Neuromuscular junction is a synapse between motoneurons and skeletal muscles, where acetylcholine receptors (AChRs) are concentrated to control muscle contraction. Studies of this synapse have contrib Show more
Neuromuscular junction is a synapse between motoneurons and skeletal muscles, where acetylcholine receptors (AChRs) are concentrated to control muscle contraction. Studies of this synapse have contributed to our understanding of synapse assembly and pathological mechanisms of neuromuscular disorders. Nevertheless, underlying mechanisms of NMJ formation was not well understood. To this end, we took a novel approach - studying mutant genes implicated in congenital myasthenic syndrome (CMS). We showed that knock-in mice carrying N88K, a prevalent CMS mutation of Rapsyn (Rapsn), died soon after birth with profound NMJ deficits. Rapsn is an adapter protein that bridges AChRs to the cytoskeleton and possesses E3 ligase activity. In investigating how N88K impairs the NMJ, we uncovered a novel signaling pathway by which Agrin-LRP4-MuSK induces tyrosine phosphorylation of Rapsn, which is required for its self-association and E3 ligase activity. Our results also provide insight into pathological mechanisms of CMS. Show less
The current study reports a new, simple and fast method using a flake-like dysprosium molybdate (Dy2MoO6; FL-DyM) nanostructured material to detect the antibiotic drug metronidazole (METZ). This nanoc Show more
The current study reports a new, simple and fast method using a flake-like dysprosium molybdate (Dy2MoO6; FL-DyM) nanostructured material to detect the antibiotic drug metronidazole (METZ). This nanocomposite material was employed on the surface of a glassy carbon electrode (GCE) to develop the electrode (FL-DyM/GCE). Further, the synthesized FL-DyM was systematically characterized by powder X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray diffraction (EDS), elemental mapping, X-ray photoelectron spectroscopy (XPS), and Brunauer-Emmett-Teller (BET) analyses. Cyclic (CV) and differential pulse voltammetry (DPV) techniques were used to study the electrochemical properties. The FL-DyM/GCE-based sensor demonstrated excellent selectivity and sensitivity for the detection of the drug METZ, which could be attributed to the strong affinity of FL-DyM towards the -NO2 group in METZ, and the good electrocatalytic activity and conductivity of FL-DyM. The fabrication and optimization of the working electrode were accomplished with CV and DPV obtained by scan rate and pH studies. Compared to the bare GCE and other rare-earth metal molybdates, the FL-DyM/GCE sensor displayed a superior electrocatalytic activity response for METZ detection. The sensor demonstrated a good linear relationship over the concentration range of 0.01-2363 μM. The quantification and detection limits were found to be 0.010 μM and 0.0030 μM, respectively. The FL-DyM/GCE sensor displayed excellent selectivity, repeatability, reproducibility, and stability for the detection of METZ in human urine and commercial METZ tablet samples, which validates the new technique for efficient drug sensing in practical applications. Show less
Xianpeng Shi, Man Zhu, Yuan Kang+3 more · 2018 · Phytomedicine : international journal of phytotherapy and phytopharmacology · Elsevier · added 2026-04-24
Colorectal cancer remains the third most common malignancies and migration is one of the main factors for its high mortality rate. Brucine, a natural plant alkaloid, has been proved to possess a varie Show more
Colorectal cancer remains the third most common malignancies and migration is one of the main factors for its high mortality rate. Brucine, a natural plant alkaloid, has been proved to possess a variety of pharmacological functions including anti-tumor activities. The aim of this study was to investigate the inhibitory effect of brucine on the colorectal cancer and the underlying mechanism. In this study, colony formation assay and transwell assay were used to investigate the effect of brucine on LoVo cells viability and migration. Immunofluorescence assay, western blot assay and Gelatin zymography assay were used to study the mechanism of brucine. Xenograft model in nude mice was induced to investigate the in vivo effect of brucine on LoVo cells. Brucine could significantly decrease the viability, inhibit the colony formation and induce the apoptosis of LoVo cells. Brucine could also suppress the migration of LoVo cells in a dose-dependent manner. Western blot analysis elucidated that the inhibition of migration was associated with the decreasing expression of matrix metalloproteinases including MMP2, MMP3 and MMP9. Moreover, we found that treatment of brucine could downregulate the expression of Frizzled-8, Wnt5a, APC and GSNK1A1, and increase the expression of AXIN1. Meanwhile, brucine also decreased the phosphorylation level of LRP5/6 and GSK3β, and increased the level of p-β-catenin. Xenografted model in nude mice study also revealed that oral administration of brucine could inhibit the growth and migration of LoVo cells by activating the expression of AXIN1 and p-β-catenin. Brucine could suppress the migration of the colorectal cancer in vitro and in vivo and the effect was associated with the inhibition of the Wnt/β-catenin signaling pathway. Show less
