👤 Xiu-Wu Bian

Advanced glycation end products (AGEs) are stable products produced by the reaction of macromolecules such as proteins, lipids or nucleic acids with glucose or other reducing monosaccharides, which can be identified by immunohistochemistry in the senile plaques and neurofibrillary tangles of Alzheimer's disease (AD) patients. Growing evidence suggests that AGEs are important risk factors for the development and progression of AD. 1,8-cineole (CIN) is a monoterpenoid compound which exists in many plant essential oils and has been proven to have neuroprotective activity, but its specific effect and molecular mechanisms are not clear. In this study, AGEs-induced neuronal injury and intracerebroventricular-AGE animals as the possible models for AD were employed to investigate the effects of CIN on AD pathology as well as the molecular mechanisms involved both in vivo and in vitro. Our study demonstrated that CIN could ameliorate tau phosphorylation by down-regulating the activity of GSK-3β and reducing Aβ production by inhibiting the activity of BACE-1 both in vivo and in vitro. It is suggested that CIN has certain therapeutic value in the treatment of AD. Show less

To investigate the mechanism of serum interleukin-6 (IL-6) change in disease progression of interstitial nephritis. This is a retrospective study. From November 2017 to November 2019, 87 patients with interstitial nephritis treated in our hospital were enrolled and divided into an acute group (n=42) and a chronic group (n=45) based on pathological results of renal biopsies. Forty healthy individuals after physical examination during the same period were enrolled into the reference group. Serum IL-6 levels were determined using the enzyme-linked immunosorbent assay (ELISA). Among the three groups, patients in the acute group showed the highest IL-6 level (P<0.001). The acute group obtained higher serum advanced oxidation protein products (AOPP) levels and glomerular filtration rate (GFR) than the other two groups (P<0.05). The acute group showed lower levels of CD34 Serum IL-6 shows a great potential as an important marker of disease progression in interstitial nephritis. Show less

Spexin (SPX) is a pleiotropic peptide with highly conserved protein sequence from fish to mammals and its biological actions are mediated by GalR2/GalR3 receptors expressed in target tissues. Recently, SPX has been confirmed to be a novel satiety factor in fish species but whether the peptide has a similar function in mammals is still unclear. Using the mouse as a model, the functional role of SPX in feeding control and the mechanisms involved were investigated. After food intake, serum SPX in mice could be up-regulated with elevations of transcript expression and tissue content of SPX in the glandular stomach but not in other tissues examined. As revealed by immunohistochemical staining, food intake also intensified SPX signals in the major cell types forming the gastric glands (including the foveolar cells, parietal cells, and chief cells) within the gastric mucosa of glandular stomach. Furthermore, IP injection of SPX was effective in reducing food intake with parallel attenuation in transcript expression of NPY, AgRP, NPY type 5 receptor (NPY5R), and ghrelin receptor (GHSR) in the hypothalamus, and these inhibitory effects could be blocked by GalR3 but not GalR2 antagonism. In agreement with the central actions of SPX, similar inhibition on feeding and hypothalamic expression of NPY, AgRP, NPY5R, and GHSR could also be noted with ICV injection of SPX. In the same study, in contrast to the drop in NPY5R and GHSR, SPX treatment could induce parallel rises of transcript expression of leptin receptor (LepR) and melanocortin 4 receptor (MC4R) in the hypothalamus. These findings, as a whole, suggest that the role of SPX as a satiety factor is well conserved in the mouse. Apparently, food intake can induce SPX production in glandular stomach and contribute to the postprandial rise of SPX in circulation. Through GalR3 activation, this SPX signal can act within the hypothalamus to trigger feedback inhibition on feeding by differential modulation of feeding regulators (NPY and AgRP) and their receptors (NPY5R, GHSR, LepR, and MC4R) involved in the feeding circuitry within the CNS. Show less

