RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 Show more
RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 acts as a critical replication stress regulator to promote RPA stability on chromatin. DOCK7 is phosphorylated by ATR and then recruited by MDC1 to the chromatin and replication fork during replication stress. DOCK7-mediated Rac1/Cdc42 activation leads to the activation of PAK1, which subsequently phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response. Moreover, DOCK7 is overexpressed in ovarian cancer and depleting DOCK7 sensitizes cancer cells to camptothecin. Taken together, our results highlight a novel role for DOCK7 in regulation of the replication stress response and highlight potential therapeutic targets to overcome chemoresistance in cancer. Show less
Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated wit Show more
Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated with GC metastasis. However, the specific molecular mechanisms underlying this relationship remain to be unveiled. In this study, we assessed the impact of gastrin and the Wnt/β-catenin inhibitor XAV939 on the epithelial-mesenchymal transition (EMT) of the SGC-7901 and MKN45 GC cell lines, and we determined that gastrin-17 significantly decreased E-cadherin expression and upregulated the expression of Snail1 and N-cadherin in GC cells. In addition, gastrin 17 also significantly increased the expression of Wnt3α in a dose-dependent manner. Consistent with these results, gastrin-17 promoted GC cell invasion, proliferation, and migration in a dose-dependent fashion, and these effects were inhibited by XAV939. Together, these results indicated that gastrin-17 induced GC cell EMT, migration, and invasion via the Wnt/β-catenin signaling pathway, which suggests that this gastrin/Wnt/β-catenin signaling axis may represent a therapeutic target for the prevention of GC metastasis. Show less
Lung cancer is one of the most prevalent cancers in both men and women worldwide. The nucleic acid G4 structures have been implicated in the transcriptional programmes of cancer-related genes in some Show more
Lung cancer is one of the most prevalent cancers in both men and women worldwide. The nucleic acid G4 structures have been implicated in the transcriptional programmes of cancer-related genes in some cancers such as lung cancer. However, the role of the dominant G4 resolvase DHX36 in the progression of lung cancer remains unknown. In this study, by bioinformatic analysis of public datasets (TCGA and GEO), we find DHX36 is an independent prognosis indicator in non-small-cell lung carcinoma (NSCLC) with subtype dependence. The stable lentiviral knockdown of the DHX36 results in accelerated migration and aggregation of the S-phase subpopulation in lung cancer cells. The reduction of DHX36 level de-sensitises the proliferation response of lung cancer cells to chemotherapeutic drugs such as paclitaxel with cell dependence. The knockdown of this helicase leads to promoted tumour growth, demonstrated by a 3D fluorescence spheroid lung cancer model, and the stimulation of cell colony formation as shown by single-cell cultivation. High throughput proteomic array indicates that DHX36 functions in lung cancer cells through regulating multiple signalling pathways including activation of protein activity, protein autophosphorylation, Fc-receptor signalling pathway, response to peptide hormone and stress-activated protein kinase signalling cascade. A causal transcriptomic analysis suggests that DHX36 is significantly associated with mRNA surveillance, RNA degradation, DNA replication and Myc targets. Therefore, we unveil that DHX36 presents clinical significance and plays a role in tumour suppression in lung cancer, and propose a potentially new concept for an anti-cancer therapy based on helicase-specific targeting. Show less
Recent evidence supports an association between lipid metabolism dysfunction and the pathology of schizophrenia which has led to the search for peripheral blood-based biomarkers. The purpose of this s Show more
Recent evidence supports an association between lipid metabolism dysfunction and the pathology of schizophrenia which has led to the search for peripheral blood-based biomarkers. The purpose of this study was to investigate the proteins involved in lipid metabolism (especially apolipoprotein) and to explore their potential as biomarkers for schizophrenia. Using multiple reaction monitoring mass spectrometry (MRM-MS), we quantified 22 proteins in serum samples of 109 healthy controls (HCs) and 111 patients with schizophrenia (SCZ), who were divided into discovery and validation sets. We found serum apolipoprotein A4 (ApoA4) to be significantly decreased in SCZ patients compared to HCs (p=1.61E-05). Moreover, the serum ApoA4 level served as an effective diagnostic