Screening and identifying the gene mutation of EXT1, EXT2 and EXT3 associated with multiple exostosis (ME) and the expression in tumor tissues. Nine patients with multiple exostosis were collected and Show more
Screening and identifying the gene mutation of EXT1, EXT2 and EXT3 associated with multiple exostosis (ME) and the expression in tumor tissues. Nine patients with multiple exostosis were collected and genomic DNA was extracted. Polymerase chain reaction (PCR) amplification and direct sequencing techniques were used to screen all exons, 5' and 3' ends of the EXT1, EXT2 and EXT3 related causative genes. EXT1, EXT2 and EXT3 gene were screened and quantified by RNA-SEQ and RT-qPCR. The concentration of calcitonin gene-related peptide (CGRP) in peripheral blood of tumor patients and normal controls was detected by ELISA. Between the two patients with ME, the EXT1 gene was found in one patient to have c.79 T>A mutation, which caused the change of p.M27T, the non polar methionine was replaced by the high frequency mutation of polar threonine, and the rest of patients was found the splicing mutation c.1284 + 8 delAT of the heterozygosity of the EXT1 gene. The serum CGRP concentration of ME patients (623 + 49 pg/ml) was significantly higher than that of normal controls (196 + 68 pg/ml), and EXT1 mutation patients were also higher than non mutation patients. Show less
To characterize the association between epilepsy, use of antiepileptic drugs (AEDs), and the risk of hyperlipidemia, we conducted a nationwide population-based cohort study with data obtained from the Show more
To characterize the association between epilepsy, use of antiepileptic drugs (AEDs), and the risk of hyperlipidemia, we conducted a nationwide population-based cohort study with data obtained from the National Health Insurance Research Database of Taiwan. The effects of AEDs on lipogenic gene expression were also examined in vitro. We identified 3617 cases involving patients, whose epilepsy was newly diagnosed between 2000 and 2011, and selected a comparison cohort comprising 14,468 patients without epilepsy. The Cox proportional hazards model was used to evaluate the association between epilepsy, AED use, and hyperlipidemia. The incidence rate of hyperlipidemia was higher in the epilepsy cohort than in the comparison cohort, with an adjusted hazard ratio (aHR) of 1.21 [95% confidence interval (CI): 1.06-1.38] after adjusting for comorbidities and medications. Epilepsy patients not taking AEDs had a higher risk of hyperlipidemia (aHR 1.65; 95% CI 1.35-2.03). Among AEDs, only valproate treatment showed a higher risk of hyperlipidemia (aHR 1.53; 95% CI 1.01-2.33), although the dose-dependent effect did not reach statistical significance. In vitro studies with two hepatic cell lines showed that valproate may exert its effects by activating the liver X receptor alpha (LXRα) signaling pathway, inducing the expression of lipogenesis-related genes and increasing cellular lipid contents. In silico calculations concluded that valproate can bind stably with the ligand-binding domain of LXRα. Thus, valproate-induced hepatic lipogenic gene expression may occur through LXRα activation. Predicting the 'off-target' effects of valproate may prove valuable in developing antiepileptic agents with fewer adverse reactions. Monitoring blood lipid levels throughout the course of treatment is recommended. Show less
Plant growth and development are highly coordinated by hormones, including brassinosteroid (BR) and gibberellin (GA). Although much progress has been made in understanding the fundamental signaling tr Show more
Plant growth and development are highly coordinated by hormones, including brassinosteroid (BR) and gibberellin (GA). Although much progress has been made in understanding the fundamental signaling transduction in BR and GA, their relationship remains elusive in rice. Here, we show that BR suppresses the level of OsmiR159d, which cleaves the target OsGAMYBL2 gene. The OsmiR159d-OsGAMYBL2 pair functions as an early BR-responsive module regulating the expression of BU1, a BR-regulated gene involved in BR signaling, and CPS1 and GA3ox2, two genes in GA biosynthesis, by binding to the promoters of these genes. Furthermore, OsGSK2, a key negative player in BR signaling, interacts with OsGAMYBL2 and prevents it from being degraded under 24-epibrassinolide treatment, whereas SLR1, a rice DELLA protein negatively regulating GA signaling, interacts with OsGAMYBL2 and prevents OsGAMYBL2 from binding to the target gene promoter. GA signaling induces degradation of OsGAMYBL2 and, consequently, enhances BR signaling. These results demonstrate that a BR-responsive module acts as a common component functioning in both BR and GA pathways, which connects BR signaling and GA biosynthesis, and thus coordinates the regulation of BR and GA in plant growth and development. Show less