This study aims to characterize the expression of ANGPTL4 in ovarian granulosa cells (GCs) and its association with polycystic ovary syndrome (PCOS). This study included 104 PCOS patients and 112 women in control group undergoing The RT-qPCR results showed that ANGPTL4 expression in the control group was significantly lower than that in the PCOS group ( Our study revealed higher ANGPTL4 expression in ovarian GCs with PCOS. Its association with glucose and lipid metabolism showed that ANGPTL4 might play an important role in PCOS metabolism and pathogenesis. Show less

Hypoxia, a strong and selective pressure, has been involved in invasion, metastasis, and angiogenesis of tumor cells. Our study performed the transcriptome profiles of 666 non-small-cell lung cancer (NSCLC) patients. Various bioinformatic approaches were combined to evaluate the immune cell infiltration in the high hypoxia risk patients. In addition, in vitro experiments were performed to assess the effects of tumor-associated neutrophils (TANs) on NSCLC cells proliferation, migration and invasion and to reveal the underlying mechanisms. We divided NSCLC into two groups (Cluster1/2) based on the expression profiles of hypoxia-associated genes. Compared with the Cluster1 subgroup, the Cluster2 had a worse prognosis. Significant enrichment analysis revealed that PI3K/AKT/mTOR signaling pathway and TANs were highly related to hypoxia microenvironment. Eleven hypoxia-related genes (FBP1, NDST2, ADM, LDHA, DDIT4, EXT1, BCAN, IGFBP1, PDGFB, AKAP12, and CDKN3) were scored by LASSO COX regression to yield risk scores, and we revealed a significant difference in overall survival (OS) between the low- and high-risk groups. Mechanistically, CXCL6 in hypoxic cancer cells promoted the migration of TANs in vitro, and in turn promote NSCLC cells proliferation, migration and invasion. In summary, this study revealed a 11-hypoxia gene signature that predicted OS of NSCLC patients, and improved our understanding of the role of TANs in hypoxia microenvironment. Show less

NRBF2, a regulatory subunit of the ATG14-BECN1/Beclin 1-PIK3C3/VPS34 complex, positively regulates macroautophagy/autophagy. In this study, we report that NRBF2 is required for the clearance of apoptotic cells and alleviation of inflammation during colitis in mice. NRBF2-deficient mice displayed much more severe colitis symptoms after the administration of ulcerative colitis inducer, dextran sulfate sodium salt (DSS), accompanied by prominent intestinal inflammation and apoptotic cell accumulation. Interestingly, we found that Show less

Lung resident mesenchymal stem cells (LR-MSCs) contribute to the progression of idiopathic pulmonary fibrosis (IPF). We aimed to investigate the molecular mechanism underlying LR-MSCs regulation upon transforming growth factor (TGF)-β1 stimulation. We induced fibrogenic differentiation of LR-MSCs isolated from mice by TGF-β1. Several stem cell markers were detected by flow cytometric analysis. Protein expression level was tested by Western blotting and mRNA level was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability, proliferation and apoptosis were measured. TGF-β1 promoted fibrogenic differentiation of LR-MSCs and upregulated β-catenin and p-glycogen synthase kinase-3β, suggesting the activation of Wnt signaling. MicroRNA (MiR)-124-3p was significantly upregulated in TGF-β1 treated LR-MSCs compared to untreated cells. Intriguingly, silence of miR-124 reversed the TGF-β1-induced changes in cell viability and proliferation, and also led to a decrease of cell apoptosis. Additionally, in miR-124 silenced cells, α-smooth muscle actin, collagen I and fibronectin were downregulated compared to control cells. We ultimately identified a new target of miR-124, AXIN1, which was repressed by miR-124. In conclusion, miR-124 regulates AXIN1 to activate Wnt signaling and therefore plays a crucial role in the TGF-β1-induced fibrogenic differentiation. Show less

