👤 Guang-Da Xiang

Diabetes mellitus (DM) affects bone metabolism and causes osteoporosis. Musashi 1 (MSI1), a member of the Musashi family, regulates protein expression by targeting protein mRNA and has been reported to play an important role in osteogenic differentiation. Therefore, this paper attempts to explore the role of MSI1 in diabetic osteoporosis and discussing its specific mechanism. The glucose concentration for high glucose (HG) and control MC3T3-E1 cells were 30 and 5.5 mM. MC3T3-E1 cells induced by high glucose (HG) were used to simulate diabetic osteoporosis in vivo. The interaction between MSI1 and microtubule actin crosslinking factor 1 (MACF1) was confirmed by RNA Immunoprecipitation (RIP). The mRNA and protein expressions of MSI1 and MACF1 in MC3T3-E1 cells and HG-induced MC3T3-E1 cells after indicated transfection were tested by Real-time quantitative polymerase chain reaction (RT-qPCR) assay and western blot. After transfection, the proliferation, apoptosis, and osteogenic differentiation of HG-induced MC3T3-E1 cells were detected by cell counting kit (CCK)-8, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), alkaline phosphatase (ALP) activity assay, and alizarin red staining. The expression of Wnt/β-catenin signaling pathway-related proteins in HG-induced MC3T3-E1 cells after transfection was detected by western blot. This work shows that MSI1 can combine with MACF1. The expression of MSI1 and MACF1 was increased in HG-induced MC3T3-E1 cells. Upregulation of MSI1 promoted the proliferative and differentiative capabilities, but inhibited the apoptosis of HG-insulted MC3T3-E1 cells, which could be reversed by MACF1 knockdown. MSI1 stabilizes MACF1 to suppress apoptosis and promote osteogenic differentiation in HG-induced MC3T3-E1 cells by inhibiting Wnt/β-catenin signaling pathway. Show less

Tubulin polymerization promoting protein 3 (TPPP3), a member of the tubulin polymerization family, participates in cell progressions in several human cancers, its biological function and the underlying mechanisms in glioblastoma multiforme (GBM) remain unclear. Here, we investigated the role and application value of TPPP3 in gliomas and found that the expression of TPPP3 in glioma was higher than that in normal brain tissue (NBT), and increased with the grade of glioma. Up-regulation of TPPP3 expression in glioblastoma cells confer stronger ability of migration, invasion, proliferation and lower apoptosis in vitro. Inhibition of TPPP3 expression in GBM could reduce the migration, invasion, proliferation and induce the apoptosis of glioblastoma cells. TPPP3 affected the process of EMT by regulating the expression of Snail 1 protein. In clinical data analysis, we found a positive correlation between TPPP3 and Snail1 protein expression levels in glioblastomas. Low TPPP3 expression leads to better survival expectations in glioblastomas patients. The content of this study paves the way for further in-depth exploration of the role of TPPP3 in glioblastoma in the future, and provides new treatment and research directions. Show less

African swine fever virus (ASFV) causes a devastating viral hemorrhagic disease in domestic pigs and Eurasian wild boars, posing a foremost threat to the swine industry and pig farming. The development of an effective vaccine is urgently needed, but has been hampered by the lack of an in-depth, mechanistic understanding of the host immune response to ASFV infection and the induction of protective immunity. In this study, we report that immunization of pigs with Semliki Forest Virus (SFV) replicon-based vaccine candidates expressing ASFV p30, p54, and CD2v, as well as their ubiquitin-fused derivatives, elicits T cell differentiation and expansion, promoting specific T cell and humoral immunity. Due to significant variations in the individual non-inbred pigs in response to the vaccination, a personalized analysis was conducted. Using integrated analysis of differentially expressed genes (DEGs), Venn, KEGG and WGCNA, Toll-like receptor, C-type lectin receptor, IL17 receptor, NOD-like receptor and nucleic acid sensor-mediated signaling pathways were demonstrated to be positively correlated to the antigen-stimulated antibody production and inversely correlated to the IFN-γ secreting cell counts in peripheral blood mononuclear cells (PBMCs). An up-regulation of CIQA, CIQB, CIQC, C4BPA, SOSC3, S100A8 and S100A9, and down-regulation of CTLA4, CXCL2, CXCL8, FOS, RGS1, EGR1 and SNAI1 are general in the innate immune response post-the second boost. This study reveals that pattern recognition receptors TLR4, DHX58/DDX58 and ZBP1, and chemokines CXCL2, CXCL8 and CXCL10 may play important roles in regulating this vaccination-stimulated adaptive immune response. Show less

