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
In recent years, accumulating evidence has highlighted the critical role of miR-627-5p in the occurrence and progression of various cancers. However, its specific role and mechanism in cervical cancer Show more
In recent years, accumulating evidence has highlighted the critical role of miR-627-5p in the occurrence and progression of various cancers. However, its specific role and mechanism in cervical cancer (CC) remain unclear. This study aimed to elucidate the mechanism by which miR-627-5p inhibits the malignant progression of CC and assess its potential clinical implications. In C33A cells, the mRNA expression levels of ANGPTL4 and miR-627-5p were analyzed using qRT-PCR. The miR-627-5p mimics and their control (miR-NC) were transfected into C33A cells to determine whether miR-627-5p directly regulates ANGPTL4 expression. A comprehensive suite of assays, including CCK-8, migration, transwell, flow cytometry, and Western blotting, was conducted to evaluate how miR-627-5p modulates the malignant biological behavior of CC cells. Rescue experiments were performed by overexpressing ANGPTL4. In C33A cells, miR-627-5p expression was reduced, whereas ANGPTL4 expression was elevated. Further analysis confirmed that miR-627-5p negatively regulates ANGPTL4 by directly targeting its 3'-UTR. Functional assays demonstrated that miR-627-5p inhibits proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) while promoting apoptosis and S-phase arrest in C33A cells, effects that were reversed by ANGPTL4 overexpression. These findings highlight the potential of miR-627-5p as both a biomarker and a therapeutic target for CC. By inhibiting EMT and regulating ANGPTL4 expression, miR-627-5p may provide a novel avenue for improving therapeutic strategies, particularly in advanced or metastatic CC. Moreover, miRNA-based therapies, supported by advanced delivery systems such as nanoparticle carriers, could enhance the stability and precision of miR-627-5p applications. This study lays the groundwork for future research integrating miR-627-5p into precision medicine approaches for CC treatment. 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
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
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
Calcific aortic stenosis (CAS) is frequently accompanied by systemic comorbidities, but their causal relationships and shared genetic architecture remain poorly defined. We aimed to map the multisyste Show more
Calcific aortic stenosis (CAS) is frequently accompanied by systemic comorbidities, but their causal relationships and shared genetic architecture remain poorly defined. We aimed to map the multisystem comorbidity network of CAS and clarify underlying genetic mechanisms. In 467 484 participants from the UK Biobank, observational and polygenic phenome-wide association studies evaluated associations between CAS and 1571 phenotypes, integrating disease-trajectory analyses to visualise temporal patterns. Associations replicated across observational and polygenic analyses were tested using two-sample Mendelian randomisation (MR) based on 22 CAS-related variants from FinnGen. Polygenic risk score (PRS) analyses excluding specific genes assessed their contributions, particularly LPA and plasma lipoprotein(a) (Lp(a)) levels. CAS was associated with higher risks of 42 cardiovascular and non-cardiovascular conditions, most prominently metabolic, endocrine, haematological and respiratory disorders. Temporal analyses showed that circulatory and metabolic diseases typically precede other comorbidities in CAS trajectories. MR findings were consistent with causal effects of CAS on multiple cardiovascular diseases, iron-deficiency anaemia, mental disorders and pleural effusion. When LPA variants were removed from the CAS PRS or plasma Lp(a) concentration was adjusted for, most associations lost significance, indicating a shared LPA/Lp(a)-mediated genetic pathway. CAS is embedded within a broad multisystem comorbidity network, driven largely by genetic variation at LPA and elevated Lp(a). These findings highlight pleiotropic mechanisms linking valvular calcification with systemic disease and support LPA-targeted therapies as a promising avenue for reducing the multisystem burden of CAS. 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
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
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
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
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
BackgroundAlthough abnormalities in circulating lipids and lipoproteins are associated with increased cancer risk, their specific impact on lung cancer progression and prognosis is still unclear. This Show more
