The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascu Show more
The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients. Show less
Mitophagy plays a critical role in maintaining mitochondrial quality and cellular homeostasis. But the specific contribution of mitophagy-related E3 ubiquitin ligases to prognoses remains largely unex Show more
Mitophagy plays a critical role in maintaining mitochondrial quality and cellular homeostasis. But the specific contribution of mitophagy-related E3 ubiquitin ligases to prognoses remains largely unexplored. In this study, we identified a novel mitophagy-related E3 ubiquitin ligase prognostic signature using least absolute shrinkage and selector operator (LASSO) and multivariate Cox regression analyses in breast cancer. Based on median risk scores, patients were divided into high-risk and low-risk groups. Functional enrichment analyses were conducted to explore the biological differences between the two groups. Immune infiltration, drug sensitivity, and mitochondrial-related phenotypes were also analyzed to evaluate the clinical implications of the model. A four-gene signature (ARIH1, SIAH2, UBR5, and WWP2) was identified, and Kaplan-Meier analysis demonstrated that the high-risk group had significantly worse overall survival (OS). The high-risk patients exhibited disrupted mitochondrial metabolism and immune dysregulation with upregulated immune checkpoint molecules. Additionally, the high-risk group exhibited higher sensitivity to several drugs targeting the Akt/PI3K/mTORC1 signaling axis. Accompanying mitochondrial metabolic dysregulation, mtDNA stress was elevated, contributing to activation of the senescence-associated secretory phenotype (SASP) in the high-risk group. In conclusion, the identified signature provides a robust tool for risk stratification and offers insights into the interplay between mitophagy, immune modulation, and therapeutic responses for breast cancer. Show less
The phosphorylation of signal transducer and activator of transcription 3 (STAT3) monomer at S727 promotes its mitochondrial localisation and regulates mitochondrial function, thus exerting a protecti Show more
The phosphorylation of signal transducer and activator of transcription 3 (STAT3) monomer at S727 promotes its mitochondrial localisation and regulates mitochondrial function, thus exerting a protective effect on tumour cells. However, no inhibitor drugs targeting mitochondrial STAT3 (mitoSTAT3) or S727-STAT3 phosphorylation have been identified. Here, we report a novel diterpenoid extracted from Isodon sculponeatus, sculponeatin A (sptA), induces mitochondrial dysfunction in non-small cell lung cancer (NSCLC) by targeting mitoSTAT3 degradation. xCELLigence real-time cell analysis assay and high-content analysis were performed to measure cytotoxicity. Mitochondrial function was assessed by transmission electron microscopy, mitochondrial permeability transition pore opening and Seahorse cellular flux assays. The effects of sptA on the upstream signalling pathway of mitochondrial dysfunction were measured by Western blot, gene alterations and other approaches. Immunofluorescence and live cell imaging were performed to visualise the expression and position of mitoSTAT3. Nude mice and zebrafish were modelled with subcutaneous xenografts. Pharmacokinetics of sptA were examined in rats. Drug toxicity was evaluated in zebrafish. sptA inhibited mitochondrial respiration in NSCLC cells. sptA induced mitochondrial dysfunction by promoting the degradation of mitoSTAT3. sptA promoted WW domain containing E3 ubiquitin protein ligase 2 (WWP2)-mediated ubiquitination and degradation of mitoSTAT3 through direct binding. sptA inhibited tumour growth in vivo. Evaluation of drug toxicity in zebrafish showed that overdose of sptA may cause heart damage. These findings suggest that pharmacological targeting the degradation of mitoSTAT3 by sptA may provide therapeutic benefits against NSCLC. Show less
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported Show more
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Show less
Autoantibodies hold promise for diagnosing lung cancer. However, their effectiveness in early-stage detection needs improvement. In this study, we investigated novel IgG and IgM autoantibodies for det Show more
