Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti Show more
Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti-inflammatory activities, its clinical application is limited by a narrow therapeutic window. In the present study, we developed phosphatidylserine-exposing nanovesicles (Col@PSVs) that leverage the innate phagocytic capacity of macrophage-derived foam cells by presenting surface "eat-me" signals, thereby enabling targeted immune modulation. The synergistic collaboration between Col and PSVs allows low-dose Col to retain robust anti-inflammatory efficacy while mitigating dose-dependent toxicity. Mechanistically, Col@PSVs potently suppress CCR7-mediated NF-κB signaling activation in foam cells, leading to a marked downregulation of pro-inflammatory cytokine and disruption of inflammatory cascades. In ApoE Show less
Recipients' age has emerged as a key factor that impacts on acute renal allograft rejection and graft survival. Age-related functional and structural changes in the immune system have been observed, y Show more
Recipients' age has emerged as a key factor that impacts on acute renal allograft rejection and graft survival. Age-related functional and structural changes in the immune system have been observed, yet the precise influence of aged immunity on kidney transplant remains unclear. In an initial retrospective analysis of clinical data gathered from two major centers in China and Germany, we found a correlation between aging and mitigated rejection outcomes in kidney recipients. To study the mechanism, we performed kidney transplantation on mice and observed attenuated allograft rejection in senescent recipients. Single-cell transcriptome analysis of allograft kidneys indicated a protective role of p21 Show less
Gallstone disease (GD) is a common gastrointestinal disorder with a significant genetic component. Despite known risk factors, the genetic basis of GD remains incompletely understood. We aimed to iden Show more
Gallstone disease (GD) is a common gastrointestinal disorder with a significant genetic component. Despite known risk factors, the genetic basis of GD remains incompletely understood. We aimed to identify novel genetic loci associated with GD, explore their clinical implications and investigate their therapeutic potential. We conducted a genome-wide association study from the UK Biobank followed by a meta-analysis, integrating summary statistics from the FinnGen R11, with further replication from Biobank Japan. Using systematic bioinformatic approaches, we performed gene prioritisation, colocalisation analysis, transcriptome-wide association study, Mendelian randomisations, cross-trait genetic correlations, phenome-wide association study, clinical investigations and gene-environment interactions by leveraging data from the FinnGen, Genotype-Tissue Expression project and Liver Cell Atlas single-cell transcriptomics data set. Our study highlighted novel susceptibility loci near candidate genes (ie, This study provides new insights into the genetic basis of GD and highlights the role of hepatocytes in GD pathogenesis. These findings have implications for the personalised prevention strategies and new therapeutic interventions in individuals predisposed to GD. Show less
This experiment investigated the response of carcass composition, digestive function, hepatic lipid metabolism, intestinal microbiota, and serum metabolomics to excessive or restrictive dietary energy Show more
This experiment investigated the response of carcass composition, digestive function, hepatic lipid metabolism, intestinal microbiota, and serum metabolomics to excessive or restrictive dietary energy in Ningxiang pigs. A total of 36 Ningxiang pigs (210 ± 2 d, 43.26 ± 3.21 kg) were randomly assigned to three treatments (6 pens of 2 piglets each) and fed a control diet (CON, digestive energy (DE) 13.02 MJ/kg,), excessive energy diet (EE, 15.22 MJ/kg), and restrictive energy diet (RE, DE 10.84 MJ/kg), respectively. Results showed that EE significantly increased the apparent digestibility of crude protein and total energy ( The findings suggest RE had no obvious negative effect on carcass traits of Ningxiang pigs. Apart from exacerbated body fat deposition, EE promoted fat accumulation in the liver by up-regulating the expression of lipogenic genes. Dietary energy changes affect hepatic bile acid metabolism, which may be mediated through the glycerophospholipid metabolism pathway, as well as disturbances in the gut microbiota. Show less
Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP Show more
Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP85, NUP107, or NUP133 in immortalized human podocytes activates CDC42, an important effector of SRNS pathogenesis. However, it is unknown whether or not loss of NUP160 dysregulates CDC42 in the podocytes. Here, we generated a podocyte-specific Nup160 knockout mouse model with double-fluorescent (mT/mG) Cre reporter genes using CRISPR/Cas9 and Cre/loxP technologies. We investigated nephrotic syndrome-associated phenotypes in the Nup160podo-/- mice, and performed single-cell transcriptomic and proteomic analysis of glomerular suspension cells and cultured primary podocytes, respectively. The Nup160podo-/- mice exhibited progressive proteinuria and fusion of podocyte foot processes. We found decreased Cdc42 protein and normal Cdc42 transcriptional level in the podocytes of the Nup160podo-/- mice using analysis of single-cell transcriptomes and proteomes. We subsequently observed that Cdc42 protein decreased in both kidney tissues and cultured primary podocytes of the Nup160podo-/- mice, although Cdc42 mRNA levels were elevated in the cultured primary podocytes of the Nup160podo-/- mice. We also found that Cdc42 activity was significantly reduced in the cultured primary podocytes of the Nup160podo-/- mice. In conclusion, loss of Nup160 dysregulated Cdc42 in the podocytes of the Nup160podo-/- mice with proteinuria and fusion of podocyte foot processes. Our findings suggest that the dysregulation of CDC42 may contribute to the pathogenesis of SRNS in patients with mutations in NUP160. Show less
Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contr Show more
Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contributing to stroke remains poorly understood. This study aims to investigate the association between the apoB/apoA1 ratio and intracranial or extracranial atherosclerosis. We enrolled 408 patients with acute ischemic stroke who had never been treated with statins or fibrates. Based on the images from computed tomography angiography (CTA), the patients were categorized into four groups: intracranial atherosclerosis stenosis (ICAS, n = 136), extracranial carotid atherosclerosis stenosis (ECAS, n = 45), combined intracranial and extracranial atherosclerosis stenosis (COAS, n = 73), and non-cerebral atherosclerosis stenosis (NCAS, n = 154). Demographic characteristics, clinical factors, and serum lipid levels were collected and then compared across groups. The apoB/apoA1 ratio was significantly higher in patients with ICAS, ECAS and COAS compared to those in the NCAS group. Multivariable logistic regression analysis demonstrated that the ApoB/ApoA1 ratio was independently associated with ICAS, but not with ECAS. ROC curve analysis showed that the ApoB/ApoA1 ratio had a good diagnostic ability for ICAS, with an area under the curve (AUC) of 0.764, an optimal cut-off value of 0.8122, a sensitivity of 81.3%, and a specificity of 59.8%. An higher apoB/apoA1 ratio is associated with ICAS in ischemic stroke patients. Show less
BackgroundAlthough abnormalities in circulating lipids and lipoproteins are associated with increased cancer risk, their specific impact on lung cancer progression and prognosis is still unclear. This Show more
BackgroundAlthough abnormalities in circulating lipids and lipoproteins are associated with increased cancer risk, their specific impact on lung cancer progression and prognosis is still unclear. This study retrospectively assessed the influence of preoperative lipid and lipoprotein levels on non-small cell lung cancer progression and prognosis, stratified by age.MethodsIn this retrospective study, we analyzed 849 patients to investigate the association between lipid markers and lung cancer progression, and examined postoperative prognosis in a subset of 222 patients. Data was analyzed using restricted cubic spline curves, Kaplan-Meier survival analysis, and Cox proportional hazards models.ResultsA significant nonlinear relationship was observed between total cholesterol (TC), high-density lipoprotein (HDL), ApoB, ApoAI, ApoE, and baseline tumor diameter (BSLD) (PTC = 0.025; PHDL < 0.001; PApoB = 0.037; PApoAI =0.001; PApoE < 0.001). In contrast, Lp(a) showed a significant linear relationship with BSLD (P = 0.002). The Cox regression analysis revealed that triglyceride (TG) (hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.28-0.92, P = 0.025) was significantly negatively associated with lung cancer mortality in patients under 58 years. For patients over 58 years, higher ApoB levels were linked to a reduced risk of lung cancer death (HR = 0.59, 95% CI: 0.36-0.97, P = 0.038).ConclusionThis study reveals a significant negative correlation between ApoAI and HDL levels with BSLD, while Lp(a) shows a positive correlation. In terms of long-term prognosis, high-serum ApoB are associated with a lower mortality risk in all lung cancer patients, and high-serum TG levels associated with reduced mortality risk in patients aged under 58 while high-serum TC levels associated with reduced mortality risk in patients over 58, with high Lp(a) levels indicating a greater risk of mortality in older patients. Show less
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Al Show more
