👤 Quanzi Bai

Host immune response have a pivotal role in the course of Mycobacterium tuberculosis (Mtb) infection. IL27 plays both pro-inflammatory and anti-inflammatory activities in infectious diseases via STAT1/STAT3 mechanism. To investigate the association of single nucleotide polymorphisms (SNPs) of IL27 and STAT3 on the susceptibility of tuberculosis, we conducted a large size of case-control study in western Chinese Han population. A total of seven SNPs were genotyped using multiplex ligation detection reaction method in 900 patients with tuberculosis and 1534 healthy controls. Variants of three SNPs (rs181206, rs17855750, rs26528) within IL27 gene, the genotype and allele frequencies of rs17855750 were significantly different (p = .013, p = .004, respectively) between the TB patients and healthy controls. Subjects carrying C allele for rs17855750 showed a decreased tuberculosis risk (OR = 0.75, 95% CI = 0.62-0.91, p = .004). Genetic model analysis revealed that dominant modal was associated with lower TB risk (OR = 0.74, 95% CI = 0.60-0.92, p = .042). Haplotype of ACG (representing rs181206, rs17855750 and rs26528) showed a reduced risk to TB (OR = 0.79, 95% CI = 0.65-0.96, p = .017). There were no significant differences between TB cases and healthy controls in the variants of four SNPs (rs1053005, rs2293152, rs744166, rs4796793) within STAT3 gene. The polymorphisms of IL27, rs17855750, but not rs181206 and rs26528, plays a protective role on the susceptibility to TB. Show less

IL-27 is an anti-inflammatory cytokine that has been shown to have potent anti-tumor activity. We recently reported that systemic delivery of IL-27 using recombinant adeno-associated virus (rAAV) induced depletion of Tregs and significantly enhanced the efficacy of cancer immunotherapy in a variety of mouse tumor models. A potential caveat of systemic delivery of IL-27 using rAAV is that there is no practical method to terminate IL-27 production when its biological activity is no longer needed. Therefore, in this work, we tested if directly injecting AAV-IL-27 into tumors could lead to similar anti-tumor effect yet avoiding uncontrolled IL-27 production. We found that high levels of IL-27 was produced in tumors and released to peripheral blood after AAV-IL-27 intra-tumoral injection. AAV-IL-27 local therapy showed potent anti-tumor activity in mice bearing plasmacytoma J558 tumors and modest anti-tumor activity in mice bearing B16.F10 tumors. Intra-tumoral injection of AAV-IL-27 induced infiltration of immune effectors including CD8 Show less

Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK. Show less

Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Show less

Diabetes is a recognized high-risk factor for the development of atherosclerosis, in which macroautophagy/autophagy is emerging to play essential roles. The retention of low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Here, we identified that high glucose could promote atherosclerosis by stimulating transcytosis of LDL. By inhibiting AMPK-MTOR-PIK3C3 pathway, high glucose suppresses the CAV-CAVIN-LC3B-mediated autophagic degradation of CAV1; therefore, more CAV1 is accumulated in the cytosol and utilized to form more caveolae in the cell membrane and facilitates the LDL transcytosis across endothelial cells. For a proof of concept, higher levels of lipids were accumulated in the subendothelial space of umbilical venous walls from pregnant women with gestational diabetes mellitus (GDM), compared to those of pregnant women without GDM. Our results reveal that high glucose stimulates LDL transcytosis by a novel CAV1-CAVIN1-LC3B signaling-mediated autophagic degradation pathway. 3-MA: 3-methyladenine; ACTB: actin beta; AMPK: AMP-activated protein kinase; Bafi: bafilomycin A Show less

Esophageal cancer is one of the most common cancers worldwide with poor prognosis and high mortality. The transcription factor Expression of Cumulatively, these results establish an important mechanism by which decrease in miR-203 expression potentiates metastatic progression in EC via USP26-mediated stabilization of Snail1. Hence, miR-203 can serve as a biomarker of metastasis in EC and is a potential target for therapeutic intervention in EC. Show less