Autoantibodies hold promise for diagnosing lung cancer. However, their effectiveness in early-stage detection needs improvement. In this study, we investigated novel IgG and IgM autoantibodies for detecting early-stage lung adenocarcinoma (Early-LUAD) by employing a multi-step approach, including Human Proteome Microarray (HuProtTM) discovery, focused microarray verification, and ELISA validation, on 1246 individuals consisting of 634 patients with Early-LUAD (stage 0-I), 280 patients with benign lung disease (BLD), and 332 normal healthy controls (NHCs). HuProtTM selected 417 IgG/IgM candidates, and focused microarray further verified 55 significantly elevated IgG/IgM autoantibodies targeting 32 tumor-associated antigens in Early-LUAD compared to BLD/NHC/BLD+NHC. A novel panel of 10 autoantibodies (ELAVL4-IgM, GDA-IgM, GIMAP4-IgM, GIMAP4-IgG, MGMT-IgM, UCHL1-IgM, DCTPP1-IgM, KCMF1-IgM, UCHL1-IgG, and WWP2-IgM) demonstrated a sensitivity of 70.5% and a specificity of 77.0% or 80.0% for distinguishing Early-LUAD from BLD or NHC in ELISA validation. Positive predictive values for distinguishing Early-LUAD from BLD with nodules ≤ 8 mm, 9-20 mm, and > 20 mm significantly increased from 47.27%, 52.00%, and 62.90% [low-dose computed tomography (LDCT) alone] to 79.17%, 71.13%, and 87.88% (10-autoantibody panel combined with LDCT), respectively. The combined risk score (CRS), based on the 10-autoantibody panel, sex, and imaging maximum diameter, effectively stratified the risk for Early-LUAD. Individuals with 10 ≤ CRS ≤ 25 and CRS > 25 indicated a higher risk of Early-LUAD compared to the reference (CRS < 10), with adjusted odds ratios of 5.28 [95% confidence interval (CI): 3.18-8.76] and 9.05 (95% CI: 5.40-15.15), respectively. This novel panel of IgG and IgM autoantibodies offers a complementary approach to LDCT in distinguishing Early-LUAD from benign nodules. Show less
Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulat Show more
Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulates cell proliferation and differentiation. Whether WWP2 plays a regulatory role in AKI remains to be elucidated. We aimed to investigate the implication of WWP2 in AKI and its underlying mechanism in the present study. We utilized renal tissues from patients with AKI and established AKI models in global or tubule-specific knockout (cKO) mice strains to study WWP2's implication in AKI. We also systemically analyzed ubiquitylation omics and proteomics to decipher the underlying mechanism. In the present study, we found that WWP2 expression significantly increased in the tubules of kidneys with AKI. Global or tubule-specific knockout of WWP2 significantly aggravated renal dysfunction and tubular injury in AKI kidneys, whereas WWP2 overexpression significantly protected tubular epithelial cells against cisplatin. WWP2 deficiency profoundly affected autophagy in AKI kidneys. Further analysis with ubiquitylation omics, quantitative proteomics and experimental validation suggested that WWP2 mediated poly-ubiquitylation of CDC20, a negative regulator of autophagy. CDC20 was significantly decreased in AKI kidneys, and selective inhibiting CDC20 with apcin profoundly alleviated renal dysfunction and tubular injury in the cisplatin model with or without WWP2 cKO, indicating that CDC20 may serve as a downstream target of WWP2 in AKI. Inhibiting autophagy with 3-methyladenine blocked apcin's protection against cisplatin-induced renal tubular cell injury. Activating autophagy by rapamycin significantly protected against cisplatin-induced AKI in WWP2 cKO mice, whereas inhibiting autophagy by 3-methyladenine further aggravated apoptosis in cisplatin-exposed WWP2 KO cells. Taken together, our data indicated that the WWP2/CDC20/autophagy may be an essential intrinsic protective mechanism against AKI. Further activating WWP2 or inhibiting CDC20 may be novel therapeutic strategies for AKI. Show less
Elevated circulating lactate serves as a critical biomarker in sepsis, yet the epigenetic mechanisms by which lactate influences disease progression remain unclear. This study aims to identify lactate Show more
Elevated circulating lactate serves as a critical biomarker in sepsis, yet the epigenetic mechanisms by which lactate influences disease progression remain unclear. This study aims to identify lactate-associated genes in sepsis, decode their regulatory roles, and assess their potential as therapeutic targets. We performed transcriptome-wide bioinformatic analyses to identify lactylation-related differentially expressed genes (DEGs) between sepsis patients and healthy controls. Pathway enrichment highlighted immune signaling circuits. Five DEGs (ZC3H4, RBM10, PCBP2, RBM25, HNRNPM) were prioritized via ROC analysis, and their combined expression formed a prognostic signature with strong predictive power (AUC > 0.85). Validation in murine sepsis-induced acute lung injury (ALI) models (cecal ligation-puncture and LPS challenge) confirmed significant upregulation of these five genes by qRT-PCR. RBM25 was selected for deeper functional study. Mechanistic assays implicate an RBM25-Acly axis that couples altered metabolism to histone lactylation and transcriptional reprogramming. Notably, we propose the RBM25-Acly axis that couples altered metabolism to histone lactylation and transcriptional reprogramming. Our work uncovers a novel metabolic-epigenetic circuit in sepsis driven by lactylation, with RBM25 and its regulation of ACLY as a key node. The lactylation-based gene signature offers a high-fidelity prognostic tool, and targeting the RBM25-Acly pathway may open new therapeutic avenues. These findings lay a foundation for precision interventions that integrate metabolic and epigenetic strategies in sepsis care. Show less