tool, achieving area under the receiver operating characteristic curves (AUROC) of 0.840 in the discovery set and 0.791 in the validation set. Additionally, apolipoprotein F (ApoF), angiotensinogen (AGT), and alpha1-antichymotrypsin (ACT) levels were significantly higher in patients with schizophrenia than in healthy controls. These proteins combined with ApoA4, provided higher diagnostic accuracy for schizophrenia in the discovery set (AUROC=0.901) and in the validation set (AUROC=0.879). Our results suggest that the serum level of ApoA4 is a novel potential biomarker for schizophrenia. The proteins identified in this study expand the pool of biomarker candidates for schizophrenia and may be linked to the underlying mechanism of the disease. Show less
Post-synaptic density 93 (PSD-93) mediates glutamate excitotoxicity induced by ischemic brain injury, which then induces microglial inflammatory response. However, the underlying mechanisms of how PSD Show more
Post-synaptic density 93 (PSD-93) mediates glutamate excitotoxicity induced by ischemic brain injury, which then induces microglial inflammatory response. However, the underlying mechanisms of how PSD-93 mediates the crosstalk between neurons and microglia in the post-synaptic dense region remain elusive. CX3 chemokine ligand 1 (CX3CL1) is a chemokine specifically expressed in neurons while its receptor CX3CR1 is highly expressed in microglia. In this study, we examined the interaction of PSD-93 and CX3CL1 in the crosstalk between neurons and microglia in acute ischemic stroke. We utilized male C57BL/6 mice to establish the middle cerebral artery occlusion model (MCAO) and designed a fusion small peptide Tat-CX3CL1 (357-395aa) to inhibit PSD-93 and CX3CL1 interaction. The combination peaks of PSD-93 and CX3CL1 at 6 hr after I/R were observed. The binding sites were located at the 420-535 amino acid sequence of PSD-93 and 357-395 amino acid sequence of CX3CL1. Tat-CX3CL1 (357-395aa) could inhibit the interaction of PSD-93 and CX3CL1 and inhibited the pro-inflammatory cytokine IL-1β and TNF-α expression and provided neuroprotection following reperfusion. Together, these data suggest that PSD-93 binds CX3CL1 to activate microglia and initiate neuroinflammation. Specific blockade of PSD-93-CX3CL1 interaction reduces I/R induced neuronal cell death, and provides a new therapeutic target for ischemic stroke. Show less
Multiple Osteochondroma is an abnormal skeleton development autosomal dominant genetic disease which caused by the mutation of EXT1 gene. In this study, we generated induced pluripotent stem cells (iP Show more
Multiple Osteochondroma is an abnormal skeleton development autosomal dominant genetic disease which caused by the mutation of EXT1 gene. In this study, we generated induced pluripotent stem cells (iPSCs) from the mesenchymal stem cells (MSCs) of a 12-year-old male patient by reprogramming MSCs with non-integrative vectors. The iPSCs line expresses pluripotent markers, has a normal male karyotype and can differentiate into the three germ layers. Show less
Gastric cancer (GC) remains one of the most frequent cancers worldwide. Previous studies have shown that E3 ubiquitin ligase E3C (UBE3C) promotes the progression of multiple types of cancer. However, Show more
Gastric cancer (GC) remains one of the most frequent cancers worldwide. Previous studies have shown that E3 ubiquitin ligase E3C (UBE3C) promotes the progression of multiple types of cancer. However, little is known about the expression and molecular mechanism of UBE3C in GC. In this study, UBE3C is upregulated in clinical GC samples and RNA-seq data from The Cancer Genome Atlas, and the UBE3C upregulation is correlated with poor clinical outcomes in patients with GC. In vitro, knockdown of UBE3C suppresses proliferation and enhances apoptosis in GC cells by inhibiting β-catenin signaling pathway. In contrast, in vitro overexpression of UBE3C promotes GC cell proliferation and inhibits apoptosis through the upregulation of β-catenin signaling by promoting ubiquitination of AXIN1. In vivo, knockdown of UBE3C inhibits tumor growth in a nude mouse model. Concurrently, the UBE3C knockdown resulted in an increase of AXIN1 and a reduction of β-catenin in the nucleus and cytoplasm in the xenograft tumor tissues. Our results demonstrate that UBE3C promotes GC progression through activating the β-catenin signaling via degradation of AXIN1. Our data suggest that UBE3C exerts oncogenic effects in GC and thus provides a promising prognostic biomarker and a potential therapeutic target for GC therapy. Show less
The RNA-binding motif protein 10 (RBM10) is involved in alternative splicing and modifies mRNA post-transcriptionally. RBM10 is abnormally expressed in the lung, breast, and colorectal cancer, female Show more