Human bocavirus (HBoV) is a member of the genus Bocavirus, family Parvoviridae, and subfamily Parvovirus and was first identified in nasopharyngeal aspirates of Swedish children with acute respiratory tract infection (ARTI) in 2005. It is the causative agent of nasopharyngeal aspirate disease and death in children. The HboV genomic structure is a linear single-stranded DNA (ssDNA). Its clinical pathogenic characteristics have been extensively studied, however, at present the molecular mechanism underlying the pathogenesis of HBoV infection is not completely clear. In this study, a total of 293 differentially expressed proteins (DEPs) between ARTI cases and healthy plasma samples were characterized using isobaric tags for relative and absolute quantitation (iTRAQ)-coupled bioinformatics analysis, among which 148 were up-regulated and 135 were down-regulated. Gene Ontology (GO) and Cluster of Orthologous Groups of proteins (COG) annotated an enrichment of DEPs in complement activation and biological processes like immunity, inflammation, signal transduction, substance synthesis, and metabolism. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis enriched DEPs mainly in the Wnt signaling pathway (ko04310), PPAR signaling pathway (ko03320), intestinal immune network for IgA production (ko04672), complement and coagulation cascades (ko04610), Toll-like receptor signaling pathway (ko04620) and B cell receptor signaling pathway (ko04662). Further, expression levels of three candidate proteins (upregulated PPP2R1A and CUL1, and downregulated CETP) were validated using western blotting. Our investigation is the first analysis of the proteomic profile of HBoV-infected ARTI cases using the iTRAQ approach, providing a foundation for a better molecular understanding of the pathogenesis of ARTI in children. Show less

A typical feature of the contextual fear memory is increased fear generalization with time. Though much attention has been given to the neural structures that underlie the long-term consolidation of a contextual fear memory, the molecular mechanisms regulating fear generalization remain unclear. We observed that retrieval of contextual fear in a novel context at a remote time point increased coupling of neuronal nitric oxide synthase (nNOS) with postsynaptic density-95 (PSD-95) and c-Fos expression in the anterior cingulate cortex (ACC). Disrupting nNOS-PSD-95 coupling in the ACC decreased the expression of Histone deacetylase 2 (HDAC Show less

The correlations between genotype and phenotype in hypertrophic cardiomyopathy (HCM) have not been established. Mutation of α-actin gene (ACTC1) is a rare cause of HCM. This study aimed to explore novel genotype-phenotype correlations in HCM patients with the variants in ACTC1 and myosin-binding protein (MYBPC3) genes in three unrelated Chinese families. Clinical, electrocardiographic, and echocardiographic examinations were performed in three Han pedigrees. Exon and boarding intron analysis of 96 cardio-disease-related genes was performed using second-generation sequencing on three probands. The candidate variants were validated in 14 available family members and 300 unrelated healthy controls by bi-directional Sanger sequencing. The pathogenicity and conservation were calculated using MutationTaster, PolyPhen-2, SIFT, and Clustal X. Pathogenicity classification of the variants was based on American College of Medical Genetics and Genomics (ACMG) guidelines. Nine members fulfilled diagnostic criteria for HCM with clinical characteristics, electrocardiographic, and echocardiographic findings. Two candidate variants in ACTC1 p.Asp26Asn (ACTC1-D26N) and MYBPC3 p.Arg215Cys (MYBPC3-R215C) were identified in patients. Only ACTC1-D26N strongly co-segregated with the HCM phenotype. Seven patients who harbored variant ACTC-D26N only were diagnosed with non-obstructive HCM, and four of these patients exhibited a triphasic left ventricular (LV) filling pattern. Two patients carrying both ACTC1-D26N and MYBPC3-R215C variants showed a higher LV outflow tract pressure gradient. Bioinformatics analysis revealed that the two variants were deleterious and highly conserved across species. According to ACMG guidelines, ACTC1-D26N is classified as a likely pathogenic mutation. The second variation MYBPC3-R215C may function as a genetic modifier, which remains uncertain here. Novel p.(Asp26Asn) mutation of ACTC1 was associated with HCM phenotype, and the penetrance is extremely high (∼81.8%) in adults. The second variation, MYBPC3-R215C may function as a genetic modifier, which remains uncertain here. Show less

Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD. Show less

Macrophage-derived foam-cell formation plays a crucial role in the development of atherosclerosis, and liver X receptor alpha (LXRα) is a key regulator of lipid metabolism in macrophages. Homocysteine (Hcy) is an independent risk factor of atherosclerosis; however, the regulation of lipid metabolism and role of LXRα induced by Hcy in macrophages is still unknown. The present study aimed to investigate the potential role of Hcy in disordered lipid metabolism and atherosclerotic lesions, especially the effects of Hcy on cholesterol efflux in macrophages and the possible mechanisms. In vitro, lipid accumulation and cholesterol efflux were evaluated in THP-1 macrophages with Hcy intervention. Real-time quantitative PCR and western blot analyses were used to assess mRNA and protein levels. In vivo, atherosclerotic lesions and lipid profiles were evaluated by methionine diet-induced hyperhomocysteinemia (HHcy) in ApoE Hcy promoted lipid accumulation and inhibited cholesterol efflux in THP-1 macrophages. HHcy mice showed increased lesion area and lipid accumulation in plaque. Both studies in vitro and in vivo showed decreased expression of ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1). T0901317 treatment increased ABCA1 and ABCG1 levels; reversed macrophage-derived foam-cell formation in THP-1 macrophages and reduced atherosclerotic lesions in ApoE Inhibition of LXRα-mediated ABCA1/ABCG1-dependent cholesterol efflux from macrophages is a novel mechanism in Hcy-accelerated atherosclerosis. Show less

To identify specific miRNAs involved in sepsis-induced AKI and to explore their targeting pathways. The expression profiles of miRNAs in serum from patients with sepsis-induced AKI (n = 6), sepsis-non AKI (n = 6), and healthy volunteers (n = 3) were investigated by microarray assay and validated by quantitative PCR (qPCR). The targets of the differentially expressed miRNAs were predicted by Target Scan, mirbase and Miranda. Then the significant functions and involvement in signaling pathways of gene ontology (GO) and KEGG pathways were analyzed. Furthermore, eight miRNAs were randomly selected out of the differentially expressed miRNAs for further testing by qPCR. qPCR analysis confirmed that the expressions levels of hsa-miR-23a-3p, hsa-miR-4456, hsa-miR-142-5p, hsa-miR-22-3p and hsa-miR-191-5p were significantly lower in patients with sepsis compared with the healthy volunteers, while hsa-miR-4270, hsa-miR-4321, hsa-miR-3165 were higher in the sepsis patients. Statistically, miR-4321; miR-4270 were significantly upregulated in the sepsis-induced AKI compared with sepsis-non AKI, while only miR-4321 significantly overexpressed in the sepsis groups compared with control groups. GO analysis showed that biological processes regulated by the predicted target genes included diverse terms. They were related to kidney development, regulation of nitrogen compound metabolic process, regulation of cellular metabolic process, cellular response to oxidative stress, mitochondrial outer membrane permeabilization, etc. Pathway analysis showed that several significant pathways of the predicted target genes related to oxidative stress. miR-4321 was involved in regulating AKT1, mTOR and NOX5 expression while miR-4270 was involved in regulating PPARGC1A, AKT3, NOX5, PIK3C3, WNT1 expression. Function and pathway analysis highlighted the possible involvement of miRNA-deregulated mRNAs in oxidative stress and mitochondrial dysfunction. This study might help to improve understanding of the relationship between serum miRNAs and sepsis-induced AKI, and laid an important foundation for further identification of the potential mechanisms of sepsis-induced AKI and oxidative stress and mitochondrial dysfunction. Show less

