, interleukin (IL)-6, and TNF-α levels were measured by magnetic Luminex assay. BALF albumin (BA) and serum albumin (SA) were evaluated by enzyme-linked immunosorbent assay. BALF and serum ANGPTL4 concentrations were higher in patients with ARDS than in controls and were even higher in non-survivors than in survivors. The serum ANGPTL4 level was higher in indirect (extrapulmonary) ARDS than in direct (pulmonary) ARDS. Furthermore, BALF and serum ANGPTL4 levels correlated well with angiopoietin-2, IL-6, and TNF-α levels in BALF and serum. BALF ANGPTL4 was positively correlated with the BA/SA ratio (an indicator of pulmonary vascular permeability), and serum ANGPTL4 was associated with the severity of multiple organ dysfunction syndrome based on SOFA and APACHE II scores. Moreover, serum ANGPTL4 was better able to predict 28-day ARDS-related mortality (AUC 0.746, P < 0.01) than the APACHE II score or PaO2/FiO2 ratio. Serum ANGPTL4 was identified as an independent risk factor for mortality in a univariate Cox regression model (P < 0.001). ANGPTL4 levels were elevated in patients with ARDS and significantly correlated with disease severity and mortality. ANGPTL4 may be a novel prognostic biomarker in ARDS. Show less

To screen for obstructive sleep apnea (OSA) biomarkers, isobaric tags for relative and absolute quantitation (iTRAQ)-labeled quantitative proteomics assay was used to identify differentially expressed proteins (DEPs) during chronic intermittent hypoxia (CIH). The iTRAQ technique was applied to compare DEPs in the serum of a CIH rat model and control group. Biological analysis of DEPs was performed using Gene Ontology and Kyoto Encyclopedia to explore related biological functions and signaling pathways. Enzyme-linked immunosorbent assay (ELISA) was performed to validate their expression in sera from patients with OSA and CIH rats. Twenty-three DEPs (fold change ≥1.2 or ≤0.833, p<0.05) were identified, and two DEPs (unique peptides>3 and higher coverage) were further verified by ELISA in the CIH rat model and OSA subject: apolipoprotein A-IV (APOA4, p<0.05) and Tubulin alpha-1A chain (TUBA1A, p<0.05). Both groups showed significant differences in the expression levels of DEPs between the CIH and control groups and the severe OSA and non-OSA groups. APOA4 was found to be upregulated and TUBA1A downregulated in both the sera from OSA patients and CIH rats, on comparing proteomics results with clinical results. There were two pathways that involved three DEPs, the mitogen-activated protein kinase (MAPK) signaling pathway (p<0.05) and cytokine-cytokine receptor interaction (p<0.05). APOA4 and TUBA1A may be potential novel biomarkers for CIH and OSA, and may play an important role in the development of OSA complications. Show less

Glucose homeostasis is tightly controlled by balance between glucose production and uptake in liver tissue upon energy shortage condition. Altered glucose homeostasis contributes to the pathophysiology of metabolic disorders including diabetes and obesity. Here, we aimed to analyse the change of proteomic profile upon prolonged fasting in mice with isobaric tag for relative and absolute quantification (iTRAQ) labelling followed by liquid chromatography-mass spectrometry (LC/MS) technology. Adult male mice were fed or fasted for 16 hours and liver tissues were collected for iTRAQ labelling followed by LC/MS analysis. A total of 322 differentially expressed proteins were identified, including 189 upregulated and 133 downregulated proteins. Bioinformatics analyses, including Gene Ontology analysis (GO), Kyoto encyclopaedia of genes and genomes analysis (KEGG) and protein-protein interaction analysis (PPI) were conducted to understand biological process, cell component, and molecular function of the 322 differentially expressed proteins. Among 322 hepatic proteins differentially expressed between fasting and fed mice, we validated three upregulated proteins (Pqlc2, Ehhadh and Apoa4) and two downregulated proteins (Uba52 and Rpl37) by western-blotting analysis. In cultured HepG2 hepatocellular cells, we found that depletion of Pqlc2 by siRNA-mediated knockdown impaired the insulin-induced glucose uptake, inhibited GLUT2 mRNA level and suppressed the insulin-induced Akt phosphorylation. By contrast, knockdown of Pqlc2 did not affect the cAMP/dexamethasone-induced gluconeogenesis. In conclusion, our study provides important information on protein profile change during prolonged fasting with iTRAQ- and LC-MS/MS-based quantitative proteomics, and identifies Pqlc2 as a potential regulator of hepatic glucose metabolism and insulin signalling pathway in this process. Show less

