Angiopoietin‑like 4 (ANGPTL4), a member of the angiopoietin family, plays critical roles in angiogenesis, lipid metabolism and inflammation. It has been demonstrated that ANGPTL4 has significant influ Show more
Angiopoietin‑like 4 (ANGPTL4), a member of the angiopoietin family, plays critical roles in angiogenesis, lipid metabolism and inflammation. It has been demonstrated that ANGPTL4 has significant influence on various diseases. Accumulating evidence has highlighted the impacts of ANGPTL4 on human malignancies. ANGPTL4 is commonly overexpressed in various types of cancer, such as breast, non‑small cell lung, gastric and colorectal cancer. Its upregulation promotes tumor growth, invasion, metastasis and angiogenesis, as well as metabolic reprogramming and resistance to programmed cell death, radiotherapy and chemotherapy. However, ANGPTL4 has also exhibited antitumor effects under certain conditions, indicating its complex roles in tumor biology. The transcriptional regulation of ANGPTL4 is influenced by multiple factors, such as HIF‑1, PPARs, TGF‑β and long non‑coding RNAs. In terms of signaling pathways, STATs, PI3K/AKT and COX-2/PGE2 are important in regulating cellular processes. The present review summarizes the biological functions of ANGPTL4 in tumors and its association with patient prognosis. Furthermore, the key molecular mechanisms and potential reasons for its dual roles in cancer are also discussed. In conclusion, ANGPTL4 is a valuable diagnostic biomarker and a potential therapeutic target for human cancers. Show less
Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent Show more
Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent (postnatal day 20-42) and adult (postnatal day 60-82) mice differ in performance on a pure tone Go/No-Go auditory discrimination task of varying difficulty. Using dense electrophysiological recordings, we measured spiking activity at single neuron resolution in the auditory cortex while mice were engaged in the task. As compared to adults, adolescent mice showed lower auditory discrimination performance in a difficult task. This difference in performance was due to higher response variability and weaker cognitive control expressed as higher lick bias. Adolescent and adult neuronal responses differed only slightly in representations of pure tones when measured outside the context of learning and the task. However, cortical representations after learning within the context of the task were markedly different. We found differences in stimulus- and choice-related activity at the single neuron level representations, as well as lower population-level decoding of the difficult task in adolescents. Overall, cortical decoding in adolescents was lower and slower, especially for difficult sound discrimination, reflecting immature cortical representations of sounds and choices. Notably, we found age-related differences, which were more pronounced after learning, reflecting the combined impact of age and learning. Our findings highlight distinct neurophysiological and behavioral profiles in adolescence, underscoring the ongoing development of cognitive control mechanisms and cortical plasticity during this sensitive developmental period. 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
Ambient fine particulate matter (PM2.5) has emerged as a critical environmental threat to ocular health; however, the underlying molecular mechanisms affecting the retinal pigment epithelium (RPE) rem Show more
Ambient fine particulate matter (PM2.5) has emerged as a critical environmental threat to ocular health; however, the underlying molecular mechanisms affecting the retinal pigment epithelium (RPE) remain largely uncharacterized. This study aimed to investigate transcriptomic alterations in RPE cells following PM2.5 exposure and to identify key regulatory pathways involved. Next-generation sequencing (NGS) was used to investigate differential gene expression in ARPE-19 cells upon PM2.5 exposure. Bioinformatic analyses, including pathway enrichment and gene set enrichment analysis (GSEA), were performed to identify affected signaling cascades. Functional assays-including cell viability, wound healing, and Transwell migration-were conducted to evaluate phenotypic changes. Quantitative RT-PCR (Reverse Transcription Polymerase Chain Reaction) and ELISA (Enzyme-Linked Immunosorbent Assay) validated gene expression and transforming growth factor-beta (TGF-β) secretion. TGF-β stimulation and receptor inhibition were applied to dissect pathway involvement. Comprehensive analysis revealed substantial changes in gene expression profiles, with pathway enrichment highlighting the activation of cell migration-related pathways such as focal adhesion, regulation of actin cytoskeleton, extracellular matrix (ECM)-receptor interaction, tight junction, and adherens junction. Notably, the TGF-β, MAPK (Mitogen-Activated Protein Kinase), and PI3K/AKT (Phosphoinositide 3-Kinase / Protein Kinase B) pathways were significantly modulated. Functional assays showed that PM2.5 exposure enhanced ARPE-19 cell viability and migratory capacity. Among the differentially expressed genes, angiopoietin-like 4 (ANGPTL4) was markedly upregulated following PM2.5 stimulation. Pharmacological inhibition of TGF-β signaling abrogated PM2.5-induced ANGPTL4 expression, suggesting a pivotal role of the TGF-β pathway in mediating these effects. These findings demonstrate that PM2.5 induces transcriptomic reprogramming and activates the TGF-β signaling cascade in RPE cells, thereby enhancing cellular migration. Specifically, ANGPTL4 was identified as a key downstream effector of this pathway. This study provides novel insights into the molecular mechanisms by which air pollution contributes to retinal disease pathogenesis and suggests potential therapeutic targets for preventing PM2.5-induced retinal injury. Show less
Products encoded by approximately 30% of the mammalian genome exit the endoplasmic reticulum via the coat complex II (COPII) system en route to their functional destination. Among these cargoes, APOB- Show more
