Patients with schizophrenia (SCZ) face multiple health challenges due to the complication of chronic diseases and psychiatric disorders. Among these, cardiovascular comorbidities are the leading cause Show more
Patients with schizophrenia (SCZ) face multiple health challenges due to the complication of chronic diseases and psychiatric disorders. Among these, cardiovascular comorbidities are the leading cause of their life expectancy being 15-20 years shorter than that of the general population. Identifying comorbidity patterns and uncovering differences in immune and metabolic function are crucial steps toward improving prevention and management strategies. A retrospective cross-sectional study was conducted using electronic medical records of inpatients discharged between 2015 and 2024 from a municipal psychiatric hospital in China. The study included patients diagnosed with Schizophrenia, Schizotypal, and Delusional Disorders (SSDs) (ICD-10: F20-F29). Comorbidity patterns were identified through latent class analysis (LCA) based on the 20 most common comorbid conditions among SSD patients. To investigate differences in peripheral blood metabolic and immune function, linear regression or generalized linear models were applied to 44 laboratory test indicators collected during the acute episode. The Benjamini-Hochberg method was used for p-value correction, and the false discovery rate (FDR) was calculated, with statistical significance set at FDRβ<β0.05. Among 3,697 inpatients with SSDs, four distinct comorbidity clusters were identified: SSDs only (Class 1), High-Risk Metabolic Multisystem Disorders (Class 2, nβ=β39), Low-Risk Metabolic Multisystem Disorders (Class 3, nβ=β573), and Sleep Disorders (Class 4, nβ=β205). Compared to Class 1, Class 2 exhibited significantly elevated levels of apolipoprotein A (ApoA; Ξ²β=β90.62), apolipoprotein B (ApoB; Ξ²β=β0.181), mean platelet volume (MPV; Ξ²β=β0.994), red cell distribution width-coefficient of variation (RDW-CV; Ξ²β=β1.182), antistreptolysin O (ASO; Ξ²β=β276.80), and absolute lymphocyte count (ALC; Ξ²β=β0.306), along with reduced apolipoprotein AI (ApoAI; Ξ²β=β-0.173) and hematocrit (HCT; Ξ²β=β-35.13). Class 3 showed moderate increases in low-density lipoprotein cholesterol (LDL-C; Ξ²β=β0.113), MPV (Ξ²β=β0.267), white blood cell count (WBC; Ξ²β=β0.476), and absolute neutrophil count (ANC; Ξ²β=β0.272), with decreased HCT (Ξ²β=β-9.81). Class 4 was characterized by elevated aggregate index of systemic inflammation (AISI; Ξ²β=β81.07), neutrophil-to-lymphocyte ratio (NLR; Ξ²β=β0.465), and systemic inflammation response index (SIRI; Ξ²β=β0.346), indicating a heightened inflammatory state. The comorbidity patterns of patients with SCZ can be distinctly classified. During the acute episode, those with comorbid metabolic disorders exhibit a higher risk of cardiovascular diseases and immune system abnormalities, while patients with comorbid sleep disorders present a pronounced systemic inflammatory state and immune dysfunction. This study provides a basis for the chronic disease management and anti-inflammatory treatment, while also offering objective biomarker insights for transdiagnostic research. Show less
Polygonum multiflorum Thunb., a plant rich in diverse bioactive constituents, has been widely used in East Asia in functional foods and medicine to ameliorate inflammatory disorders through its multi- Show more
Polygonum multiflorum Thunb., a plant rich in diverse bioactive constituents, has been widely used in East Asia in functional foods and medicine to ameliorate inflammatory disorders through its multi-component activity. The effectiveness of these botanical extracts is thought to involve complex interactions among diverse constituents; however, the molecular basis of such interactions remains insufficiently understood. In this study, we explored the anti-inflammatory properties of the ethanol extract of Polygonum multiflorum (PME) through a combination of chemical profiling and computational analysis. PME was found to reduce the production of nitric oxide, inducible nitric oxide synthase, and interleukin-6 in LPS-stimulated RAW 264.7 macrophages. Using HS-SPME-GC-MS in conjunction with network pharmacology, we identified 32 volatile constituents, among which five core compounds were predicted to be associated with three inflammation-related targets: ESR1, FASN, and NR1H3. Dual-ligand molecular docking and molecular dynamics simulations suggested that the sequence of ligand binding may influence the stability and interaction patterns of protein-ligand complexes, offering insights into possible mechanisms of synergy and antagonism mediated by key residues such as ARG394 in ESR1. Overall, these findings contribute to a better understanding of how binding order and structural context may shape constituent-target interactions, providing a basis for the further development of multi-component natural product strategies against inflammation. This study underscores the relevance of incorporating multi-ligand dynamics into natural product research and presents an integrated experimental-computational framework to investigate the cooperative or competitive behaviors of functional food constituents, thereby supporting the rational design of optimized multi-target formulations. Show less
Hyperlipidemia is a common metabolic disorder and a risk factor for cardiovascular disease. The traditional medicine herb, Hippophae rhamnoides L., known as sea buckthorn, has anti-obesity and lipid-l Show more
