Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicat Show more
Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicated in the development of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), a fatal and progressive lung vascular disease. Transforming growth factor β 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
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
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
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
Background Myeloid/lymphoid neoplasm with eosinophilia and rearrangement of FGFR1(MLN-FGFR1), also referred to as 8p11 myeloproliferative syndrome (EMS), arises from aberrant FGFR1 gene rearrangement Show more
Background Myeloid/lymphoid neoplasm with eosinophilia and rearrangement of FGFR1(MLN-FGFR1), also referred to as 8p11 myeloproliferative syndrome (EMS), arises from aberrant FGFR1 gene rearrangement in bone marrow hematopoietic stem cells, resulting in the transformation of myeloid/lymphoid cells into neoplastic growths. The clinical and laboratory features of affected individuals are influenced by the specific partner genes. Purpose This article aims to report a case of MLN-FGFR1 involving a novel CNTRL::FGFR1 splicing variant and to discuss its clinicopathological characteristics and treatment challenges. Methods/Results We report a case of MLN-FGFR1 in a 35-year-old male patient presenting with leukocytosis, lymphadenopathy, hepatosplenomegaly, and a mixed population of B lymphoblasts, T lymphoblasts, and monoblasts in the bone marrow and lymph nodes. Comprehensive molecular profiling, including chromosomal karyotyping, fluorescence in situ hybridization (FISH), targeted transcriptome sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing, identified a novel splicing variant of the CNTRL::FGFR1 fusion, resulting from a t(8;9)(p11;q33) translocation. This novel splicing variant involves an in-frame fusion between exon 38 of CNTRL and exon 11 of FGFR1, retaining the kinase domain of FGFR1 and leading to its constitutive activation. Despite multiple treatment regimens, the patient failed to achieve complete remission (CR). Conclusion The findings highlight the urgent need for targeted therapies, such as FGFR inhibitors, to improve outcomes in patients with FGFR1-rearranged malignancies. 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
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
Lipid profiles are largely determined by genetic variants, and lipid metabolism plays a crucial role in Alzheimer's disease. To investigate whether lipid profile variability in response to diverse sta Show more
Lipid profiles are largely determined by genetic variants, and lipid metabolism plays a crucial role in Alzheimer's disease. To investigate whether lipid profile variability in response to diverse statins could be affected by cholesterol metabolism-related genetic variants in Alzheimer's disease.. This prospective observational pharmacogenetic study was conducted at the Universidade Federal de São Paulo (Unifesp), Brazil. Consecutive outpatients were prospectively followed for lipid profile variations over one year, estimated by the associations between statin therapy and the following variants: rs2695121 (NR1H2), rs3846662 (HMGCR), rs11669576 (LDLR8), rs5930 (LDLR10), rs5882 and rs708272 (CETP), rs7412 and rs429358 (APOE), and ACE insertion/deletion polymorphism. All polymorphisms in the 189 patients were in Hardy-Weinberg equilibrium. Statins resulted in lower total cholesterol and LDL cholesterol levels, whereas the effects on HDL cholesterol varied according to the statin used. Atorvastatin resulted in lower triglyceride level variations than simvastatin. APOE-ε4 carriers showed a better response to atorvastatin in elevating HDL-cholesterol than APOE-ε4 non-carriers. Carriers of the ACE insertion allele had cumulatively lower total cholesterol and LDL-cholesterol levels, regardless of statin therapy, but lower triglyceride levels when using atorvastatin. Carriers of rs11669576-G had lower total cholesterol and LDL-cholesterol levels when using simvastatin, and lower total cholesterol and triglycerides when using atorvastatin. Concerning CETP haplotypes, carriers of rs5882-A and rs708272-A benefitted the most from statins, which lowered total cholesterol and increased HDL-cholesterol levels, and from atorvastatin lowering triglycerides; however, the effects of atorvastatin lowering total cholesterol and LDL-cholesterol were more pronounced for carriers of rs5882-GG/rs708272-GG. Lipid profile variations may be pharmacogenetically mediated in Alzheimer's disease, thus, confirming their high heritability. 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
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
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
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
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
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. FOXO1 fusion indicates poor prognosis and lead to dysregulation of transcriptioanal network. This study aims to investigate cli Show more
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. FOXO1 fusion indicates poor prognosis and lead to dysregulation of transcriptioanal network. This study aims to investigate clinical characteristics and therapeutic targets concerning FOXO1 fusion status. 65 pediatric RMS patients were enrolled. Clinical data were analyzed using Kaplan-Meier estimates and Cox regression. Surgically resected tumor tissues were subject to single-cell RNA sequencing (scRNA-seq). Patient-derived xenograft (PDX) was establish and dissociated to cells for high-throughput drug screening. Among the 65 patinets (36 patients with embryonal RMSs (ERMSs), 15 patients with alveolar RMSs (ARMSs) and 14 patients with other types of RMSs), 73.3% of ARMSs were defined as fusion positive (FP) while 6 ERMS (ERMS)s were also FP. Cox regression analysis identified FOXO1 fusion as a risk factor alone and combined with pathologic subtype, sex and age or metastasis status. scRNA-seq revealed distinct transcription factor networks between FP and FN RMS, showing up-regulated activity of OLIG2, NHLH1, SNAI1, TFF3 and other TFs related to neural development and differentiation. MAPK, PI3K-Akt, and mTOR pathways were enriched in FP-RMS tumor cells. High-throughput drug screening of PDX-derived cells identified sensitive drugs targeting FP-RMS specific signatures. AMG-337 was selected and validated for its anti-tumor effect. FOXO1 fusion status influences RMS clinical outcomes, including rare FP-ERMS cases. scRNA-seq combined with drug screening identified MET as a promising therapeutic target in FP-RMS. Show less