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P Show less

Large tumor suppressor kinase 1 (LATS1), one of the predominant components of the Hippo pathway, has been characterized as a key player controlling the proliferation and invasion of cancer cells, including gastric cancer (GC) cells. However, the mechanism by which the functional stability of LATS1 is modulated has yet to be elucidated. Online prediction tools, immunohistochemistry and western blotting assays were used to explore the expression of WW domain-containing E3 ubiquitin ligase 2 (WWP2) in GC cells and tissues. Gain- and loss-of-function assays, as well as rescue experiments were performed to determine the role of the WWP2-LATS1 axis in cell proliferation and invasion. Additionally, the mechanisms involving WWP2 and LATS1 were assessed by coimmunoprecipitation (Co-IP), immunofluorescence, cycloheximide and in vivo ubiquitination assays. Our results demonstrate a specific interaction between LATS1 and WWP2. WWP2 was markedly upregulated and correlated with disease progression and a poor prognosis in GC patients. Moreover, ectopic WWP2 expression facilitated the proliferation, migration and invasion of GC cells. Mechanistically, WWP2 interacts with LATS1, resulting in its ubiquitination and subsequent degradation, leading to increased transcriptional activity of YAP1. Importantly, LATS1 depletion abolished the suppressive effects of WWP2 knockdown on GC cells. Furthermore, WWP2 silencing attenuated tumor growth by regulating the Hippo-YAP1 pathway in vivo. Our results define the WWP2-LATS1 axis as a critical regulatory mechanism of the Hippo-YAP1 pathway that promotes GC development and progression. Video Abstract. Show less

Epithelial ovarian cancer (EOC) is a fatal gynecological malignancy. This study explored the mechanism of TAZ in regulating drug sensitivity of cisplatin (DDP-)-resistant EOC cells through the ANGPTL4/SOX2 axis. The A2780/DDP cells were prepared by stepwise progressive concentration method. The drug resistance and TAZ expression in EOC cells were determined. Drug sensitivity was measured after TAZ overexpression in A2780 cells and TAZ downregulation in A2780/DDP cells, respectively. The effects of TAZ knockdown on apoptosis rate, stemness, and cancer stem cell (CSC) marker (CD44, OCT4, and ALDH1A) levels in A2780/DDP and DDP-treated A2780/DDP cells were assessed. The binding of TAZ and ANGPTL4 was verified using ChIP-qPCR, and ANGPTL4 and SOX2 levels were determined. The effects of different combined treatments of TAZ, ANGPTL4, and SOX2 on drug sensitivity of A2780/DDP cells and DDP-treated A2780/DDP cells were evaluated. TAZ was upregulated in drug-resistant EOC cells. TAZ knockdown significantly increased the drug sensitivity of A2780/DDP cells, while TAZ overexpression markedly decreased the drug sensitivity of A2780 cells. TAZ silencing promoted apoptosis of drug-resistant EOC cells and inhibited cell stemness. TAZ targeted ANGPTL4 and TAZ silencing enhanced drug sensitivity of A2780/DDP cells by inhibiting ANGPTL4. ANGPTL4 overexpression elevated SOX2 expression, and SOX2 downregulation reduced the drug resistance and promoted the apoptosis of A2780/DDP cells. TAZ regulates DDP sensitivity of drug-resistant EOC cells via the ANGPTL4/SOX2 axis. Show less

The Apolipoprotein A5 (APOA5) rs662799 was significantly associated with blood lipid level at genome-wide significance level. Whether dynamic changes of adiposity influence the effect of lipid loci on long-term blood lipid profile remains unclear. We assessed interactions of 5-year body mass index (BMI) change and rs662799 genotypes with risk of incident dyslipidemia and longitudinal changes in serum lipids in a prospective cohort. We included 4329 non-dyslipidemia participants aged ≥ 40 years at baseline from a well-defined community-based cohort and followed up for an average of 5 years. BMI and blood lipids were measured at baseline and follow-up. The association of each rs662799 A-allele with risk of incident dyslipidemia was stronger along with the increase in BMI change level, with the odds ratios (OR) increasing from 1.03 in the lowest tertile of BMI change (< 0.02 kg/m BMI changes significantly modulate rs662799 genetic contribution to dyslipidemia and long-term lipid profile, which provide new evidence for personalized clinical management of lipids according to individual genetic background. Show less