Hyperlipidemia is a common metabolic disorder and a risk factor for cardiovascular disease. The traditional medicine herb, Hippophae rhamnoides L., known as sea buckthorn, has anti-obesity and lipid-lowering effects, while Silybum marianum (L.) Gaertn, known as milk thistle, has hepatoprotective properties and exhibits antioxidant effects. To evaluate the effect of sea buckthorn and milk thistle solid beverage (H-S solid beverage) in alleviating hyperlipidemia in rats and explore the underlying mechanisms by analyzing plasma and liver metabolomics, lipidomics, and liver transcriptomics. A hyperlipidemic rat model was established after 2 weeks of high-fat diet (HFD) feeding in Sprague Dawley rats. The administered doses of H-S solid beverage were 0.30 g/kg/d, 0.15 g/kg/d and 0.075 g/kg/d. Serum biochemical parameter detection, histopathological section analysis, untargeted plasma and liver metabolomics, lipidomics, and liver transcriptomics were performed to determine the therapeutic effects of H-S solid beverage and predict the related pathways in rats with hyperlipidemia. Changes in genes and proteins related to lipid metabolism were detected using real-time quantitative polymerase chain reaction and western blotting. Eighty-nine components were identified in H-S solid beverage using ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry, with flavonoids being the major constituents. The H-S solid beverage significantly reduced body weight, liver index, body fat percentage, lipid accumulation, and liver injury in HFD-fed rats. Fatty acids (FA), bile acid, phosphatidyl ethanolamine, phosphatidylcholine, triglyceride, cholesterol ester, diglyceride and phosphatidylinositol levels were significantly altered in the liver and plasma. Moreover, the transcriptomic analysis suggested that H-S solid beverage significantly altered the hepatic gene expression of cholesterol synthesis (Pdk4, Hmgcs1, and Dhcr24), lipogenesis (Scd, Angptl4, and Angptl8), and FA Ξ²-oxidation (Cpt1Ξ±, PparΞ΄, Acsl, Pgc-1Ξ±, and Pla2g2d). The solid beverage of sea buckthorn and milk thistle was firstly demonstrated to ameliorate HFD-induced hyperlipidemia. The lipid-lowering and hepatoprotective effects of H-S solid beverage significantly regulated cholesterol synthesis and de novo lipogenesis, as well as FA Ξ²-oxidation. In summary, this study highlights the potential of H-S solid beverages for the treatment of hyperlipidemia. Show less
Dietary interventions with food-derived natural products have emerged as a promising strategy to alleviate obesity. This study aims to investigate the anti-obesity effect of
Post traumatic stress disorder (PTSD) is a serious and persistent mental diseases. Nowadays, Treatment of PTSD patients in clinical practice is mainly based on drug therapy accompanied by psychologica Show more
Post traumatic stress disorder (PTSD) is a serious and persistent mental diseases. Nowadays, Treatment of PTSD patients in clinical practice is mainly based on drug therapy accompanied by psychological therapy. However, the therapeutic effect is unsatisfactory. It is urgent to detect how to treat PTSD patients. Here, we found that ginsenoside can significantly relieve PTSD symptoms in mice model. Rg3, one of the main pharmacological components of ginsenoside, prevents PTSD by promoting alternatively activated M2 phenotype microglia while inhibiting classically activated inflammatory M1 phenotype microglia. Mechanistically, Rg3 up-regulates fibroblast growth factor receptor 1 (FGFR1) expression in microglia to suppress excessive activation of microglia and reduce neuronal apoptosis. Importantly, knocking down FGFR1 expression in BV2 cells promoted a pro-inflammatory phenotype of BV2 cells, while over-expressing FGFR1 reversed this effect. In vivo PTSD mice model results showed that knockdown FGFR1 prevents the therapeutic effect of Rg3, which indicates that FGFR1 is an essential target of PTSD. Our results reveal that Rg3 may be a potential drug to treat PTSD patients. Show less
Lifestyle improvement may help reverse prediabetes. Indicators such as Life's Essential 8 (LE8) and biological aging measures (phenotypic age, cardiovascular biological age) partially reflect metaboli Show more
Lifestyle improvement may help reverse prediabetes. Indicators such as Life's Essential 8 (LE8) and biological aging measures (phenotypic age, cardiovascular biological age) partially reflect metabolic status in prediabetes, but their predictive value for cardiovascular mortality and stroke in this population remains unclear. We analyzed data from 74,678 White participants with prediabetes in the UK Biobank, defined by either HbA1c (5.7-6.4%) or fasting glucose (6.1-6.9Β mmol/L). Follow-up continued until October 10, 2023. Cox regression was used to examine associations between LE8, phenotypic age (PhenoAge), cardiovascular biological age (CBA), and outcomes of cardiovascular (CVD) mortality and stroke. Restricted cubic spline (RCS) models identified biological age risk thresholds. Mediation analysis assessed whether proteins such as CST3, EFEMP1, FES, IGFBP2, IGFBP6, LPA, PCSK9, and TIMP1 mediated these effects. Over a median follow-up of 13.4Β years, 2263 participants died from CVD causes. Each 1-year increase in CBA or PhenoAge was associated with aβ~β10% higher risk of CVD mortality (CBA aHRβ=β1.10; PhenoAge aHRβ=β1.09; both Pβ<β0.001), while each 1-point increase in LE8 score was linked to a 3% lower risk (HRβ=β0.97, Pβ<β0.001). The risk biological ages for these two indicators were also identified: PhenoAgeββ₯β58.52Β years and CBAββ₯β62.42Β years. Similar trends were observed for stroke. Mediation analysis revealed that CST3, TIMP1, IGFBP2, and IGFBP6 contributed to the biological pathways between aging/lifestyle and CVD outcomes. The combined LE8 and PhenoAge model showed the strongest predictive performance for CVD mortality (AUCβ=β0.716) and stroke (AUCβ=β0.638) over 15Β years. LE8 combined with phenotypic age provides prognostic value for CVD outcomes in prediabetes. These findings highlight the potential of lifestyle modification and delayed biological aging in reversing prediabetes and underscore comorbidity-related proteins as promising therapeutic targets. Show less
Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a li Show more
Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a lipoprotein lipase (LPL) activity inhibitor, can inhibit triglycerides (TGs) decomposition, and fibroblast growth factor 21 (FGF21) enhances fatty acids' Ξ²-oxidation in liver. We constructed a novel fusion protein combining the anti-ANGPTL3 nanobody FD03 and FGF21 (FD03-FGF21), which exerted appropriate binding affinities to ANGPTL3 and Ξ²-Klotho respectively. Our results showed FD03-FGF21 restored bioactivity of LPL which inhibited by ANGPTL3 and activated downstream pathway of FGF21 in iLite FGF21 assay-ready cells. Next, FD03-FGF21 showed a significant therapeutic effect in MAFLD mice, including attenuation of metabolic dyslipidemia, hepatic lipid accumulation, and impaired glucose tolerance. Compared to other treatments, FD03-FGF21 achieved the most significant therapeutic effect with a 79.78Β % attenuation of low-density lipoprotein cholesterol (LDL-C) and a 95.8Β % reduction of hepatic lipid accumulation. Mechanistically, transcriptomic analysis revealed that differential expression genes (DEGs) were principally clustered into lipid metabolism and oxidative stress pathways after the fusion protein treatment, especially the key lipid metabolism genes of LDLR and CD36 were significantly upregulated and downregulated respectively, as confirmed by WB. Furthermore, lipidomic and metabolomic analysis indicated the fusion protein ameliorated disorders in lipid and protein metabolism mainly through the downregulation of DG and upregulation of PC. Hepatic oxidative stress and inflammation were significantly reduced after administration of the fusion protein in MAFLD mice. Collectively, FD03-FGF21 represents an effective therapeutic strategy for MAFLD therapy through ameliorating lipid metabolism and oxidative stress. Show less
Xiang Lian, Xiaoyan Li, Kexin Wang+3 more Β· 2025 Β· Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics Β· added 2026-04-24
To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestation Show more
To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestations and gene variation. Two patients (patient 1 and 2) with FH who visited Beijing Anzhen Hospital Affiliated to Capital Medical University in 2018 were selected as research subjects. A retrospective study method was used to collect clinical and family history data of the two patients. And 2 mL of peripheral venous blood from each of the two patients was collected, and genomic DNA extraction was performed on the blood samples. Sanger sequencing was used to validate the variant sites of the two patients detected by whole-exome sequencing (WES). Pathogenicity of variants was classified based on the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the "ACMG Guidelines"), and the impact of variant was analyzed using multiple bioinformatics tools including SIFT, PolyPhen-2, and SWISS-MODEL. This study has been approved by Beijing Anzhen Hospital Affiliated to Capital Medical University (Ethics No. 2024215X). Patient 1 initially presented with early-onset coronary heart disease, with initial lipid levels of serum total cholesterol (TC) 9.86 mmol/L (normal reference value: 3.10~5.20 mmol/L) and serum low-density lipoprotein cholesterol (LDL-C) 8.37 mmol/L (normal reference value: 1.27~3.12 mmol/L) on admission. Patient 1 initially underwent treatment with rosuvastatin combined with ezetimibe for one month, but the lipid-lowering effect was not significant. The lipid-lowering therapy was then adjusted to atorvastatin combined with ezetimibe and probucol. After one year of treatment, the patient developed paroxysmal chest pain symptoms. A follow-up lipid profile showed a serum TC level of 4.50 mmol/L and a LDL-C level of 3.55 mmol/L. The lipid-lowering regimen was continued, and the serum LDL-C levels were maintained between 2.65 and 3.66 mmol/L. Patient 2 was found to have an abnormally high blood lipid level and carotid artery hardening during physical examination, with an initial blood lipid level of serum TC 11.82 mmol/L and serum LDL-C 9.63 mmol/L. After receiving rosuvastatain therapy, the lipid-lowering effect was significant. WES revealed that patient 1 carried the heterozygous variants c.1871ββββdel(p.Ile624del) and c.1747C>T (p.His583Tyr) in the LDLR gene (NMββββ ββ.4), while patient 2 carried the heterozygous variants c.1747C>T (p.His583Tyr) in the LDLR gene and c.6936ββββinv (p.Ile2313Val) in the APOB gene (NMβββββββ. According to the ACMG Guidelines, the LDLR gene c.1747C>T (p.His583Tyr) was classified as a pathogenic variant (PS3+PM1+PM2_supporting+PM5+PP2+PP3), and c.1871ββββdel (p.Ile624del) was classified as a pathogenic variant (PS3+PS4+PM2_supporting+PM1+PM4); the APOB gene c.6936ββββinv (p.Ile2313Val) was classified as a variant of uncertain clinical significance (PM2_supporting BP4). Patients 1 and 2 in this study were patients with complex heterozygous variant FH, and their genotypic differences may be related to the differences in clinical serum LDL-C levels and the efficacy of hypolipidemic agents. Show less
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediat Show more
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediated inflammation remain incompletely elucidated, and a specific inflammatory marker that captures the pro-inflammatory activity of the APOE Ξ΅4 allele remains elusive. As a composite peripheral blood biomarker, Systemic immune-inflammation index (SII) is a novel marker of inflammation. This study aimed to investigate the association between APOE alleles and Systemic Immune-Inflammation Index. A total of 13,926 participants (9,098 males and 4,828 females) were recruited from The Peopleβs Liberation Army General Hospital (November 2017 to July 2019). APOE alleles (Ξ΅2, Ξ΅3, and Ξ΅4) were determined by genotyping rs429358 and rs7412 SNPs. SII was calculated as (platelet count Γ neutrophil count)/lymphocyte count. Multivariable linear regression models (adjusted for demographics, lifestyle, and clinical covariates) and subgroup analyses were performed to assess the APOE-SII associations, with Ξ΅3 as the reference. The frequencies of APOE alleles Ι3, Ι2, and Ι4 were70.7%, 13.8%, and 15.5% respectively in 13,926 Chinese patients. The mean SII was lower in Ι2 carriers than in Ι3 (373.74*10βΉ/L vs. 403.53*10βΉ/L, APOE contributes to elevated disease risk by inducing a state of chronic low-grade inflammation, resulting from modulation of both adaptive and innate immune responses. Show less
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup Show more