Inorganic phosphorus (Pi) deficiency significantly impacts plant growth, development, and photosynthetic efficiency. This study evaluated 206 rice accessions from a MiniCore population under both Pi-s Show more
Inorganic phosphorus (Pi) deficiency significantly impacts plant growth, development, and photosynthetic efficiency. This study evaluated 206 rice accessions from a MiniCore population under both Pi-sufficient (Pi Show less
Quantitative reverse transcription PCR (qRT-PCR) can screen applicable reference genes of species, and reference genes can be used to reduce experimental errors. Sudan grass (
The pivotal role of lysosomal function in preserving neuronal homeostasis is recognized, with its dysfunction being implicated in neurodegenerative processes, notably in Parkinson's disease (PD). Yet, Show more
The pivotal role of lysosomal function in preserving neuronal homeostasis is recognized, with its dysfunction being implicated in neurodegenerative processes, notably in Parkinson's disease (PD). Yet, the molecular underpinnings of lysosome-related genes (LRGs) in the context of PD remain partially elucidated. We collected RNA-seq data from the brain substantia nigra of 30 PD patients and 20 normal subjects from the GEO database. We obtained molecular classification clusters from the screened lysosomal expression patterns. The lysosome-related diagnostic model of Parkinson's disease was constructed by XGBoost and Random Forest. And we validated the expression patterns of signature LRGs in the diagnostic model by constructing a PD rat model. Finally, the linkage between PD and cancer through signature genes was explored. The expression patterns of the 33 LRGs screened can be divided into two groups of PD samples, enabling exploration of the variance in biological processes and immune elements. Cluster A had a higher disease severity. Subsequently, critical genes were sieved through the application of machine learning methodologies culminating in the identification of two intersecting feature genes (ACP2 and LRP2). A PD risk prediction model was constructed grounded on these signature genes. The model's validity was assessed through nomogram evaluation, which demonstrated robust confidence validity. Then we analyzed the correlation analysis, immune in-filtration, biological function, and rat expression validation of the two genes with common pathogenic genes in Parkinson's disease, indicating that these two genes play an important role in the pathogenesis of PD. We then selected ACP2, which had a significant immune infiltration correlation, as the entry gene for the pan-cancer analysis. The pan-cancer analysis revealed that ACP2 has profound associations with prognostic indicators, immune infiltration, and tumor-related regulatory processes across various neoplasms, suggesting its potential as a therapeutic target in a range of human diseases, including PD and cancers. Our study comprehensively analyzed the molecular grouping of LRGs expression patterns in Parkinson's disease, and the disease progression was more severe in cluster A. And the PD diagnosis model related to LRGs is constructed. Finally, ACP2 is a potential target for the relationship between Parkinson's disease and tumor. Show less
Lipid remodeling is crucial for cold tolerance in plants. However, the precise alternations of lipidomics during cold responses remain elusive, especially in maize (Zea mays L.). In addition, the key Show more
Lipid remodeling is crucial for cold tolerance in plants. However, the precise alternations of lipidomics during cold responses remain elusive, especially in maize (Zea mays L.). In addition, the key genes responsible for cold tolerance in maize lipid metabolism have not been identified. Here, we integrate lipidomic, transcriptomic, and genetic analysis to determine the profile of lipid remodeling caused by cold stress. We find that the homeostasis of cellular lipid metabolism is essential for maintaining cold tolerance of maize. Also, we detect 210 lipid species belonging to 13 major classes, covering phospholipids, glycerides, glycolipids, and free fatty acids. Various lipid metabolites undergo specific and selective alterations in response to cold stress, especially mono-/di-unsaturated lysophosphatidic acid, lysophosphatidylcholine, phosphatidylcholine, and phosphatidylinositol, as well as polyunsaturated phosphatidic acid, monogalactosyldiacylglycerol, diacylglycerol, and triacylglycerol. In addition, we identify a subset of key enzymes, including ketoacyl-acyl-carrier protein synthase II (KAS II), acyl-carrier protein 2 (ACP2), male sterility33 (Ms33), and stearoyl-acyl-carrier protein desaturase 2 (SAD2) involved in glycerolipid biosynthetic pathways are positive regulators of maize cold tolerance. These results reveal a comprehensive lipidomic profile during the cold response of maize and provide genetic resources for enhancing cold tolerance in crops. Show less