Yeast is one of the best-understood biological systems for genetic research. Over the last 40 years, geneticists have striven to search for homologues of tumor suppressors in yeast to simplify cancer research. The star tumor suppressor p21, downstream target of p53, is one of the primary factors on the START point through negatively regulating CycD/E-CDK, the yeast counterpart Cln3-Cdk1. Not like yeast Whi5 that was identified as the analog of the retinoblastoma tumor suppressor protein (Rb) and hence promoted to uncover the mechanism of its cancer suppression, homologue of p21 had not been found in yeast. Our lab identified Cip1 in budding yeast as a novel negative regulator of G1-Cdk1 and proposed that Cip1 is an analog of human p21. Recently, we demonstrated a dual repressive function of Cip1 on START timing via the redundant Cln3 and Ccr4 pathways. This work in yeast may help clarify the complex regulation in human p53-p21 signaling cascade. In this review, we will discuss the yeast paralogs of star tumor suppressors in the control of G1/S transition and present the new findings in this field. Show less

Aspergillus fumigatus is a well-known opportunistic pathogen that causes invasive aspergillosis (IA) infections with high mortality in immunosuppressed individuals. Morphogenesis, including hyphal growth, conidiation, and cell wall biosynthesis is crucial in A. fumigatus pathogenesis. Based on a previous random insertional mutagenesis library, we identified the putative polysaccharide synthase gene Afcps1 and its para-log Afcps2. Homologs of the cps gene are commonly found in the genomes of most fungal and some bacterial pathogens. Afcps1/cpsA is important in sporulation, cell wall composition, and virulence. However, the precise regulation patterns of cell wall integrity by Afcps1/cpsA and further effects on the immune response are poorly understood. Specifically, our in-depth study revealed that Afcps1 affects cell-wall stability, showing an increased resistance of ΔAfcps1 to the chitinmicrofibril destabilizing compound calcofluor white (CFW) and susceptibility of ΔAfcps1 to the β-(1,3)-glucan synthase inhibitor echinocandin caspofungin (CS). Additionally, deletion of Afcps2 had a normal sporulation phenotype but caused hypersensitivity to Na Show less

The 3-hydroxyanthranilic acid (3-HAA), a derivative of kynurenine, was reported to suppress tumor growth. However, the function of 3-HAA largely remains unclear. Here, we report that 3-hydroxyanthranilic acid (3-HAA) is lower in tumor cells, while adding exogenous 3-HAA induces apoptosis in hepatocellular carcinoma by binding YY1. This 3-HAA binding of YY1 leads to phosphorylation of YY1 at the Thr 398 by PKCζ, concomitantly enhances YY1 chromatin binding activity to increase expression of target genes. These findings demonstrate that 3-HAA is a ligand of YY1, suggesting it is a promising therapeutic candidate for HCC. Show less

FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including A total of 196 patients with IHH were enrolled in this study. Whole-exome sequencing was performed to identify variants, which was verified by PCR and Sanger sequencing. Four heterozygous Our study greatly enriched the genotypic and phenotypic spectra of Show less