The RNA-binding motif protein 10 (RBM10) is involved in alternative splicing and modifies mRNA post-transcriptionally. RBM10 is abnormally expressed in the lung, breast, and colorectal cancer, female genital tumors, osteosarcoma, and other malignant tumors. It can inhibit proliferation, promote apoptosis, and inhibit invasion and metastasis. RBM10 has long been considered a tumor suppressor because it promotes apoptosis through the regulation of the MDM2-p53 negative feedback loop, Bcl-2, Bax, and other apoptotic proteins and inhibits proliferation through the Notch signaling and rap1a/Akt/CREB pathways. However, it has been recently demonstrated that RBM10 can also promote cancer. Given these different views, it is necessary to summarize the research progress of RBM10 in various fields to reasonably analyze the underlying molecular mechanisms, and provide new ideas and directions for the clinical research of RBM10 in various cancer types. In this review, we provide a new perspective on the reasons for these opposing effects on cancer biology, molecular mechanisms, research progress, and clinical value of RBM10. Show less
The IL family of cytokines participates in immune response and regulation. We previously found that soluble IL-6 receptor plays an important role in the host antiviral response. In this study, we dete Show more
The IL family of cytokines participates in immune response and regulation. We previously found that soluble IL-6 receptor plays an important role in the host antiviral response. In this study, we detected the IL-6-IL-27 complex in serum and throat swab samples from patients infected with influenza A virus. A plasmid expressing the IL-6-IL-27 complex was constructed to explore its biological function. The results indicated that the IL-6-IL-27 complex has a stronger antiviral effect than the individual subunits of IL-6, IL-27A, and EBV-induced gene 3. Furthermore, the activity of the IL-6-IL-27 complex is mainly mediated by the IL-27A subunit and the IL-27 receptor α. The IL-6-IL-27 complex can positively regulate virus-triggered expression of IFN and IFN-stimulated genes by interacting with adaptor protein mitochondrial antiviral signaling protein, potentiating the ubiquitination of TNF receptor-associated factors 3 and 6 and NF-κB nuclear translocation. The secreted IL-6-IL-27 complex can induce the phosphorylation of STAT1 and STAT3 and shows antiviral activity. Our results demonstrate a previously unrecognized mechanism by which IL-6, IL-27A, and EBV-induced gene 3 form a large complex both intracellularly and extracellularly, and this complex acts in the host antiviral response. Show less
Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain Show more
Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet ( Show less
The prevalence of metabolic syndrome (Mets) is closely related to an increased incidence of cardiovascular events. Angiopoietin-like protein 4 (ANGPTL4) is contributory to the regulation of lipid meta Show more
The prevalence of metabolic syndrome (Mets) is closely related to an increased incidence of cardiovascular events. Angiopoietin-like protein 4 (ANGPTL4) is contributory to the regulation of lipid metabolism, herein, may provide a target for gene-aimed therapy of Mets. This observational case control study was designed to elucidate the relationship between ANGPTL4 gene single nucleotide polymorphism (SNP) rs1044250 and the onset of Mets, and to explore the interaction between SNP rs1044250 and weight management on Mets. We have recruited 1018 Mets cases and 1029 controls in this study. The SNP rs1044250 was genotyped with blood samples, base-line information and Mets-related indicators were collected. A 5-year follow-up survey was carried out to track the lifestyle interventions and changes in Mets-related indicators. ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference (OR 1.618, 95% CI [1.119-2.340]; p = 0.011), elevated blood pressure (OR 1.323, 95% CI [1.002-1.747]; p = 0.048), and Mets (OR 1.875, 95% CI [1.363-2.580]; p < 0.001). The follow-up survey shows that rs1044250 CC genotype patients with weight gain have an increased number of Mets components (M [Q1, Q3]: CC 1 (0, 1), CT + TT 0 [- 1, 1]; p = 0.021); The interaction between SNP rs1044250 and weight management is a risk factor for increased systolic blood pressure (β = 0.075, p < 0.001) and increased diastolic blood pressure (β = 0.097, p < 0.001), the synergistic effect of weight management and SNP rs1044250 is negative (S < 1). ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference and elevated blood pressure, therefore, for Mets. However, patients with wild type SNP 1044250 are more likely to have Mets when the body weight is increased, mainly due to elevated blood pressure. Show less
To investigate the mechanism of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in Müller cell (MC) viability and neuroprotection in diabetic retinopathy (DR), w Show more