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup (KSS) significantly attenuated hepatic steatosis in rats. This study explored the main components of KSS and the mechanisms by which it exerts its protective effects against NAFLD. Twenty-four 6-week-old male Sprague-Dowley (SD) rats were randomly assigned to three treatments: feeding a normal standard diet, a high-fat diet, or a high-fat diet plus gavage KSS. The effects of KSS treatment on hepatic lipid accumulation were assessed using biochemical, histological, and molecular experiments. The amounts of KSS ingredients were measured using biochemical assays. Network pharmacology analyses were performed to identify the hub genes of KSS targets and enriched pathways. CCK-8 assay was used to determine the effect of free fatty acids (FFA), lycopene, and estrogen on HepG2 viability. Quantitative Real-Time polymerase chain reaction (qRT-PCR) and Western blot assays were performed to determine the effect of KSS or lycopene on estrogen signaling and expression of lipid metabolism-related molecules. Statistical analyses were performed using GraphPad Prism and SPSS. KSS alleviated fat deposition in rat liver tissue and affected the expression of hepatic lipid synthesis, catabolism, and oxidative molecules. Lycopene was identified as the ingredient with the highest amount in KSS. Network pharmacology analyses showed that the hub genes were enriched in the estrogen signaling pathway. Cellular experiments showed that lycopene increased the expression of Estrogen Receptor Ξ± (ERΞ±), Carnitine palmitoyltransferase 1βA ( KSS ameliorated abnormal lipid metabolism in patients with NAFLD. Lycopene was the major component of KSS, and it affected estrogen signaling and the expression of lipid metabolism molecules. In short, both KSS and LYC could change lipid metabolism by lowering lipid accumulation and raising lipolysis. Show less
The Roucongrong Pill (RCRP), originating from the historical General Medical Collection of Royal Benevolence, is frequently used to treat postmenopausal osteoporosis (PMOP). Despite its prevalent appl Show more
The Roucongrong Pill (RCRP), originating from the historical General Medical Collection of Royal Benevolence, is frequently used to treat postmenopausal osteoporosis (PMOP). Despite its prevalent application, the specific anti-osteoporotic mechanisms of RCRP remain to be elucidated. This study aims to elucidate the therapeutic mechanism of RCRP in the context of ovariectomy (OVX)-induced PMOP in rats. By employing an integrative approach, the research combines medicinal chemistry, gut microbiota (GM) profiling, metabolomics, MetOrigin traceability, network pharmacology, molecular docking, and molecular dynamics simulations to deliver a comprehensive analysis. Sprague-Dawley (SD) rats underwent bilateral OVX to establish a PMOP model. The therapeutic efficacy of RCRP was evaluated through bone metrics (BMD, bone strength, BV/TV, Tb.Sp), hematoxylin and eosin (H&E) histological assessment, and bone metabolism markers (OPG, BALP, TRACP-5b, Ξ²-CTX, RANKL). Fecal metabolomics and 16S rDNA sequencing were employed to assess the influence of RCRP on GM and metabolite profiles. Furthermore, MetOrigin facilitated the traceability analysis of relevant metabolites. Molecular docking identified potential RCRP compounds with anti-PMOP activity, while their stability and protein interactions were assessed through molecular dynamics simulations. Network pharmacology further confirms the targets of action. RCRP alleviated PMOP in rats, enhancing bone strength, cortical and trabecular BMD, BV/TV, and serum OPG levels, while reducing Tb.Sp, serum BALP, TRACP-5b, Ξ²-CTX, and RANKL concentrations. A total of twenty-six distinct metabolites were identified, of which ten-tribufos, sulfoacetic acid, betamethasone dipropionate, 9-oxooctadeca-10,12,15-trienoic acid, menatetrenone, piperlongumine, maltopentaose, enol-phenylpyruvate, catechol, pentaacetate, and (+)-2-methylpropanoic acid-exhibited correlations with six GM species: Turicibacter, Roseburia, Colidextribacter, Helicobacter, Odoribacter, and Lachnoclostridium, as determined by Spearman's correlation analysis. Notably, MetOrigin revealed the microbial metabolism of taurine and hypotaurine, along with host-specific steroid hormone synthesis. Computational docking studies demonstrated robust interactions between five RCRP-derived steroids (hydroxyecdysone, corticosterone, trilostane, 5Ξ±-androstan-3,6,17-trione, and cortisol) and key enzymes (estradiol 17Ξ±-dehydrogenase and UDP-glucuronosyltransferase), suggesting a potential enhancement of therapeutic efficacy against PMOP. Furthermore, molecular dynamics simulations indicated stable interactions between hydroxyecdysone and two proteins, with binding free energies of -67.427Β kJ/mol and -156.948Β kJ/mol, respectively. Through network pharmacology and molecular docking approaches, potential targets of these metabolites were identified, including estrogen receptors ESR1 and ESR2, dual specificity phosphatase 6 (DUSP6), sex hormone-binding globulin (SHBG), prostaglandin E receptor 4 (PTGER4), cannabinoid receptor 2 (CNR2), cathepsin K (CTSK), and androgen receptor (AR). RCRP effectively mitigates OVX-induced bone loss in PMOP rats by modulating GM and associated metabolites, along with their potential targets and key metabolic pathways, including taurine and hypotaurine metabolism, as well as steroid hormone biosynthesis. These findings offer new insights into the therapeutic mechanisms by which RCRP may alleviate PMOP. Show less
NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome plays a pivotal role in the progression of cerebral ischemia/reperfusion injury (CI/RI). We aimed to investigate the implication o Show more
NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome plays a pivotal role in the progression of cerebral ischemia/reperfusion injury (CI/RI). We aimed to investigate the implication of WW domain-containing protein 2 (WWP2), an E3 ubiquitin ligase, in CI/RI and its mechanism. Microglia were subjected to oxygen-glucose deprivation/reoxygenation, and mice were subjected to middle cerebral artery occlusion (MCAO) for modeling. WWP2 was reduced in the brain tissues of mice with MCAO/R. WWP2 overexpression in microglia inhibited the NLRP3 inflammasome activation to alleviate MCAO/R-induced injury and microglia-induced neurotoxicity. WWP2 inhibited the mitochondrial translocation of NLRP3 by degrading mitochondrial antiviral-signaling protein (MAVS) to block its interaction with NLRP3, and MAVS overexpression in microglia promoted the NLRP3 activation to exacerbate MCAO/R and neurotoxicity. The nuclear export of TAR DNA-binding protein 43 (TDP-43) in MCAO/R promoted the WWP2 degradation via the (UG)n element of the 3'UTR of WWP2. TDP-43 overexpression also impaired the blockade of NLRP3 activation and exacerbated neurotoxicity in the presence of WWP2. Overall, our investigations demonstrate that nuclear export of TDP-43 in microglia activates NLRP3 inflammasome and exacerbates CI/RI by blocking MAVS degradation through (UG)n element-mediated instability of WWP2. Show less