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Although the RNA moiety of most R-loops originates from linear transcripts, circular RNAs (circRNAs), outputs from back-splicing, can also hybridize with the complementary strand of a DNA duplex. However, how circRNA-associated R-loops (ciR-loops) are monitored remains elusive. Here, we identify the DEAD-box RNA helicase Brr2 as an evolutionarily-conserved ciR-loop repressor with dual roles in inhibiting circRNA generation and resolving harmful ciR-loops. Accumulation of ciR-loops caused by loss-of-function of this dual-action factor induces antisense transcription and premature transcription termination for many genes and generates significant DNA damage, which further leads to a series of defects in DNA replication, cell division and cell proliferation. We propose that functional integration of multilayered regulation by a single protein can be an efficient double protection against genome instability. Show less
The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in medi Show more
The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in mediating immune suppression. However, the precise mechanisms underlying PMN-MDSCs infiltration into the tumor immune microenvironment (TIME) and their immunosuppressive functions remain poorly understood. In this investigation, we observed that PMN-MDSCs were up-regulated during stomach carcinogenesis, with gastric cancer (GC) cells secreting CCL26 to promote the infiltration of PMN-MDSCs into the TIME via the CX3CR1 receptor. The infiltrating CX3CR1 Show less
Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims Show more
Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims to investigate its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in Chinese healthy volunteers. A randomized, double-blind, placebo-controlled and dose-escalation Phase I study was conducted as follows: a single dose (2.5 mg) and once-weekly administration for 2 weeks to reach target doses (5, 10 and 15 mg) by titration. A total of 40 volunteers received at least one dose of BGM0504 or placebo. The PK profile of BGM0504 was investigated over a wide dose range and supported once-weekly administration. It was observed that C BGM0504 was generally safe and well tolerated with favourable PK profile and potential role in weight loss was also confirmed. These findings support subsequent development of BGM0504 for type 2 diabetes mellitus (T2DM) and obesity. Show less
Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in inn Show more
Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in innate immunity, play pivotal regulatory roles in sepsis pathogenesis. While Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, is traditionally believed to exert immunosuppressive effects through membrane anchoring, its involvement in macrophage polarization during sepsis remains unclear. This study investigated the spatial distribution of PD-L1 in macrophages and its regulatory effects on inflammatory responses during sepsis. This study investigated PD-L1’s regulatory role in macrophage polarization through RNA sequencing, Immunoprecipitation-mass spectrometry, molecular docking, and site-directed mutagenesis, with preliminary validation in C57BL/6 mice. Using GEO database analysis combined with qRT-PCR and Western blotting, we confirmed elevated PD-L1 expression in sepsis and M1-polarized macrophages. Laser scanning confocal microscopy demonstrated dual localization of PD-L1, appearing both on the plasma membrane and intracellularly within M1 macrophages. RNA sequencing revealed PD-L1’s promotion of M1 polarization through enhanced AIM2 expression in the NOD-like receptor pathway. Integrated analyses employing mass spectrometry, molecular docking, site-directed mutagenesis, and Western blotting demonstrated PD-L1 binding to AIM2, which augmented expression of downstream effector molecules (IL-18 and IFN-γ) and potentiated STAT1 activation. Silencing AIM2 by siRNA or IL-18 antagonism reversed PD-L1-induced M1 markers (IL-27, IL-6, iNOS/NO). PD-L1 was further shown to exacerbate pathological progression in septic mouse models. Our study demonstrated that sepsis-induced PD-L1 overexpression in macrophages exacerbates pathological progression by upregulating AIM2 expression, binding to AIM2 to enhance IL-18 production, which activates STAT1 to drive M1 polarization. The online version contains supplementary material available at 10.1186/s12964-025-02578-1. Show less
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases Show more
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases such as obesity. Several randomized controlled trials (RCTs) targeting obese or overweight populations have found that individuals with different genotypes exhibit varying responses to the same lifestyle intervention (gene-lifestyle intervention interactions). To date, more than 20 genes, including Show less
Fatty acid desaturase 1 (FADS1) is significantly and specifically upregulated following diabetic corneal injury. However, its role in diabetic keratopathy remains unclear. This study aimed to investig Show more