The liver is the center for uptake, synthesis, packaging, and secretion of lipids and lipoproteins. The research on lipid metabolism in pigs is limited. The objective of the present study is to identify the genes related to lipid metabolism and oxidative stress in pigs by using transcriptomic analysis. Liver segments were collected from 60 Jinhua pigs for the determination of liver lipid content. The 7 pigs with the highest and lowest liver lipid content were set as group H and group L, respectively. Liver segments and serum samples were collected from each pig of the H and L groups for RNA sequencing and the determination of triglycerides (TG) content and high-density lipoprotein cholesterol (HDL) content, respectively. The HDL content in the serum of pigs in the H group was significantly higher than the L group ( Show less

Pancreatic cancer (PC) is a lethal type of cancer for which effective therapies are limited. Long non‑coding RNAs (lncRNAs) represent a critical type of regulator category, mediating the tumorigenesis and development of various tumor types, including PC. However, the expression patterns and functions of numerous lncRNAs in PC remain poorly understood. In the present study, linc01614 was identified as a PC‑related lncRNA. linc01614 was notably upregulated in PC tissues and cell lines and was associated with the poor disease‑free survival of patients with PC according to the analysis of The Cancer Genome Atlas‑derived datasets. Functionally, linc01614 knockdown suppressed PC cell proliferation, migration and invasion Show less

Aberrant expression of tripartite motif 11 (TRIM11) and the Wnt/ To investigate the molecular changes linking the dysregulation of TRIM11 and Wnt/ The expression levels of TRIM11 were detected in GC tissues and cells by immunohistochemistry and western blotting. The role of TRIM11 in the growth, proliferation, and invasion of gastric cancer cells was observed by a series of cell functional experiments and further verified in vivo. Co-immunoprecipitation (Co-IP), immunofluorescence, cycloheximide, and western blotting assays and other experiments were conducted to explore the mechanisms of TRIM11 underlying the regulation of the Wnt/ Using Co-IP assays, we identified TRIM11 as a potent binding partner of Axin1 in GC cells. Elevated TRIM11 levels were significantly correlated with unfavorable clinical outcomes and poor survival in patients with GC. In addition, TRIM11 promoted the cell proliferation and invasion capacities of GC cells in vitro and tumor growth in vivo. Mechanistic investigations revealed that TRIM11 destabilized Axin1 protein by interacting with Axin1, thus inducing the activation of the Wnt/ Collectively, our findings not only establish a pivotal TRIM11-Axin1- Show less

β-Secretase (BACE1) is the vital enzyme in the pathogenic processes of Alzheimer's disease (AD). However, the development of a powerful tool with sensitivity for BACE1 determination in vivo is a challenge. A novel NIR fluorescent probe HBAE was synthetized from 2-hydroxy-3-methylbenzaldehyde and 2-amino-benzenethiol by 5 steps. The fluorescence mechanism in the ESIPT systems of HBAE probe was insighted with time-dependent density functional theory (TD-DFT) at the TDPBE0 level with the def2-TZVP approach. The corresponding docking between HBAE and BACE1 (PDB: 5I3Y) was performed through the ducking method by DOCK6.8. Then the BBB permeability of HBAE is verified by transwell orifice plate. 22-month-old male AD-model (5XFAD) mice and age-matched wild-type mice were employed to observe the brain kinetics by intravenous injection. Finally, Immunohistochemistry was performed on the AD brain section to reveal the levels of BACE1 in hippocampus and cortex areas and other regions in AD mice through the brain tissue slices by HBAE. The NIR fluorescent probe HBAE was successfully applied in imaging BACE1 in AD model mice. The capability of HBAE in reflecting different level of BACE1 was performed by the specific imaging of the hippocampus region. We reported the first ESIPT near-infrared fluorescence probe HBAE for monitoring endogenous BACE1 in the AD live model mice, thus offering a versatile chemical tool for visualizing in the pathological processes of AD live brains. Remarkably, high resolution images showed the localization of red fluorescence stains in hippocampus of the AD brain. This study provides a promising way for functional insights from protein BACE1 in vivo. Show less