To identify distinct sleep quality profiles among patients undergoing maintenance hemodialysis (MHD) using latent profile analysis (LPA), and examine differences in perceived stigma across these sleep Show more
To identify distinct sleep quality profiles among patients undergoing maintenance hemodialysis (MHD) using latent profile analysis (LPA), and examine differences in perceived stigma across these sleep quality subtypes. From December 2024 to March 2025, a total of 334 MHD patients were recruited via convenience sampling from the nephrology departments of two tertiary hospitals in Xinjiang, China. Data were collected using structured questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), the Self-Rating Depression Scale (SDS), and the Social Impact Scale (SIS), along with sociodemographic and clinical information. LPA was employed to identify latent subgroups of sleep quality based on PSQI components. Multinomial logistic regression was used to determine predictors of sleep profile membership. Differences in stigma scores across sleep profiles were analyzed using non-parametric equivalents. Three distinct sleep profiles were identified: Class 1 - "overall better sleep", Class 2 - "short sleep duration and low efficiency", and Class 3 - "poor sleep quality with high medication use". Multinomial logistic regression identified comorbid heart failure (OR=2.867, Patients with MHD exhibit heterogeneous patterns of sleep disturbance, which are associated with varying levels of perceived stigma. Those with the poorest sleep quality and highest reliance on medication experience the most pronounced stigma. Tailored interventions addressing sleep-related issues and psychosocial factors may help reduce stigma and improve patient well-being. Show less
In preliminary research and literature review, we identified a potential link between chronic obstructive pulmonary disease (COPD) and lipid metabolism. Therefore, this study employed Mendelian random Show more
In preliminary research and literature review, we identified a potential link between chronic obstructive pulmonary disease (COPD) and lipid metabolism. Therefore, this study employed Mendelian randomization (MR) analysis to investigate the potential causal connection between blood lipids and COPD. A genome-wide association study (GWAS) on COPD was conducted, encompassing a total of 112,583 European participants from the MRC-IEU. Additionally, extensive UK Biobank data pertaining to blood lipid profiles within European cohorts included measurements for low-density lipoprotein cholesterol (LDL-C) with 440,546 individuals, high-density lipoprotein cholesterol (HDL-C) with 403,943 individuals, triglycerides (TG) with 441,016 individuals, total cholesterol (TC) with 187,365 individuals, apolipoprotein A-I (apoA-I) with 393,193 individuals, and apolipoprotein B (apoB) with 439,214 individuals. Then, MR analyses were performed for lipids and COPD, respectively. The primary analytical technique employed was the inverse-variance weighted (IVW) approach, which included a 95% confidence interval (CI) to calculate the odds ratio (OR). Additionally, a sensitivity analysis was conducted to assess the dependability of the MR analysis outcomes. MR analysis was primarily based on IVW, unveiled a causal link between COPD and LDL-C (OR=0.994, 95% CI (0.989, 0.999), P=0.019), TG (OR=1.005, 95% CI (1.002, 1.009), P=0.006), and apoA-I (OR=0.995, 95% CI (0.992, 0.999), P=0.008), in addition, no causal link was found with HDL-C, TC, apoB. Sensitivity analysis demonstrated the robustness of these causal relationships. However, through multivariate MR(MVMR) and multiple testing correction, LDL-C and TG had no causal effect on the outcome. ApoA-I remained a protective factor for the risk of COPD (OR=0.994, 95% CI (0.990-0.999), P=0.008). Through MR analysis, this study offers evidence of a causal link between apoA-I with COPD. This further substantiates the potential role of lipid metabolism in COPD, and has significant clinical implications for the prevention and management of COPD. Show less
Hui Wang, Timothy S Chang, Beth A Dombroski+64 more Β· 2025 Β· Movement disorders : official journal of the Movement Disorder Society Β· Wiley Β· added 2026-04-24
The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear pa Show more
Zinc finger protein 750 (ZNF750) has been identified as a potential tumor suppressor across multiple malignancies. Nevertheless, the specific involvement of ZNF750 in the regulation of mesenchymal cel Show more
Zinc finger protein 750 (ZNF750) has been identified as a potential tumor suppressor across multiple malignancies. Nevertheless, the specific involvement of ZNF750 in the regulation of mesenchymal cell differentiation and bone homeostasis has yet to be elucidated. In the current study, we observed a substantial presence of ZNF750 in bone tissue and noted alterations in its expression during osteogenic differentiation of mesenchymal progenitor cells. Functional experiments indicated that ZNF750 promoted osteogenic differentiation while impeding adipogenic differentiation from mesenchymal stem/progenitor cells. Further mechanistic investigations revealed that ZNF750 transcriptionally suppressed the expression of Snail family transcriptional repressor 1 (SNAI1) by binding to the proximal promoter region of Snai1 gene, thereby activating Wnt/Ξ²-catenin signaling. SNAI1 exerted opposing effects on cell differentiation towards osteoblasts and adipocytes in comparison to ZNF750. The overexpression of SNAI1 counteracted the dysregulated osteogenic and adipogenic differentiation induced by ZNF750. Furthermore, the transplantation of Znf750-silenced bone marrow stromal cells into the marrow of wild-type mice resulted in a reduction in cancellous and cortical bone mass, alongside a decrease in osteoblasts and an increase in marrow adipocytes, while the number of osteoclasts remained unchanged. This study presents the first demonstration that ZNF750 regulates the differentiation of osteoblasts and adipocytes from mesenchymal stem/progenitor cells by transcriptionally deactivating SNAI1 signaling, thereby contributing to the maintenance of bone homeostasis. It suggests that ZNF750 may represent a promising therapeutic target for metabolic bone disorders such as osteoporosis. Show less