Fatty acid desaturase 1 (FADS1) is significantly and specifically upregulated following diabetic corneal injury. However, its role in diabetic keratopathy remains unclear. This study aimed to investigate the impact of FADS1 on wound healing and functional recovery of the diabetic corneal epithelium and explore its potential mechanisms. Using high-glucose-induced corneal epithelial cells and a streptozotocin-induced type 1 diabetic mouse model, FADS1 expression was suppressed via FADS1 small interfering RNA (siRNA). Cell migration was assessed using scratch and transwell assays. Wound healing and functional recovery of the corneal epithelium were evaluated using sodium fluorescein staining, anterior segment optical coherence tomography, hematoxylin and eosin staining, and immunofluorescence staining. FADS1 knockdown promoted wound healing and functional recovery of the diabetic corneal epithelium both in vivo and in vitro. Suppression of FADS1 enhanced high-glucose-induced corneal epithelial cell migration, which was dependent on elevated levels of the upstream metabolite γ-linolenic acid. This effect was mediated through the activation of the mitogen-activated protein kinase signaling pathway and the accumulation of autophagosomes. After diabetic corneal epithelial injury, FADS1 expression is specifically upregulated. Knockdown of FADS1 promotes wound healing and functional recovery, suggesting a novel therapeutic strategy for diabetic keratopathy. Show less
Insulin supply is the golden standard for type 1 diabetes mellitus (T1DM) therapy. Is there a drug-reduction application for reversing glucose metabolism disabled and diabetic neuropathy (DN), and is Show more
Insulin supply is the golden standard for type 1 diabetes mellitus (T1DM) therapy. Is there a drug-reduction application for reversing glucose metabolism disabled and diabetic neuropathy (DN), and is it suitable for the young and elderly populations? Reducing T1DM-associated DN, and maintaining glucose metabolism require using the anti-aging gene Klotho to regulate specific signaling cascades. This study applied five 16:8 intermittent fasting (16-h fasting, 8-h eating; 168if) protocols by different executing times to young and elderly diabetic mice to evaluate whether 168if is age-dependent and how it alters Klotho-related signaling molecules. Blood glucose levels were efficiently reduced when 168if was implemented in the early stage of T1DM onset (DNf group) of young and elderly mice. Another four groups failed to reduce blood sugar. However, the DNf protocol was unsuitable for diabetic elderly mice because it posed a higher mortality risk for this population. Young DNf mice exhibited reduced thermal hyperalgesia and mechanical allodynia and reversed Klotho downregulation and protein kinase C epsilon (PKCε) upregulation compared with DN mice. Furthermore, young DNf mice exhibited normalization of fibroblast growth factor receptor 1 (FGFR1) and nuclear factor κB (NF-κB) expression, which is involved in Klotho-related glucose metabolism and anti-inflammation. The expression densities of PKCε, Klotho, FGFR1, and NF-κB were linear to neuropathic manifestations. This study demonstrated the effectiveness of 168if application in the early stage of T1DM onset, a straightforward and convenient dietary control method, as a blood glucose control for achieving pharmaceutical reduction and relieving neuropathic pain in young T1DM patients. Show less
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as Show more
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as no recurrence through 5-year follow-up, helps identify potentially cured patients, yet predictive clinicopathologic features in stage I invasive NSCLC need clarification. This study sought to identify such features to enable risk-adapted surveillance. We analyzed a prospectively collected dataset of patients with stage I invasive NSCLC who underwent R0 resection between 2008 and 2015. Cox regression analysis was used to evaluate the association between clinicopathologic features and disease recurrence, aiming to identify independent prognostic factors. A total of 1,817 patients met the inclusion criteria. The 5-year cumulative incidence of recurrence was 14.6%. Female sex, tumor size ≤2 cm, lepidic-predominant adenocarcinoma (LPA) histologic type, presence of a ground-glass opacity (GGO) component, and solid component size ≤10 mm were identified as independent prognostic factors. A risk stratification system was subsequently developed, classifying patients into two groups: a low-risk group (with ≥4 factors; n=341) and an elevated-risk group (with <4 factors; n=1,476). Kaplan-Meier analysis revealed statistically significant differences in recurrence-free survival (RFS), overall survival (OS), and lung cancer-specific survival (LCSS) between the two groups (P<0.001). The low-risk group is considered to represent the population within the surgical curative time window. Patients with stage I invasive NSCLC who meet at least four of the following five criteria-female sex, tumor size ≤2 cm, solid component ≤10 mm, presence of a GGO component, and LPA histologic type-may be considered within the "surgical curative time window" and may therefore qualify for reduced surveillance intensity. Show less
Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically Show more
Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically identify Cpn's therapeutic targets and pathways in Western diet (WD)-induced obesity using integrated network pharmacology, transcriptomics, and experimental validation. A Western diet (WD)-induced mice model was used to evaluate the effectiveness of Cpn in ameliorating obesity. A network pharmacology analysis was then employed to identify the potential anti-obesity targets of Cpn. GO functional enrichment and KEGG pathway analysis were performed to elucidate the potential functions of the identified targets, followed by constructing a protein-protein interaction network to screen the core targets. Meanwhile, quantitative transcriptomics was conducted to validate and broaden the network pharmacology findings. Finally, molecular docking and quantitative real-time PCR assay were used for the core target validation. Cpn treatment effectively alleviated obesity-related symptoms in WD-induced mice. The metabolic pathway, insulin signaling pathway, HIF-1 signaling pathway, FoxO signaling pathway, lipid and atherosclerosis pathway, and core targets including CPS1, HRAS, MAPK14, PAH, ALDOB, AKT1, GSK3B, HSP90AA1, BHMT2, EGFR, CASP3, MAT1A, APOM, APOA2, APOC3, and APOA1 are involved in regulating the therapeutic effect of Cpn. This study comprehensively uncovers the potential mechanism of Cpn against obesity based on network pharmacology and quantitative transcriptomics, which provides evidence for revealing the pathogenesis of obesity, suggesting that Cpn is a possible lead compound for anti-obesity treatment. Show less
Ruotong Li, Wenye Zhao, Jiaxin Zhang+7 more · 2025 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
The global increase in muscle weakness poses a critical public health concern. Nutritional interventions that improve muscular function hold promise as a therapeutic potential. Vitamin A (VA) and its Show more
The global increase in muscle weakness poses a critical public health concern. Nutritional interventions that improve muscular function hold promise as a therapeutic potential. Vitamin A (VA) and its active metabolites have been implicated in muscle development and the transformation of muscle fiber types. However, conventional VA formulations are restricted by poor stability and low bioavailability. In this study, a stable Nano VA was utilized to systematically evaluate its effects on muscle development and exercise performance in mice, as well as to explore its underlying mechanisms. A total of 44 male C57BL/6J mice were randomly divided into four groups: (i) normal control (NC), (ii) 5 mg/kg Nano VA (5 NVA), (iii) 10 mg/kg Nano VA (10 NVA), and (iv) 10 mg/kg VA (10 VA). The 10 NVA group demonstrated significantly improved muscle strength and swimming endurance, compared with the NC group. Further examination suggested a significant increase in myofiber diameter, cross-sectional area, and the content of fast-twitch fibers. Additionally, Nano VA treatment improved glucose tolerance and insulin sensitivity. To elucidate the mechanism by which Nano VA enhances muscle locomotor ability, transcriptomics and metabolomics data identified 111 differentially expressed genes and 253 differential metabolites. Of these, Angptl4, Ppp1r3a, and Cyp26b1 were identified as candidate regulators of muscle development and myofiber type transformation. In conclusion, Nano VA regulates muscle development and promotes muscle fiber type conversion, thus improving muscle strength and endurance in mice. Moreover, Nano VA facilitates mitigating and improving myasthenia gravis-related conditions. Show less
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, infla Show more
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, inflammatory factors, and GSD remain unclear. The aim of this study is to explore the causal relationships among these 3 factors. This study employed 2-sample Mendelian Randomization (TSMR) and 2-step MR to investigate the causal relationships and potential mediation effects among 91 inflammatory factors, 6 lipid metabolism-related molecules (HDL-C, LDL-C, TG, total cholesterol, ApoA1, and ApoB), and GSD. We opted for 4 distinct MR analysis methods including inverse variance weighted method, weighted median method, MR-Egger regression method and MR-PRESSO analysis. Sensitivity analyses included MR-Egger intercept tests, Cochran's Q statistic, Steiger tests, and leave-one-out analyses. Product of coefficients method was used to estimate mediation proportion. TSMR analysis revealed that every 1-unit increase in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), the risk of GSD decreased by 16.5%, 10.2%, 8.4%, and 13.1%, respectively. Inflammatory factors such as Natural killer cell receptor 2B4 (CD244), Macrophage colony-stimulating factor 1 (CSF-1), and interleukin-18 receptor 1 (IL-18R1) were identified as risk factors for GSD, while Fibroblast growth factor 19 levels (FGF19), Interleukin-1-alpha levels (IL-1α), and Interleukin-8 levels (IL-8) were found to be protective. Mediation analysis through 2-step MR identified potential pathways involving ApoA1--IL-8--GSD (P = .084) and IL-1α--ApoB--GSD (P = .117). This study provides robust evidence of causal links between specific lipid metabolites and GSD, as well as suggestive causal associations for several inflammatory factors. However, mediation analysis did not support significant roles for lipids or inflammatory factors as mediators in GSD pathogenesis. Future research could be further pursued in areas such as drug target intervention and mechanistic studies. Show less
Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti- T Show more
Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti- TNBC mechanisms of UA by network pharmacology and experimental validation. TNBC cell lines MDA-MB-231 and BT-549 cells were treated with UA. A CCK-8 assay was performed to detect cell growth, while flow cytometry assessed cell cycle arrest and apoptosis. The underlying mechanism and potential targets of UA for TNBC treatment were investigated by network pharmacology, including PharmMapper database, GO, KEGG enrichment, and PPI analysis. The protein expressions and phosphorylation levels of FGFR1, AKT, and ERK were measured by western blot. Pull-down assay, cellular thermal shift assay (CETSA), and molecular docking were used to analyze the interaction between UA and FGFR1. Xenograft models were established to examine the effect of UA on TNBC tumor growth. UA effectively reduced cell viability, induced apoptosis, and arrested cell cycle in TNBC cells. Moreover, UA significantly regulated the expression of Bcl-2 and Bax to induce apoptosis. The results of network pharmacology and western blot suggested that UA reduced FGFR1/AKT/ERK pathway. Furthermore, pull-down, CETSA, and molecular docking results revealed that UA directly bound to FGFR1. In the xenograft model, UA inhibited the growth by suppressing FGFR1. In this study, we employed network pharmacology and experimental approaches to elucidate the mechanism of UA on TNBC. The results demonstrated that UA targeted FGFR1 to inhibit TNBC via mediating FGFR1/AKT/ERK pathway. Our findings demonstrate that UA inhibits the FGFR1/AKT/ERK pathway by directly targeting FGFR1, thereby suppressing TNBC progression and supporting its potential as a therapeutic agent for TNBC treatment. Show less
Despite advancements in treatment, coronary artery disease (CAD) remains a significant global health concern. Although lipoprotein(a) [Lp(a)] is recognized as a crucial cardiovascular risk factor asso Show more
Despite advancements in treatment, coronary artery disease (CAD) remains a significant global health concern. Although lipoprotein(a) [Lp(a)] is recognized as a crucial cardiovascular risk factor associated with increased risk, the prognostic value of using Lp(a) levels in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) remains debatable. This review aimed to investigate the association between Lp(a) levels and recurrent ischemic events in patients with ACS undergoing PCI. This systematic review included studies with individuals aged ≥18 years diagnosed with ACS who underwent PCI and had Lp(a) measurements. The included studies were sourced from the PubMed database, with a focus on articles published between January 2020 and January 2025. Keywords related to Lp(a) and cardiovascular diseases were used in the search. Data extraction involved a review of titles and abstracts followed by quality assessment using the QUADAS-2 tool. The final analysis included 10 studies with a combined population of 20,896 patients from diverse regions, including Japan, India, Egypt, China, and South Korea. Key findings indicate that elevated Lp(a) levels are significantly associated with adverse cardiovascular outcomes, including myocardial infarction and mortality, both in hospital and during long-term follow-up. This review highlights Lp(a) as a critical biomarker for predicting recurrent cardiovascular events in ACS patients post-PCI. The consistent correlation between elevated Lp(a) levels and adverse outcomes underscores the necessity of routine monitoring and targeted management of Lp(a) to mitigate residual cardiovascular risk. Show less
Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-se Show more
Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-serving as promising reservoirs of such inhibitors. Nevertheless, comprehensive screening and mechanistic characterization of their inhibitory potential remain limited. This study sought to identify potent AChE inhibitors from YGE, investigate their mechanisms of action, and assess their therapeutic prospects for AD. Methodologically, an integrated approach was employed, combining ultrafiltration-liquid chromatography (UF-LC) for rapid inhibitor screening, molecular docking and dynamics simulations for mechanistic insight, two-stage high-speed countercurrent chromatography for compound isolation, enzyme kinetics to delineate inhibition modalities, and network pharmacology to uncover relevant AD-related targets. The findings identified seven active constituents with notable AChE inhibition, among which parishins A and G were obtained at high purity (98.26% and 97.26%, respectively) and exhibited mixed-type inhibition with low IC Show less
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with no effective pharmacological treatments. The causal role of triglycerides (TGs) in AAA development remains unclear and contr Show more