miRs play critical roles in oxidative stress-related retinopathy pathogenesis. miR-365 was identified in a previously constructed library from glyoxal-treated rat Müller cell. This report explores epi Show more
miRs play critical roles in oxidative stress-related retinopathy pathogenesis. miR-365 was identified in a previously constructed library from glyoxal-treated rat Müller cell. This report explores epigenetic alterations in Müller cells under oxidative stress to develop a novel therapeutic strategy. To examine the miR-365 expression pattern, in situ hybridization and quantitative RT-PCR were performed. Bioinformatical analysis and dual luciferase report assay were applied to identify and confirm target genes. Streptozotocin (STZ)-treated rats were used as the diabetic retinopathy (DR) model. Lentivirus-mediated anti-miR-365 was delivered subretinally and intravitreally into the rats' eyes. The functional and structural changes were evaluated by electroretinogram (ERG), histologically, and through examination of expression levels of metallopeptidase inhibitor 3 (Timp3), glial fibrillary acidic protein (Gfap), recoverin (Rcvrn) and vascular endothelia growth factor A (Vegfa). Oxidative stress factors and pro-inflammatory cytokines were analyzed. miR-365 expression was confirmed in the glyoxal-treated rat Müller cell line (glyoxal-treated rMC-1). In the retina, miR-365 mainly localized in the inner nuclear layer (INL). The increased miR-365 participated in Müller cell gliosis through oxidative stress aggravation, as observed in glyoxal-treated rMC-1 and DR rats before 6 weeks. Timp3 was a target and negatively regulated by miR-365. When miR-365 was inhibited, Timp3 expression was upregulated, Müller cell gliosis was alleviated, and retinal oxidative stress was attenuated. Visual function was also partially rescued as detected by ERG. miR-365 was found to be highly expressed in the retina and the abnormality of miR-365/Timp3 pathway is closely related to the pathology, like Müller gliosis, and the visual injury in DR. The mechanism might be through oxidative stress, and miR-365/Timp3 could be a potential therapeutic target for treating DR. Show less
Schizophrenia (SCZ) is associated with differences in subcortical brain volumes and intracranial volume (ICV). However, little is known about the underlying etiology of these brain alterations. Here, Show more
Schizophrenia (SCZ) is associated with differences in subcortical brain volumes and intracranial volume (ICV). However, little is known about the underlying etiology of these brain alterations. Here, we explored whether brain structure volumes and SCZ share genetic risk factors. Using conditional false discovery rate (FDR) analysis, we integrated genome-wide association study (GWAS) data on SCZ (n = 82315) and GWAS data on 7 subcortical brain volumes and ICV (n = 11840). By conditioning the FDR on overlapping associations, this statistical approach increases power to discover genetic loci. To assess the credibility of our approach, we studied the identified loci in larger GWAS samples on ICV (n = 26577) and hippocampal volume (n = 26814). We observed polygenic overlap between SCZ and volumes of hippocampus, putamen, and ICV. Based on conjunctional FDR < 0.05, we identified 2 loci shared between SCZ and ICV implicating genes FOXO3 (rs10457180) and ITIH4 (rs4687658), 2 loci shared between SCZ and hippocampal volume implicating SLC4A10 (rs4664442) and SPATS2L (rs1653290), and 2 loci shared between SCZ and volume of putamen implicating DCC (rs4632195) and DLG2 (rs11233632). The loci shared between SCZ and hippocampal volume or ICV had not reached significance in the primary GWAS on brain phenotypes. Proving our point of increased power, 2 loci did reach genome-wide significance with ICV (rs10457180) and hippocampal volume (rs4664442) in the larger GWAS. Three of the 6 identified loci are novel for SCZ. Altogether, the findings provide new insights into the relationship between SCZ and brain structure volumes, suggesting that their genetic architectures are not independent. Show less
Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, Show more
Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, guide treatment, and enable cascade screening. The genetic basis among the Hong Kong Chinese population is largely unknown. We aimed to report on 28 unrelated patients with positive genetic findings detected from January 2006 to December 2015. Sanger sequencing was performed for 28 unrelated patients with a clinical diagnosis of channelopathies or cardiomyopathies, testing for the following genes: There were 17 males and 11 females; their mean age at diagnosis was 39 years (range, 1-80 years). The major clinical presentations included syncope, palpitations, and abnormal electrocardiography findings. A family history was present in 13 (46%) patients. There were 26 different heterozygous mutations detected, of which six were novel-two in We have characterised the genetic heterogeneity in channelopathies and cardiomyopathies among Hong Kong Chinese patients in a 10-year case series. Correct interpretation of genetic findings is difficult and requires expertise and experience. Caution regarding issues of non-penetrance, variable expressivity, phenotype-genotype correlation, susceptibility risk, and digenic inheritance is necessary for genetic counselling and cascade screening. Show less