Acne is a common and chronic inflammatory dermatosis of sebaceous gland units of the human hair follicle. Acne is closely related to immune cytokines and cells including T helper 17cells (Th17 cells). Mis-regulated glycolipid metabolism also plays a vital role in the process. This investigation aimed to explore the role of IL-17 in signaling pathways controlling sebaceous gland lipoprotein metabolism in a rat model of acne. We generated the rat ear acne model, and investigated the pathological changes of acne skin tissue by histological analysis and the changes in the critical factors including DEFB1, GPR65, FADS1, and FADS2 by Western Blot in this model. There were more Th17 cells in the rat ear acne model than in the control mice. The expression levels of DEFB1, GPR65, FADS1, FADS2 and MOGAT1 were significantly upregulated in serum and tissue from rat acne model, which could be concluded that the Th17 cells play a major role in the pathogenesis of acne based. Although acne is associated with immune effects and glycolipid metabolism, inhibition of IL-17 signaling pathway might be a novel way for acne therapy. Our findings also suggest a new strategy for targeted therapy of acne. Show less

To investigate potential biomarkers for distinguishing biological viability of hepatic cystic echinococcosis. Using Luminex assay we measured plasma concentrations of cytokine and chemokine in patients with active and non-active cysts (hepatic cystic echinococcosis (HCE), n = 47) and stable/progressive hepatic alveolar echinococcosis (HAE, n = 38), and in comparable infection-free volunteers (n = 48). Disease progression was staged according to the classification standard. Compared with healthy controls, enhanced elevation was found of T helper 22 type cytokine interleukin (IL)-22 and chemokines Eotaxin, interferon-γ inducible protein-10, monocyte chemoattractant protein-1, and stromal cell-derived factor-1α concentrations in HAE patients, and IL-22, growth-related oncogene α, monocyte chemoattractant protein-1, regulated on activation normal T-expressed and secreted, and stromal cell-derived factor-1α concentrations in HCE patients (P < 0.05-0.001). For HCE patients, only IL-27 concentrations in non-active HCE were significantly lower than in active HCE. In logistic regression analysis, IL-27 <20.79 pg/mL was an independent risk factor for HCE biological viability with receiver operating characteristic analysis at a 44.23 pg/mL cut-off resulting in 0.72 area under the curve. Our findings correlate multiple cytokine and chemokine secretion patterns in HAE and HCE patients with different disease progression stages. IL-27 could serve as a referring biomarker for distinguishing HCE biological viability and provide a preliminary foundation for clinical decision-making. Show less

IL-27, a heterodimeric cytokine of the IL-12 family, has diverse influences on the development of multiple inflammatory diseases. In this study, we identified the protective role of IL-27/IL-27R in host defense against Show less

Ovarian Cancer (OC) remains the first leading cause of gynecologic malignancy. The survival rate from Serous Ovarian Cancer (SOC) is very low, and the present prognostic predictors of SOC are not very sensitive or specific. The present study aimed to investigate Microtubule-Actin Cross-Linking Factor 1 (MACF1) expression in SOC tissues (including paraffin-embedded and fresh tissues) and to assess its expression and significant value in patients with SOC. A total of 18 fresh SOC tissues and their paired paratumor tissues were performed with reverse-transcription quantitative PCR analysis to detect MACF1 mRNA expression. Moreover, 175 paraffin-embedded SOC tissues and 41 paratumor tissues were assessed for MACF1 expression using immunohistochemistry. The mRNA and protein expression of MACF1, both were higher in cancer tissues than that in paratumor tissues, and the high expression of MACF1 was associated with shorter Recurrence Free Survival (RFS) and Overall Survival (OS) in patients with SOC. Furthermore, multivariate regression analysis showed that high MACF1 expression was an independent poor survival predictor of patients with SOC. MACF1 is upregulated in SOC, and it may be used as a useful prognostic biomarker in SOC. Show less

Coarctation of the aorta (CoA) is a common congenital cardiovascular malformation with aortic narrowing in the region of the ligamentum arteriosum. Hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy that is characterized by left ventricular wall thickening and likely left ventricular outflow tract (LVOT) obstruction. They are two irrelevant diseases, and their coexistence has not been reported before. Here, we described a young female patient who concurrently has CoA and HCM. The patient has had hypertension since 18-years old and complained of chest discomfort on effort and fatigue thereafter. Initially, she was diagnosed as having hypertrophic cardiomyopathy and primary hypertension. The presence of CoA was not found until she was 35 years old when she had an onset of paroxysmal supraventricular tachycardia (PSVT) and presented with syncope. Failure of the ablation procedure Here, we reported the diagnostic challenges, management, and 8-yeasr follow-up findings in a rare case of CoA combined with HCM. The case highlighted the importance for physicians to exclude CoA in young hypertensive patients, and proved the efficacy of stent repair in treating CoA in older patients. Show less