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)-22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR-22. Inhibition of miR-22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR-22 and E-cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR-22 and inhibiting E-cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy. Show less

Genetic studies based on single-nucleotide polymorphisms have provided valuable insights into the genetic architecture of complex diseases. However, a large fraction of heritability for most of these diseases remains unexplained, and the impact of small insertions and deletions (InDels) has been neglected. We performed a comprehensive screen on the exome sequence data of 1,326 genes using the SOAP-PopIndel method for InDels in 32,043 Chinese Han individuals and identified 29 unreported InDels within 25 susceptibility genes associated with psoriasis. Specifically, we identified 12 common, 9 low-frequency, and 8 rare InDels that explained approximately 1.29% of the heritability of psoriasis. Further analyses identified KIAA0319, RELN, NCAPG, ABO, AADACL2, LMAN1, FLG, HERC5, CCDC66, LEKR1, AFF3, ABCG2, ANXA7, SYTL2,GIPR, METTL1, and FYCO1 as unreported genes for psoriasis. In addition, identified InDels were associated with the following reported genes: IFIH1, ERAP1, ERAP2, LNPEP, UBLCP1, and STAT3; unreported independent associations for exonic InDels were found within GJB2 and ZNF816A. Our study enriched the genetic basis and pathogenesis of psoriasis and highlighted the non-negligible impact of InDels on complex human diseases. Show less

To screen differentially expressed proteins in the blood dairy cows with inactive ovaries caused by a negative energy balance and to determine the roles of the identified proteins in the development of inactive ovaries.Holstein cows at 14 to 21 days postpartum in an intensive dairy farm were examined for their energy balance (EB) status by blood β-hydroxybutyrate (BHBA) and assigned to the inactive ovary (IO) group (n = 50) and the normal oestrus control (CON) group (n = 50) at 60 to 90 days postpartum by means of the oestrus manifestation, rectal examination and B-ultrasound examination. Fourteen differentially expressed proteins from 61 proteins in the plasma of dairy cows with IOs were identified by iTRAQ/LC-MS/MS and GO, KEGG, and PATHWAY analysis. Eleven expressed proteins were upregulated, and 3 expressed proteins were downregulated. Among the 10 differentially expressed proteins verified by Western blot or ELISA, the relative expression levels of ALDOB, IGFBP2, ITIH3 and LDHB in mixed samples and single samples were consistent with the proteomic protein results. PKM2, GPX3, ALDOB, RBP4 and AHSG were significantly different between the two groups (P < 0.05); APOA4 and SPAM1 were not significantly different (P > 0.05) but were still downregulated in the ovarian resting group. This study confirmed that 14 plasma differential proteins in the inactive ovaries of postpartum dairy cows were associated with follicular development, and these findings provide a foundation for further research on the mechanism and prevention of inactive ovaries in dairy cows. Show less

Dyslipidemia contributes to the risk of many diseases, including stroke, cardiovascular disease and metabolic-related diseases. Previous studies have indicated that single nucleotide polymorphisms (SNPs) are associated with different levels of serum lipid. Therefore, this study explored the relationship between the A total of 3,850 participants from Jilin Province, China, were enrolled in our study, and their serum lipid levels were measured. Six functional SNPs ( All SNPs conformed to Hardy-Weinberg equilibrium. Logistic regression analysis revealed that rs5072, rs5128 and rs651821 were associated with hypertriglyceridemia, rs5104 and rs651821 were associated with low-HDL cholesterolemia in overall group. rs651821 was associated with hypertriglyceridemia and low-HDL cholesterolemia in both the male and female group. However, among females, rs5072 was observed to be associated with hypertriglyceridemia. Haplotype analysis showed that haplotypes TGCCGC and CAGCGC were associated with dyslipidemia in the overall, male and female groups. SNPs in the Show less