Despite advances in colorectal cancer (CRC) treatment, most advanced CRC patients who experience disease progression after chemotherapy, targeted therapy, and immunotherapy face a situation in which there is no available medicine. Thus, new therapeutic drugs for CRC are urgently needed. Studies have shown that cholesteryl ester transfer protein (CETP) has a vital role in tumor development and is a possible target for CRC therapy. We found that Evacetrapib, a CETP inhibitor, suppressed CRC cell growth by inhibiting the Wnt/β-catenin signaling pathway and activating the c-Jun NH2-terminal kinase (JNK) signaling pathway in CRC. Therefore, Evacetrapib displays an anti-cancer effect and is a possible option for treating CRC. Show less

The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese subjects. This is a multi-center study in China, including three hospitals from Beijing, Nanchang, and Changsha. Healthy Chinese subjects aged 18-45 years with unknown genotypes were included. All subjects received a single oral dose of 90 mg of ticagrelor. Platelet aggregation and the area under the concentration-time curve for ticagrelor and its major active metabolite in plasma samples were assessed. Genome-wide association studies and candidate gene association analysis related to ticagrelor were performed. One hundred and seventy-five native Chinese subjects were enrolled and completed the study. According to the p value, the threshold of ticagrelor population was 6.57 × 10 Genetic variation affects the pharmacokinetics and pharmacodynamics of ticagrelor in healthy individuals. The detection of NUP153, SVEP1 gene variation will be helpful for pharmacodynamic prediction and evaluation, and the regulation of these genes may be the target of new drug development. Further studies are required to confirm the results and explore whether these single-nucleotide polymorphisms are associated only with platelet activity or also with cardiovascular events and all-cause mortality. NCT03161002. Show less

Early diagnosis and prognosis evaluation are of great significance to hepatitis E virus (HEV)-related acute liver failure (HEV-ALF) patients. We collected serum samples from 200 health controls (HCs), 200 patients with acute hepatitis E (AHE), and 200 HEV-ALF patients to evaluate serum exosome-derived carbamoyl phosphate synthase 1 (CPS1) levels and determine its diagnostic and prognostic value. The exosome-derived CPS1 levels in the HEV-ALF group were significantly higher than those in the AHE and HCs groups. The AUC of exosome-derived CPS1 to predict the occurrence of HEV-ALF was 0.850 (0.811-0.883). Both logistical regression and orthogonal partial least squares discriminant analysis (OPLS-DA) showed that exosome-derived CPS1 is an independent risk factor for HEV-ALF. The exosome-derived CPS1 levels were positively correlated with organ failure and the outcomes in HEV-ALF patients. The exosome-derived CPS1 levels in the worsening group were significantly higher than those in the fluctuating and the improving groups. The AUC of serum exosome-derived CPS1 to predict 30-day mortality was 0.829 (0.770-0.879), which was significantly greater than that of the Child-Pugh, KCH, and MELD models. The level of serum exosome-derived CPS1 might serve as a promising diagnostic and prognostic biomarker for HEV-ALF patients, which may provide better guidance for the diagnosis, prognosis, and treatment of HEV-ALF patients. Show less

Dabieshan cattle are a typical breed of southern Chinese cattle that have the characteristics of muscularity, excellent meat quality and tolerance to temperature and humidity. Based on 148 whole-genome data, our analysis disclosed the ancestry components of Dabieshan cattle with Chinese indicine (0.857) and East Asian taurine (0.139). The Dabieshan genome demonstrated a higher genomic diversity compared with the other eight populations, supported by the observed nucleotide diversity, linkage disequilibrium decay and runs of homozygosity. The candidate genes were detected by a selective sweep, which might relate to the fertility ( Show less

Sudden cardiac death (SCD), based on sudden cardiac ejection cessation, is an unexpected death. Primary cardiomyopathies, including dilated cardiomyopathy (DCM), are one of main causes of SCD. The DCM is characterized by a cardiac dilatation and a reduced systolic function with a prevalence of 1/250 in adults. The DCM has been reported with more than 60 disease-causing genes, and We identified a 29-year-old female who died of SCD. We performed a whole-exome sequencing (WES) to detect her genetic etiology and used minigene modeling and immunohistochemistry staining to verify the pathogenicity. We determined that the woman died of SCD caused by DCM due to an identified novel synonymous variant of We may have identified the first deleterious synonymous variant of Show less

