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
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
Mesenchymal cells constitute the primary structural support elements within endometriotic lesions, yet their pivotal roles in endometriotic pathogenesis remain largely uncharted. This study aimed to c Show more
Mesenchymal cells constitute the primary structural support elements within endometriotic lesions, yet their pivotal roles in endometriotic pathogenesis remain largely uncharted. This study aimed to construct a single-cell atlas of endometriosis using samples from three ovarian tissues affected by endometriosis and three normal ovarian tissues. Through the utilization of scRNA-seq, we have unveiled six distinct mesenchymal subclusters in normal and endometriosis-afflicted ovaries, elucidating the diverse functions of mesenchymal populations in endometriosis. Our comprehensive analysis has revealed that mesenchymal cells predominantly engage in three key functions: ribosome-mediated protein synthesis and processing, cell adhesion facilitating intercellular support and communication, and a range of metabolic processes. Furthermore, our findings have identified several pivotal differentially expressed genes (e.g. C3, FN1, COL3A1, COL1A1, NRXN3), primarily associated with the complement and coagulation cascades, extracellular matrix (ECM) regulation, ECM receptor interactions, and cell adhesion molecules. In essence, our study provides a comprehensive transcriptomic dataset and novel insights into adhesive molecule and integrin networks within mesenchymal subclusters in endometriosis. This, in effect, has deepened the understanding of the pathomechanisms governing this condition. 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
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
Angiopoietin-like 3 (ANGPTL3) is a major regulator of lipoprotein metabolism. ANGPTL3 deficiency results in lower levels of triglycerides, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C), and may Show more
Angiopoietin-like 3 (ANGPTL3) is a major regulator of lipoprotein metabolism. ANGPTL3 deficiency results in lower levels of triglycerides, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C), and may protect from cardiovascular disease. ANGPTL3 oligomerizes with ANGPTL8 to inhibit lipoprotein lipase (LPL), the enzyme responsible for plasma triglyceride hydrolysis. Independently of ANGPTL8, oligomers of ANGPTL3 can inhibit endothelial lipase (EL), which regulates circulating HDL-C and LDL-C levels through the hydrolysis of lipoprotein phospholipids. The N-terminal region of ANGPTL3 is necessary for both oligomerization and lipase inhibition. However, our understanding of the specific residues that contribute to these functions is incomplete. In this study, we performed mutagenesis of the N-terminal region to identify residues important for EL inhibition and oligomerization. We also assessed the presence of different ANGPTL3 species in human plasma. We identified a motif important for lipase inhibition, and protein structure prediction suggested that this region interacted directly with EL. We also found that recombinant ANGPTL3 formed a homotrimer and was unable to inhibit EL activity when trimerization was disrupted. Surprisingly, we observed that human plasma contained more monomeric ANGPTL3 than trimeric ANGPTL3. An important implication of these findings is that previous correlations between circulating ANGPTL3 and circulating triglyceride-rich lipoproteins need to be revisited. 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
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 prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced Show more
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced extracellular vesicles have emerged as key players in inducing angiogenesis by transferring noncoding RNAs. However, the specific role of CRC-derived hypoxic extracellular vesicles (H-EVs) in regulating premetastatic microenvironment (PMN) formation by inducing angiogenesis remains unclear. Our study demonstrates that H-EVs induce angiogenesis and liver metastasis. Through microRNA microarray analysis, we identified a reduction in miR-6084 levels within H-EVs. We found that miR-6084 inhibited angiogenesis by being transferred to endothelial cells via EVs. In endothelial cells, miR-6084 directly targeted angiopoietin like 4 (ANGPTL4) mRNA, thereby suppressing angiogenesis through the ANGPTL4-mediated JAK2/STAT3 pathway. Furthermore, we uncovered that specificity protein 1 (SP1) acted as a transcription factor regulating miR-6084 transcription, while hypoxia-inducible factor 1A (HIF1A) decreased miR-6084 expression by promoting SP1 protein dephosphorylation and facilitating ubiquitin-proteasome degradation in SW620 cells. In clinical samples, we observed low expression of miR-6084 in plasma-derived EVs from CRC patients with liver metastasis. In summary, our findings suggest that CRC-derived H-EVs promote angiogenesis and liver metastasis through the HIF1A/SP1/miR-6084/ANGPTL4 axis. Additionally, miR-6084 holds promise as a diagnostic and prognostic biomarker for CRC liver metastasis. 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