Variants of the G protein-coupled receptor 75 (GPR75) are associated with a lower BMI in large-scale human exome-sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Show more
Variants of the G protein-coupled receptor 75 (GPR75) are associated with a lower BMI in large-scale human exome-sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Using random germline mutagenesis in mice, we identified a missense allele (Thinner) of Gpr75 that resulted in a lean phenotype and verified the decreased body weight and fat weight in Gpr75-knockout (Gpr75-/-) mice. Gpr75-/- mice displayed reduced food intake under high-fat diet (HFD) feeding, and pair-feeding normalized their body weight. The endogenous GPR75 protein was exclusively expressed in the brains of 3xFlag-tagged Gpr75-knockin (3xFlag-Gpr75) mice, with consistent expression across different brain regions. GPR75 interacted with Gαq to activate various signaling pathways after HFD feeding. Additionally, GPR75 was localized in the primary cilia of hypothalamic cells, whereas the Thinner mutation (L144P) and human GPR75 variants in individuals with a lower BMI failed to localize in the cilia. Loss of GPR75 selectively inhibited weight gain in HFD-fed mice but failed to suppress the development of obesity in leptin ob-mutant (Lepob-mutant) mice and adenylate cyclase 3-mutant (Adcy3-mutant) mice on a chow diet. Our data reveal that GPR75 is a ciliary protein expressed in the brain and plays an important role in regulating food intake. Show less
The present study, as one part of a larger project that aimed to investigate the effects of dietary berberine (BBR) on fish growth and glucose regulation, mainly focused on whether miRNAs involve in B Show more
The present study, as one part of a larger project that aimed to investigate the effects of dietary berberine (BBR) on fish growth and glucose regulation, mainly focused on whether miRNAs involve in BBR's modulation of glucose metabolism in fish. Blunt snout bream Megalobrama amblycephala (average weight of 20.36 ± 1.44 g) were exposed to the control diet (NCD, 30% carbohydrate), the high-carbohydrate diet (HCD, 43% carbohydrate) and the berberine diet (HCB, HCD supplemented with 50 mg/kg BBR). After 10 weeks' feeding trial, intraperitoneal injection of glucose was conducted, and then, the plasma and liver were sampled at 0 h, 1 h, 2 h, 6 h, and 12 h. The results showed the plasma glucose levels in all groups rose sharply and peaked at 1 h after glucose injection. Unlike the NCD and HCB groups, the plasma glucose in the HCD group did not decrease after 1 h, while remained high level until at 2 h. The NCD group significantly increased liver glycogen content at times 0-2 h compared to the other two groups and then liver glycogen decreased sharply until at times 6-12 h. To investigate the role of BBR that may cause the changes in plasma glucose and liver glycogen, miRNA high-throughput sequencing was performed on three groups of liver tissues at 2 h time point. Eventually, 20 and 12 differentially expressed miRNAs (DEMs) were obtained in HCD vs NCD and HCB vs HCD, respectively. Through function analyzing, we found that HCD may affect liver metabolism under glucose loading through the NF-κB pathway; and miRNAs regulated by BBR mainly play roles in adipocyte lipolysis, niacin and nicotinamide metabolism, and amino acid transmembrane transport. In the functional exploration of newly discovered novel:Chr12₁₈₈₉₂, we found its target gene, adenylate cyclase 3 (adcy3), was widely involved in lipid decomposition, amino acid metabolism, and other pathways. Furthermore, a targeting relationship of novel:Chr12₁₈₈₉₂ and adcy3 was confirmed by double luciferase assay. Thus, BBR may promote novel:Chr12₁₈₈₉₂ to regulate the expression of adcy3 and participate in glucose metabolism. Show less
Epilepsy is a common neurological disorder characterized by recurrent epilepsy episodes. As a non-pharmacological treatment, the ketogenic diet has been widely applied in treating epilepsy. However, t Show more
Epilepsy is a common neurological disorder characterized by recurrent epilepsy episodes. As a non-pharmacological treatment, the ketogenic diet has been widely applied in treating epilepsy. However, the exact therapeutic mechanism of the ketogenic diet for epilepsy remains unclear. This study investigates the molecular mechanisms of the ketogenic diet in regulating fatty acid metabolism and activating the ADCY3-initiated cAMP signaling pathway to enhance neuronal inhibition and thereby treat epilepsy. Meta-analysis reveals that the ketogenic diet is superior to the conventional diet in treating epilepsy. Animal experiments demonstrate that the ketogenic diet is more effective than the conventional diet in treating epilepsy, with the best results achieved using the classic ketogenic diet. Transcriptome sequencing analysis identifies six essential genes, among which ADCY3 shows increased expression in the ketogenic diet. In vivo experiments confirm that the activation of the cAMP-PKA signaling pathway by ADCY3 enhances neuronal inhibition and improves epilepsy control. Clinical observations indicate that the ketogenic diet improves patient epilepsy episodes by regulating the ADCY3-initiated cAMP signaling pathway. Show less
Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. T Show more
Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP-1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP-1R and GIPR signaling together additively inhibits allergen-induced lung and airway inflammation. WT (C57BL/6J), GLP-1R knockout (KO), GIPR KO, and GLP-1R/GIPR double KO (DKO) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen-induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2). Alt-Ext-induced IL-33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other strains. Furthermore, Alt-Ext-induced protein expression of IL-5, IL-13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP-1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM-1 expression on lung epithelial cells was increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other 3 strains. Deficiency of both GLP-1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP-1R and GIPR signaling should be explored for the treatment of asthma. Show less
Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GI Show more
Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GIP has been regarded as a hormone-like peptide to regulate the local metabolic environment. In this study, we investigated the antioxidant role of GIP on the neuron and explored the possible mechanism. Cell counting Kit-8 (CCK-8) was used to measure cell survival. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect apoptosis in vitro and in vivo. Reactive oxygen species (ROS) levels were probed with 2', 7'-Dichloro dihydrofluorescein diacetate (DCFH-DA), and glucose intake was detected with 2-NBDG. Immunofluorescence staining and western blot were used to evaluate the protein level in cells and tissues. Hematoxylin-eosin (HE) staining, immunofluorescence staining and tract-tracing were used to observe the morphology of the injured spinal cord. Basso-Beattie-Bresnahan (BBB) assay was used to evaluate functional recovery after spinal cord injury. GIP reduced the ROS level and protected cells from apoptosis in cultured neurons and injured spinal cord. GIP facilitated wound healing and functional recovery of the injured spinal cord. GIP significantly improved the glucose uptake of cultured neurons. Meanwhile, inhibition of glucose uptake significantly attenuated the antioxidant effect of GIP. GIP increased glucose transporter 3 (GLUT3) expression via up-regulating the level of hypoxia-inducible factor 1α (HIF-1α) in an Akt-dependent manner. GIP increases GLUT3 expression and promotes glucose intake in neurons, which exerts an antioxidant effect and protects neuronal cells from oxidative stress both in vitro and in vivo. Show less
The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether Show more
The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism. Show less
Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, which affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mende Show more
Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, which affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (P-value < 5×10 Show less
Melanocortin-4 receptor (MC4R) functions as a crucial neuroendocrine G protein-coupled receptor (GPCR) in the central nervous system of mammals, displaying agonist-independent constitutive activity th Show more
Melanocortin-4 receptor (MC4R) functions as a crucial neuroendocrine G protein-coupled receptor (GPCR) in the central nervous system of mammals, displaying agonist-independent constitutive activity that is mainly determined by its N-terminal domain. We previously reported that zebrafish MC4R exhibited a much higher basal cAMP level in comparison to mammalian MC4Rs. However, the functional evolution of constitutive activities in chordate MC4Rs remains to be elucidated. Here we cloned and compared the constitutive activities of MC4Rs from nine vertebrate species and showed that the additive action of the N-terminus with the extracellular region or transmembrane domain exhibited a combined pharmacological effect on the MC4R constitutive activity. In addition, we demonstrated that four residues of F149, Q156, V163, and K164 of the second intracellular loop played a vital role in determining MC4R constitutive activity. This study provided novel insights into functional evolution and identified a key motif essential for constitutive modulation of MC4R signaling. Show less
Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-ove Show more
Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-overlapping functions. However, the mechanism by which MC4R in the arcuate nucleus (ARC) region regulates energy balance and insulin resistance remains unclear. The MC4R POMC neuron-specific ablation of MC4R in the ARC region promoted food intake, impaired energy expenditure, leading to increased weight gain and impaired systemic glucose homeostasis. Additionally, MC4R ablation reduced the activation of POMC neuron, and is not tissue-specific for peripheral regulation, suggesting the importance of its central regulation. Mechanistically, sequencing analysis and Co-IP assay demonstrated a direct interaction of MC4R with Kir2.1. Knockdown of Kir2.1 in POMC neuron-specific ablation of MC4R restored the effect of MC4R ablation on energy expenditure and systemic glucose homeostasis, indicating by reduced body weight and ameliorated insulin resistance. Hypothalamic POMC neuron-specific knockout of MC4R affects energy balance and insulin sensitivity by regulating Kir2.1. Kir2.1 represents a new target and pathway that could be targeted in obesity. Show less
Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP Show more
Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11α signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific Gq/11α inhibitor was delivered to the PVN; this provided evidence that a Gsα-independent signaling pathway, namely Gq/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11α may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects. Show less
Youwen Yuan, Kangli Li, Xueru Ye+12 more · 2024 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activit Show more
Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activity remain largely unknown. Here, cardiotrophin-like cytokine factor 1 (CLCF1) is identified as a negative regulator of thermogenesis in BAT. Adenovirus-mediated overexpression of CLCF1 in BAT greatly impairs the thermogenic capacity of BAT and reduces the metabolic rate. Consistently, BAT-specific ablation of CLCF1 enhances the BAT function and energy expenditure under both thermoneutral and cold conditions. Mechanistically, adenylate cyclase 3 (ADCY3) is identified as a downstream target of CLCF1 to mediate its role in regulating thermogenesis. Furthermore, CLCF1 is identified to negatively regulate the PERK-ATF4 signaling axis to modulate the transcriptional activity of ADCY3, which activates the PKA substrate phosphorylation. Moreover, CLCF1 deletion in BAT protects the mice against diet-induced obesity by promoting BAT activation and further attenuating impaired glucose and lipid metabolism. Therefore, our results reveal the essential role of CLCF1 in regulating BAT thermogenesis and suggest that inhibiting CLCF1 signaling might be a potential therapeutic strategy for improving obesity-related metabolic disorders. Show less
The goat breeding industry on the Tibetan Plateau faces strong selection pressure to enhance fertility. Consequently, there is an urgent need to develop goat lines with higher fertility and adaptabili Show more
The goat breeding industry on the Tibetan Plateau faces strong selection pressure to enhance fertility. Consequently, there is an urgent need to develop goat lines with higher fertility and adaptability. The ovary, as a key organ determining reproductive performance, is regulated by a complex transcriptional network involving numerous protein-coding and non-coding genes. However, the molecular mechanisms of the key mRNA-miRNA-lncRNA regulatory network in goat ovaries remain largely unknown. This study focused on the histology and differential mRNA/miRNA/lncRNA between Chuanzhong black goat (CBG, high productivity, multiple births) and Tibetan goat (TG, strong adaptability, single birth) ovaries. Histomorphological analysis showed that the medulla proportion in CBG ovaries was significantly reduced compared to TG. RNA-Seq and small RNA-Seq analysis identified 1218 differentially expressed (DE) mRNAs, 100 DE miRNAs, and 326 DE lncRNAs, which were mainly enriched in ovarian steroidogenesis, oocyte meiosis, biosynthesis of amino acids and protein digestion, and absorption signaling pathways. Additionally, five key mRNA-miRNA-lncRNA interaction networks regulating goat reproductive performance were identified, including Show less
The existence of chronic pain increases susceptibility to virus and is now widely acknowledged as a prominent feature recognized as a major manifestation of long-term coronavirus disease 2019 (COVID-1 Show more