Digestive system carcinoma is one of the most devastating diseases worldwide. Lack of valid clinicopathological parameters as prognostic factors needs more accurate and effective biomarkers for high-confidence prognosis that guide decision-making for optimal treatment of digestive system carcinoma. The aim of the present study was to establish a novel model to improve prognosis prediction of digestive system carcinoma, with a particular interest in transcription factors (TFs). A TF-related prognosis model of digestive system carcinoma with data from TCGA database successively were processed by univariate and multivariate Cox regression analyses. Then, for evaluating the prognostic prediction value of the model, ROC curve and survival analysis were performed by external data from GEO database. Furthermore, we verified the expression of TFs expression by qPCR in digestive system carcinoma tissue. Finally, we constructed a TF clinical characteristics nomogram to furtherly predict digestive system carcinoma patient survival probability with TCGA database. By Cox regression analysis, a panel of 17 TFs (NFIC, YBX2, ZBTB47, ZNF367, CREB3L3, HEYL, FOXD1, TIGD1, SNAI1, HSF4, CENPA, ETS2, FOXM1, ETV4, MYBL2, FOXQ1, ZNF589) was identified to present with powerful predictive performance for overall survival of digestive system carcinoma patients based on TCGA database. A nomogram that integrates TFs was established, allowing efficient prediction of survival probabilities and displaying higher clinical utility. The 17-TF panel is an independent prognostic factor for digestive system carcinoma, and 17 TFs based nomogram might provide implication an effective approach for digestive system carcinoma patient management and treatment. Show less

The ovarian hormones estrogen and progesterone (EP) are implicated in breast cancer causation. A specific consequence of progesterone exposure is the expansion of the mammary stem cell (MSC) and luminal progenitor (LP) compartments. We hypothesized that this effect, and its molecular facilitators, could be abrogated by progesterone receptor (PR) antagonists administered in a mouse model. Ovariectomized FVB mice were randomized to 14 days of treatment: sham, EP, EP + telapristone (EP + TPA), EP + mifepristone (EP + MFP). Mice were then sacrificed, mammary glands harvested, and mammary epithelial cell lineages separated by flow cytometry using cell surface markers. RNA from each lineage was sequenced and differential gene expression was analyzed using DESeq. Quantitative PCR was performed to confirm the candidate genes discovered in RNA seq. ANOVA with Tukey post hoc analysis was performed to compare relative expression. Alternative splicing events were examined using the rMATs multivariate analysis tool. Significant increases in the MSC and luminal mature (LM) cell fractions were observed following EP treatment compared to control (p < 0.01 and p < 0.05, respectively), whereas the LP fraction was significantly reduced (p < 0.05). These hormone-induced effects were reversed upon exposure to TPA and MFP (p < 0.01 for both). Gene Ontology analysis of RNA-sequencing data showed EP-induced enrichment of several pathways, with the largest effect on Wnt signaling in MSC, significantly repressed by PR inhibitors. In LP cells, significant induction of Wnt4 and Rankl, and Wnt pathway intermediates Lrp2 and Axin2 (confirmed by qRTPCR) were reversed by TPA and MFP (p < 0.0001). Downstream signaling intermediates of these pathways (Lrp5, Mmp7) showed similar effects. Expression of markers of epithelial-mesenchymal transition (Cdh1, Cdh3) and the induction of EMT regulators (Zeb1, Zeb2, Gli3, Snai1, and Ptch2) were significantly responsive to progesterone. EP treatment was associated with large-scale alternative splicing events, with an enrichment of motifs associated with Srsf, Esrp, and Rbfox families. Exon skipping was observed in Cdh1, Enah, and Brd4. PR inhibition reverses known tumorigenic pathways in the mammary gland and suppresses a previously unknown effect of progesterone on RNA splicing events. In total, our results strengthen the case for reconsideration of PR inhibitors for breast cancer prevention. Show less