5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/β-catenin signalling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β-catenin signalling by 5-HT. The expression of various 5-HT receptors was studied by quantitative real-time polymerase chain reaction (qPCR) in HCC cell lines as well as in 33 pairs of HCC tumours and corresponding adjacent non-tumour tissues. Receptors 5-HT1D (21/33, 63.6%), 5-HT2B (12/33, 36.4%) and 5-HT7 (15/33, 45.4%) were overexpressed whereas receptors 5-HT2A (17/33, 51.5%) and 5-HT5 (30/33, 90.1%) were reduced in HCC tumour tissues. In vitro data suggests 5-HT increased total β-catenin, active β-catenin and decreased phosphorylated β-catenin protein levels in serum deprived HuH-7 and HepG2 cells compared to control cells under serum free medium without 5-HT. Activation of Wnt/β-catenin signalling was evidenced by increased expression of β-catenin downstream target genes, Axin2, cyclin D1, dickoppf-1 (DKK1) and glutamine synthetase (GS) by qPCR in serum-deprived HCC cell lines treated with 5-HT. Additionally, biochemical analysis revealed 5-HT disrupted Axin1/β-catenin interaction, a critical step in β-catenin phosphorylation. Increased Wnt/β-catenin activity was attenuated by antagonist of receptor 5-HT7 (SB-258719) in HCC cell lines and patient-derived primary tumour tissues in the presence of 5-HT. SB-258719 also reduced tumour growth in vivo. This study provides evidence of Wnt/β-catenin signalling activation by 5-HT and may represent a potential therapeutic target for hepatocarcinogenesis. Show less

Dyslipidemia is common in polycystic ovary syndrome (PCOS). This study was aimed to investigate whether fatty acid desaturase genes (FADS), a dyslipidemia-related gene cluster, are associated with PCOS. We scanned variations of FADS genes using our previous data of genome-wide association study (GWAS) for PCOS and selected rs174570 for further study. The case-control study was conducted in an independent cohort of 1918 PCOS cases and 1889 age-matched controls and family-based study was conducted in a set of 243 core family trios with PCOS probands. Minor allele frequency (allele T) of rs174570 was significantly lower in PCOS cases than that in age-matched controls (P = 2.17E-03, OR = 0.85), even after adjustment of BMI and age. PCOS subjects carrying CC genotype had higher testosterone level and similar lipid/glucose level compared with those carrying TT or TC genotype. In trios, transmission disequilibrium test (TDT) analysis revealed risk allele C of rs174570 was significantly over-transmitted (P = 2.00E-04). Decreased expression of FADS2 was detected in PCOS cases and expression quantitative trait loci (eQTL) analysis revealed the risk allele C dosage was correlated with the decline of FADS2 expression (P = 0.002). Our results demonstrate that FADS1-FADS2 are susceptibility genes for PCOS. Show less

Angiotensin II (Ang II) and Ang-(1-7) are key effector peptides of the renin-angiotensin system. The present study aimed to investigate the effects of Ang-(1-7) on Ang II-stimulated cholesterol efflux and the associated molecular mechanisms. Differentiated THP-1 macrophages were treated with Ang II (1 µM) and/or Ang-(1-7) (10 and 100 nM) for 24 h and the cholesterol efflux and gene expression levels were assessed. Pharmacological inhibition of peroxisome proliferator-activated receptor (PPAR)γ and mitogen-activated protein kinases (MAPKs) were performed to identify the signaling pathways involved. The results demonstrated that Ang II significantly inhibited the cholesterol efflux from cholesterol-loaded THP-1 macrophages. Treatment with Ang-(1-7) led to a dose-dependent restoration of cholesterol efflux in the Ang II-treated cells. The co-treatment with Ang-(1-7) and Ang II significantly increased the expression levels of adenosine triphosphate (ATP)-binding cassette (ABC)A1 and ABCG1 compared with treatment with Ang II alone. This was coupled with increased expression levels of PPARγ and liver X receptor (LXR)α. The pharmacological inhibition of PPARγ significantly (P<0.05) eliminated the Ang-(1-7)-mediated induction of ABCA1 and ABCG1 mRNA expression. Treatment with Ang-(1-7) caused the inactivation of c-Jun N-terminal kinases (JNK) and p38 MAPK signaling in the Ang II-treated THP-1 macrophages. In addition, the inhibition of JNK or p38 MAPK signaling using specific pharmacological inhibitors mimicked the Ang-(1-7)-induced expression of PPARγ and LXRα. In conclusion, the data demonstrated that treatment with Ang-(1-7) promoted cholesterol efflux in Ang II-treated THP-1 macrophages, partly through inactivation of p38 and JNK signaling and by inducing the expression of PPARγ and LXRα. Ang (1-7) may, therefore, have therapeutic benefits for the treatment of atherosclerosis. Show less

ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in reverse cholesterol transport and anti-atherosclerosis. Liver X receptor alpha (LXRα) can stimulate cholesterol efflux through ABCA1. It has been well known that adiponectin has cardiovascular protection. In this study, we attempted to clarify the effect of adiponectin on expression of ABCA1, and explored the role of LXRα in the regulation of ABCA1 in RAW 264.7 macrophages. Our results showed that adiponectin increased ABCA1 expression at both the mRNA and protein levels in a dose-dependent and time-dependent manner. Consequently, adiponectin promoted cholesterol efflux and decreased cholesterol content in RAW 264.7 macrophages. Moreover, adiponectin up-regulated the expression of LXRα in a dose-dependent and time-dependent manner in RAW 264.7 macrophages. LXRα small interfering RNA completely abolished the promotion effects of adiponectin. In summary, adiponectin up-regulates ABCA1 expression via the LXRα pathway in RAW 264.7 macrophages. This novel insight could prove useful for developing new treatment strategies for cardiovascular diseases. Show less

Global quantification of the single amino-acid variations (SAAVs) is essential to investigate the roles of SAAVs in disease progression. However, few efforts have been made on this issue due to the lack of high -throughput approach. Here we presented a strategy by integration of the stable isotope dimethyl labeling with variation-associated database search to globally quantify the SAAVs at the first time. A protein database containing 87,745 amino acid variant sequences and 73,910 UniProtKB/Swiss-Prot canonical protein entries was constructed for database search, and higher energy collisional dissociation combined with collision-induced dissociation fragmentation modes were applied to improve the quantification coverage of SAAVs. Compared with target proteomics in which only a few sites could be quantified, as many as 282 unique SAAVs sites were quantified between hepatocellular carcinoma (HCC) and normal human liver tissues by our strategy. The variation rates in different samples were evaluated, and some interesting SAAVs with significant increase normalized quantification ratios, such as T1406N in CPS1 and S197R in HTATIP2, were observed to highly associate with HCC progression. Therefore, the newly developed strategy enables the large-scale comparative analysis of variations at the protein level and holds a promising future in the research related to variations. Show less

Adenosine triphosphate-binding cassette transporter A1 (ABCA1) and ABCG1 play crucial roles in reverse cholesterol transport, and have anti-atherosclerosis effects, and liver X receptor alpha (LXRα) can stimulate cholesterol efflux through these transporters. Angiotensin (Ang)-(1-7) can protect endothelial cells, inhibit smooth muscle cell growth, ameliorate inflammation and exert anti-atherosclerotic effects. In the present study, we attempted to clarify the effect of Ang-(1-7) on expression of ABCA1 and ABCG1, and explored the role of LXRα in the regulation of ABCA1 and ABCG1 in THP-1 macrophages that had been incubated with angiotensin-II (AngII). Ang-(1-7) increased ABCA1 and ABCG1 expression in a concentration-dependent manner at both the mRNA and protein levels, promoted cholesterol efflux, and decreased cholesterol content in THP-1 macrophages treated with AngII. Furthermore, Ang-(1-7) upregulated the expression of LXRα in a concentration-dependent manner in these cells. LXRα small interfering RNA, as well as the Mas receptor antagonist A-779, completely abolished these effects of Ang-(1-7). In summary, Ang-(1-7) upregulates ABCA1 and ABCG1 expression in THP-1 macrophages treated with AngII through the Mas receptor, via the LXRα pathway. This novel insight into the molecular mechanism underlying Ang-(1-7) and AngII interaction could prove useful for developing new strategies for treatment of cardiovascular diseases. Show less