To explore the molecular mechanism of insulin on proliferation and differentiation of MC3T3-E1 cell under high glucose conditions. We first investigated the effect of different concentrations of insulin on the osteoblast cell proliferation and cell differentiation at various time points by MTT analysis, cell cycle analysis, and expression detection of differentiation genes. Then, we used 200 ng/mL of insulin to treat the osteoblast cell at different time points for identifying the common differentially expressed mRNAs among various time points by RNA sequencing. Thirdly, we performed the gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis to explore the biological function of these common differentially expressed mRNAs. The results showed that insulin promoted the cell proliferation and differentiation of osteoblast cell. In RNA sequencing, a total of 31 common differentially expressed mRNAs were identified between different time points. Mt1, Tmem135, Avp, and Dlg2 were found to be associated with the new bone formation. In addition, three important signalling pathways, namely, lysosome, glutamatergic synapse, and chemokine signalling pathways, were found in the KEGG enrichment analysis. Our work demonstrated that insulin could promote the osteoblast cell proliferation and cell differentiation, which may play a key role in bone formation. SIGNIFICANCE OF THE STUDY: Our result showed that insulin could promote the proliferation and differentiation of osteoblast at both cellular and molecular levels, which may promote the new bone formation in the osteoblasts. Show less

Ovarian cancer (OC) is xenogeneic that is influenced by many generated factors related to epigenetic factors to accelerate tumor metastasis. This study was conducted with the objective of investigating the effect of microRNA-23a-3p (miR-23a) on the biological characteristics of OC stem cells by targeting discs large homolog 2 (DLG2). OC-related differentially expressed genes were screened by microarray-based gene expression analysis, after which a list of miRNAs that regulate the genes was predicted. In total, 50 patients diagnosed with OC were enrolled in this study. DLG2 positive protein expression was measured in OC tissues. The interaction between DLG2 and miR-23a was predicted and analyzed through luciferase activity measurement. With the intervention of miR-23a and/or DLG2 expression in OC stem cells, the expression of miR-23a, DLG2, Bax, Bcl-2, Oct-4, and Nanog was determined. Afterward, different cell experiments were conducted to examine the regulation effect of miR-23a in OC stem cells. Tumor formation in vivo was also evaluated in nude mice. DLG2 had low expression in OC. The results showed that there was a decrease in the expression of Bcl-2, Oct-4, and Nanog, while DLG2 and Bax were increased as a result of miR-23a depletion. In addition, when miR-23a was suppressed, cell viability, migration, invasion, cloning, and renewal abilities of OC stem cells were decreased, while apoptosis ability was enhanced. As a target gene of miR-23a, DLG2 downregulation reversed the suppressive function of miR-23a in the inhibition of OC development. Finally, in vivo experiment verified that miR-23a downregulation restrained the tumor growth in OC stem cells. In conclusion, our findings suggested that the inhibition of miR-23a results in the suppression of OC progression by releasing DLG2, which provides new understanding on the potential therapeutic effect of miR-23a inhibition in OC patients. Show less

Growth and fat deposition are important economic traits due to the influence on production in pigs. In this study, a dataset of 1200 pigs with 345,570 SNPs genotyped by sequencing (GBS) was used to conduct a GWAS with single-marker regression method to identify SNPs associated with body weight and backfat thickness (BFT) and to search for candidate genes in Landrace and Yorkshire pigs. A total of 27 and 13 significant SNPs were associated with body weight and BFT, respectively. In the region of 149.85-149.89 Mb on SSC6, the SNP (SSC6: 149876737) for body weight and the SNP (SSC6: 149876507) for BFT were in the same locus region (a gap of 230 bp). Two SNPs were located in the DOCK7 gene, which is a protein-coding gene that plays an important role in pigmentation. Two SNPs located on SSC8: 54567459 and SSC11: 33043081 were found to overlap weight and BFT; however, no candidate gene was found in these regions. In addition, based on other significant SNPs, two positional candidate genes, NSRP1 and CADPS, were proposed to influence weight. In conclusion, this is the first study report using GBS data to identify the significant SNPs for weight and BFT. A total of four particularly interesting SNPs and one potential candidate genes (DOCK7) were found for these traits in domestic pigs. This study improves our knowledge to better understand the complex genetic architecture of weight and BFT, but further validation studies of these candidate loci and genes are recommended in pigs. Show less

Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We studied the mechanism of life-long Integration of virus DNA into OBI host's genome, of which may induce hepatocyte transformation. We applied HBV capture sequencing on single cells from an OBI patient who, developed multiple HCC tumors and underwent liver resection in May 2013 at Tongji Hospital in China. Despite with the undetectable virus DNA in serum, we determined the pattern of viral integration in tumor cells and adjacent non-tumor cells and obtained the details of the viral arrangement in host genome, and furthermore the HBV integrated region in cancer genome. HBV captured sequencing of tissues and individual cells revealed that samples from multiple tumors shared two viral integration sites that could affect three host genes, including CSMD2 on chr1 and MED30/EXT1 on chr8. Whole genome sequencing further indicated one hybrid chromosome formed by HBV integrations between chr1 and chr8 that was shared by multiple tumors. Additional 50 poorly differentiated liver tumors and the paired adjacent non-tumors were evaluated and functional studies suggested up-regulated EXT1 expression promoted HCC growth. We further observed that the most somatic mutations within the tumor cell genome were common among the multiple tumors, suggesting that HBV associated, multifocal HCC is monoclonal in origin. Through analyzing the HBV integration sites in multifocal HCC, our data suggested that the tumor cells were monoclonal in origin and formed in the absence of active viral replication, whereas the affected host genes may subsequently contribute to carcinogenesis. Show less

To detect EXT1 and EXT2 gene mutations in two pedigrees affected with hereditary multiple exostosis (HME). The coding regions and exon/intron boundaries of the EXT1 and EXT2 genes were analyzed by targeted next-generation sequencing (NGS). Suspected mutations were confirmed by Sanger sequencing of the probands, their family members and 200 unrelated healthy controls. Gross deletion was confirmed by quantitative PCR (qPCR) analysis and multiple ligation-dependent probe amplification (MLPA) analysis. Two mutations were detected in the pedigrees, which included EXT2 gene c.337₃₃₈insG mutation in pedigree 1 and deletion of entire EXT1 in pedigree 2. Analysis of sequencing data revealed that a novel heterozygous mutation (c.337₃₃₈insG) in EXT2 gene in proband 1 and his father. The same mutation was not found among healthy family members and 200 unrelated healthy controls. As shown by NGS and MLPA analysis, proband 2 carried a heterozygous deletion of entire EXT1 gene. The same deletion was also found in her mother by qPCR. Mutations of the EXT1 and EXT2 genes probably underlie the HME in both pedigrees. NGS combined with Sanger sequencing, qPCR and MLPA is effective for attaining the diagnosis. Show less

Mono-2-ethylhexyl phthalate (MEHP) is a major bioactive metabolite in the widely used industrial plasticizer diethylhexyl phthalate (DEHP) that has been found to be toxic to the liver. The aim of this study is to determine whether MEHP exposure can change the expression of fatty acid metabolism-related genes in HepG2 cells, which might be related to non-alcoholic fatty liver disease (NAFLD). The results revealed that exposure to MEHP promoted lipid accumulation in HepG2 cells. The levels of intracellular triglycerides in the hepatocytes increased after exposure to 0.8-100 μM MEHP for 24 h and 48 h. The genetic expressions of SREBP-1c, ChREBP, ACC1, FASN, and SCD significantly increased at 6 h after exposure to MEHP. At 24 h, the expression of the SREBP-1c and ChREBP genes remained increased, while the expression of the FASN and SCD genes decreased. At 48 h, the expression of SREBP-1c, ChREBP, ACC1, FASN, and SCD decreased. Furthermore, the levels of proteins including ACC1, FASN, SCD, and ChREBP (except SREBP-1c) increased at 24 h. These findings suggest that MEHP exposure can promote fatty acid synthesis in hepatocytes by regulating the expression of relevant genes and proteins, contributing to NAFLD. Show less