Lung adenocarcinoma (LUAD) is one of the main causes of cancer-related mortality, with a strong tendency to metastasize early. Transforming growth factor-β (TGF-β) signaling is a powerful regulator to promote metastasis of LUAD. Here, we screened long non-coding RNAs (lncRNAs) responsive to TGF-β and highly expressed in LUAD cells, and finally obtained our master molecular LINC00152. We proved that the TGF-β promoted transcription of LINC00152 through the classical TGF-β/SMAD3 signaling pathway and maintained its stability through the RNA-binding protein HuR. Moreover, LINC00152 increased ZEB1, SNAI1 and SNAI2 expression via increasing the interactions of HuR and these transcription factors, ultimately promoting epithelial-mesenchymal transition of LUAD cell and enhancing LUAD metastasis in vivo. These data provided evidence that LINC00152 induced by TGF-β promotes metastasis depending HuR in lung adenocarcinoma. Designing targeting LINC00152 and HuR inhibitors may therefore be an effective therapeutic strategy for LUAD treatment. Show less

Blood-brain barrier (BBB) injury is involved in the pathogenesis of sepsis-associated encephalopathy. In this study, we used dihydroartemisinin (DHA), a derivative of artemisinin, to treat a cecal ligation and puncture (CLP)-induced mouse sepsis model and a tumour necrosis factor α (TNF-α)-stimulated human cerebral microvessel endothelial cells (hCMEC)/D3 cell line. We found that DHA decreased BBB permeability and increased the expression of the tight junction protein occludin (OCLN) in the CLP model. In hCMEC/D3 cells, DHA decreased TNF-α-induced hyperpermeability and increased the expression of OCLN. DHA also repressed SNAI1 expression in the CLP mouse model and in TNF-α-stimulated hCMEC/D3 cells. These data suggest that DHA protects BBB permeability during sepsis by stimulating the expression of OCLN, by downregulating the expression of the SNAI1 transcription factor. Show less

The melanocortin receptors (MCRs) are important for numerous biological pathways, including feeding behavior and energy homeostasis. In addition to endogenous peptide agonists, this receptor family has two naturally occurring endogenous antagonists, agouti and agouti-related protein (AGRP). At the melanocortin-4 receptor (MC4R), the AGRP ligand functions as an endogenous inverse agonist in the absence of agonist and as a competitive antagonist in the presence of agonist. At the melanocortin-3 receptor (MC3R), AGRP functions solely as a competitive antagonist in the presence of agonist. The molecular interactions that differentiate AGRP's inverse agonist activity at the MC4R have remained elusive until the findings reported herein. Upon the basis of homology molecular modeling approaches, we previously postulated a unique interaction between the D189 position of the hMC4R and Asn114 of AGRP. To further test this hypothesis, six D189 mutant hMC4Rs (D189A, D189E, D189N, D189Q, D189S, and D189K) were generated and pharmacologically characterized resulting in the discovery of differences in inverse agonist activity of AGRP and an 11 macrocyclic compound library. These data support the hypothesized interaction between the hMC4R D189 position and Asn114 residue of AGRP and define critical ligand-receptor molecular interactions responsible for the inverse agonist activity of AGRP at the hMC4R. Show less

Asprosin, coiled-coil domain-containing 80(CCDC80) and angiopoietin-like4(ANGPTL4) are newly discovered adipocytokine that affects glucose tolerance, insulin resistance and cardiovascular diseases. The goal of this study was to investigate if a relationship exists among asprosin, CCDC80 and ANGPTL4 and inflammatory bowel disease (IBD). Fifty subjects with newly diagnosed IBD and fifty healthy individuals were enrolled. Patients were treated with standard therapies for 3 months. Plasma asprosin, CCDC80 and ANGPTL4 levels were measured with enzyme-linked immunosorbent assay. High resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperemia (flow-mediated dilation, FMD) and after sublingual glyceryltrinitrate.Compare with healthy individuals, plasma CCDC80,erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and homeostasis modelassessment of insulin resistance (HOMA-IR) were significantly higher (p < 0.05, respectively), whereas plasma asprosin,ANGPTL4 levels and FMD were significantly lower inboth UC and CD patients(p <0.05). Plasma CCDC80 levels were significantly higher in patients with CD (p<0.05), while plasma asprosin and ANGPTL4 levels were lower (p<0.05) as compared with those in patients with UC. Standard therapies increased plasma asprosin, ANGPTL4 levels and FMD in both UC and CD (p<0.05),UC and CD patientswhile decreased plasma CCDC80, ESR, CRP levels and HOMA-IR (p<0.05). The changes in HOMA-IR and FMD were correlated with the changes in plasma asprosin, CCDC80 and ANGPTL4 levels over the study period (p<0.05). Plasma asprosin, CCDC80 and ANGPTL4 levels may be applied as a significant marker for early stage of insulin resistance and atherosclerosis in IBD, especially of CD. Show less