Hypertrophic cardiomyopathy (HC) is a hereditary heterogeneous cardiovascular disorder. Existing data have been of predominantly Caucasian samples, and a large study is needed in Chinese population. The present study was intended to explore the genetic basis and clinical characteristics correlated with different genotypes in a large cohort of Chinese patients. Direct gene sequencing of β-myosin heavy chain (MYH7), myosin binding protein-C (MYBPC3), and cardiac troponin T (TNNT2) was performed in 136 unrelated Chinese HC patients. Clinical evaluations were conducted. In total, 32 mutations were identified in 36 patients (27%), including 10 novel ones. Distribution of mutations was 56% (MYBPC3), 31% (MYH7), and 13% (TNNT2), respectively. Double mutations were identified in 3% patients. The occurrence of HC-associated sarcomeric mutations was associated with an earlier age of onset, increased left ventricular hypertrophy, a higher incidence of syncope, previous family history, and sudden cardiac death. No statistical difference was identified in patients carrying MYBPC3 and MYH7 mutations with regard to clinical characteristics and outcomes. Patients with double mutations were associated with malignant progression in the study. In conclusion, MYBPC3 is the most predominant gene in HC. Multiple mutations are common in MYH7, MYBPC3, and TNNT2. The present study suggests a large diversity of HC and a prognostic role of genotype. Show less

Nest breakdown and primordial folliculogenesis of the mouse ovary can be inhibited by progesterone (P4) and Notch signaling inhibitors. However, the relationship between these two signals during this process remains unknown. In the present study, transcript levels of Jagged2, Notch1, and their target, Hey2, increased markedly in ovaries during the beginning stage of folliculogenesis (17.5 days post coitus (dpc) to birth). Maternal P4 levels decreased simultaneously. We found that maternal midpregnancy P4 levels significantly inhibited Jagged2, Notch1, and Hey2 expression, and follicle formation in vitro. Maintaining high maternal P4 levels by daily injection also significantly suppressed the expression of Jagged2, Notch1, and Hey2, and follicle formation during late pregnancy. Based on immunohistochemistry, Jagged2 was localized in oocytes and Notch1 was strongly stained in pre-granulosa cells in 19.5 dpc ovaries. Suppression of their function by antibody addition and RNAi markedly inhibited nest breakdown and follicle formation. Taken together, these results demonstrate that maternal P4 levels during midpregnancy can inhibit the expression of Jagged2 and Notch1, which are involved in primordial folliculogenesis, in the mouse fetal ovary. Show less

To screen the MYBPC3 gene mutations in Han Chinese patients with hypertrophic cardiomyopathy (HCM). Sixty-six patients with HCM were enrolled for the study. The exons in the functional regions of MYBPC3 were amplified with PCR and the products were sequenced. Four novel mutations and four common polymorphisms were identified in this patient cohort. A Lys301fs mutation in exon10 was evidenced in a H30, and when he was 47 years old, he had the chest tightness, shortness of breath with septal hypertrophy of 18.7mm; a Asp463stop mutation in exon17 was detected in a H48, he was 24 years old 24-year-old when a medical examination showed ventricular septal hypertrophy of 15.4 mm; both Gly523Arg mutation in exon18 and Tyr847His mutation in exon26 were found in a H53 with onset age 36 years old, feeling chest tightness after excise and his ventricular septal hypertrophy was 27 mm that time. MYBPC3 mutations occurred in 4.5% patients in this cohort. These mutations were not found in 100 non-HCM control patients. MYBPC3 mutation is presented in a small portion of Han Chinese patients with HCM. Show less