This study aimed to analyse the latent profiles of moral sensitivity of nursing students and to explore the different types of influencing factors. A cross-sectional study. Convenience sampling method Show more
This study aimed to analyse the latent profiles of moral sensitivity of nursing students and to explore the different types of influencing factors. A cross-sectional study. Convenience sampling method was used to select nursing students from five hospitals in Zunyi City, Guizhou Province, from July to September 2024. The demographic characteristics questionnaire and the Chinese version of the Nursing Student Moral Sensitivity Scale (MSQ-ST) were used as survey tools. Latent profile analysis (LPA) was performed on the moral sensitivity of nursing students. Logistic regression was used to analyse the influencing factors of different profiles. A total of 805 nursing students completed the questionnaire, of which 787 were valid, with a validity rate of 97.76%. The results of latent profile analysis showed that the moral sensitivity of nursing students was divided into two latent profiles: "low moral sensitivity group" (18.68%) and "high moral sensitivity group" (81.32%), and the results of logistic regression analysis showed that the level of hospital, the length of internship and the frequency of training on moral education were the factors influencing the moral sensitivity of nursing students (p < 0.05). In this study, we have demonstrated that there are two categories of moral sensitivity in nursing students, and that demographic traits have an impact on moral sensitivity in nursing students. These findings may provide a valuable theoretical foundation for nursing educators in developing the moral awareness of nursing students. No patient or public contribution. 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
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
This study evaluated the efficacy and safety of tafolecimab in patients with type 2 diabetes (T2D) and hypercholesterolemia by a post-hoc analysis of pooled data from three phase 3 trials. Data from u Show more
This study evaluated the efficacy and safety of tafolecimab in patients with type 2 diabetes (T2D) and hypercholesterolemia by a post-hoc analysis of pooled data from three phase 3 trials. Data from up to 12 weeks were analyzed to assess the effects of tafolecimab 450 mg every four weeks (Q4W) in patients with T2D and hypercholesterolemia. The primary endpoint was the percentage change in low-density lipoprotein cholesterol (LDL-C) levels from baseline to week 12. Secondary endpoints included the proportion of participants achieving LDL-C levels below 1.8 mmol/L at weeks 12, the proportion of patients achieving LDL-C ≥ 50% reduction and LDL-C < 1.4 mmol/L, as well as percentage changes from baseline to week 12 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), lipoprotein(a) [Lp(a)], and triglyceride (TG) levels. The reduction in LDL-C from baseline was significantly greater in patients receiving tafolecimab than in those receiving placebo (estimated treatment difference: - 64.02%, 95% confidence interval: [- 68.08%, - 59.96%], P < 0.0001). The proportion of patients achieving a reduction of over 50% and an absolute LDL-C value below 1.4 mmol/L was significantly higher in the tafolecimab group than that in the placebo group (P < 0.0001). Furthermore, a significantly greater proportion of patients in the tafolecimab group achieved LDL-C levels below 1.8 mmol/L at week 12 compared to the placebo group (P < 0.0001). The tafolecimab group also showed significant reductions in TG, non-HDL-C, apo B, and Lp(a) from baseline to week 12 compared to the placebo group (all P < 0.001). The incidence of adverse events was generally similar between the two groups. Tafolecimab 450 mg Q4W demonstrated a superior lipid-lowering efficacy and favorable safety profile compared to placebo. This suggests it could be a promising new treatment option for Chinese patients with T2D and hypercholesterolemia. 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