Ventricular septal defect (VSD) is a fatal congenital heart disease showing severe consequence in affected infants. Early diagnosis plays an important role, particularly through genetic variants. Existing panel-based approaches of variants mining suffer from shortage of large panels, costly sequencing, and missing rare variants. Although a trio-based method alleviates these limitations to some extent, it is agnostic to novel mutations and computational intensive. Considering these limitations, we are studying a novel variants mining algorithm from trio-based sequencing data and apply it on a VSD trio to identify associated mutations. Our approach starts with irrelevant Show less

The goal of this study is to investigate the associations of apolipoprotein A5 ( This case-control study included 710 subjects (355 patients with CAD and 355 controls) who were recruited from a cross-sectional study. Three single nucleotide polymorphisms (SNPs) rs662799 (-1131T>C), rs651821 (-3A>G) and rs2075291 (G185C) in Based on these data, variants of the Show less

Primary open angle glaucoma (POAG) is the most prevalent form of glaucoma, accounting for approximately 90% of all cases. The aqueous humor (AH), a biological fluid in the anterior and posterior chambers of the eye, is involved in a multitude of functions including the maintenance of IOP and ocular homeostasis. This fluid is very close to the pathologic site and is also known to have a significant role in glaucoma pathogenesis. The purpose of this study was to identify proteomic alterations in AH from patients with POAG. AH samples were extracted from 47 patients undergoing cataract surgery (controls: n = 32; POAG: n = 15). Proteomic analysis of the digested samples was accomplished by liquid-chromatography-mass spectrometry. The identified proteins were evaluated using a variety of statistical and bioinformatics methods. A total of 33 proteins were significantly altered in POAG subjects compared with the controls. The most abundant proteins in POAG subjects are IGKC (13.56-fold), ITIH4 (4.1-fold), APOC3 (3.36-fold), IDH3A (3.11-fold), LOC105369216 (2.98-fold). SERPINF2 (2.94-fold), NPC2 (2.88-fold), SUCLG2 (2.70-fold), KIAA0100 (2.29-fold), CNOT4 (2.23-fold), AQP4 (2.11-fold), COL18A1 (2.08-fold), NWD1 (2.07-fold), and TMEM120B (2.06-fold). A significant increasing trend in the odds ratios of having POAG was observed with increased levels of these proteins. Proteins identified in this study are implicated in signaling, glycosylation, immune response, molecular transport, and lipid metabolism. The identified candidate proteins may be potential biomarkers associated with POAG development and may lead to more insight in understanding the mechanisms underlying the pathogenesis of this disease. Show less

Genetic analyses of psychiatric illnesses, such as bipolar disorder (BPD), have revealed essential information regarding the underlying pathological mechanisms. While such studies in populations of European ancestry have achieved prominent success, understanding the genetic risk factors of these illnesses (especially BPD) in Chinese population remains an urgent task. Given the lack of genome-wide association study (GWAS) of BPD in Chinese population from Mainland China, replicating the previously reported GWAS hits in distinct populations will provide valuable information for future GWAS analysis in Han Chinese. In the present study, we have recruited 1146 BPD cases and 1956 controls from Mainland China for genetic analyses, as well as 65 Han Chinese brain amygdala tissues for mRNA expression analyses. Using this clinical sample, one of the largest Han Chinese BPD samples till now, we have conducted replication analyses of 21 single nucleotide polymorphisms (SNPs) extracted from previous GWAS of distinct populations. Among the 21 tested SNPs, 16 showed the same direction of allelic effects in our samples compared with previous studies; 6 SNPs achieved nominal significance (p < 0.05) at one-tailed test, and 2 additional SNPs showed marginal significance (p < 0.10). Aside from replicating previously reported BPD risk SNPs, we herein also report several intriguing findings: (1) the SNP rs174576 was associated with BPD in our Chinese sample and in the overall global meta-analysis, and was significantly correlated with FADS1 mRNA in diverse public RNA-seq datasets as well as our in house collected Chinese amygdala samples; (2) two (partially) independent SNPs in MAD1L1 were both significantly associated with BPD in our Chinese sample, which was also supported by haplotype analysis; (3) a rare SNP rs78089757 in 10q26.13 region was a genome-wide significant variant for BPD in East Asians, and this SNP was near monomorphic in Europeans. In sum, these results confirmed several significant BPD risk genes. We hope this Chinese BPD case-control sample and the current brain amygdala tissues (with continuous increasing sample size in the near future) will provide helpful resources in elucidating the genetic and molecular basis of BPD in this major world population. Show less