To investigate the mechanism of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in Müller cell (MC) viability and neuroprotection in diabetic retinopathy (DR), we examined the role of VEGF in MC viability and BDNF production, and the effect of BDNF on MC viability under diabetic conditions. Mouse primary MCs and cells of a rat MC line, rMC1, were used in investigating MC viability and BDNF production under diabetic conditions. VEGF-stimulated BDNF production was confirmed in mice. The mechanism of BDNF-mediated MC viability was examined using siRNA knockdown. Under diabetic conditions, recombinant VEGF (rVEGF) stimulated MC viability and BDNF production in a dose-dependent manner. rBDNF also supported MC viability in a dose-dependent manner. Targeting BDNF receptor tropomyosin receptor kinase B (TRK-B) with siRNA knockdown substantially downregulated the activated (phosphorylated) form of serine/threonine-specific protein kinase (AKT) and extracellular signal-regulated kinase (ERK), classical survival and proliferation mediators. Finally, the loss of MC viability in 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 Show more
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
The present work aimed to identify the roles of WWP2 (an E3 ubiquitin-protein ligase) and protein phosphatase 1 regulatory subunit 3A (PPP1R3A) in different pathological stages of cardiac arrhythmia d Show more
The present work aimed to identify the roles of WWP2 (an E3 ubiquitin-protein ligase) and protein phosphatase 1 regulatory subunit 3A (PPP1R3A) in different pathological stages of cardiac arrhythmia development. Leptin-deficient mice (C57BLKS-Lepr Show less
How autophagy initiation is regulated and what the functional significance of this regulation is are unknown. Here, we characterized the role of yeast Vac8 in autophagy initiation through recruitment Show more
How autophagy initiation is regulated and what the functional significance of this regulation is are unknown. Here, we characterized the role of yeast Vac8 in autophagy initiation through recruitment of PIK3C3-C1 to the phagophore assembly site (PAS). This recruitment is dependent on the palmitoylation of Vac8 and on its middle ARM domains for binding PIK3C3-C1. Vac8-mediated anchoring of PIK3C3-C1 promotes PtdIns3P generation at the PAS and recruitment of the PtdIns3P binding protein Atg18-Atg2. The mouse homolog of Vac8, ARMC3, is conserved and functions in autophagy in mouse testes. Mice lacking ARMC3 have normal viability but show complete male infertility. Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella. These studies uncovered a function of Vac8/ARMC3 in PtdIns3-kinase anchoring at the PAS and its physical significance in mammalian spermatogenesis with a germ tissue-specific autophagic function. Show less
Propofol is a kind of common intravenous anaesthetic agent that plays an anti-tumor role in a variety of cancers, including ovarian cancer. However, the working mechanism of Propofol in ovarian cancer Show more
Propofol is a kind of common intravenous anaesthetic agent that plays an anti-tumor role in a variety of cancers, including ovarian cancer. However, the working mechanism of Propofol in ovarian cancer needs further exploration. The viability and metastasis of ovarian cancer cells were assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell assays. Flow cytometry was used to evaluate the cell cycle and apoptosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the abundance of circular RNA vacuolar protein sorting 13 homolog C (circVPS13C) and microRNA-145 (miR-145). The target relationship between miR-145 and circVPS13C was predicted by circinteractome database and verified by dual-luciferase reporter assay, RNA-binding protein immunoprecipitation (RIP) assay and RNA-pull down assay. Western blot assay was used to detect the levels of phosphorylated extracellular regulated MAP kinase (p-ERK), ERK, p-MAP kinse-ERK kinase (p-MEK) and MEK, in ovarian cancer cells. Propofol treatment suppressed the viability, cell cycle and motility and elevated the apoptosis rate of ovarian cancer cells. Propofol up-regulated miR-145 in a dose-dependent manner. Propofol exerted an anti-tumor role partly through up-regulating miR-145. MiR-145 was a direct target of circVPS13C. Propofol suppressed the progression of ovarian cancer through up-regulating miR-145 via suppressing circVPS13C. Propofol functioned through circVPS13C/miR-145/MEK/ERK signaling in ovarian cancer cells. Propofol suppressed the proliferation, cell cycle, migration and invasion and induced the apoptosis of ovarian cancer cells through circVPS13C/miR-145/MEK/ERK signaling in vitro. Show less