Recombinant human growth hormone (rhGH) has been widely used in clinical treatment and technology has achieved a great development in different long-acting formulations. Genetic polymorphisms may play Show more
Recombinant human growth hormone (rhGH) has been widely used in clinical treatment and technology has achieved a great development in different long-acting formulations. Genetic polymorphisms may play a role in the varies of individual responses in treatment process. This article gives an overview of the genetic polymorphisms research of growth hormone in recent years. We conducted a scoping literature search of PubMed for all English-language publications to identify studies on recombinant human growth hormone and genetic polymorphism from 2000 to 2016. Included studies were all peer-reviewed primary journal articles. Two authors independently screened titles/abstracts, downloading full-text publications meeting inclusion criteria. In all, 96 studies were included and analyzed. We found that besides some well known factors ,such as races, age, gender, weight, several kinds of gene polymorphism reported ever can also affect the growth hormone response in GHD or non-GHD patients, including GHR-Exon 3, IGF(CA)19, IGFBP-3, APOB, CETP, SOCS2, VDR, LEPR and STAT5B. Serum IGF-1 is a good parameter of GH treatment response. But it is influenced by various factors, including races, age, gender, weight, initial IGF-1 level, injection concentration and frequency. Gene polymorphism research has been a research hopspot in recent years, may helping understand the pathogeny and pharmacogenomics of these response varieties during GH treatment. Show less
N-Hydroxysuccinimide (NHS)-esters are widely used to label proteins nonselectively on free amino groups. Such broad labeling can be disadvantageous because it can interfere with protein structure or f Show more
N-Hydroxysuccinimide (NHS)-esters are widely used to label proteins nonselectively on free amino groups. Such broad labeling can be disadvantageous because it can interfere with protein structure or function and because stoichiometry is poorly controlled. Here we describe a simple method to transform NHS-esters into site-specific protein labeling on N-terminal Cys residues. MESNA addition converts NHS-esters to chemoselective thioesters for N-Cys modification. This labeling strategy was applied to clarify mechanistic features of the ubiquitin E3 ligase WWP2 including its interaction with one of its substrates, the tumor suppressor PTEN, as well as its autoubiquitination molecularity. We propose that this convenient protein labeling strategy will allow for an expanded application of NHS-esters in biochemical investigation. Show less
Hypothyroidism is a disease with a genetic component. The present study aimed to identify the potential causative gene mutation in a family with hypothyroidism and to investigate its potential patholo Show more
Hypothyroidism is a disease with a genetic component. The present study aimed to identify the potential causative gene mutation in a family with hypothyroidism and to investigate its potential pathology. DNA was extracted from the affected individual and his parents, maternal aunt and maternal grandmother. Whole exome sequencing was used to examine their exomes. The potential causative genes that may have an autosomal dominant mode of inheritance were selected after variant calling and filtering. Bioinformatics analysis was utilized to predict the deleteriousness of the identified variants, and multiple sequence alignment and conserved protein domain analyses were performed using online software. Finally, Sanger sequencing was used to validate the identified variants. In the present study, a total of 50 variants were screened based on the autosomal dominant mode of inheritance. Two variants, the fatty acid synthase (FASN) and apolipoprotein B receptor (APOBR) genes, were further analyzed, as they were highly associated with hypothyroidism. Genotyping results revealed that two mutations, c.G7192T (p.A2398S) in the FASN gene and c.C1883G (p.T628R) in the APOBR gene, were fully co‑segregated with established hypothyroidism phenotypes in the family. These mutations were located in the conserved α/β‑hydrolase fold and Na+/Ca2+ exchanger superfamily domain of FASN and APOBR, respectively. In conclusion, the present study demonstrated that the FASN c.G7192T and APOBR c.C1883G mutations may be the potential causative variants in this Chinese hypothyroidism pedigree. Show less
Little is known about the association of the dedicator of cytokinesis 7 (DOCK7 rs1748195) and angiopoietin like 3 (ANGPTL3 rs12563308) single nucleotide polymorphisms (SNPs) and their haplotypes with Show more