Polycomb chromobox (CBX) proteins are involved in gene silencing to function as oncogenes or tumor suppressors through the polycomb repressive complex (PRC1). CBX4 has been implicated in the progression of human cancers, but its role and clinical significance in breast cancer remain unclear. Here, we show that CBX4 is up-regulated in breast cancer and exerts oncogenic activities via miR-137-mediated activation of Notch1 signaling pathway. CBX4 expression was increased in breast cancer, compared with the nontumorous tissues. High CBX4 expression was closely correlated with tumor metastasis, advanced clinical stage and poor overall survival in a cohort of 179 patients with breast cancer. In vitro studies demonstrated that CBX4 overexpression enhanced, whereas CBX4 knockdown inhibited cell growth and migration. Mechanistically, in a PRC1-dependent manner, CBX4 inhibited the promoter activity of miR-137 and suppressed its expression. miR-137 decreased the expression of Notch1, Jag1 and Hey2 via targeting their 3'-UTRs. The suppression of Notch1 by siRNA or overexpression of miR-137 markedly attenuated CBX4-promoted phenotypes. Collectively, these findings indicate that CBX4 promotes breast cancer via miR-137-mediated Notch1 signaling. Our data, therefore, suggest that CBX4 serve as a prognostic biomarker and that targeting CBX4/miR-137 axis may provide therapeutic potent in the treatment of breast cancer. Show less

Multiple evidence has indicated that myelin injury is common in Alzheimer's disease (AD). However, whether myelin injury is an early event in AD and the relationship between it and cognitive function is still elusive. Spatial memory of 5XFAD mice was determined by Morris water maze at 1 and 3 months old. Meanwhile, the deposition of Aβ, the expression of myelin basic protein (MBP), LINGO-1, NgR, and myelin ultrastructure in many memory-associated brain regions were detected in one-month-old and three-month-old mice (before and after LINGO-1 antibody administration) using immunostaining, Western blot (WB), and transmission electron microscopy (TEM), respectively. No abnormal Aβ deposition was found in one-month-old 5XFAD mice. However, spatial memory deficits were proved in accordance with an obvious demyelination in memory-associated brain regions in one-month-old mice and both deteriorated with age. Administration of LINGO-1 antibody could obviously restore the myelin impairments in CA1 and DG region and partially ameliorate spatial memory deficits. Our results demonstrated that myelin injury was an early event in 5XFAD mice even prior to emergence of deposition of Aβ. Intervention with the LINGO-1 antibody could attenuate impaired spatial memory deficits by remyelination, which suggested that myelin injury was involved in spatial memory deficits and remyelination may be a potential therapeutic strategy in early stage of AD or mild cognitive impairments. Show less