Liver X receptor α (LXRα; NR1H3) is an important transcription factor that can facilitate milk fat synthesis by regulating the transcription of FASN in mice and goats. Nevertheless, the lipid synthesi Show more
Liver X receptor α (LXRα; NR1H3) is an important transcription factor that can facilitate milk fat synthesis by regulating the transcription of FASN in mice and goats. Nevertheless, the lipid synthesis related to LXRα and its regulation on FASN in the buffalo mammary gland remain elusive. Here, we demonstrated that the mRNA and protein expression of LXRα in buffalo mammary tissue increased in lactation compared with that in the dry-off period. Overexpression of NR1H3 enhanced the lipid droplet formation and triacylglycerol concentration in buffalo mammary epithelial cells (BuMEC), whereas the knockdown of NR1H3 resulted in a decrease in the number of lipid droplets. At the same time, NR1H3 also affected the expression of regulatory factors (INSIG1, INSIG2, SREBF1, and PPARG) related to milk fat synthesis and that of genes involved in de novo synthesis (FASN, ACACA, and SCD), and uptake and transport (LPL, CD36, and FABP3) of fatty acids as well as triacylglycerol synthesis (GPAM, APGAT6, and DGAT1). Luciferase reporter assays indicated that overexpression of NR1H3 resulted in an increase in the activity of FASN promoter, whereas the knockdown of NR1H3 had an opposite effect. When NR1H3 was overexpressed, mutations in LXRE or SRE could decrease the promoter activity of FASN. Furthermore, mutagenesis of both LXRE and SRE within the FASN promoter completely eliminated the induced activity of LXRα. Our results reveal that buffalo LXRα promotes milk fat synthesis through regulating the expression of FASN by directly interacting with FASN promoter and affecting the SREBF1 expression. This study underscores a crucial role of LXRα in regulating lipid synthesis of the buffalo mammary gland. Show less
Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have bee Show more
Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies. Show less
Homo- or heterodimerization of G protein-coupled receptors (GPCRs) generally alters the normal functioning of these receptors and mediates their responses to a variety of physiological stimuli in vivo Show more
Homo- or heterodimerization of G protein-coupled receptors (GPCRs) generally alters the normal functioning of these receptors and mediates their responses to a variety of physiological stimuli in vivo. It is well known that melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) are key regulators of appetite and energy homeostasis in the central nervous system (CNS). However, the GPCR partners of MC3R and MC4R are not well understood. Our objective is to analyze single cell RNA-seq datasets of the hypothalamus to explore and identify novel GPCR partners of MC3R and MC4R and examine the pharmacological effect on the downstream signal transduction and membrane translocation of melanocortin receptors. We conducted an integrative analysis of multiple single cell RNA-seq datasets to reveal the expression pattern and correlation of GPCR families in the mouse hypothalamus. The emerging GPCRs with important metabolic functions were selected for cloning and co-immunoprecipitation validation. The positive GPCR partners were then tested for the pharmacological activation, competitive binding assay and surface translocation ELISA experiments. Based on the expression pattern of GPCRs and their function enrichment results, we narrowed down the range of potential GPCR interaction with MC3R and MC4R for further confirmation. Co-immunoprecipitation assay verified 23 and 32 novel GPCR partners that interacted with MC3R and MC4R in vitro. The presence of these GPCR partners exhibited different effects in the physiological regulation and signal transduction of MC3R and MC4R. This work represented the first large-scale screen for the functional GPCR complex of central melanocortin receptors and defined a composite metabolic regulatory GPCR network of the hypothalamic nucleuses. Show less
Microribonucleic acid-155 (microRNA155) and microRNA29 are reported to inhibit glucose metabolism in some cell and animal models, but no evidence from susceptible populations that examines the relatio Show more