BackgroundAlthough abnormalities in circulating lipids and lipoproteins are associated with increased cancer risk, their specific impact on lung cancer progression and prognosis is still unclear. This study retrospectively assessed the influence of preoperative lipid and lipoprotein levels on non-small cell lung cancer progression and prognosis, stratified by age.MethodsIn this retrospective study, we analyzed 849 patients to investigate the association between lipid markers and lung cancer progression, and examined postoperative prognosis in a subset of 222 patients. Data was analyzed using restricted cubic spline curves, Kaplan-Meier survival analysis, and Cox proportional hazards models.ResultsA significant nonlinear relationship was observed between total cholesterol (TC), high-density lipoprotein (HDL), ApoB, ApoAI, ApoE, and baseline tumor diameter (BSLD) (PTC = 0.025; PHDL < 0.001; PApoB = 0.037; PApoAI =0.001; PApoE < 0.001). In contrast, Lp(a) showed a significant linear relationship with BSLD (P = 0.002). The Cox regression analysis revealed that triglyceride (TG) (hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.28-0.92, P = 0.025) was significantly negatively associated with lung cancer mortality in patients under 58 years. For patients over 58 years, higher ApoB levels were linked to a reduced risk of lung cancer death (HR = 0.59, 95% CI: 0.36-0.97, P = 0.038).ConclusionThis study reveals a significant negative correlation between ApoAI and HDL levels with BSLD, while Lp(a) shows a positive correlation. In terms of long-term prognosis, high-serum ApoB are associated with a lower mortality risk in all lung cancer patients, and high-serum TG levels associated with reduced mortality risk in patients aged under 58 while high-serum TC levels associated with reduced mortality risk in patients over 58, with high Lp(a) levels indicating a greater risk of mortality in older patients. Show less
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
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
Disrupting liver immune homeostasis drives inflammation. Recent evidence shifts immunoregulatory focus to hepatocytes, though the mechanisms remain poorly defined. Forkhead box O1 (FoxO1) is a critica Show more
Disrupting liver immune homeostasis drives inflammation. Recent evidence shifts immunoregulatory focus to hepatocytes, though the mechanisms remain poorly defined. Forkhead box O1 (FoxO1) is a critical homeostasis regulator, but its function in liver immune homeostasis is unknown. We aimed to clarify the role of hepatocyte FoxO1 in liver immune homeostasis and inflammation. Human liver FoxO1 expression and its association with inflammation were analyzed in patients with various inflammation-related liver diseases. Hepatocyte-specific Foxo1 knockout (FoxO1 △hepa ) mice were established. Hepatocyte-specific gene interference was employed in alcoholic hepatitis and hepatic schistosomiasis murine models. Transcriptomic, single-cell RNA sequencing, and CUT&Tag analyses were performed to elucidate the underlying mechanisms. Hepatocyte FoxO1 levels in human inflammatory livers declined prevalently and were inversely correlated with inflammation and fibrosis. Around 15-18 weeks after birth, FoxO1 △hepa mice exhibited mild spontaneous hepatic inflammation with natural killer T (NKT) cell and neutrophil accumulation. NKT cell depletion in FoxO1 △hepa mice with alcoholic hepatitis or hepatic schistosomiasis (HS) significantly reduced neutrophil accumulation and protected against liver inflammation and damage. Mechanistically, FoxO1 promoted retinoic acid synthesis to induce hepatocyte CD1d expression, which is necessary for regulating NKT cell apoptosis. Innovatively, decreased JMJD1C expression in hepatocytes caused histone H3 lysine 9 (H3K9) dimethylation at the Foxo1 promoter, repressing its transcription and disrupting local immune homeostasis. Our findings uncover a hitherto unrecognized mechanism for hepatocyte-based control of liver inflammation, in which hepatocyte FoxO1 maintained by JMJD1C restrains local NKT cells and neutrophils via CD1d induction, providing promising targets for inflammatory liver diseases. 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
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
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
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
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
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
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphon Show more