Gastric cancer (GC) is one of the most common cancers and is the second-leading cause of cancer-associated morbidity worldwide. Oxysterols are oxidized derivatives of cholesterol that may be important in many biological processes, but the levels and roles of oxysterols in gastric tumours remain to be elucidated. The levels of cholesterol, oxysterols and sulfated oxysterols in human gastric tumour tissues, adjacent normal mucosal tissues, cancerous gastric juice and gastric juice obtained from healthy subjects were detected by LC-MS. It was found that the levels of 24(R/S),25-EC and 27HC in human gastric tumour tissues and cancerous gastric juice were significantly increased compared with those of adjacent normal mucosal tissues and gastric juice from healthy subjects. Compared with normal gastric mucosal tissue, the levels of sulfated 25-hydroxycholesterol (25HC3S) and the ratio of 25HC3S/25HC were decreased in human gastric tumour tissues, which might be related to the dramatically decreased SULT2A1 expression in gastric tumour tissue. Both 24(R/S),25-EC and 27HC suppressed gastric cancer proliferation, which was not altered by LXRα-siRNA treatment. The suppression of cell proliferation induced by 27HC was attenuated by LXRβ-siRNA, but the suppression of cell proliferation induced by 24(R/S),25-EC was intensified by LXRβ-siRNA. Both 24(R/S),25-EC and 27HC dramatically inhibited HGC-27 cell migration, which was attenuated by the co-transfection of cells with LXRα-siRNA and LXRβ-siRNA, but not LXRα-siRNA or LXRβ-siRNA alone. In conclusion, the accumulated 24(R/S),25-EC and 27HC in human gastric tumour tissues might play important roles in gastric cancer development. Show less

Paeoniflorin (PF), an effective composition that is extracted from Radix Paeoniae Alba, plays a role in protecting against various kidney diseases. However, the mechanism of PF on nephrotic syndrome (NS) remains unclear. The aim of this study was to investigate the protective role of PF on Adriamycin (ADR)-induced NS in vivo and vitro as well as its potential mechanism. In animal study, PF significantly decreased the levels of 24-h urine protein, blood urea nitrogen, serum creatinine, total cholesterol and triglycerides in NS rats, but increased the total protein and albumin levels. Hematoxylin-eosin (HE) staining revealed that the kidney lesion was resolved upon PF treatment. After treatment with PF, the morphology and number of podocytes in renal tissue were restored to normal. PF increased expression of synaptopodin and decreased expression of desmin, demonstrating a protective effect in podocyte injury. Further studies revealed that PF upregulated Peroxisome proliferator-activated receptor gamma (PPARγ) and restrained Angiopointin-like 4 (ANGPTL4) in kidney tissue. In vitro study, PF reduced Caspase3 and Bax and increased Bcl-2, indicating that the apoptosis rate of podocytes induced by ADR was reduced by PF. Furthermore, PF ameliorated podocyte injury by upregulating synaptopodin and reducing desmin. In accordance with animal study, PF downregulated ANGPTL4 by activating PPARγ. However, the therapeutic effects of PF were reversed by GW9662 (PPARγ inhibitor), likely by suppressing ANGPTL4 degradation. In general, these results demonstrate that PF has a good therapeutic effect on NS by activating PPARγ and subsequently inhibiting ANGPTL4. Show less

Hypocalcemia is an important metabolic disease of dairy cows during the transition period, although the effect of hypocalcemia on biological function in dairy cows remains unknown. In this study, proteomic, mass spectrum, bioinformatics and western blotting were employed to identify differentially expressed proteins related to serum Ca concentration. Serum samples from dairy cows were collected at three time points: 3rd days before calving (day -3), the day of calving (day 0), and 3rd days after calving (day +3). According to the Ca concentration on day 0, a total of 27 dairy cows were assigned to one of three groups (clinical, subclinical, and healthy). Samples collected on day -3 were used for discovery of differentially expressed proteins, which were separated and identified via proteomic analysis and mass spectrometry. Bioinformatics analysis was performed to determine the function of the identified proteins (gene ontology and pathway analysis). The differentially expressed proteins were verified by western blot analysis. There were 57 differential spots separated and eight different proteins were identified. Vitamin D-binding protein precursor (group-specific component, GC), alpha-2-macroglobulin (A2M) protein, and apolipoprotein A-IV were related to hypocalcemia by bioinformatics analysis. Due to its specific expression (up-regulated in clinical hypocalcemia and down-regulated in subclinical hypocalcemia), A2M was selected for validation. The results were consistent with those of proteomic analysis. A2M was as an early detection index for distinguishing clinical and subclinical hypocalcemia. The possible pathogenesis of clinical hypocalcemia caused by GC and apolipoprotein A-IV was speculated. The down-regulated expression of GC was a probable cause of the decrease in calcium concentration. Show less