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
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
USP10 is a critical deubiquitinating enzyme within the ubiquitin-specific protease family, playing multifaceted roles in cellular physiology and disease pathogenesis. Structurally composed of a G3BP1- Show more
USP10 is a critical deubiquitinating enzyme within the ubiquitin-specific protease family, playing multifaceted roles in cellular physiology and disease pathogenesis. Structurally composed of a G3BP1-interacting motif, a N-terminal domain (mediating most protein interactions), and a catalytic USP domain (residues 415-795, catalytic triad C424-H736-D751), USP10 regulates diverse cellular pathways by stabilizing key proteins through deubiquitination. It exhibits context-dependent functional duality, particularly in cancer: USP10 promotes tumorigenesis in various cancers (e.g., glioblastoma, esophageal, pancreatic, breast cancers) by stabilizing oncoproteins like CCND1, YAP1, HDAC7, and RUNX1, enhancing proliferation, metastasis, and immune evasion. Conversely, it suppresses tumors (e.g., NSCLC, CRC, thyroid cancer) by stabilizing tumor suppressors like p53, PTEN, and Axin1, inhibiting pathways such as Wnt/β-catenin. Beyond oncology, USP10 contributes to neurodegenerative diseases (neuroprotective in PD/ALS, neurotoxic in AD via Tau stabilization), viral immunity (inhibits SARS-CoV-2 infection), inflammatory responses, male reproduction, and metabolic/cardiovascular disorders. Its regulatory mechanisms include phosphorylation (e.g., by AMPK, AKT, ATM) controlling subcellular localization and activity, and ubiquitination via USP13. USP10's therapeutic significance drives inhibitor development (Spautin-1, D1, Wu-5, P22077, Parthenolide), though cross-reactivity within the USP family due to conserved catalytic domains remains a challenge. Novel strategies like PROTACs and engineered ubiquitin variants (UbVs) offer promise for future selective targeting of USP10 dysregulation in diverse diseases. A comprehensive understanding of its structure and context-specific functions is essential for exploiting its full therapeutic potential. 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
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
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
For small ruminants, meat quality-an economically significant characteristic-results from the combined effects of genetic, dietary, and physiological elements. However, the contribution of gastrointes Show more
For small ruminants, meat quality-an economically significant characteristic-results from the combined effects of genetic, dietary, and physiological elements. However, the contribution of gastrointestinal (GI) tract gene expression to meat quality remains unclear. Here, we performed bulk RNA-seq on 130 samples from Liangshan Black Sheep and Meigu Black Goats, including 10 GI tract segments and semitendinosus muscle, integrating these data with measurements of amino acid composition, fatty acid profiles, and volatile flavor compounds. We found distinct, segment-specific transcriptional programs across the GI tract, with major functional shifts at the rumen-reticulum, omasum-abomasum, and abomasum-duodenum transitions. In the ileum and jejunum, genes involved in lipid metabolism showed links to fatty acid profiles, whereas genes governing amino acid metabolism in the small intestine were connected to the amino acid composition of muscle. Cecum- and colon-enriched genes were linked to flavor precursor biosynthesis. Species-specific differences revealed that sheep muscle contained higher levels of key amino acids (Asp, Glu, Hyp, Cys, Tyr), whereas goats showed higher α-linolenic acid and other polyunsaturated fatty acids. This work establishes a gut-muscle transcriptomic axis in small ruminants, identifying candidate genes (e.g., 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
The dysregulation of T cell differentiation was associated with cognitive impairment. Recently, the peripheric β-secretase (BACE1) has been suggested as a regulator of T cell differentiation, which wa Show more
