Micro-RNAs regulate multiple biological behaviors of cancers, making them potential targets of new cancer therapies. MiR-1181 has been demonstrated to perform oncogenic or tumor-suppressing function i Show more
Micro-RNAs regulate multiple biological behaviors of cancers, making them potential targets of new cancer therapies. MiR-1181 has been demonstrated to perform oncogenic or tumor-suppressing function in a tissue-dependent way, but its role in hepatocellular carcinoma (HCC) was unclear. Here, we showed that miR-1181 was significantly overexpressed in HCC tissues when compared with tumor-adjacent normal ones or normal liver tissues from donated organ, and that inhibition of miR-1181 could repress the growth of HCC cells. Through bioinformatics analysis and luciferase reporter assays, we found that axis inhibition protein 1 (AXIN1) was a direct target of miR-1181, and the expression of AXIN1 showed a negative correlation with that of miR-1181 in HCC. Therefore, these data indicated an oncogenic function of miRNA-1181 in the development of HCC and a potential target for the clinical treatment of HCC. Show less
The melanocortin-4 receptor (MC4R) acts as a member of G-protein coupled receptors and participate in food intake and energy expenditure. Melanocortin 2 receptor accessory protein 2 (MRAP2) plays a cr Show more
The melanocortin-4 receptor (MC4R) acts as a member of G-protein coupled receptors and participate in food intake and energy expenditure. Melanocortin 2 receptor accessory protein 2 (MRAP2) plays a critical role in regulating MC4R signaling in mammals and zebrafish. However, evidence on their interaction in other teleost species remains elusive. Here, we cloned and assessed the evolutionary aspect and pharmacological modulation of MRAP2 on MC4R signaling in Nile tilapia (Oreochromis niloticus). Tissue distribution analysis of tmc4r and tmrap2 confirmed their co-expression in the brain region. tMRAP2 protein could form antiparallel homo-dimer and directly interacted with tMC4R in vitro and presence of tMRAP2 led to the reduction of agonist response and surface expression of tMC4R. Overall, our findings provide a comparative overview on the evolutionary conservation, genomic distribution, tissue-specific expression and pharmacological profile of the MC4R and MRAP2 in another non-mammalian teleost. Show less
Despite progress in diagnostics and treatment for preeclampsia, it remains the foremost cause of maternal and foetal perinatal morbidity and mortality worldwide. Over recent years, various lines of ev Show more
Despite progress in diagnostics and treatment for preeclampsia, it remains the foremost cause of maternal and foetal perinatal morbidity and mortality worldwide. Over recent years, various lines of evidence have emphasized long non-coding RNAs (lncRNAs) which function as an innovative regulator of biological behaviour, as exemplified by proliferation, apoptosis and metastasis. However, the role of lncRNAs has not been well described in preeclampsia. Here, we identified a lncRNA, PVT1, whose expression was down-regulated in qRT-PCR analyses in severe preeclampsia. The effects of PVT1 on development were studied after suppression and overexpression of PVT1 in HTR-8/SVneo and JEG3 cells. PVT1 knockdown notably inhibited cell proliferation and stimulated cell cycle accumulation and apoptosis. Exogenous PVT1 significantly increased cell proliferation. Based on analysis of RNAseq data, we found that PVT1 could affect the expression of numerous genes, and then investigated the function and regulatory mechanism of PVT1 in trophoblast cells. Further mechanistic analyses implied that the action of PVT1 is moderately attributable to its repression of ANGPTL4 via association with the epigenetic repressor Ezh2. Altogether, our study suggests that PVT1 could play an essential role in preeclampsia progression and probably acts as a latent therapeutic marker; thus, it might be a useful prognostic marker when evaluating new therapies for patients with preeclampsia. Show less
This study aimed to assess the association between the angiopoietin-like protein 4 gene ( Genotypes of the The rs2967605 CT/TT genotypes were associated with a decreased risk of CAD (adjusted OR = 0.6 Show more
This study aimed to assess the association between the angiopoietin-like protein 4 gene ( Genotypes of the The rs2967605 CT/TT genotypes were associated with a decreased risk of CAD (adjusted OR = 0.68, 95% CI = 0.47-0.99, The observed associations suggest that the 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
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
Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormon Show more
Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10 In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study). Show less
Foot-and-mouth disease (FMD) is a highly contagious disease that results in enormous economic loses worldwide. Although the protection provided by vaccination is limited during early infection, it is Show more