To compare the gene mutation between Chinese patients with familial and sporadic hypertrophic cardiomyopathy (HCM). Peripheral blood samples were collected from 36 patients with familial HCM (FHCM) and 50 patients with sporadic HCM (SHCM), all un-related and from different provinces of China. PCR was used to amplify the 26 protein-coding axons of beta-myosin heavy chain (MYH7), 16 exons for cardiac troponin T (TNNT2), and 38 exons for cardiac myosin-binding protein C (MYBPC3). The amplified products were sequenced and compared with the standard sequence in the genBank so as to determine the potential mutation sites. (1) 13 of the 36 FHCM patients (36.1%) harbored 3 different mutations in MYH7 gene: Arg663His in exon18, Glu924Lys in exon 23, and Ile736Thr in exon 20. Of the 50 SHCM patients, only 1 (2%) harbored MYH7 gene missence mutation: Ile736Thr located in exon 20. (2) TNNT2 was not identified in all SHCM patients and FHCM patients. (3) MYBPC3 was not identified in all SHCM patients. Four FHCM patients harbored 2 different mutations: Arg502Trp in exon 18 and Arg346fs in exon 13 respectively. MYH7 and MYBPC3 may be the dominant disease-causing genes in Chinese familial HCM patients; however the mutation rate of MYH7 and MYBPC3 genes is significantly lower in the SHCM patients compared with the FHCM patients. TNNT2 seems not the predominant disease-causing gene in all Chinese patients with HCM. Show less

The aim of this study was to screen the disease-causing gene mutations and investigate the genotype-phenotype correlation in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy (HCM). There are 91 family members from these 10 pedigrees and 5 members were normal mutated carriers, 23 members were HCM patients (14 male) aged from 1.5 to 73 years old. The functional regions of myosin heavy chain gene (MYH7), cardiac myosin-binding protein C (MYBPC3) and cardiac troponin T gene (TNNT2) were screened with PCR and direct sequencing technique. Clinical information from all patients was also evaluated in regard to the genotype. Mutations were found in 5 out of 10 pedigrees. Mutations in MYH7 (Arg663His, Glu924Lys and Ile736Thr) were found in 3 pedigrees and 3 patients from these pedigrees suffered sudden death at age 20-48 years old during sport. Mutations in MYBPC3 were found in 2 pedigrees, 1 with complex mutation (Arg502Trp and splicing mutation IVS27 + 12C > T) and 1 with novel frame shift mutation (Gly347fs) and the latter pedigree has sudden death history. No mutation was identified in TNNT2. Although the Han Chinese is a relatively homogeneous ethnic group, different HCM gene mutations were responsible for familiar HCM suggesting the heterogeneity nature of the disease-causing genes and HCM MYH7 mutations are associated with a higher risk of sudden death in this cohort. Furthermore, identical mutation might result in different phenotypes suggesting that multiple factors might be involved in the pathogenesis of familiar HCM. Show less

To explore the disease-causing gene mutation in Chinese with hypertrophic cardiomyopathy (HCM). The peripheral venous blood samples were collected from 5 HCM families without consanguinity, including 5 probands, 2 males and 3 females, 28 sporadic HCM patients, 18 males and 10 females, and 80 healthy controls. The exons in the functional regions of cardiac myosin-binding protein C (MYBPC3) were amplified with PCR and the amplified products were sequenced. A frame shift mutation-Arg346fs mutation in exon 13, the first mutation identified in Chinese-was discovered in one family with HCM. However, the members of the same HCM family with the Arg346fs mutation showed differences in phenotype and prognosis. Cardiac myosin-binding protein C (MYBPC3) may be one of the main disease-causing genes. The heterogeneity of phenotype suggests that multiple factors may be involved in the pathogenesis. Show less