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphone-poses significant challenges to students' learning and daily life. Prior research on nomophobia has predominantly adopted a variable-centered perspective. However, if nomophobia is heterogeneous across subgroups, acknowledging this heterogeneity may inform the advancement of more tailored and productive therapeutic methods. Latent profile analysis (LPA) was conducted separately among high school students (N = 446) and college students (N = 667) to identify potential subgroup heterogeneity in nomophobia. To examine cross-group similarities in nomophobia profiles, a multi-group LPA was employed. Based on multiple model fit criteria, a three-profile solution-high nomophobia, moderate nomophobia, and low nomophobia-was identified for both groups. However, the multi-group LPA provided only partial support for the similarity of nomophobia profiles across educational stages, specifically in terms of configural and dispersion similarity. While similar nomophobia profiles emerged across groups, the partial equivalence suggests that intervention strategies for nomophobia may not be universally applicable across different educational levels. Additional studies should investigate the mechanisms underlying students' nomophobia profiles and to inform differentiated interventions for educators, institutions, and policymakers. Show less
Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been Show more
Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been limited by phenotyping challenges and small sample sizes. We test associations of rare and ultra-rare coding variants with proton density fat fraction (PDFF) and MASLD case-control status in 736,010 participants of diverse ancestries from the UK Biobank, All of Us, and BioMe and performed a trans-ancestral meta-analysis. We then developed models to accurately predict PDFF and MASLD status in the UK Biobank and tested associations with these predicted phenotypes to increase statistical power. The trans-ancestral meta-analysis with PDFF and MASLD case-control status identifies two single variants and two gene-level associations in APOB, CDH5, MYCBP2, and XAB2. Association testing with predicted phenotypes, which replicates more known genetic variants from GWAS than true phenotypes, identifies 16 single variants and 11 gene-level associations implicating 23 additional genes. Two variants were polymorphic only among African ancestry participants and several associations showed significant heterogeneity in ancestry and sex-stratified analyses. In total, we identified 27 genes, of which 3 are monogenic causes of steatosis (APOB, G6PC1, PPARG), 4 were previously associated with MASLD (APOB, APOC3, INSR, PPARG), and 23 had supporting clinical, experimental, and/or genetic evidence. Our results suggest that trans-ancestral association analyses can identify ancestry-specific rare and ultra-rare coding variants in MASLD pathogenesis. Furthermore, we demonstrate the utility of machine learning in genetic investigations of difficult-to-phenotype diseases in trans-ancestral biobanks. 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
Gestational exposure to micro- and/or nanoparticles (M/NPs) may be closely associated with adverse maternal and offspring outcomes involving multiple organ dysfunctions. Organ functional change is ach Show more
Gestational exposure to micro- and/or nanoparticles (M/NPs) may be closely associated with adverse maternal and offspring outcomes involving multiple organ dysfunctions. Organ functional change is achieved through metabolic adaptation in response to changes in the external environment; yet, intricacies of these organ dysfunctions and underlying metabolic changes remain poorly understood, particularly at spatial suborgan level. Using a pregnant mouse model exposed to polystyrene (PS)-M/NPs (sizes: 100 nm, 5 μm, 10 mg/L in drinking water) from gestation day 1 to 18, we construct a comprehensive multisub-organ lipid metabolic landscape. This analysis integrates MALDI-mass spectrometry imaging with histological assessment to monitor changes in maternal suborgans-placenta-fetus unit. Our findings reveal distinct metabolic responses between maternal and fetal organs to gestational PS-M/NPs exposure. We identify potential targeted suborgans and spatial biomarkers associated with PS-M/NPs exposure according to histological damage and metabolic remodeling, including placental junctional and labyrinth zone (e.g., phosphatidylserine, phosphatidylethanolamine [PE]), renal cortex of maternal kidney (e.g., ceramide [Cer], PE, sphingomyelin [SM], phosphatidylglycerol [PG], phosphatidylserine), ventricular muscular layer and interventricular septum of maternal heart (e.g., PE, lysophosphatidylethanolamine [LPE], lysophosphatidic acid [LPA]), fetal brain and spinal cord (e.g., Cer), and fetal liver (e.g., Cer). Furthermore, phosphatidylserine synthesis and glycolipid metabolism pathways are found to be exclusively enriched following PS-NP and PS-MP exposure in the multiorgan network, respectively. We propose an M/NPs scale-exposed suborgan effect framework, which provides a molecular foundation and potential spatial biomarkers for elucidating intersub-organ interactions in response to M/NPs exposure and their role in mediating pregnancy state. 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