Carbamoyl phosphate synthetase 1 (CPS1), which is the antigen for the hepatocyte paraffin 1 antibody, exhibits focal immunoreactivity in adenocarcinoma from the gastrointestinal tract, but its expression profiles and roles in gastric cancer (GC) remain largely unknown. The present study aimed to determine the expression pattern and prognostic value of CPS1 in Correa's cascade using tissues from 32 patients with chronic atrophic gastritis with intestinal metaplasia (IM), 62 patients with low- or high-grade intraepithelial neoplasia (IN) and 401 patients with GC. The expression of CPS1 was diffuse and strongly positive in 32 cases (100%) of IM of the glandular epithelium, and gradually downregulated in Correa's cascade, with a strongly positive ratio of 21 (70%) in low-grade IN and 4 (12.5%) in high-grade IN. The levels of CPS1 expression were significantly higher in diffuse-type GC, with 37 (26%) cases strongly positive for CPS1, compared with 14 (8%) in intestinal-type and 11 (13%) cases in mixed-type GC. In intestinal-type GC, CPS1 expression was completely lost in 107 (62%) of cases, which was associated with an advanced Tumor-Node-Metastasis stage (P=0.031) and depth of invasion (P=0.037). Kaplan-Meier analysis suggested that low CPS1 expression levels were independently associated with a short overall survival (OS) time in the three types of GC (P<0.001 in intestinal-type, P=0.003 in diffuse-type and P=0.018 in mixed-type GC). Furthermore, low levels of CPS1 mRNA and high methylation levels in the CPS1 promoter were associated with a short OS time in patients with GC. These results suggested that the expression of CPS1 was progressively downregulated in Correa's cascade, and that CPS1 may serve as a prognostic marker for patients with GC, regardless of tumor type. Show less

Hereditary multiple exostoses (HME), also referred to as multiple osteochondromas, is an autosomal dominant skeletal disease characterized by the development of multiple overgrown benign bony tumors capped by cartilage and is associated with bone deformity, joint limitation, and short stature. Mutations in exostosin glycosyltransferase (EXT)1 and EXT2 genes, which are located on chromosomes 8q24.1 and 11p13, contribute to the pathogenesis of HME. In the present study, a genetic analysis of a four-generation Chinese family with HME was conducted using whole-exome sequencing (WES), followed by validation using Sanger sequencing. A novel heterozygous frameshift mutation in exon 5 of EXT2 (c.944dupT, p.Leu316fs) was identified in all affected individuals but was not detected in any unaffected individuals. This mutation results in a frameshift that introduces a premature termination codon at position 318 (p.Leu316fs) with the ability to produce a truncated EXT2 protein that lacks the last 433 amino acids at its C-terminal to indicate a defective exostosin domain and the absence of the glycosyltransferase family 64 domain, or to lead to the degradation of mRNAs by nonsense-mediated mRNA decay, which is critical for the function of EXT2. Our results indicate that WES is effective in extending the EXT mutational spectra and is advantageous for genetic counseling and the subsequent prenatal diagnosis. Show less

Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder, which typically manifests as skeletal dysplasia, mainly involving long bones and knees, ankles, elbows, wrists, shoulders, and pelvis. Previous studies have demonstrated that mutations in exostosin glycosyl transferase-1 ( Show less