Microribonucleic acid-155 (microRNA155) and microRNA29 are reported to inhibit glucose metabolism in some cell and animal models, but no evidence from susceptible populations that examines the relationship between microRNA155 or microRNA29 and type 2 diabetes mellitus currently exists. Furthermore, target genes regulated by microRNA155 and microRNA29 that affect glucose and lipid metabolism remain unknown. Human participants were divided into normal weight (n = 72), obesity (n = 120) and type 2 diabetes (n = 59) groups. The contents of microRNA155 and microRNA29 abundance in serum were measured, and candidate genes potentially related to glucose and lipid metabolism targeted by either microRNA155 or microRNA29 were screened. Overexpression of microRNA155 and microRNA29 in HepG2 cells was used to verify candidate gene expression, and measure the effects on glucose and lipid metabolism. Serum levels of microRNA155 and microRNA29 show a significant increase in individuals with obesity and type 2 diabetes compared with normal weight individuals. Identified target genes for microRNA155 were MAPK14, MAP3K10, DUSP14 and PRKAR2B. Identified target genes for microRNA29 were PEX11A and FADS1. Overexpression of microRNA155 or microRNA29 in HepG2 cells was found to downregulate the expression of identified target genes, and result in inhibition of triglyceride synthesis and glucose incorporation. MicroRNA155 and microRNA29 were significantly higher in type 2 diabetes patients compared with the control patients, their levels were also positively correlated with fasting plasma glucose levels, and over-expression of microRNA155 or microRNA29 were found to downregulate glucose and lipid metabolism target genes, and reduce lipid synthesis and glucose incorporation in HepG2 cells. Show less
Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypot Show more
Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type mice, but shows blunted/absent efficacy in CNS-Gipr KO mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism. Show less
To explore the role and mechanism of miR-125a-3p in rheumatoid arthritis (RA) progression. The RA-tissues and fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) were used in this study. q Show more
To explore the role and mechanism of miR-125a-3p in rheumatoid arthritis (RA) progression. The RA-tissues and fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) were used in this study. qRT-PCR, western blot and ELISA assay were performed to detect the expression levels of IL-6, IL-β and ΤΝF-α. Dual-luciferase reporter gene assay was used to observe the binding effect of miR-125a-3p and MAST3, and CCK-8 was used to observe the effect of miR-125a-3p on the proliferation of RA-FLS. miR-125a-3p was significantly downregulated in the RA-tissues and RA-FLS, and miR-125a-3p could inhibit the proliferation and reduce the inflammation response of RA-FLS. Besides, MAST3 was found as a target of miR-125a-3p, and increased MAST3 could reverse the effects of miR-125a-3p on RA-FLS including decreased proliferation, reduced inflammation level and the inactivation of Wnt/β-catenin and NF-κB pathways. This study suggests that miR-125a-3p could inactivate the Wnt/β-catenin and NF-κB pathways to reduce the proliferation and inflammation response of RA-FLS via targeting MAST3. Show less
XiaoYan Guo, Qinqin Zheng, Mingrui Lin+2 more · 2021 · Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics · added 2026-04-24
To explore the genetic basis for a pedigree affected with hereditary multiple osteochondroma (HMO). Peripheral blood samples were collected from the proband and members of his pedigree with informed c Show more
To explore the genetic basis for a pedigree affected with hereditary multiple osteochondroma (HMO). Peripheral blood samples were collected from the proband and members of his pedigree with informed consent. Following extraction of genomic DNA, all coding exons and flanking intronic sequences (-10 bp) of the EXT1 and EXT2 genes were subjected to targeted capture and next generation sequencing (NGS). Suspected variant was verified by Sanger sequencing. A heterozygous nonsense variant (c.1911C>A) was found in exon 10 of the EXT1 gene in the proband and his affected father but not in a healthy sister and normal controls. The variant was classified as a pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (PVS1+PM2+PP1). Bioinformatic analysis predicted that the c.1911C>A variant may be disease-causing via nonsense-mediated mRNA decay and anomalous splicing. The c.1911C>A variant probably underlay the disease in this pedigree. Discovery of this variant enriched the variant spectrum of HMO. Show less
EMT is an important biological process in the mechanism of tumor invasion and metastasis. However, there are still many unknowns about the specific mechanism of EMT in tumor. At present, a comprehensi Show more