Alzheimer's disease (AD) represents a neurodegenerative condition characterized by steadily increasing prevalence and incidence, arising significant challenge to both patients and social insurance. Ho Show more
Alzheimer's disease (AD) represents a neurodegenerative condition characterized by steadily increasing prevalence and incidence, arising significant challenge to both patients and social insurance. However, the etiology of AD remains controversial so far, and pathogenesis is far more complicated. Presently, no definitive therapeutic methodologies were available for AD, and only partial symptomatic relief can be achieved. Consequently, early diagnosis and intervention are emergently needed for AD patients. The diagnostic criteria for AD are continuously evolving, and biomarker testing is becoming increasingly critical for diagnosis. Currently, the diagnosis of AD primarily relies on the detection of pathological proteins through cerebrospinal fluid (CSF) testing and positron emission tomography (PET). However, factors such as high costs, operational contraindications, and invasiveness limited the application of these technologies, making them particularly challenging to implement in large-scale clinical trials and screenings. Core fluid biomarkers for AD including Ξ²-amyloid (AΞ²), phosphorylated tau protein (p-tau), total tau protein (t-tau), and their combinations were found in CSF. Although these biomarkers were demonstrated with significant specificity and sensitivity, challenges remain high concerning the collection of CSF. Blood-derived biomarkers for AΞ² and tau proteins are essential for preliminary screening, diagnosis, and monitoring of AD. Additionally, other bodily fluids such as saliva, urine, and tears have been investigated for their potential as biomarkers, offering unique characteristics and applications. Emerging biomarkers, including neurofilament light chain (NfL), neurogranin (Ng), Beta-site APP cleaving enzyme 1 (BACE1), synaptosome associated protein 25 (SNAP-25), as well as inflammation-related and gene-related factors, provided valuable insights into the diagnosis and pathogenesis of AD from diverse perspectives. Despite the substantial progress made in AD biomarker research, there are still baskets of limitations concerning the complication of the disease. The current review focused on the reported literature to summarize the biomarkers associated with AD. By critically analyzing studies published over the past decade, we aimed to strengthen the recent research progress, theoretical frameworks, and unresolved challenges related to AD biomarkers. Show less
NRBF2, a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, plays a crucial role in learning and memory processes, yet its specific impact on memory and t Show more
NRBF2, a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, plays a crucial role in learning and memory processes, yet its specific impact on memory and the underlying molecular mechanisms remains unclear. Here, we utilized NRBF2 knockout mice to examine its influence on the time course of fear memory. Employing quantitative PCR, Western blot analysis, behavioral tests, and electrophysiology, we investigated the mechanisms through which NRBF2 affects memory processing. We observed an increase in This study offer new insights into the role of NRBF2 and highlight the potential of targeting NRBF2 as a therapeutic strategy for addressing cognitive deficits associated with various disorders. Show less
Despite substantial progress in low-density lipoprotein cholesterol (LDL-C)-lowering strategies, residual cardiovascular risk remains. Apolipoprotein C3 (APOC3) has emerged as a novel target for lower Show more
Despite substantial progress in low-density lipoprotein cholesterol (LDL-C)-lowering strategies, residual cardiovascular risk remains. Apolipoprotein C3 (APOC3) has emerged as a novel target for lowering triglycerides. Multiple clinical trials of small-interfering RNA therapeutics targeting APOC3 are currently underway. To investigate whether genetically predicted lower APOC3 is associated with a reduction in cardiovascular risk and if the combined exposure to APOC3 and LDL-C-lowering variants is associated with a reduction in the risk of coronary heart disease (CHD). This was a population-based genetic association study with 2βΓβ2 factorial mendelian randomization. Included were participants of European ancestry in the UK Biobank. Data were analyzed from November 2023 to July 2024. Genetic scores were constructed to mimic the effects of APOC3, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. Plasma lipid and lipoprotein levels, CHD, and type 2 diabetes (T2D). This study included 401β―548 UK Biobank participants (mean [SD] age, 56.9 [8.0] years; 216β―901 female [54.0%]). Genetically predicted lower APOC3 was associated with a lower risk of CHD (odds ratio [OR], 0.96; 95% CI, 0.93-0.98) and T2D (0.97; 95% CI, 0.95-0.99). Genetically lower APOC3 and PCSK9 were associated with a similar magnitude of risk reduction in CHD per 10-mg/dL decrease in apolipoprotein B (ApoB) level (APOC3: 0.70; 95% CI, 0.59-0.83; PCSK9: 0.71; 95% CI, 0.65-0.77). Combined exposure to genetically lower APOC3 and PCSK9 was associated with an additive lower risk of CHD (APOC3: 0.96; 95% CI, 0.92-0.99; PCSK9: 0.93; 95% CI, 0.90-0.97; combined: 0.90; 95% CI, 0.86-0.93). Genetically lower HMGCR was also associated with a lower risk of CHD, and the risk was further reduced when combined with APOC3 (0.93; 95% CI, 0.90-0.97). Genetically predicted lower APOC3 was associated with a reduced risk of CHD that is comparable with that associated with lower PCSK9 per unit decrease in ApoB. Combined exposure to APOC3 and LDL-C-lowering variants was associated with an additive reduction in CHD risk. Future studies are warranted to investigate the therapeutic potential of these combined therapies, particularly among high-risk patients who cannot achieve therapeutic targets with existing lipid-lowering therapies. Show less