17β Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is the key enzyme in the biosynthesis of testosterone, which is an attractive therapeutic target for prostate cancer (PCa). H10, a novel curcumin analogue, was identified as a potential 17β-HSD3 inhibitor. The pharmacokinetic study of H10 in rats were performed by intraperitoneal (i.p.), intravenous (i.v.) and oral (p.o.) administration. In addition, the inhibitory effects of H10 against liver CYP3A4 were investigated in vitro using human liver microsomes (HLMs). The acute and chronic toxicological characteristics were characterized using single-dose and 30 d administration. All the mice were alive after i.p. H10 with dose of no more than 100 mg/kg which are nearly the maximum solubility in acute toxicity test. The pharmacokinetic characteristics of H10 fitted with linear dynamics model after single dose. Furthermore, H10 could bioaccumulate in testis, which was the target organ of 17β-HSD3 inhibitor. H10 distributed highest in spleen, and then in liver both after single and multiple i.p. administration. Moreover, H10 showed weak inhibition towards liver CYP3A4, and did not cause significant changes in aspartate transaminase (AST) and alanine transaminase (ALT) levels after treated with H10 for continuously 30 d. Taken together, these preclinical characteristics laid the foundation for further clinical studies of H10. Show less

Our objective was to examine differences in cytokine/chemokine response in chronic hepatitis B(CHB) patients to understand the immune mechanism of HBsAg loss (functional cure) during antiviral therapy. We used an unbiased machine learning strategy to unravel the immune pathways in CHB nucleo(t)side analogue-treated patients who achieved HBsAg loss with peg-interferon-α(peg-IFN-α) add-on or switch treatment in a randomised clinical trial. Cytokines/chemokines from plasma were compared between those with/without HBsAg loss, at baseline, before and after HBsAg loss. Peg-IFN-α treatment resulted in higher levels of IL-27, IL-12p70, IL-18, IL-13, IL-4, IL-22 and GM-CSF prior to HBsAg loss. Probabilistic network analysis of cytokines, chemokines and soluble factors suggested a dynamic dendritic cell driven NK and T cell immune response associated with HBsAg loss. Bayesian network analysis showed a dominant myeloid-driven type 1 inflammatory response with a MIG and I-TAC central module contributing to HBsAg loss in the add-on arm. In the switch arm, HBsAg loss was associated with a T cell activation module exemplified by high levels of CD40L suggesting T cell activation. Our findings show that more than one immune pathway to HBsAg loss was found with peg-IFN-α therapy; by myeloid-driven Type 1 response in one instance, and T cell activation in the other. Show less

Vaccines stimulate various immune factors critical to protective immune responses. However, a comprehensive picture of vaccine-induced immune factors and pathways have not been systematically collected and analyzed. To address this issue, we developed VaximmutorDB, a web-based database system of vaccine immune factors (abbreviated as "vaximmutors") manually curated from peer-reviewed articles. VaximmutorDB currently stores 1,740 vaccine immune factors from 13 host species (e.g., human, mouse, and pig). These vaximmutors were induced by 154 vaccines for 46 pathogens. Top 10 vaximmutors include three antibodies (IgG, IgG2a and IgG1), Th1 immune factors (IFN-γ and IL-2), Th2 immune factors (IL-4 and IL-6), TNF-α, CASP-1, and TLR8. Many enriched host processes (e.g., stimulatory C-type lectin receptor signaling pathway, SRP-dependent cotranslational protein targeting to membrane) and cellular components (e.g., extracellular exosome, nucleoplasm) by all the vaximmutors were identified. Using influenza as a model, live attenuated and killed inactivated influenza vaccines stimulate many shared pathways such as signaling of many interleukins (including IL-1, IL-4, IL-6, IL-13, IL-20, and IL-27), interferon signaling, MARK1 activation, and neutrophil degranulation. However, they also present their unique response patterns. While live attenuated influenza vaccine FluMist induced significant signal transduction responses, killed inactivated influenza vaccine Fluarix induced significant metabolism of protein responses. Two different Yellow Fever vaccine (YF-Vax) studies resulted in overlapping gene lists; however, they shared more portions of pathways than gene lists. Interestingly, live attenuated YF-Vax simulates significant metabolism of protein responses, which was similar to the pattern induced by killed inactivated Fluarix. A user-friendly web interface was generated to access, browse and search the VaximmutorDB database information. As the first web-based database of vaccine immune factors, VaximmutorDB provides systematical collection, standardization, storage, and analysis of experimentally verified vaccine immune factors, supporting better understanding of protective vaccine immunity. Show less