The existence of chronic pain increases susceptibility to virus and is now widely acknowledged as a prominent feature recognized as a major manifestation of long-term coronavirus disease 2019 (COVID-19) infection. Given the ongoing COVID-19 pandemic, it is imperative to explore the genetic associations between chronic pain and predisposition to COVID-19. We conducted genetic analysis at the single nucleotide polymorphism (SNP), gene, and molecular levels using summary statistics of genome-wide association study (GWAS) and analyzed the drug targets by summary data-based Mendelian randomization analysis (SMR) to alleviate the multi-site chronic pain in COVID-19. Additionally, we performed a latent causal variable (LCV) method to investigate the causal relationship between chronic pain and susceptibility to COVID-19. The cross-trait meta-analysis identified 19 significant SNPs shared between COVID-19 and chronic pain. Coloc analysis indicated that the posterior probability of association (PPH4) for three loci was above 70% in both critical COVID-19 and COVID-19, with the corresponding top three SNPs being rs13135092, rs7588831, and rs13135092. A total of 482 significant overlapped genes were detected from MAGMA and CPASSOC results. Additionally, the gene ANAPC4 was identified as a potential drug target for treating chronic pain (P=7.66E-05) in COVID-19 (P=8.23E-03). Tissue enrichment analysis highlighted that the amygdala (P=7.81E-04) and prefrontal cortex (P=8.19E-05) as pivotal in regulating chronic pain of critical COVID-19. KEGG pathway enrichment further revealed the enrichment of pleiotropic genes in both COVID-19 (P=3.20E-03,Padjust=4.77E-02,hsa05171) and neurotrophic pathways (P=9.03E-04,Padjust =2.55E-02,hsa04621). Finally, the latent causal variable (LCV) model was applied to find the genetic component of critical COVID-19 was causal for multi-site chronic pain (P=0.015), with a genetic causality proportion (GCP) of was 0.60. In this study, we identified several functional genes and underscored the pivotal role of the inflammatory system in the correlation between the paired traits. Notably, heat shock proteins emerged as potential objective biomarkers for chronic pain symptoms in individuals with COVID-19. Additionally, the ubiquitin system might play a role in mediating the impact of COVID-19 on chronic pain. These findings contribute to a more comprehensive understanding of the pleiotropy between COVID-19 and chronic pain, offering insights for therapeutic trials. Show less
Diabetes mellitus (DM) is a major metabolic disease endangering global health, with diabetic nephropathy (DN) as a primary complication lacking curative therapy. Sporoderm-broken spores of
The global burden of renal diseases is increasingly severe, underscoring the need for in-depth exploration of the molecular mechanisms underlying renal disease progression and the development of poten Show more
The global burden of renal diseases is increasingly severe, underscoring the need for in-depth exploration of the molecular mechanisms underlying renal disease progression and the development of potential novel biomarkers or therapeutic targets. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine involved in the regulation of key biological processes, such as glucose and lipid metabolism, inflammation, vascular permeability, and angiogenesis, all of which play crucial roles in the pathogenesis of kidney diseases. Over the past 2 decades, ANGPTL4 has been regarded as playing a pivotal role in the progression of various kidney diseases, prompting significant interest from the scientific community regarding its potential clinical utility in renal disorders. This review synthesizes the available literature, provides a concise overview of the molecular biological effects of ANGPTL4, and highlights its relationship with multiple renal diseases and recent research advancements. These findings underscore the important gaps that warrant further investigation to develop novel targets for the prediction or treatment of various renal diseases. Show less
Fetal growth restriction (FGR) is a common complication of pregnancy, which seriously endangers fetal health and still lacks effective therapeutic targets. Clostridium difficile (C. difficile) is asso Show more
Fetal growth restriction (FGR) is a common complication of pregnancy, which seriously endangers fetal health and still lacks effective therapeutic targets. Clostridium difficile (C. difficile) is associated with fetal birth weight, and its membrane vesicles (MVs) are pathogenic vectors. However, the role of C. difficile and its MVs in FGR remains unclear. Here we found that supplementation with C. difficile altered the characteristics of gut microbiota and reduced the birth weight in mice. Interestingly, C. difficile MVs entered placenta, inhibited trophoblast motility, and induced fetal weight loss in mice. Mechanistically, C. difficile MVs activated the PPAR pathway via enhancing the transcriptional activity of PPARγ promoter, consequently inhibiting trophoblast motility. Moreover, PPARγ expression was significantly elevated in FGR placenta, and negatively correlated with fetal birth weight. Together, our findings reveal the significance of C. difficile and its MVs in FGR, providing new insights into the mechanisms of FGR development. Show less
Senescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, typ Show more
Senescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, type 2 diabetes exacerbates this aging process. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has well-established cardiovascular benefits and, in recent years, has been posited to possess anti-aging properties. However, there are no reported data on their improvement of cardiomyocytes function through the alleviation of aging. Consequently, our study aims to investigate the mechanism by which SGLT2i exerts anti-aging and protective effects at the cardiac level through its action on the FOXO1-ANGPTL4 pathway. To elucidate the underlying functions and mechanisms, we established both in vivo and in vitro disease models, utilizing mice with diabetic cardiomyopathy (DCM) induced by type 2 diabetes mellitus (T2DM) through high-fat diet combined with streptozotocin (STZ) administration, and AC16 human cardiomyocyte cell subjected to stimulation with high glucose (HG) and palmitic acid (PA). These models were employed to assess the changes in the senescence phenotype of cardiomyocytes and cardiac function following treatment with SGLT2i. Concurrently, we identified ANGPTL4, a key factor contributing to senescence in DCM, using RNA sequencing (RNA-seq) technology and bioinformatics methods. We further clarified ANGPTL4 role in promoting pathological aging of cardiomyocytes induced by hyperglycemia and hyperlipidemia through knockdown and overexpression of the factor, as well as analyzed the impact of SGLT2i intervention on ANGPTL4 expression. Additionally, we utilized chromatin immunoprecipitation followed by quantitative real-time PCR (ChIP-qPCR) to confirm that FOXO1 is essential for the transcriptional activation of ANGPTL4. The therapeutic intervention with SGLT2i alleviated the senescence phenotype in cardiomyocytes of the DCM mouse model constructed by high-fat feeding combined with STZ, as well as in the AC16 model stimulated by HG and PA, while also improving cardiac function in DCM mice. We observed that the knockdown of ANGPTL4, a key senescence-promoting factor in DCM identified through RNA-seq technology and bioinformatics, mitigated the senescence of cardiomyocytes, whereas overexpression of ANGPTL4 exacerbated it. Moreover, SGLT2i improved the senescence phenotype by suppressing the overexpression of ANGPTL4. In fact, we discovered that SGLT2i exert their effects by regulating the upstream transcription factor FOXO1 of ANGPTL4. Under conditions of hyperglycemia and hyperlipidemia, compared to the control group without FOXO1, the overexpression of FOXO1 in conjunction with SGLT2i intervention significantly reduced both ANGPTL4 mRNA and protein levels. This suggests that the FOXO1-ANGPTL4 axis may be a potential target for the cardioprotective effects of SGLT2i. Collectively, our study demonstrates that SGLT2i ameliorate the pathological aging of cardiomyocytes induced by a high glucose and high fat metabolic milieu by regulating the interaction between FOXO1 and ANGPTL4, thereby suppressing the transcriptional synthesis of the latter, and consequently restoring cardiac function. Show less
This study aimed to investigate the possible mechanisms by which ANGPTL4 is involved in the pathogenesis of choroidal neovascularization (CNV) and subretinal fibrosis. Differentially expressed genes i Show more
This study aimed to investigate the possible mechanisms by which ANGPTL4 is involved in the pathogenesis of choroidal neovascularization (CNV) and subretinal fibrosis. Differentially expressed genes in retinal pigmented epithelium (RPE)-choroid-sclera complex tissues from nAMD patients and control individuals were identified via the GEO database, followed by GO and KEGG analyses. A Venn diagram was used to identify EndMT-related DEGs. A logistic regression model was constructed to screen for prognostic genes. Laser-induced CNV mouse models were established and validated with FFA and OCTA. The expression of ANGPTL4 and EndMT-related markers in the RPE-choroid-sclera complex was measured via RT‒qPCR and Western blotting. TGF-β2-induced HUVECs were used as EndMT cell models, and specific siRNAs targeting ANGPTL4 (si-ANGPTL4) were designed and screened. The effects of ANGPTL4 knockdown on the migration and invasion of HUVECs were also examined. Laser-induced CNV mouse models were constructed, and an intravitreal injection of cholesterol-modified si-ANGPTL4 was used to knock down ANGPTL4. FFA, OCTA and immunofluorescence staining were used to observe CNV formation and subretinal fibrosis, and the expression of ANGPTL4 and EndMT-related markers was determined. ANGPTL4 expression was significantly increased in mice with CNV and colocalized with IB4. In TGF-β2-induced EndMT, ANGPTL4 was also upregulated, and its knockdown led to the inhibition of EndMT and cell migration and invasion, while its overexpression promoted the EndMT process. ANGPTL4 knockdown reduced the formation of CNV and subretinal fibrosis in mice with CNV by suppressing EndMT. ANGPTL4 may promote CNV and subretinal fibrosis through EndMT, suggesting that ANGPTL4 may be a novel potential target for nAMD therapy. Show less