EMT is an important biological process in the mechanism of tumor invasion and metastasis. However, there are still many unknowns about the specific mechanism of EMT in tumor. At present, a comprehensive analysis of EMT-related genes in colorectal cancer (CRC) is still lacking. All the data were downloaded from public databases including TCGA database (488 tumor samples and 52 normal samples) as the training set and the GEO database (GSE40967 including 566 tumor samples and 19 normal samples, GSE12945 including 62 tumor samples, GSE17536 including 177 tumor samples, GSE17537 including 55 tumor samples) as the validation sets. One hundred and sixty-six EMT-related genes (EMT-RDGs) were selected from the Molecular Signatures Database. Bioinformatics methods were used to analyze the correlation between EMT-RDGs and CRC prognosis, metastasis, drug efficacy, and immunity. We finally obtained nine prognostic-related EMT-RDGs (FGF8, NOG, PHLDB2, SIX2, SNAI1, TBX5, TIAM1, TWIST1, TCF15) through differential expression analysis, Unicox and Lasso regression analysis, and then constructed a risk prognosis model. There were significant differences in clinical characteristics, 22 immune cells, and immune functions between the high-risk and low-risk groups and the different states of the nine prognostic-related EMT-RDGs. The methylation level and mutation status of nine prognostic-related EMT-RDGs all affect their regulation of EMT. The Cox proportional hazards regression model was also constructed by the methylation sites of nine prognostic-related EMT-RDGs. In addition, the expression of FGF8, PHLDB2, SIX2, and SNAIL was higher and the expression level of NOG and TWIST1 was lower in the non-metastasis CRC group. Nine prognostic-related EMT-RDGs also affected the drug treatment response of CRC. Targeting these nine prognostic-related EMT-RDGs can regulate CRC metastasis and immune, which is beneficial for the prognosis of CRC patients, improve drug sensitivity in CRC patients. Show less
Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingx Show more
Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingxin Recipe IV (DXR IV) was further improved from the DXR according to the traditional use. However, the mechanism of DXR IV in atherosclerosis is unclear. This study aimed to illustrate whether DXR IV improve atherosclerosis through modulating the lipid metabolism and gut microbiota in atherosclerosis mice. 40 male ApoE DXR IV exerted the anti-atherosclerosis effect by inhibiting the excessive cholesterol deposition in aorta and regulating the level of TG, TC, LDL-C and HDL-C. The composition of gut microbiota was changed. Interestingly, the relative abundance of Muribaculaceae and Ruminococcaceae increased after DXR IV administration, whereas the abundance of Erysipelotrichaceae decreased, which have been beneficial to lipid metabolism. Nine potential metabolic biomarkers, including acetate, butyrate, propionate, alanine, succinate, valerate, xylose, choline, glutamate, were identified, which were related to fatty acid metabolism. Further, the pathway of fatty acid was detected by the RT-qPCR and western blotting. Compared with model group, the level of LXR-α and SREBP1 decreased significantly in DXR IV group while LXR-β, SREBP2 showed no statistical significance. It indicated that DXR IV modulated lipid metabolism by LXR-α/SREBP1 but not LXRβ and SREBP2. DXR IV exhibits potential anti-atherosclerosis effect, which is closely related to lipid metabolism and the gut microbiota. This study may provide novel insights into the mechanism of DXR IV on atherosclerosis and a basis for promising clinical usage. Show less
Aspirin can prevent or inhibit inflammation-related cancers, such as colorectal cancer and hepatocellular carcinoma (HCC). However, the effectiveness of chemotherapy may be compromised by activating o Show more
Aspirin can prevent or inhibit inflammation-related cancers, such as colorectal cancer and hepatocellular carcinoma (HCC). However, the effectiveness of chemotherapy may be compromised by activating oncogenic pathways in cancer cells. Elucidation of such chemoresistance mechanisms is crucial to developing novel strategies to maximize the anti-cancer effects of aspirin. Here, we report that aspirin markedly induces CREB/ATF1 phosphorylation in HCC cells, which compromises aspirin's anti-HCC effect. Inhibition of AMP-activated protein kinase (AMPK) abrogates the induction of CREB/ATF1 phosphorylation by aspirin. Mechanistically, activation of AMPK by aspirin results in decreased expression of the urea cycle enzyme carbamoyl-phosphate synthase 1 (CPS1) in HCC cells and xenografts. Treatment with aspirin or CPS1 knockdown stimulates soluble adenylyl cyclase expression, thereby increasing cyclic AMP (cAMP) synthesis and stimulating PKA-CREB/ATF1 signaling. Importantly, abrogation of aspirin-induced CREB/ATF1 phosphorylation could sensitize HCC to aspirin. The bis-benzylisoquinoline alkaloid berbamine suppresses the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), leading to protein phosphatase 2A-mediated downregulation of CREB/ATF1 phosphorylation. The combination of berbamine and aspirin significantly inhibits HCC in vitro and in vivo. These data demonstrate that the regulation of cAMP-PKA-CREB/ATF1 signaling represents a noncanonical function of CPS1. Targeting the PKA-CREB/ATF1 axis may be a strategy to improve the therapeutic effects of aspirin on HCC. Show less