Ring1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell-cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer. Show less

To explore FGF1 and miR-143-3p expression in hepatocellular carcinoma (HCC) cells and its related mechanisms. Eighty-two HCC patients treated at our hospital from January 2018 to January 2019 were enrolled as Group A, while further 80 healthy people undergoing physical examinations during the same time period were enrolled as Group B. HCC cells and normal human liver cells were purchased, with HepG2 and SMMC-7721 cells transfected with pcDNA3.1-FGF1, si-FGF1, NC, miR-143-3p-inhibitor and miR-143-3p-mimics. FGF1 and miR-143-3p expression was detected by qRT-PCR. The expression of N-cadherin, vimentin, Snail, Slug, E-cadherin and γ-catenin was detected by Western Blotting (WB). Cell proliferation was detected by MTT assay. Cell invasion was detected by Transwell. Cell apoptosis was detected by flow cytometry (FCM). FGF1 was highly expressed but miR-143-3p was poorly expressed in HCC cells. Areas under the curves (AUCs) of the two indicators were > 0.8. The indicators were correlated with the age, gender, tumor invasion, degree of differentiation, tumor location and TNM staging of the patients. Silencing FGF1 and overexpressing miR-143-3p could promote cell apoptosis, inhibit cell growth, cell epithelial-mesenchymal transition (EMT) and the expression of N-cadherin, vimentin, Snail and Slug, and increase the expression of E-cadherin and γ-catenin. Dual luciferase reporter gene assay (DLRGA) confirmed that FGF1 and miR-143-3p had a targeted relationship. The rescue experiment showed that the proliferation, invasion and apoptosis of HepG2 and SMMC-7721 cells in the miR-143-3p-mimics+pcDNA3.1-FGF1 and miR-143-3p-inhibitor+Si-FGF1 groups were not different from those in the miR-NC group. Inhibiting FGF1 can upregulate miR-143-3p-mediated Hedgehog signaling pathway, and affect cells' EMT, proliferation and invasion, so FGF1 is expected to become a potential therapeutic target for HCC. Show less

Neoadjuvant chemotherapy (NACT) remains an attractive alternative for controlling locally advanced cervical cancer. However, approximately 15-34% of women do not respond to induction therapy. To develop a risk stratification tool, 56 patients with stage IB-IIB cervical cancer are included in 2 research centers from the discovery cohort. Patient-specific somatic mutations led to NACT non-responsiveness are identified by whole-exome sequencing. Next, CRISPR/Cas9-based library screenings are performed based on these genes to confirm their biological contribution to drug resistance. A 15-gene classifier is developed by generalized linear regression analysis combined with the logistic regression model. In an independent validation cohort of 102 patients, the classifier showed good predictive ability with an area under the curve of 0.80 (95% confidence interval (CI), 0.69-0.91). Furthermore, the 15-gene classifier is significantly associated with patient responsiveness to NACT in both univariate (odds ratio, 10.8; 95% CI, 3.55-32.86; Show less

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the melanocortin 4 receptor (MC4R), gene which are associated with risk of obesity. Since obesity is an established risk factor of cancer, several studies have examined the association between SNPs near the MC4R gene and cancer risk, but the findings are inconsistent. The present study aimed to perform a meta-analysis to clarify the association between SNPs near MC4R and cancer risk. The PubMed and Embase databases were searched for potentially eligible publications. All studies that evaluated the association between MC4R rs17782313 SNP (or its proxy rs12970134) and cancer risk were included. The pooled odds ratios with 95% confidence intervals (CIs) were calculated using the random-effects model. And subgroup analysis by cancer type (colorectal cancer, endometrial cancer and breast cancer) was conducted for further investigate the association. A total of 6 eligible studies (6517 cases and 16,886 controls) were included in the present meta-analysis. The results indicated that MC4R rs17782313 SNP was moderately associated with cancer risk (odds ratio = 1.12, 95% CI = 1.01-1.24). However, the subgroup analysis between different cancer types shows that rs17782313 is only associated with colorectal cancer but not the endometrial cancer and breast cancer. Risk factor in colorectal cancer was both significantly associated with rs17782313 with and without adjustment for body mass index; while the risk factor of the endometrial cancer and breast cancer were both not associated with the rs17782313 with and without adjustment for body mass index. There was no publication bias for the association between MC4R rs17782313 and cancer risk. The present meta-analysis confirmed the moderate association between MC4R rs17782313 and cancer risk. Show less