Sepsis is the dysregulated immune response to an infection and is a leading cause of mortality. Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of death fro Show more
Sepsis is the dysregulated immune response to an infection and is a leading cause of mortality. Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of death from sepsis, and increasing levels of HDL by inhibition of cholesteryl ester transfer protein (CETP) has been shown to decrease mortality in mouse models of sepsis. The objective of this study was to investigate the cellular mechanisms by which CETP inhibition and HDL lead to improved survival during sepsis. We found that HDL inhibits lipopolysaccharide (LPS)-induced activation of IL-1β in a mouse model of sepsis. The activation of IL-1β was dependent on the activity of scavenger receptor class B type 1 (SR-B1), and knockdown of SR-B1 significantly attenuated LPS-induced production of IL-1β in macrophages. Additionally, we found that LPS-induced SR-B1 internalization occurs through the endosome-lysosome pathway, which is also likely responsible for LPS degradation in the macrophages. Furthermore, we revealed that raising HDL by CETP inhibition markedly enhanced HDL-mediated anti-inflammatory effects in response to LPS stimulation, and these effects were not due to CETP itself but rather were HDL-dependent. Finally, we show that pharmacological inhibition of CETP significantly improved endotoxemia-induced mortality by inhibiting IL-1β production in the liver and circulation after LPS injection. Pathologically, CETP inhibition attenuated LPS-induced diffuse alveolar damage and hepatocyte necrosis, which may contribute to the improved mortality in mice treated with the CETP inhibitor anacetrapib. Taken together, our findings uncover a cellular mechanism by which HDL attenuates LPS-induced pro-inflammatory response via SR-B1-mediated LPS degradation. 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
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
Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocu Show more
Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including APP, RARRES2, FAM3A, HAMP, CAMP, GNLY, and PI3. Senescent RPE cells expressed lower levels of APP and RARRES2 mRNA, accompanied by increased intracellular retention of E. coli in a bactericidal assay. Silencing APP, not RARRES2, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (BACE1) and γ-secretase (PS1), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration. Show less
Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. Howeve Show more
Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. However, limited research has been conducted on the effects of polystyrene nanoplastic (PS-NPs) on intracranial cholesterol metabolic pathways. In this study, we exposed whole-brain organoids (WBOs) to PS-NPs and identified significant changes in endoplasmic reticulum stress and cholesterol biosynthesis pathways through whole-transcriptome sequencing. To investigate potential mechanisms of altered cholesterol pathways, we constructed a Transwell neuronal-astrocyte co-culture model. Results demonstrated that PS-NPs induced significant endoplasmic reticulum stress in astrocytes, specifically manifested by elevated levels of ATF4 and CHOP, along with increased autophagy indicated by the elevated LC3-II/I ratio. PS-NPs significantly inhibited the AKT/ACLY pathway of cholesterol biosynthesis, leading to marked reductions in acetyl-CoA and cholesterol within astrocytes (P < 0.05). In addition, PS-NPs led to a significant reduction of apolipoprotein APOE, which hindered cholesterol transport and ultimately inhibited synaptin (SYN) formation. In summary, PS-NPs induce endoplasmic reticulum stress and autophagy in astrocytes, impair cholesterol de novo synthesis and apolipoprotein-mediated transport, ultimately inhibiting neuronal synaptogenesis. Furthermore, specific inhibition of ERs restored cholesterol synthesis in astrocytes and neuronal synapses. This study demonstrates that PS-NPs produce neurotoxic effects by affecting cholesterol homeostasis in the brain. 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
Jia Min Chen, Yan Wang, Yan Shi · 2025 · Clinical, cosmetic and investigational dermatology · added 2026-04-24
Omega-3 polyunsaturated fatty acids (PUFAs) are potential targets for the treatment of skin diseases due to their anti-inflammatory and immunomodulatory effects. By leveraging a genetic approach known Show more
Omega-3 polyunsaturated fatty acids (PUFAs) are potential targets for the treatment of skin diseases due to their anti-inflammatory and immunomodulatory effects. By leveraging a genetic approach known as Mendelian randomization (MR), we sought to determine the causal impact of PUFAs on the likelihood of developing skin diseases among individuals of European ancestry. We integrated GWAS data from the CHARGE consortium and UK Biobank to identify genetic instruments for omega-3 PUFAs and desaturase activity, using two-sample MR to assess their associations with six skin diseases. Elevated levels of omega-3 fatty acids were found to substantially lower the probability of experiencing atopic dermatitis (0.92, [0.85,0.98]), while increased DPA levels correlated with a substantial increase in the probability of squamous cell carcinoma occurrence (2.25, [1.29,3.92]). Increased DHA levels were also associated with a reduced risk of atopic dermatitis (0.90, [0.84,0.96]) but increased the risk of solar dermatitis (1.38, [1.09,1.73]). In addition, tissue-type specific MR analysis revealed that elevated FADS1 expression in fibroblasts significantly inhibited atopic dermatitis development (β = -0.181, [-0.276,-0.0853]), while elevated FADS2 expression in non-sun-exposed skin tissues was associated with a reduced risk of squamous cell carcinoma (β = -0.562, [-0.833,-0.029]). Conversely, heightened FADS2 expression was strongly linked to a greater likelihood of developing atopic dermatitis in both sun-exposed and sun-protected skin areas (β = 0.107, [0.0348,0.179]; β = 0.192, [0.114,0.0270], respectively). This study reveals the causal role of omega-3 PUFAs and FADS expression in specific tissues and blood in skin diseases. These findings underscore the potential of PUFA biosynthesis pathways as therapeutic targets for skin disease interventions. 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
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