The dysregulation of T cell differentiation was associated with cognitive impairment. Recently, the peripheric β-secretase (BACE1) has been suggested as a regulator of T cell differentiation, which was increased in both cognitive impairment (CI) and type 2 diabetes mellitus (T2DM) in CI patients. However, the relationship between T cell dysfunction and CI remains unclear. To address this question, we measured T cell subtypes and BACE1 enzyme activity in a clinical cohort and 5xFAD mice. We found that both IFNγ+ Th1 and Tc1 cells were increased in the CI and T2DM-CI groups, which were associated with worsening cognitive function. The elevated IFNγ + Th1 and Tc1 cells were also observed in 8-month-old 5xFAD mice. The elevated BACE1-mediated INSR cleavage was associated with increased IFNγ + Th1 and Tc1 cells. These findings demonstrate the potential role of elevated BACE1 in IFNγ+ T cells and CI. Show less
The KIT/c-KIT proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin cancer commonly caused by Merkel cell polyomavirus (MCPyV). Here, we demonstrated that trun Show more
The KIT/c-KIT proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin cancer commonly caused by Merkel cell polyomavirus (MCPyV). Here, we demonstrated that truncated MCPyV-encoded large T-antigen (LT) suppressed macroautophagy/autophagy by stabilizing and sequestering KIT in the paranuclear compartment via binding VPS39. KIT engaged with phosphorylated BECN1, thereby enhancing its association with BCL2 while diminishing its interaction with the PIK3C3 complex. This process ultimately resulted in the suppression of autophagy. Depletion of KIT triggered both autophagy and apoptosis, and decreased LT expression. Conversely, blocking autophagy in KIT-depleted cells restored LT levels and rescued apoptosis. Additionally, stimulating autophagy efficiently increased cell death and inhibited tumor growth of MCC xenografts in mice. These insights into the interplay between MCPyV LT and autophagy regulation reveal important mechanisms by which viral oncoproteins are essential for MCC cell viability. Thus, autophagy-inducing agents represent a therapeutic strategy in advanced MCPyV-associated MCC. 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
This study aimed to elucidate the correlations among dyslipidemia, immune function, and clinical outcomes in patients with acute-on-chronic liver failure (ACLF), with particular emphasis on the clinic Show more
This study aimed to elucidate the correlations among dyslipidemia, immune function, and clinical outcomes in patients with acute-on-chronic liver failure (ACLF), with particular emphasis on the clinical significance of lipid metabolism and cellular immune parameters in hepatitis B virus-associated ACLF (HBV-ACLF). A retrospective analysis was conducted on 803 patients with HBV-ACLF admitted to the Shanghai Public Health Clinical Center from January 2014 to January 2024. Patients were stratified into deceased (n = 414) and survival (n = 389) groups based on clinical outcomes. Clinical baseline data, lipid metabolic indices, and cellular immune parameters were collected. The Spearman correlation coefficient was utilized to assess the correlation between lipid metabolic indices and cellular immune parameters, and a multivariate Cox proportional hazards model was applied to analyze risk factors for mortality. Compared to the survival group, lipid metabolism indices in the deceased group were significantly reduced (P < 0.05). Lipid metabolism indices, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (APOA1), apolipoprotein B (APOB), total cholesterol (TC), and triglycerides (TG), demonstrated significant negative correlations with the severity of liver failure (P < 0.05). Correlation analysis with lymphocyte subset counts revealed positive correlations between low-density lipoprotein, TG, TC, APOB, and CD3 + T cells, CD4 + T cells, CD8 + T cells, and CD45 + T cells (P < 0.05). APOA1 and HDL-C were positively correlated with B cells and NK cells (P < 0.05). TG and APOB showed significant negative correlations with the CD4/CD8 ratio (P < 0.05). Multivariate Cox analysis identified age, creatinine, total bilirubin, international normalized ratio (INR), hepatic encephalopathy, and hepatorenal syndrome as independent risk factors affecting the short-term prognosis of HBV-ACLF, while sodium, APOA1, and APOB were identified as independent protective factors for ACLF (HR = 0.984, 95% CI: 0.974-0.995, P < 0.001, HR = 0.267,95% CI: 0.120-0.596, P = 0.001, HR = 0.486, 95% CI: 0.282-0.838, P = 0.010). Patients with HBV-ACLF exhibit decreased levels of TC, TG, LDL-C, HDL-C, APOA1, and APOB. These alterations in serum lipid profiles are associated with immune dysfunction and disease progression in HBV-ACLF. Notably, APOA1 and APOB serve as protective factors against 90-day mortality in hospitalized ACLF patients. Further investigation is warranted to elucidate the relationship between lipid metabolism disturbances and peripheral immunity in ACLF. Show less