Rare partial/complete loss-of-function mutations in the melanocortin-4 receptor (MC4R) gene are the most common cause of Mendelian obesity in European populations, but their contribution to obesity in the Mexican population is unclear. We investigated whether deleterious mutations in MC4R contribute to obesity in Mexican children and adults. We provide evidence that the MC4R p.Ile269Asn (rs79783591) mutation may have arisen in modern human populations from a founder event in native Mexicans. The MC4R Isoleucine 269 is perfectly conserved across 184 species, which suggests a critical role for the amino acid in MC4R activity. Four in silico tools (SIFT, PolyPhen-2, CADD, MutPred2) predicted a deleterious impact of the p.Ile269Asn substitution on MC4R function. The MC4R p.Ile269Asn mutation was associated with childhood (Ncontrols = 952, Ncases = 661, odds ratio (OR) = 3.06, 95% confidence interval (95%CI) [1.94-4.85]) and adult obesity (Ncontrols = 1445, Ncases = 2,487, OR = 2.58, 95%CI [1.52-4.39]). The frequency of the MC4R p.Ile269Asn mutation ranged from 0.52 to 0.59% and 1.53 to 1.59% in children and adults with normal weight and obesity, respectively. The MC4R p.Ile269Asn mutation co-segregated perfectly with obesity in 5 multigenerational Mexican pedigrees. While adults with obesity carrying the p.Ile269Asn mutation had higher BMI values than noncarriers, this trend was not observed in children. The MC4R p.Ile269Asn mutation accounted for a population attributable risk of 1.28% and 0.68% for childhood and adult obesity, respectively, in the Mexican population. The MC4R p.Ile269Asn mutation may have emerged as a founder mutation in native Mexicans and is associated with childhood and adult obesity in the modern Mexican population. Show less

Epigenetic regulation of gene expression has been reported in the pathogenesis of metabolic disorders such as diabetes and liver steatosis in humans. However, the molecular mechanisms of fatty liver hemorrhagic syndrome (FLHS) in chickens have been rarely studied. H3K27ac chromatin immunoprecipitation coupled with high-throughput sequencing and high-throughput RNA sequencing was performed to compare genome-wide H3K27ac profiles and transcriptomes of liver tissue between healthy and FLHS chickens. In total, 1,321 differential H3K27ac regions and 443 differentially expressed genes were identified (| log2Fold change| ≥ 1 and Show less

Hypertriglyceridemia is a risk factor for a series of diseases, such as cardiovascular disease (CVD), diabetes and nonalcoholic fatty liver disease (NAFLD). Angiopoietin-like proteins (ANGPTLs) family, especially ANGPTL3, ANGPTL4 and ANGPTL8, which regulate lipoprotein lipase (LPL) activity, play pivotal roles in triglyceride (TG) metabolism and related diseases/complications. There are many transcriptional and post-transcriptional factors that participate in physiological and pathological regulation of ANGPTLs to affect triglyceride metabolism. This review is intended to focus on the similarity and difference in the expression, structural features, regulation profile of the three ANGPTLs and inhibitory models for LPL. Description of the regulatory factors of ANGPTLs and the properties in regulating the lipid metabolism involved in the underlying mechanisms in pathological effects on diseases will provide potential therapeutic approaches for the treatment of dyslipidemia related diseases. Show less