Insulin-independent glucose metabolism, including anaerobic glycolysis that is promoted in resistance training, plays critical roles in glucose disposal and systemic metabolic regulation. However, the underlying mechanisms are not completely understood. In this study, through genetically manipulating the glycolytic process by overexpressing human glucose transporter 1 (GLUT1), hexokinase 2 (HK2) and 6-phosphofructo-2-kinase-fructose-2,6-biphosphatase 3 (PFKFB3) in mouse skeletal muscle, we examined the impact of enhanced glycolysis in metabolic homeostasis. Enhanced glycolysis in skeletal muscle promoted accelerated glucose disposal, a lean phenotype and a high metabolic rate in mice despite attenuated lipid metabolism in muscle, even under High-Fat diet (HFD). Further study revealed that the glucose metabolite sensor carbohydrate-response element-binding protein (ChREBP) was activated in the highly glycolytic muscle and stimulated the elevation of plasma fibroblast growth factor 21 (FGF21), possibly mediating enhanced lipid oxidation in adipose tissue and contributing to a systemic effect. PFKFB3 was critically involved in promoting the glucose-sensing mechanism in myocytes. Thus, a high level of glycolysis in skeletal muscle may be intrinsically coupled to distal lipid metabolism through intracellular glucose sensing. This study provides novel insights for the benefit of resistance training and for manipulating insulin-independent glucose metabolism. Show less

Age-related macular degeneration (AMD) is a common cause of vision loss. The epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, accompanied by oxidative damage, plays a crucial role in AMD. It is well known that manganese superoxide dismutase (MnSOD) encoded by SOD2 is a critical molecule in fighting against oxidative stress, and Snail encoded by SNAI1 is the essential transcription factor for EMT. However, the effect of MnSOD on EMT and the underlying mechanism in RPE cells remains unknown. In this study, we found that MnSOD knockdown triggered the EMT by upregulating Snail, while MnSOD overexpression reversed EMT even with TGFβ treatment in RPE cells, and the anti-oxidative stress activity of MnSOD mediated this observation. In addition, Snail depletion increased both expression and activity of MnSOD while Snail overexpression decreased MnSOD expression and activity, and Dual-luciferase reporter and ChIP assays showed that Snail directly bound to E-box (CACCTG) in the SOD2 promoter. Moreover, MnSOD over-expression and Snail interference co-treatment strengthened the anti-oxidation and EMT reversing. Therefore, our findings demonstrate that MnSOD prevents EMT of RPE cells in AMD through inhibiting oxidative injury to RPE. Moreover, a critical EMT transcription factor, Snail, functions as a new negative transcriptional factor of SOD2. Herein, the Snail-MnSOD axis forms a mutual loop in the development of AMD, which may be a novel systemic treatment target for preventing AMD. Show less

Long noncoding RNAs (lncRNAs) are currently considered to have a vital and wide range of biological functions, but the molecular mechanism underlying triglycerides metabolism remains poorly understood. This study aims to identify novel lncRNAs differentially expressed in rat livers with hypertriglyceridemia and elucidated the function role in TG metabolism. Differentially expressions of lncRNAs in rat livers with hypertriglyceridemia were identified by transcriptome sequencing and validated by real-time PCR. The role of lnc19959.2 in triglyceride metabolism was assessed both in vitro and in vivo. RNA pulldown and RIP assays were conducted to evaluate the interactions between lnc19959.2 and its target proteins. ChIP and Dual report assays were performed to detect the interactions between transcription factors and promoters of its target genes. We identified a novel lncRNA, and lnc19959.2 was upregulated in rat livers with hypertriglyceridemia. The knockdown of lnc19959.2 has profound TG lowering effects in vitro and in vivo. Subsequently, the genome-wide analysis identified that the knockdown of lnc19959.2 caused the deregulation of many genes during TG homeostasis. Further mechanism studies revealed that lnc19959.2 upregulated ApoA4 expression via ubiquitinated transcription inhibitor factor Purb, while it specifically interacted with hnRNPA2B1 to downregulate the expression of Cpt1a, Tm7sf2, and Gpam, respectively. In the upstream pathway, palmitate acid upregulated CCAAT/Enhancer-Binding Protein Beta (Cebpb) and facilitated its binding to the promoter of lnc19959.2, which resulted in significant promotion of lnc19959.2 transcriptional activity. Our findings provide novel insights into a new layer regulatory complexity of an lncRNA modulating triglyceride homeostasis by a novel lncRNA lnc19959.2. Show less