Individuals with diabetes are susceptible to cardiac dysfunction and heart failure, potentially resulting in mortality. Metabolic disorders frequently occur in patients with diabetes, and diabetes usu Show more
Individuals with diabetes are susceptible to cardiac dysfunction and heart failure, potentially resulting in mortality. Metabolic disorders frequently occur in patients with diabetes, and diabetes usually leads to remodeling of heart structure and cardiac dysfunction. However, the contribution and underlying mechanisms of metabolic and structural coupling in diabetic cardiac dysfunction remain elusive. Two mouse models of type 2 diabetes (T2DM) were used to assess alterations in glucose/lipid metabolism and cardiac structure. The potential metabolic-structural coupling molecule ACBP (acyl-coenzyme A-binding protein) was screened from 4 published datasets of T2DM-associated heart disease. In vivo loss-of-function and gain-of-function approaches were used to investigate the role of ACBP in diabetic cardiac dysfunction. The underlying mechanisms of metabolic and structural coupling were investigated by stable-isotope tracing metabolomics, coimmunoprecipitation coupled with mass spectrometry, and chromatin immunoprecipitation sequencing. Diabetic mouse hearts exhibit enhanced lipid metabolism and impaired ultrastructure with marked cardiac systolic and diastolic dysfunction. Analysis of 4 T2DM public datasets revealed that Our findings demonstrated that ACBP mediates the bidirectional regulation of cardiomyocyte metabolic and structural associations and identified a promising therapeutic target for ameliorating cardiac dysfunction in patients with T2DM. Show less
Low physical activity (LPA) significantly heightens the susceptibility of both type 2 diabetes mellitus (T2DM) and chronic renal disease. Nearly half of population diagnosed with T2DM globally worsen Show more
Low physical activity (LPA) significantly heightens the susceptibility of both type 2 diabetes mellitus (T2DM) and chronic renal disease. Nearly half of population diagnosed with T2DM globally worsen into diabetic kidney disease (DKD). Focusing on physically inactive populations, we aimed to comprehensively evaluate the trends over time and regional changes in T2DM-associated DKD attributable to LPA burden. We utilized data of the 2021 Global Burden of Disease (GBD) Study to initially assess the worldwide effects of T2DM-associated DKD attributable to LPA by computing the numbers and age-standardized rates (ASRs) of death, disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs), categorized by subtypes in 2021. Linear regression model was applied to analyze the illness burden from 1990 to 2021. Furthermore, cluster analysis was performed to assess the regional differences in disease burden across GBD regions. Lastly, to forecast the illness burden for the next 25 years, we utilized the autoregressive Integrated Moving Average (ARIMA) and Excess Risk (ER) models. In 2021, the fatalities attributed to T2DM-related DKD attributable to LPA amounted to 30835 (95%UI: 12346-51646) cases, with 698484 (95%UI: 275039-1158032) DALYs. The ASRs of death and DALYs were 0.38 (95%UI: 0.15-0.63) and 8.19 (95%UI: 3.21-13.6) per 100000 individuals, respectively. Between 1990 and 2021, there was a notable escalation in deaths, DALYs, YLDs, and YLLs, as well as their ASRs. The highest burden was observed among males, older adults (aged 70 years and above), and middle Socio-demographic Index (SDI). Significant differences were noted in the disease burden among various regions and countries as defined by the GBD study. Predictive analyses indicate a continued escalation of this burden by the year 2050. The global impact of DKD attributable to LPA remains considerable, with significant disparities noted across different genders, ages, and regions. To mitigate this burden, it is crucial to implement effective interventions aimed at addressing physical inactivity, specifically designed for targeted demographic groups. Show less
To investigate the clinical and pathological characteristics of patients with non-small cell lung cancer exhibiting coexistence of Clinical data, as well as histopathological, immunohistochemical, and Show more
To investigate the clinical and pathological characteristics of patients with non-small cell lung cancer exhibiting coexistence of Clinical data, as well as histopathological, immunohistochemical, and molecular pathological characteristics, of two patients harboring both Both patients were women aged 57 and 66 years. The two cases were diagnosed as invasive lung adenocarcinoma, and immunohistochemical staining showed that all tumor cells expressed CK7, Napsin A, TTF-1, and PD-L1. In Case 1, an Show less
Sijie Gu, Haoran Feng, Xiaomei Li+10 more Β· 2025 Β· Molecular therapy : the journal of the American Society of Gene Therapy Β· Elsevier Β· added 2026-04-24
Preventing the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the A Show more
Preventing the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the AKI-to-CKD transition and its underlying mechanisms. Renal biopsies from patients with AKI showed marked upregulation of WNT5A and its receptor, CD146, in proximal tubules, with higher expression in patients with CKD progression. In murine AKI models, Wnt5a knockdown attenuated CKD progression. Conversely, proximal tubular overexpression of Wnt5a exacerbated renal fibrosis in ischemia-reperfusion injury (IRI) mice, which was alleviated by Box5, a specific WNT5A antagonist. In vitro, WNT5A overexpression in transforming growth factor Ξ² (TGF-Ξ²)-stimulated HK-2 cells promoted CD146 upregulation, activated JNK phosphorylation, and enhanced SNAI1 expression. The genetic silencing of WNT5A/CD146 and JNK inhibition suppresses SNAI1 expression and attenuates fibrotic responses. Mechanistically, JNK-mediated c-JUN phosphorylation promoted its interaction with KLF5 at the SNAI1 promoter, driving renal fibrosis. Elevated serum levels of soluble CD146 correlated with renal function in patients with AKI and were higher in patients exhibiting CKD progression. Inhibition of WNT5A could serve as a therapeutic target for delaying renal fibrosis in AKI progression. Show less
Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is Show more
Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function. Show less
Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understandin Show more
Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understanding of the genetic basis of HF and more specific NICM subtype in the East Asian populations and evaluate the biological pathways underlying subclinical left ventricular dysfunction. We conducted a meta-analysis of genome-wide association studies (GWAS) for all-cause HF in the East Asian populations (N casesβ~β13,385) and a more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (N cases~3,603). We identified a low-frequency East-Asian enriched coding variant near MYBPC3 and a NICM specific locus. Follow up analyses demonstrated male-specific HF association at the MYBPC3 locus, and highlighted SVIL as a candidate causal gene for NICM. Moreover, we demonstrated that SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. In addition, the gene expression level of B-type natriuretic peptide (BNP) which was deemed as a hallmark for HF was further elevated by SVIL silencing in PE-stimulated H9C2 cells. RNA-sequencing analysis of H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. These results enhance our understanding of the genetic architecture of HF in the East Asian populations, and provide important insight into the biological pathways underlying NICM and sex-specific relevance of the MYBPC3 locus that warrants further replication in another datasets. Show less
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance, Migraine is a common chronic neurological disease caused by increased excitability of the Show more
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance, Migraine is a common chronic neurological disease caused by increased excitability of the central nervous system, both exerting substantial health burdens. However, the shared genetic basis and underlying molecular mechanisms remain largely unexplored. This study integrates single-cell data and Mendelian randomization (MR) analysis to identify comorbidity-associated genes and elucidate potential mechanistic links between these two conditions. Single-cell datasets from T2DM and migraine were analyzed to identify differentially expressed genes (DEGs). MR analysis was employed to prioritize key causal genes, followed by network-based functional characterization, disease-drug association analysis, cell annotation, and pseudo-time trajectory modeling. Analysis of single-cell data identified 2,128 migraine-associated and 3,833 T2DM-associated genes, with 714 genes shared between the two diseases. MR analysis highlighted AP4E1 and HSD17B12 as key regulators implicated in both conditions. Network analysis further linked these genes to lipid metabolism and vesicle transport pathways. Computational predictions revealed common comorbidities, including metabolic dysregulation and chemical-induced liver injury, as well as potential therapeutic agents such as valproic acid and bisphenol A. Single-cell annotation identified six major immune cell types in T2DM (T cells, NK cells, B cells, CD14 monocytes, CD16 monocytes, and dendritic cells), with T cells emerging as central players. In migraine, five immune cell types were identified (CD4 T cells, CD8 T cells, B cells, NK cells, and monocytes), with monocytes being the predominant cell type. Pseudo-time analysis delineated seven subpopulations of T cells and four subpopulations of monocytes, suggesting distinct functional trajectories in disease pathogenesis. However, due to the use of peripheral blood-derived single-cell data, genes primarily expressed in the central nervous system, such as CALCA and RAMP1, could not be detected, limiting the identification of certain migraine-specific pathways. This single-cell data and MR analysis investigation identifies AP4E1 and HSD17B12 as pivotal genetic determinants in T2DM-migraine comorbidity, shedding light on their molecular interplay and potential therapeutic relevance. Show less
Increasing evidence underscores the driving role of coding and non-coding variants in cancer development. Analyzing gene sets in biological processes offers deeper insights into the molecular mechanis Show more
Increasing evidence underscores the driving role of coding and non-coding variants in cancer development. Analyzing gene sets in biological processes offers deeper insights into the molecular mechanisms of carcinogenesis. Here, we developed geMER to identify candidate driver genes genome-wide by detecting mutation enrichment regions within coding and non-coding elements. We subsequently designed a pipeline to identify a core driver gene set (CDGS) that broadly promotes carcinogenesis across multiple cancers. CDGS comprising 25 genes for 25 cancers displayed instability in DNA aberrations. Variants within the TTN enrichment region may influence the folding of the I-set domain by altering local polarity or side-chain chemistry properties of amino acids, potentially disrupting its antigen-binding capacity in LUAD. Multi-omics analysis revealed that APOB emerged as a candidate oncogene in LIHC, whose genetic alterations within the enrichment region may activate key TFs, upregulate DNA methylation levels, modulate critical histone modifications, and enhance transcriptional activity in the HepG2 and A549 cell lines compared to Panc1. Additionally, CDGS mutation status was an independent prognostic factor for the pan-cancer cohort. High-risk patients tended to develop an immunosuppressive microenvironment and demonstrated a higher likelihood of responding to ICI therapy. Finally, we provided a user-friendly web interface to explore candidate driver genes using geMER ( http://bio-bigdata.hrbmu.edu.cn/geMER/ ). Show less