Very rare loss-of-function mutations in the apolipoprotein C3 (APOC3) gene have been associated with low circulating apoC-III, low triglycerides, and reduced cardiovascular risk. We aimed to analyze the impact of common APOC3 variants on key parameters of lipid metabolism and coronary artery disease in the largest sample so far. Common variants in APOC3 were tested for associations with circulating apoC-III, lipids, and apolipoprotein B (apoB) in 3041 participants of the LUdwigshafen RIsk and Cardiovascular health study (LURIC). These variants were then tested for associations with coronary artery disease in a meta-analysis comprising up to 332,389 participants of the CARDIOGRAMplusC4D consortium and the UK Biobank. The mean (standard deviation) apoC-III concentration was 14.6 (5.1) mg/dl. Seven common variants in APOC3 (rs734104, rs4520, rs5142, rs5141, rs5130, rs5128, and rs4225) were associated with circulating apoC-III (all p < 0.05). The alleles that modestly raised apoC-III were also associated with markedly higher total triglycerides and very low density lipoprotein (VLDL) triglycerides and cholesterol (all p < 0.05), but not with low density lipoprotein (LDL) cholesterol and total apoB (all p > 0.05). These variants were not associated with coronary artery disease in the CARDIOGRAMplusC4D consortium and the UK Biobank (all p > 0.1). Modest, genetically caused elevations of apoC-III are associated with a marked increase of triglyceride-rich lipoproteins but not with an increase of LDL cholesterol, total apoB, and coronary artery disease. Whether effective inhibition of apoC-III production with antisense oligomers will be instrumental to reduce cardiovascular risk remains to be demonstrated. 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 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

The aim of the present study was to identify potential serum biomarkers for insulin resistance (IR) in patients with polycystic ovary syndrome (PCOS) by comparing the differences in serum protein expression levels between PCOS patients with and without IR. PCOS patients aged from 18 to 35 years were recruited at Guangdong Women and Children's Hospital from January, 2013 to February, 2014. A total of 218 PCOS patients were enrolled and divided into the insulin resistance (PCOS‑IR) and non‑insulin resistance (PCOS‑NIR) groups according to their homeostasis model assessment of insulin resistance. Two‑dimensional difference gel electrophoresis (2D‑DIGE) and matrix‑assisted laser desorption/ionization time‑of‑flight mass spectrometry (MALDI‑TOF‑MS/MS) techniques were used to identify differences in protein expression levels between the PCOS‑IR and PCOS‑NIR groups. The present study demonstrated that the total cholesterol (TCH), triglycerides (TG), low‑density lipoprotein (LDL), fasting plasma glucose (FPG), 3‑h blood glucose (3hBG) and uric acid (UA) levels in the PCOS‑IR group were higher than those in the PCOS‑NIR group (P<0.05). Between the PCOS‑IR and PCOS‑NIR groups, a total of 20 differentially expressed protein spots were detected by 2D‑DIGE. Among these, 4 proteins, namely afamin, serotransferrin, complement C3 and apolipoprotein C3 (APOC3), were also identified by MALDI‑TOF‑MS/MS. The alteration of APOC3 was further confirmed by western blot analysis and enzyme‑linked immunosorbent assay (ELISA). The present study also confirmed that the expression level of APOC3 was positively associated with the homeostasis model assessment of insulin resistance (HOMA‑IR). On the whole, the data indicate that APOC3 may be a potential diagnostic marker for PCOS‑IR patients. Show less

Cip1, a newly identified yeast analog of p21, is a Cln3-CDK inhibitor that negatively regulates cell-cycle START. However, its function remains poorly understood. In this study, we found that deletion of Show less