Foot-and-mouth disease (FMD) is a highly contagious disease that results in enormous economic loses worldwide. Although the protection provided by vaccination is limited during early infection, it is recognized as the best method to prevent FMD outbreaks. Furthermore, the mechanism of host early responses against foot-and-mouth disease virus (FMDV) infection remains unclear. In our study, a pig kidney cell line (PK-15) was used as a cell model to reveal the mechanism of early pig responses to FMDV infection. Four non-treated control and four FMDV-treated PK-15 cells were sequenced with RNA-seq technology, and the differentially expressed genes (DEGs) were analyzed. The results showed that 1212 DEGs were in the FMDV-infected PK-15 cells, including 914 up-regulated and 298 down-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly enriched in the tumor necrosis factor (TNF), cytokine-cytokine receptor interaction, NOD-like receptor, toll-like receptor, NF-κB, and the chemokine signaling pathways. To verify the results of the DEGs, 30 immune-related DEGs (19 up-regulated and 11 down-regulated) were selected for Quantitative Reverse Transcriptase polymerase chain reaction (RT-qPCR) verification. The results showed that RT-qPCR-measured genes exhibited a similar pattern as the RNA-seq analyses. Based on bioinformatics analysis, during FMDV early infection, we found that a series of cytokines, such as interleukins (IL6), chemokines (CXCL2, CCL20 and CCL4), and transcription factors (ZFP36, FOS, NFKBIA, ZBTB3, ZNF503, ZNF283, dymeclin (DYM), and orthodenticle homeobox 1 (OTX1)) were involved in the battle between FMDV and the host. Combined with their features and functions, we propose inflammation as the main early mechanism by which the host responds to FMDV infection. These data provide an additional panel of candidate genes for deciphering the mechanisms of a host's early response against FMDV infection. Show less
Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers. Metastasis is a major leading of death in patients with CRC and many patients have metastatic disease at diagnosis Show more
Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers. Metastasis is a major leading of death in patients with CRC and many patients have metastatic disease at diagnosis. However, the underlying molecular mechanisms are still elusive. Here, we showed that JMJD1C was overexpressed in colon cancer tissues compared to normal samples and was positively associated with metastasis and poor prognosis. Silencing JMJD1C strongly inhibits CRC migration and invasion both in vitro and in vivo. Further, we found that knockdown of JMJD1C decreased the protein and mRNA levels of ATF2, mechanistically, and JMJD1C regulated the expression of ATF2 by modulating the H3K9me2 but not H3K9me1 activity. In addition, we further performed some "rescues experiments". We found that overexpression of ATF2 could reverse the abrogated migration and invasion ability by knockdown of JMJD1C in CRC. Our results demonstrated that an increase of JMJD1C was observed in colon cancer and knockdown of JMJD1C regulated CRC metastasis by inactivation of the ATF2 pathway. This novel JMJD1C/ATF2 signaling pathway may be a promising therapeutic target for CRC metastasis. Show less
Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive inborn metabolic disease characterized mainly by hyperammonemia. The fatal nature of CPS1D and its similar symptoms wi Show more
Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive inborn metabolic disease characterized mainly by hyperammonemia. The fatal nature of CPS1D and its similar symptoms with other urea cycle disorders (UCDs) make its diagnosis difficult, and the molecular diagnosis is hindered due to the large size of the causative gene CPS1. Therefore, the objective of the present study was to investigate the clinical applicability of exome sequencing in molecular diagnosis of CPS1D in Chinese population. We described two Chinese neonates presented with unconsciousness and drowsiness due to deepening encephalopathy with hyperammonemia. Whole exome sequencing was performed. Candidate mutations were validated by Sanger sequencing. In-silicon analysis was processed for the pathogenicity predictions of the identified mutations. Two compound heterozygous mutations in the gene carbamoyl phosphate synthetase 1(CPS1) were identified. One is in Case 1 with two novel missense mutations (c.2537C>T, p. Pro846Leu and c.3443T>A, p.Met1148Lys), and the other one is in Case 2 with a novel missense mutation (c.1799G>A, p.Cys600Tyr) and a previously reported 12-bp deletion (c.4088₄₀₉₉del, p.Leu 1363_Ile1366del). Bioinformatics deleterious predictions indicated pathogenicity of the missense mutations. Conversation analysis and homology modeling showed that the substituted amino acids were highly evolutionary conserved and necessary for enzyme stability or function. The present study initially and successfully applied whole exome sequencing to the molecular diagnosis of CPS1D in Chinese neonates, indicating its applicability in cost-effective molecular diagnosis of CPS1D. Three novel pathogenic missense mutations were identified, expanded the mutational spectrum of the CPS1 gene. Show less