Little is known about the association of the dedicator of cytokinesis 7 (DOCK7 rs1748195) and angiopoietin like 3 (ANGPTL3 rs12563308) single nucleotide polymorphisms (SNPs) and their haplotypes with serum lipid levels and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Chinese populations. This study aimed to detect such association in a Southern Chinese Han population. This study included 1728 subjects (CAD, 568; IS, 539; and controls, 621). Genotypes of the two SNPs were determined by the Snapshot technology. The genotypic and allelic frequencies of the rs1748195 SNP were different between CAD patients and controls (P < 0.05 for each), the rs1748195G allele frequency was higher in CAD patients than in controls (27.6% vs. 23.6%, P = 0.024). The genotypic frequencies of the rs12563308 SNP were also different between CAD patients and controls (P = 0.021). The rs1748195 SNP was associated with an increased risk of CAD after controlling for potential confounders and Bonferroni correction (P < 0.025 considered statistically significant; Recessive: OR = 1.79, 95% CI = 1.04-3.06, P = 0.017; Log-additive: OR = 1.27, 95% CI = 1.02-1.57, P = 0.014), whereas the rs12563308 SNP was associated with a decreased risk of CAD (Dominant: OR = 0.69, 95% CI = 0.45-0.94, P = 0.011; Log-additive: OR = 0.73, 95% CI = 0.49-0.89, P = 0.009). The rs1748195 SNP was also associated with an increased risk of severity to coronary artery atherosclerosis (Dominant: OR = 1.45, 95% CI = 1.07-2.11, P = 0.017; Log-additive: OR = 1.35, 95% CI = 1.09-1.82, P = 0.013). The interactions of SNP-environment on serum lipid levels and the risk of severity to coronary artery atherosclerosis, CAD and IS were noted. The rs1748195G-rs12563308T haplotype was associated with an increased angiographic severity to coronary artery atherosclerosis (OR = 1.46, 95% CI = 1.05-2.03), and the risk of CAD (OR = 1.37, 95% CI = 1.08-1.74). The interactions of haplotype-hypertension on the risk of CAD and haplotype-drinking on the risk of CAD/IS were observed. These results suggest that the DOCK-ANGPTL3 SNPs and their haplotypes were associated with the angiographic severity to coronary artery atherosclerosis and the risk of CAD and IS in the Southern Chinese Han population. Show less
The erythropoietin-producing hepatoma (EPH) receptor A2 (EphA2) belongs to the Eph family of receptor tyrosine kinases. EphA2 is highly correlated with the formation of many solid tumors and has been Show more
The erythropoietin-producing hepatoma (EPH) receptor A2 (EphA2) belongs to the Eph family of receptor tyrosine kinases. EphA2 is highly correlated with the formation of many solid tumors and has been linked to the dysregulation of signaling pathways that promote tumor cell proliferation, migration, and invasion as well as angiogenesis. Deregulation of Wnt signaling is implicated in many forms of human disease including gastric cancer. We previously reported that EphA2 promotes the epithelial-mesenchymal transition through Wnt/β-catenin signaling in gastric cancer. Herein, we present a novel mechanism by which EphA2 regulates Wnt/β-catenin signaling. EphA2 acts as a receptor for Wnt ligands and recruits Axin1 to the plasma membrane by directly binding Dvl2. The EphA2-Dvl2/Axin1 interaction was enhanced by Wnt3a treatment, suggesting that EphA2 acts as a functional receptor for the Wnt/β-catenin pathway and plays a vital role in downstream signaling. We showed that Dvl2 mediates the EphA2-Axin1 interaction by binding to the tyrosine kinase domain of EphA2. We propose that EphA2/Dvl2/Axin1 forms a complex that destabilizes the β-catenin destruction complex and allows β-catenin to translocate to the nucleus and initiate the transcription of c-MYC, the primary Wnt signaling target gene. Intriguingly, c-MYC could bind directly to the EphA2 and Wnt1 promoter to enhance their transcription. The entire process formed an EphA2-mediated feed-forward loop. A small molecular inhibitor of EphA2 potently inhibited the proliferation of gastric cancer in vitro and in vivo, including gastric cancer patient-derived xenografts. Thus, our data identify EphA2 as an excellent candidate for gastric cancer therapy. Show less
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding var Show more
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Show less
Helicase DHX36 plays essential roles in cell development and differentiation at least partially by resolving G-quadruplex (G4) structures. Here we report crystal structures of the Drosophila homolog o Show more
Helicase DHX36 plays essential roles in cell development and differentiation at least partially by resolving G-quadruplex (G4) structures. Here we report crystal structures of the Drosophila homolog of DHX36 (DmDHX36) in complex with RNA and a series of DNAs. By combining structural, small-angle X-ray scattering, molecular dynamics simulation, and single-molecule fluorescence studies, we revealed that positively charged amino acids in RecA2 and OB-like domains constitute an elaborate structural pocket at the nucleic acid entrance, in which negatively charged G4 DNA is tightly bound and partially destabilized. The G4 DNA is then completely unfolded through the 3'-5' translocation activity of the helicase. Furthermore, crystal structures and DNA binding assays show that G-rich DNA is preferentially recognized and in the presence of ATP, specifically bound by DmDHX36, which may cooperatively enhance the G-rich DNA translocation and G4 unfolding. On the basis of these results, a conceptual G4 DNA-resolving mechanism is proposed. Show less
Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be iso Show more
Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be isolated from human blood plasma using platelet β3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbβ3 integrin, and the direct apoA-IV-αIIbβ3 interaction can be detected using a single-molecule Biomembrane Force Probe. We identify that aspartic acids 5 and 13 at the N-terminus of apoA-IV are required for binding to αIIbβ3 integrin, which is additionally modulated by apoA-IV C-terminus via intra-molecular interactions. ApoA-IV inhibits platelet aggregation and postprandial platelet hyperactivity. Human apoA-IV plasma levels show a circadian rhythm that negatively correlates with platelet aggregation and cardiovascular events. Thus, we identify apoA-IV as a novel ligand of αIIbβ3 integrin and an endogenous inhibitor of thrombosis, establishing a link between lipoprotein metabolism and cardiovascular diseases. Show less
The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelan Show more
The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity. Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1, and LEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants. We predict ~650 α-melanocyte-stimulating hormone (MSH)/POMC, 8500 PCSK1, and 3600 LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway-deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants: β-MSH/POMC,PCSK1 N221D, and a PCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in the POMC, PCSK1, and LEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene. Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness. Show less
Coronary heart disease (CHD) is the most common cause of death worldwide. This study aimed to validate the association of the rs964184 polymorphism with the CHD risk and included 874 CHD patients and Show more
Coronary heart disease (CHD) is the most common cause of death worldwide. This study aimed to validate the association of the rs964184 polymorphism with the CHD risk and included 874 CHD patients and 776 controls. rs964184 polymorphism genotyping was performed using Tm-shift polymerase chain reaction. A strong association of the rs964184 polymorphism with CHD was found (genotype: X Our results indicate that both gender and age have great impacts on the association of the rs964184 polymorphism with CHD among Chinese. Show less
γ-Secretase has been a therapeutical target for its key role in cleaving APP to generate β-amyloid (Aβ), the primary constituents of senile plaques and a hallmark of Alzheimer's disease (AD) pathology Show more
γ-Secretase has been a therapeutical target for its key role in cleaving APP to generate β-amyloid (Aβ), the primary constituents of senile plaques and a hallmark of Alzheimer's disease (AD) pathology. Recently, γ-secretase-associating proteins showed promising role in specifically modulating APP processing while sparing Notch signaling; however, the underlying mechanism is still unclear. A co-immunoprecipitation (Co-IP) coupled with mass spectrometry proteomic assay for Presenilin1 (PS1, the catalytic subunit of γ-secretase) was firstly conducted to find more γ-secretase-associating proteins. Gene ontology analysis of these results identified Rab21 as a potential PS1 interacting protein, and the interaction between them was validated by reciprocal Co-IP and immunofluorescence assay. Then, molecular and biochemical methods were used to investigate the effect of Rab21 on APP processing. Results showed that overexpression of Rab21 enhanced Aβ generation, while silencing of Rab21 reduced the accumulation of Aβ, which resulted due to change in γ-secretase activity rather than α- or β-secretase. Finally, we demonstrated that Rab21 had no effect on γ-secretase complex synthesis or metabolism but enhanced PS1 endocytosis and translocation to late endosome/lysosome. In conclusion, we identified a novel γ-secretase-associating protein Rab21 and illustrate that Rab21 promotes γ-secretase internalization and translocation to late endosome/lysosome. Moreover, silencing of Rab21 decreases the γ-secretase activity in APP processing thus production of Aβ. All these results open new gateways towards the understanding of γ-secretase-associating proteins in APP processing and make inhibition of Rab21 a promising strategy for AD therapy. Show less
Atherosclerosis is the most common cause of cardiovascular disease, such as myocardial infarction and stroke. Previous study revealed that microRNA (miR)-134 promotes lipid accumulation and proinflamm Show more