To analyze the related pathogenicity gene mutations in a sudden death of hypertrophic cardiomyopathy （HCM） on whole exome level. Whole exome sequencing （WES） was been performed on a sudden death case sample with pathological features of HCM by Illumina® Hiseq 2500 platform. Using hg19 as the reference sequences, the sequencing data were analyzed. Suspicious single nucleotide variants （SNV） were screened, and the conservatism and function were analyzed by the software such as PhyloP, PolyPhen-2, SIFT, etc. After screening, a heterozygous mutation C719R was finally identified in the gene The molecular anatomy on whole exome level by second generation sequencing technology can help to define the molecular mechanism of HCM and provide a new mothed and thought for analysis of death cause. Show less

The aim of the present study is to investigate whether the single nucleotide polymorphism (SNP) in lipid metabolism related genes would affect the effectiveness of atorvastatin in both Han and Uighur populations. 200 ischemic stroke patients were treated with atorvastatin. The differences of blood lipid level and their ratios were measured. Six lipid related genes, HMGCR, APOA5, LPL, CETP, LDLR and PCSK9 were selected as candidate genes. And nine SNP loci in these six genes were genotyped by SNaPshot technique. In all patients treated with atorvastatin, the SNP rs662799 significantly affected the ratio of x0394;LDL and x0394;LDL/LDL (p < 0.05); the SNP rs320 significantly affected the ratio of x0394;LDL/LDL and x0394;(LDL/HDL)/(LDL/HDL) (p < 0.01) and the SNP rs708272 significantly affected the ratio of x0394;LDL (p < 0.05). In Han population treated with atorvastatin, the SNP rs662799 significantly affected the ratio of x0394;TG (p < 0.05); the SNP rs320 significantly affected the ratio of x0394;LDL/LDL and x0394;(LDL/HDL)/(LDL/HDL) (p < 0.01). In Uighur population treated with atorvastatin, the SNP rs2266788 significantly affected the ratio of x0394;HDL (p < 0.05); the SNP rs662799 significantly affected the ratio of x0394;LDL/LDL (p < 0.05) and the SNP rs708272 significantly affected the ratio of x0394;LDL (p < 0.05). Polymorphisms of rs662799 and rs2266788 in APOA5 gene, rs320 in LPL gene and rs708272 in CETP gene had significant association with the effect of the lipid-lowering therapy via atorvastatin calcium on ischemic stroke patients. Show less

CST has been recently identified as a mediator of various beneficial effects in animal models of sepsis. At present, no data are available concerning the levels of CST in sepsis patients. In sepsis the plasma amino acid pattern is characterized by decreased branced chain amino acids (BCAAs). We investigated the levels of plasma CST or branched-chain α-ketoacid dehydrogenase kinase (BCKDK) and their relationship to component traits in patients with sepsis. We studied 228 patients and divided them into two groups based on severity of infection. Blood samples were taken at study entry, and CST, BCKDK were measured. CST and BCKDK levels were significantly higher in patients with sepsis than in controls: the median plasma CST concentration was 103.1ng/ml (range, <83.13-189.7ng/ml) in patients with sepsis and 49.69ng/ml (range, <19.38-100.8ng/ml) in controls (p=0.0022); the median plasma BCKDK concentration was 801.7ng/ml in sepsis group and 745ng/ml in controls (p=0.0292). Additionally, there was correlation between the plasma concentrations of CST and BCKDK in sepsis patients (r We conclude that the plasma levels of CST in sepsis patients were higher than in controls, and there is a relationship between CST and BCKDK in sepsis patients. Future experimental and clinical studies are needed to evaluate CST as a novel prognostic tool in sepsis patients and its potential therapeutic use in sepsis. Show less