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with no effective pharmacological treatments. The causal role of triglycerides (TGs) in AAA development remains unclear and controversial. Mendelian randomization was applied to assess causal relationships between lipoproteins, circulating proteins, metabolites, and the risk of AAA. To test the hypothesis that elevated plasma TG levels accelerate AAA development, we used Mendelian randomization analyses integrating genetic, proteomic, and metabolomic data identified causal relationships between elevated TG-rich lipoproteins, TG metabolism-related proteins/metabolites, and AAA risk. In the angiotensin II infusion AAA model, most These findings identify hypertriglyceridemia as a key contributor to AAA pathogenesis and suggest that targeting TG-rich lipoproteins may be a promising therapeutic strategy for AAA. Show less
Cardiac hypertrophy is an independent risk factor and the primary predictor of heart failure (HF). Mitochondria are crucial for the shift from hypertrophy to heart failure. The expression of fibroblas Show more
Cardiac hypertrophy is an independent risk factor and the primary predictor of heart failure (HF). Mitochondria are crucial for the shift from hypertrophy to heart failure. The expression of fibroblast growth factor 21 (FGF21), a cardioprotective factor, is increased in patients with cardiac hypertrophy but fails to prevent heart failure. Additionally, the molecular mechanism through which FGF21 exerts its beneficial effects on hypertrophic myocardial mitochondria remains unclear. Our study investigated the effect of FGF21 on cardiac hypertrophy, elucidating its mechanism of action through the enhancement of mitophagy-mediated cardioprotection. A transverse aortic constriction (TAC) model and a phenylephrine (PE) model were applied to explore the effect and mechanism of FGF21. P62-mediated mitophagy inducer (PMI) and rapamycin (Rapa) were used to confirm that FGF21-regulated mitophagy under overload pressure conditions. FGF21 knockout markedly exacerbated TAC-induced cardiac function damage, mitochondrial damage, and mitophagy impairment. In vitro, FGF21 knockdown aggravated PE-induced cardiomyocyte hypertrophy and mitophagy dysfunction. FGF21 treatment promoted mitophagy in the TAC and PE models, but this effect was abolished in the absence of PTEN-induced putative kinase 1 (PINK1). The increase in PINK1 expression induced by Rapa can rescue impaired cardiac function and mitophagy impairment in FGF21-deficient TAC mice. Similarly, PMI enhances mitophagy, which inhibits damage to cardiac functions. A further study revealed that the expression of fibroblast growth factor receptor 1 (FGFR1) and FGF21 was opposite in heart failure. Knockdown of FGFR1 inhibited FGF21-mediated mitophagy. FGF21 promotes PINK1-mediated mitophagy to attenuate cardiac hypertrophy, and mismatched FGFR1 expression may hamper the beneficial effect of FGF21 on cardiac hypertrophy. Show less
G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as Show more
G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational Show less
While previous genome-wide association studies (GWAS) identified multiple risk loci for suicide ideation (SI) and suicide attempt (SA), there is still a limited understanding of the genetic predisposi Show more
While previous genome-wide association studies (GWAS) identified multiple risk loci for suicide ideation (SI) and suicide attempt (SA), there is still a limited understanding of the genetic predisposition underlying suicidal behaviors in diverse populations. This study aimed to conduct a large-scale investigation of the suicidality spectrum (SP) to generate new insights into its biology and epidemiology. Leveraging ancestrally diverse participants (SI N This study provides convergent genetic evidence for both shared and phenotype-specific components of suicidal behaviors and delineates their associated factors spanning from proximal clinical and behavioral traits to more distal social determinants. These findings refine our understanding of the etiology of suicidal behaviors and may inform targeted strategies for suicide prevention in both clinical and public health settings. Show less
Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. These varied responses may result from unident Show more
Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs (p < 5 × 10 Show less
The Kirgiz, a Turkic-speaking ethnic group with a rich nomadic heritage, represent a pivotal population for understanding human migration and adaptation in Central Asia. However, their genetic origins Show more