Atherosclerosis is the most common cause of cardiovascular disease, such as myocardial infarction and stroke. Previous study revealed that microRNA (miR)-134 promotes lipid accumulation and proinflammatory cytokine secretion through angiopoietin-like 4 (ANGPTL4)/lipid lipoprotein (LPL) signaling in THP-1 macrophages. ApoE KO male mice on a C57BL/6 background were fed a high-fat/high-cholesterol Western diet, from 8 to 16 weeks of age. Mice were divided into four groups, and received a tail vein injection of miR-134 agomir, miR-134 antagomir, or one of the corresponding controls, respectively, once every 2 weeks after starting the Western diet. After 8 weeks we measured aortic atherosclerosis, LPL Activity, mRNA and protein levels of ANGPTL4 and LPL, LPL/ low-density lipoprotein receptor related protein 1 Complex Formation, proinflammatory cytokine secretion and lipid levels. Despite this finding, the influence of miR-134 on atherosclerosis in vivo remains to be determined. Using the well-characterized mouse atherosclerosis model of apolipoprotein E knockout, we found that systemic delivery of miR-134 agomir markedly enhanced the atherosclerotic lesion size, together with a significant increase in proinflammatory cytokine secretion and peritoneal macrophages lipid contents. Moreover, overexpression of miR-134 decreased ANGPTL4 expression but increased LPL expression and activity in both aortic tissues and peritoneal macrophages, which was accompanied by increased formation of LPL/low-density lipoprotein receptor-related protein 1 complexes in peritoneal macrophages. However, an opposite effect was observed in response to miR-134 antagomir. These findings suggest that miR-134 accelerates atherogenesis by promoting lipid accumulation and proinflammatory cytokine secretion via the ANGPTL4/LPL pathway. Therefore, targeting miR-134 may offer a promising strategy for the prevention and treatment of atherosclerotic cardiovascular disease. Show less
Wnt/β-catenin signaling activity is maintained in homeostasis by an expanding list of molecular determinants. However, the molecular components and the regulatory mechanisms involved in its fine-tunin Show more
Wnt/β-catenin signaling activity is maintained in homeostasis by an expanding list of molecular determinants. However, the molecular components and the regulatory mechanisms involved in its fine-tuning remain to be determined. Here, we identified C9orf140, a tumor-specific protein, as a novel Axin1-interacting protein by tandem-affinity purification and mass spectrometry. We further showed that C9orf140 is a negative regulator of Wnt/β-catenin signaling in cultured cells as well as in zebrafish embryos. It functions upstream of β-catenin, outcompetes PP2A for binding to Axin1, influences the balance between phosphorylation and de-phosphorylation of β-catenin, and ultimately compromises Wnt3A-induced β-catenin accumulation. Interestingly, Wnt-induced C9orf140 expression via β-catenin. We propose that C9orf140 mediates a negative feedback loop of Wnt/β-catenin signaling by interacting with Axin1. Our results advance the current understanding of the exquisite control of Wnt/β-catenin signaling cascade, and provide evidence of the new role of C9orf140. Show less
This study was conducted to measure the concentration of branched chain amino acid (BCAA) in different species and detect the expression pattern of the liver We measured the concentration of BCAA in G Show more
This study was conducted to measure the concentration of branched chain amino acid (BCAA) in different species and detect the expression pattern of the liver We measured the concentration of BCAA in GK rats, induced T2D cynomolgus monkeys and T2D humans by liquid chromatography tandem mass spectrometry, and used real-time quantitative PCR to analyze the gene expression of In this study, we showed that GK rat BCAA concentrations were significantly reduced at 4 and 8 weeks ( Our results showed that BCAA concentrations changed at different times and by different amounts in different species and during different periods of T2D progress, and the significant changes of BCAA concentration in the three species indicated that BCAA might participate in the progress of T2D. The results suggested that the increased expression of Show less
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL Show more
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10 Show less
Brandon Podyma, Hui Sun, Eric A Wilson+5 more · 2018 · The Journal of biological chemistry · American Society for Biochemistry and Molecular Biology · added 2026-04-24
Multiple osteochondromas (MO) is an autosomal inherited disease that is characterized by benign bone tumors. However, the underlying mechanism of MO at a molecular level requires further investigation Show more
Multiple osteochondromas (MO) is an autosomal inherited disease that is characterized by benign bone tumors. However, the underlying mechanism of MO at a molecular level requires further investigation. The majority of mutations associated with MO occur in the exostosin glycosyltransferase genes ( Show less