Hereditary multiple osteochondroma (HMO) is one of the most common genetic skeletal disorders. It is caused by mutations in either EXT1 or EXT2 resulting in abnormal skeletal growth and morphogenesis. Show more
Hereditary multiple osteochondroma (HMO) is one of the most common genetic skeletal disorders. It is caused by mutations in either EXT1 or EXT2 resulting in abnormal skeletal growth and morphogenesis. However, the spectrum and frequency of EXT1 and EXT2 mutations in Chinese patients with HMO was not previously investigated.Mutations were identified by performing Sanger sequencing analysis of the complete coding regions and flanking intronic sequences of EXT1 and EXT2, followed by multiplex ligation-dependent probe amplification (MLPA) analysis to detect gene deletions or duplications that could not be identified by the Sanger sequencing method.The present study identified pathogenic mutations in 93% (68/73) of unrelated HMO probands from 73 pedigrees. Mutations in EXT1 and EXT2 were identified in 53% (39/73) and 40% (29/73) of families. We identified 58 distinct mutations in EXT1 and EXT2, including 20 frameshift mutations, 16 nonsense mutations, 7 missense mutations, 9 splice site mutations, 5 large deletions, and 1 in-frame deletion mutation. Twenty-six of these mutations were novel and 32 were previously reported. Most of the mutations in EXT1 were base deletions or insertions (21/33), whereas the majority of those in EXT2 were single base substitution (18/25).Complete sequencing of both the EXT1 and EXT2 followed by MLPA analysis is recommended for genetic analysis of Chinese patients with HMO. This study provides a comprehensive characterization of the genetic aberrations found in Chinese patients with HMO and highlights the diagnostic value of molecular genetic analysis in this particular disease. 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
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
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
Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypot Show more
Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypothalamus-mediated energy metabolism during Xenopus limb regeneration. We report that hypothalamus injury inhibits Xenopus tadpole limb regeneration. By loss-of-function and gain-of-function studies, we show that Mc4r signaling is required for limb regeneration in regeneration-competent tadpoles and stimulates limb regeneration in later-stage regeneration-defective tadpoles. It regulates limb regeneration through modulating energy homeostasis and ROS production. Even more interestingly, our results demonstrate that Mc4r signaling is regulated by innervation and α-MSH substitutes for the effect of nerves in limb regeneration. Mc4r signaling is also required for mouse digit regeneration. Thus, our findings link vertebrate limb regeneration with Mc4r-mediated energy homeostasis and provide a new avenue for understanding Mc4r signaling in the peripheral organs. 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
Jia Wang, Jianhua Gong, Li Li+7 more · 2018 · Autism research : official journal of the International Society for Autism Research · Wiley · added 2026-04-24
Increasing evidence suggests that abnormal synaptic function leads to neuronal developmental disorders and is an important component of the etiology of autism spectrum disorder (ASD). Neurexins are pr 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 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
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
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
Major depressive disorder (MDD) is a highly prevalent mental disorder affecting millions of people worldwide. However, a clear causative etiology of MDD remains unknown. In this study, we aimed to ide Show more
Major depressive disorder (MDD) is a highly prevalent mental disorder affecting millions of people worldwide. However, a clear causative etiology of MDD remains unknown. In this study, we aimed to identify critical protein alterations in plasma from patients with MDD and integrate our proteomics and previous metabolomics data to reveal significantly perturbed pathways in MDD. An isobaric tag for relative and absolute quantification (iTRAQ)-based quantitative proteomics approach was conducted to compare plasma protein expression between patients with depression and healthy controls (CON). For integrative analysis, Ingenuity Pathway Analysis software was used to analyze proteomics and metabolomics data and identify potential relationships among the differential proteins and metabolites. A total of 74 proteins were significantly changed in patients with depression compared with those in healthy CON. Bioinformatics analysis of differential proteins revealed significant alterations in lipid transport and metabolic function, including apolipoproteins (APOE, APOC4 and APOA5), and the serine protease inhibitor. According to canonical pathway analysis, the top five statistically significant pathways were related to lipid transport, inflammation and immunity. Causal network analysis by integrating differential proteins and metabolites suggested that the disturbance of phospholipid metabolism might promote the inflammation in the central nervous system. Show less
Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR. The Show more
Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR. The HL-1 atrial myocytes were subjected to uniaxial cyclic stretching for eight hours. Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism were analyzed by PCR assay (168 genes). The stretched myocytes had significantly larger cell size and higher lipid expression than non-stretched myocytes (all The Show less
Osteoblast differentiation is a multistep process delicately regulated by many factors, including cytoskeletal dynamics and signaling pathways. Microtubule actin crosslinking factor 1 (MACF1), a key c Show more
Osteoblast differentiation is a multistep process delicately regulated by many factors, including cytoskeletal dynamics and signaling pathways. Microtubule actin crosslinking factor 1 (MACF1), a key cytoskeletal linker, has been shown to play key roles in signal transduction and in diverse cellular processes; however, its role in regulating osteoblast differentiation is still needed to be elucidated. To further uncover the functions and mechanisms of action of MACF1 in osteoblast differentiation, we examined effects of MACF1 knockdown (MACF1-KD) in MC3T3-E1 osteoblastic cells on their osteoblast differentiation and associated molecular mechanisms. The results showed that knockdown of MACF1 significantly suppressed mineralization of MC3T3-E1 cells, down-regulated the expression of key osteogenic genes alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and type I collagen α1 (Col Iα1). Knockdown of MACF1 dramatically reduced the nuclear translocation of β-catenin, decreased the transcriptional activation of T cell factor 1 (TCF1), and down-regulated the expression of TCF1, lymphoid enhancer-binding factor 1 (LEF1), and Runx2, a target gene of β-catenin/TCF1. In addition, MACF1-KD increased the active level of glycogen synthase kinase-3β (GSK-3β), which is a key regulator for β-catenin signal transduction. Moreover, the reduction of nuclear β-catenin amount and decreased expression of TCF1 and Runx2 were significantly reversed in MACF1-KD cells when treated with lithium chloride, an agonist for β-catenin by inhibiting GSK-3β activity. Taken together, these findings suggest that knockdown of MACF1 in osteoblastic cells inhibits osteoblast differentiation through suppressing the β-catenin/TCF1-Runx2 axis. Thus, a novel role of MACF1 in and a new mechanistic insight of osteoblast differentiation are uncovered. Show less
Human gastric cancer (GC) is the second most common cause of cancer-related deaths worldwide and is one of the most common metastatic cancers. Tumor proliferation, apoptosis, metastasis and invasion a Show more
Human gastric cancer (GC) is the second most common cause of cancer-related deaths worldwide and is one of the most common metastatic cancers. Tumor proliferation, apoptosis, metastasis and invasion are important predictors of the invasiveness of GC and are key factors in cancer-induced death. Angiopoietin-like 4 (ANGPTL4) is a secreted protein that belongs to the angiopoietin (ANGPTL) family and is involved in the regulation of cancer metastasis. However, whether ANGPTL4 plays a role in the progression of GC remain unclear. In the present study, immunoreactivity of ANGPTL4 demonstrated that ANGPTL4 expression was upregulated in GC tissues with the development of GC. The siRNA targeting ANGPTL4 effectively knocked down ANGPTL4 in the SNU‑1 and BGC823 cell lines at the mRNA and protein levels. Following ANGPTL4 downregulation, the proliferation and invasion abilities of GC cell lines were suppressed as determined by MTT and Transwell assays, and cell apoptosis level and sensitivity to cisplatin were increased as determined by flow cytometry and MTT assay. In conclusion, these findings suggest that ANGPTL4 may be a new potential therapeutic target for GC. 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
Gastric cancer (GC) is one of the most common cancers and is the second-leading cause of cancer-associated morbidity worldwide. Oxysterols are oxidized derivatives of cholesterol that may be important Show more