The Kirgiz, a Turkic-speaking ethnic group with a rich nomadic heritage, represent a pivotal population for understanding human migration and adaptation in Central Asia. However, their genetic origins and admixture history remain largely unexplored. Here, we present the first comprehensive genomic study of Kirgiz populations from Xinjiang, China (XJ.KGZ, n = 36) and their counterparts in Kyrgyzstan (KRG), integrating genome-wide data of 2,406 global individuals. Our analyses reveal four primary ancestry components in XJ.KGZ: East Asian (41.7%), Siberian (25.6%), West Eurasian (25.2%), and South Asian (7.6%). Despite close genetic affinity (FST = 0.13%), XJ.KGZ and KRG diverged ∼447 years ago, with limited gene flow post-split. A two-wave admixture model elucidates their demographic history: an initial East-West Eurasian mixture ∼2,225 years ago, likely reflecting west-east contacts during the period of the Warring States and the Qin Dynasty, followed by secondary admixture events (∼875 to 425 years ago) linked to historical migrations under Mongol and post-Mongol rule. Local adaptation signatures implicate genes critical for cellular tight junction (e.g. PATJ), pathogen invasion (e.g. OR14I1), and cardiac functions (e.g. RYR2) with allele frequency deviations suggesting ancestry-specific selection. While no classical high-altitude adaptation genes (e.g. EPAS1) showed selection signals, RYR2 and C10orf67-implicated in hypoxia response in Tibetan fauna-displayed Western ancestry bias, hinting at convergent adaptation mechanisms. This study advances our understanding of the genetic makeup and admixture history of the Kirgiz people and provides novel insights into human dispersal in Central Asia. Show less
The extensive co-occurrence of cardiovascular diseases (CVDs), as evidenced by epidemiological studies, is supported by positive genetic correlations identified in comprehensive genetic investigations Show more
The extensive co-occurrence of cardiovascular diseases (CVDs), as evidenced by epidemiological studies, is supported by positive genetic correlations identified in comprehensive genetic investigations, suggesting a shared genetic basis. However, the precise genetic mechanisms underlying these associations remain elusive. By assessing genetic correlations, genetic overlap, and causal connections, we aim to shed light on common genetic underpinnings among major CVDs. Employing multi-trait analysis, we pursue diverse strategies to unveil shared genetic elements, encompassing SNPs, genes, gene sets, and functional categories with pleiotropic implications. Our study systematically quantifies genetic overlap beyond genome-wide genetic correlations across CVDs, while identifying a putative causal relationship between coronary artery disease (CAD) and heart failure (HF). We then pinpointed 38 genomic loci with pleiotropic influence across CVDs, of which the most influential pleiotropic locus is located at the LPA gene. Notably, 12 loci present high evidence of multi-trait colocalization and display congruent directional effects. Examination of genes and gene sets linked to these loci unveiled robust associations with circulatory system development processes. Intriguingly, distinct patterns predominantly driven by atrial fibrillation, coronary artery disease, and venous thromboembolism underscore the significant disparities between clinically defined CVD classifications and underlying shared biological mechanisms, according to functional annotation findings. Show less
Human papillomavirus (HPV) infection is a global public health issue, and HPV-related stigma can affect cervical cancer prevention. But no validated tools exist to assess HPV stigma in Chinese adult w Show more
Human papillomavirus (HPV) infection is a global public health issue, and HPV-related stigma can affect cervical cancer prevention. But no validated tools exist to assess HPV stigma in Chinese adult women infected with HPV. This study aimed to adapt and validate the HPVsStigma scale (HPV-SS) in the Chinese context. A cross-sectional study was conducted from December 2024 to February 2025 among 501 HPV-infected women in Shenzhen, China. The HPV-SS was adapted from a 12-item HIV stigma scale. Demographic characteristics, HPV-related variables, and data on mental health were collected. Factor analyses (FA) were used to assess the scale's factorial structure, reliability, and validity. The bi-factor model was used to determine the score-reporting method of the scale. Item response theory (IRT) was employed to assess the relationship between participants' stigma levels and scale scores. Latent profile analysis (LPA) was conducted to classify the participants with different HPV stigma characteristics and determine the optimal cut-off value for HPV-SS. FA showed that the 3-factor model (personalized stigma, public-disclosure concerns, and negative self-image) had the best fit among the nested models, with good reliability and validity. The bi-factor model analysis indicated that the total scale score was more meaningful than dimension scores. IRT analysis confirmed that higher HPV-SS scores represented higher stigma levels. LPA identified a 2-class model as optimal, and the optimal cut-off value of the scale for high HPV stigma was 35. This study validated the 12-item HPV-SS for Chinese women infected with HPV, with good reliability and validity. The scale can be used to evaluate HPV stigma levels, facilitating targeted interventions to improve cervical cancer prevention and the psychological well-being of affected women. Show less