The nucleic acid guanine-quadruplex structures (G4s) are involved in many aspects of cancer progression. The DEAH-box polypeptide 36 (DHX36) has been identified as a dominant nucleic acid helicase which targets and disrupts DNA and RNA G4s in an ATP-dependent manner. However, the actual role of DHX36 in breast cancer remains unknown. In this study, we observed that the gene expression of DHX36 was positively associated with patient survival in breast cancer. The abundance of DHX36 is also linked with pathologic conditions and the stage of breast cancer. By using the xenograft mouse model, we demonstrated that the stable knockdown of DHX36 via lentivirus in breast cancer cells significantly promoted tumour growth. We also found that, after the DHX36 knockdown (KD), the invasion of triple-negative breast cancer cells was enhanced. In addition, we found a significant increase in the number of cells in the S-phase and a reduction of apoptosis with the response to cisplatin. DHX36 KD also desensitized the cytotoxic cellular response to paclitaxel and cisplatin. Transcriptomic profiling analysis by RNA sequencing indicated that DHX36 altered gene expression profile through the upstream activation of TNF, IFNγ, NFκb and TGFβ1. High throughput signalling analysis showed that one cluster of stress-associated kinase proteins including p53, ROCK1 and JNK were suppressed, while the mitotic checkpoint protein-serine kinases CDK1 and CDK2 were activated, as a consequence of the DHX36 knockdown. Our study reveals that DHX36 functions as a tumour suppressor and may be considered as a potential therapeutic target in breast cancer. Show less

Metastasis is responsible for 90% of colorectal cancer (CRC)-related deaths. In the present study, we identified a novel key regulator of CRC metastasis, leucine-rich repeats and immunoglobulin-like domains protein 3 (LRIG3), which was significantly decreased in CRC tissues and cell lines. Downregulation of LRIG3 was attributed to copy number loss and promoter hypermethylation. Low LRIG3 expression was positively correlated with metastatic clinical features and shorter survival time. Functional experiments showed that knockout of LRIG3 markedly enhanced CRC cell migration and invasion ability, whereas reintroduction of LRIG3 exerted the opposite effects. Regarding the mechanism, LRIG3 could facilitate the binding of DUSP6 to ERK1/2, resulting in the dephosphorylation of ERK1/2 and subsequently downregulation of slug, an epithelial-to-mesenchymal transition trigger, thereby constraining CRC cell motility. Importantly, LRIG3 expression was strongly negatively correlated with slug or p-ERK1/2 expression in CRC tissues. Collectively, our data suggest that LRIG3 is a novel suppressor of CRC metastasis, reactivation of LRIG3 may be a promising therapeutic approach for metastatic CRC patients. Show less

Nicotine, a major addictive component in tobacco, plays an important role in the changes of body weight upon smoking and its cessation. Here we showed that nicotine-treated mice exhibited weight loss and nicotine withdrawal led to weight gain. Using TMT-based proteomic analysis, we obtained the different hypothalamic protein profiles in response to nicotine and its withdrawal. A total of ~5000 proteins were identified from the hypothalamus with 50 altered proteins upon 28-day nicotine treatment and 28 altered proteins upon 15-day nicotine withdrawal. Of the altered proteins, CASP3, LCMT2, GRIN2D, CCNT2, FADS3 and MRPS18B were inversely changed in response to nicotine and withdrawal, coincidence with the change of body weight. Of them, CASP3, LCMT2, GRIN2D and CCNT2 were found to be associated with several GO terms and KEGG pathways linking with cell apoptosis, neurotransmission and metabolism. Further Western blot and RT-qPCR analyses confirmed that the levels of the 4 proteins CASP3, LCMT2, GRIN2D and CCNT2, instead of their mRNA transcripts, altered in response to nicotine and withdrawal. Thus this study provides nicotine- and withdrawal-induced hypothalamic protein profiles and suggests potential roles of these altered proteins in the change of body weight. SIGNIFICANCE: Cigarette smoking is one of important factors harming human health. Most smokers tend to have lower body weights and smoking cessation often lead to overweight or obesity, which is an important reason for smokers to insist on smoking. It is known that nicotine, a critical component in tobacco, is associated with the alteration in body weight by affecting hypothalamic function. Through TMT-based proteomic analysis, this study identified differential hypothalamic protein profiles in response to nicotine treatment and its withdrawal, and 4 nicotine- and withdrawal-induced contrary proteins CASP3, LCMT2, GRIN2D and CCNT2 are involved in several enriched GO terms and KEGG pathways, which are associated with cell apoptosis, neurotransmission and metabolism. Our study may provide novel targets for further investigation of the molecular mechanisms of nicotine- and withdrawal-induced alteration in body weight. Show less