Gastric cancer (GC) is one of the most common cancers and is the second-leading cause of cancer-associated morbidity worldwide. Oxysterols are oxidized derivatives of cholesterol that may be important in many biological processes, but the levels and roles of oxysterols in gastric tumours remain to be elucidated. The levels of cholesterol, oxysterols and sulfated oxysterols in human gastric tumour tissues, adjacent normal mucosal tissues, cancerous gastric juice and gastric juice obtained from healthy subjects were detected by LC-MS. It was found that the levels of 24(R/S),25-EC and 27HC in human gastric tumour tissues and cancerous gastric juice were significantly increased compared with those of adjacent normal mucosal tissues and gastric juice from healthy subjects. Compared with normal gastric mucosal tissue, the levels of sulfated 25-hydroxycholesterol (25HC3S) and the ratio of 25HC3S/25HC were decreased in human gastric tumour tissues, which might be related to the dramatically decreased SULT2A1 expression in gastric tumour tissue. Both 24(R/S),25-EC and 27HC suppressed gastric cancer proliferation, which was not altered by LXRα-siRNA treatment. The suppression of cell proliferation induced by 27HC was attenuated by LXRβ-siRNA, but the suppression of cell proliferation induced by 24(R/S),25-EC was intensified by LXRβ-siRNA. Both 24(R/S),25-EC and 27HC dramatically inhibited HGC-27 cell migration, which was attenuated by the co-transfection of cells with LXRα-siRNA and LXRβ-siRNA, but not LXRα-siRNA or LXRβ-siRNA alone. In conclusion, the accumulated 24(R/S),25-EC and 27HC in human gastric tumour tissues might play important roles in gastric cancer development. Show less
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
Diabetic retinopathy (DR) is a major cause of adult blindness. Retinal Müller cells maintain water homeostasis and potassium concentration via inwardly rectifying Kir4.1 channels. Accumulation of adva Show more
Diabetic retinopathy (DR) is a major cause of adult blindness. Retinal Müller cells maintain water homeostasis and potassium concentration via inwardly rectifying Kir4.1 channels. Accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. While diabetes leads to a decrease in the Kir4.1 channels, it remains unknown whether AGEs-linked to the basement membrane (BM) affect normal Kir4.1 channels. For this study, we hypothesized that AGE-modification of laminin is detrimental to Kir4.1 channels, therefore, disrupting Müller cell function. The AGE-modified laminin-coated substrates were prepared by incubating Petri-dishes with laminin and methylglyoxal for seven days. The rat Müller cells (rMC-1) were propagated on AGE-modified laminin, and Kir4.1 expression and function were evaluated. Quantification of AGEs using ELISA revealed a dose-dependent increase in methylglyoxal-hydro-imidazolone adducts. The rMC-1 propagated on AGE-modified laminin demonstrated a decrease in Kir4.1 levels in immunofluorescence and western blot studies and a decrease in the Kir4.1 channel function. Kir4.1 decrease on AGE-modified laminin resulted in a disorganization of an actin cytoskeleton and disruption of α-dystroglycan-syntrophin-dystrophin complexes. Our studies suggest that AGE-modification of laminin is detrimental to Kir4.1 channels. By studying the role of AGEs in Kir4.1 channels we have identified a novel mechanism of Müller cell dysfunction and its subsequent involvement in DR. Show less
Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and investigat Show more
Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and investigate mechanisms that control their expression and function. We studied expression patterns and functions of 4 SCC-specific lncRNAs. We obtained 113 esophageal SCC (ESCC) and matched non-tumor esophageal tissues from a hospital in Shantou City, China, and performed quantitative reverse transcription polymerase chain reaction assays to measure expression levels of LINC01503. We collected clinical data from patients and compared expression levels with survival times. LINC01503 was knocked down using small interfering RNAs and oligonucleotides in TE7, TE5, and KYSE510 cell lines and overexpressed in KYSE30 cells. Cells were analyzed by chromatin immunoprecipitation sequencing, luciferase reporter assays, colony formation, migration and invasion, and mass spectrometry analyses. Cells were injected into nude mice and growth of xenograft tumors was measured. LINC01503 interaction with proteins was studied using fluorescence in situ hybridization, RNA pulldown, and RNA immunoprecipitation analyses. We identified a lncRNA, LINC01503, which is regulated by a super enhancer and is expressed at significantly higher levels in esophageal and head and neck SCCs than in non-tumor tissues. High levels in SCCs correlated with shorter survival times of patients. The transcription factor TP63 bound to the super enhancer at the LINC01503 locus and activated its transcription. Expression of LINC01503 in ESCC cell lines increased their proliferation, colony formation, migration, and invasion. Knockdown of LINC01503 in SCC cells reduced their proliferation, colony formation, migration, and invasion, and the growth of xenograft tumors in nude mice. Expression of LINC01503 in ESCC cell lines reduced ERK2 dephosphorylation by DUSP6, leading to activation of ERK signaling via MAPK. LINC01503 disrupted the interaction between EBP1 and the p85 subunit of PI3K, increasing AKT signaling. We identified an lncRNA, LINC01503, which is increased in SCC cells compared with non-tumor cells. Increased expression of LINC01503 promotes ESCC cell proliferation, migration, invasion, and growth of xenograft tumors. It might be developed as a biomarker of aggressive SCCs in patients. Show less