We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technolo Show more
We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technology and investigated blood pressure and phenotype in SHR. Blood pressure was measured by tail-cuff and telemetry methods. Histology and expression of liver X receptor α (LXRα), renin, Krüppel-like factor 5 (KLF5), and E-cadherin were evaluated in kidneys. Mesangial cells (MCs) were removed from glomeruli from three strains, and we evaluated the phenotype in vitro. SHR showed the salt-sensitive hypertension that was abolished in C3 knockout (KO) SHR. Proliferation of MCs from SHR was higher than that from Wistar-Kyoto (WKY) rats and showed a synthetic phenotype. Renal injury scores were higher in SHR than in WKY rats and C3 KO SHR. Expression of E-cadherin was lower, and expression of renin was higher in the nephrotubulus from SHR than WKY rats and C3 KO SHR. Expression of C3 α-chain protein and α-smooth muscle actin protein was significantly higher in renal medulla from SHR than from WKY rats. Expression of angiotensinogen, LXRα, renin, and KLF5 mRNA was increased in kidney from SHR compared with C3 KO SHR. Intrarenal angiotensin II levels were significantly higher in kidney from SHR than WKY rats and C3 KO SHR. Urinary epinephrine and norepinephrine excretions were significantly higher in SHR than in WKY rats and C3 KO SHR. These findings showed that increased C3 induces salt-sensitive hypertension with increases in urinary catecholamine excretion and intrarenal activation of the renin-angiotensin system by the dedifferentiation of mesenchymal tissues in kidney from SHR. Show less
To assess the association of genes in the high-density lipoprotein metabolic pathway (HDLMP) with polypoidal choroidal vasculopathy (PCV) and the genetic difference in the HDLMP between PCV and age-re Show more
To assess the association of genes in the high-density lipoprotein metabolic pathway (HDLMP) with polypoidal choroidal vasculopathy (PCV) and the genetic difference in the HDLMP between PCV and age-related macular degeneration (AMD). We performed a literature search in EMBASE, PubMed, and Web of Science for genetic studies on 7 single nucleotide polymorphisms (SNPs) from 5 genes in the HDLMP including cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), ATP-binding cassette transporter A1 (ABCA1), and ATP-binding cassette transporter G1 (ABCG1) in PCV. All studies were published before September 30, 2017, without language restriction. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) of each polymorphism were estimated. We also compared the association profiles between PCV and AMD and performed a sensitivity analysis. Our result is based on 43 articles. After excluding duplicates and articles without complete information, 7 studies were applicable to meta-analysis. 7 polymorphisms were meta-analyzed: CETP rs2303790/rs3764261, LIPC rs10468017/rs493258, LPL rs12678919, ABCA1 rs1883025, and ABCG1 rs57137919. We found that in Asian population, CETP rs3764261 (T allele; OR = 1.46; 95% CI: 1.28-1.665, Our study revealed 7 polymorphisms in 5 genes. Among them, CETP (rs3764261/rs2303790) and ABCG1 (rs57137919) were the major susceptibility genes for PCV in Asian population and ABCG1 (rs57137919) showed allelic diversity between PCV and AMD. Since the size for PCV and AMD was small, we need to study these genes genotyping in larger samples. Show less
In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of apoptotic bodies in regulating tissue Show more
In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of apoptotic bodies in regulating tissue homeostasis remains unclear. In this study, we used Fas-deficient MRL/lpr and Caspase 3 Show less
mRNA processing, transport, translation, and ultimately degradation involve a series of dedicated protein complexes that often assemble into large membraneless structures such as stress granules (SGs) Show more
mRNA processing, transport, translation, and ultimately degradation involve a series of dedicated protein complexes that often assemble into large membraneless structures such as stress granules (SGs) and processing bodies (PBs). Here, systematic in vivo proximity-dependent biotinylation (BioID) analysis of 119 human proteins associated with different aspects of mRNA biology uncovers 7424 unique proximity interactions with 1,792 proteins. Classical bait-prey analysis reveals connections of hundreds of proteins to distinct mRNA-associated processes or complexes, including the splicing and transcriptional elongation machineries (protein phosphatase 4) and the CCR4-NOT deadenylase complex (CEP85, RNF219, and KIAA0355). Analysis of correlated patterns between endogenous preys uncovers the spatial organization of RNA regulatory structures and enables the definition of 144 core components of SGs and PBs. We report preexisting contacts between most core SG proteins under normal growth conditions and demonstrate that several core SG proteins (UBAP2L, CSDE1, and PRRC2C) are critical for the formation of microscopically visible SGs. Show less