Products encoded by approximately 30% of the mammalian genome exit the endoplasmic reticulum via the coat complex II (COPII) system en route to their functional destination. Among these cargoes, APOB-containing lipoproteins stand out as abundant and bulky secretory particles with profound implications for human health and diseases. Recent insights into the specialized intracellular itinerary of lipoprotein metabolism and transport not only shed light on longstanding questions of lipid dynamics, but also highlight challenges faced by the COPII machinery in accommodating these complex, unconventional cargoes. Emerging evidence supports that tightly-regulated COPII condensation enables maximal capacity of cargo transport, providing a potential solution tailored for efficient lipoprotein delivery without affecting general protein secretion. This distinction suggests that targeting COPII condensation may provide new therapeutic strategies for lipid-associated diseases. Indeed, recent studies have identified manganese as a key modulator of this process, offering novel insights into its physiological relevance and potential translations. Show less
(1) Background: the epigenetic mechanisms underlying the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remain poorly understood; (2) Methods: to investigate this process, Show more
(1) Background: the epigenetic mechanisms underlying the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remain poorly understood; (2) Methods: to investigate this process, we conducted genome-wide DNA methylation sequencing to map the epigenetic changes during the AKI-CKD transition in a mouse model. By integrating DNA methylome and transcriptome analyses, we identified genes and signaling pathways regulated by DNA methylation throughout this progression; (3) Results: our analysis identified four candidate genes- Show less
Despite preclinical evidence for berberine's antidepressant potential, its pharmacological effects remain controversial.This study therefore systematically reviews animal research to clarify its mecha Show more
Despite preclinical evidence for berberine's antidepressant potential, its pharmacological effects remain controversial.This study therefore systematically reviews animal research to clarify its mechanisms and support future clinical trials. We searched PubMed, Embase, Web of Science, Cochrane Library, and OVID for studies on berberine in depression models up to March 20, 2025. Analysis used STATA 15.0 and Review Manager 5.4, with study quality assessed via SYRCLE's risk of bias tool. The meta-analysis included 18 studies (338animals). Overall, berberine significantly reduced depression-like behaviors in animal models.Specifically, BBR increased total locomotor activity in the open field test (SMD=2.79, 95% CI: 1.55, 4.02) and time spent in the center zone (SMD=2.49, 95% CI:1.61, 3.37), reduced immobility time in both the forced swim test and tail suspension test (SMD =-4.42, 95% CI:-5.77,-3.07; SMD=-4.46, 95% CI:-6.21, -2.71), increased sucrose intake in the sucrose preference test (SMD = 3.72, 95% CI: 2.37, 5.07), and reduced feeding latency in the novelty-suppressed feeding test (SMD=-5.72, 95% CI:-7.63, -3.82). However, BBR did not significantly alter the number of square crossings (SMD=1.36, 95%CI:-0.07 , 2.79) or rearing frequency (SMD=1.66, 95% CI: -0.29, 3.61) in the open field test. BBR also increased the levels of body weight, brain-derived neurotrophic factor, dopamine, serotonin, and norepinephrine,while reducing the levels of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. Preclinical studies suggest that berberine may represent a promising therapeutic agent for the treatment of depressive disorders. Its antidepressant effects appear to be closely associated with the modulation of neurotransmitter levels,reduction of oxidative stress, and inhibition of inflammatory responses.However, methodological limitations may constrain these findings. Larger, more rigorous preclinical studies are needed for confirmation. https://inplasy.com/inplasy-2025-6-0002, identifier INPLASY202560002. Show less
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, over Show more
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, overshadowing its influence on the biological effects of formulations. In this study, we reevaluated the delivery effect of CH using widely applied lipid microspheres (LM) as a model DDS. We conducted comprehensive investigations into the impact of CH on the distribution, cell uptake, and protein corona (PC) of LM at sites of cardiovascular inflammatory injury. The results demonstrated that moderate CH promoted the accumulation of LM at inflamed cardiac and vascular sites without exacerbating damage while partially mitigating pathological damage. Then, the slow cellular uptake rate observed for CH@LM contributed to a prolonged duration of drug efficacy. Network pharmacology and molecular docking analyses revealed that CH depended on LM and exerted its biological effects by modulating peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in vascular endothelial cells and estrogen receptor alpha (ERα) protein levels in myocardial cells, thereby enhancing LM uptake at cardiovascular inflammation sites. Proteomics analysis unveiled a serum adsorption pattern for CH@LM under inflammatory conditions showing significant adsorption with CH metabolism-related apolipoprotein family members such as apolipoprotein A-V (Apoa5); this may be a major contributing factor to their prolonged circulation 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
Autophagy is essential in DNA damage response by limiting damage, but its responsive activation remains unclear. RBM38 (RBM38a), an RNA-binding protein, regulates mRNA metabolism and plays a key role Show more
Autophagy is essential in DNA damage response by limiting damage, but its responsive activation remains unclear. RBM38 (RBM38a), an RNA-binding protein, regulates mRNA metabolism and plays a key role in controlling cell cycle progression, senescence, and cancer. In this study, we uncovered a novel primate-specific isoform, RBM38c, with 32 extra amino acids from exon 2, which imparts a distinct capacity to promote autophagy upon DNA damage. TP53 increases RBM38c expression upon DNA damage, while TRIM21 facilitates its K63-linked ubiquitination at lysine (K) 35. Activated RBM38c enhances its interaction with BECN1, promoting the formation of the ATG14-containing PtdIns3K-C1 complex and thus autophagy initiation. A K35R mutation or TRIM21 deficiency impairs RBM38c ubiquitination, preventing autophagy activation upon DNA damage. Moreover, RBM38c-driven autophagy protects cells from DNA damage-induced apoptosis and promotes survival, with this beneficial effect susceptible to suppression by the autophagy inhibitor 3-methyladenine. Consequently, depleting RBM38c enhances the efficacy of DNA-damaging drugs by impairing autophagy and increasing DNA damage. Clinical lung cancer samples show a positive correlation between RBM38c expression and LC3 expression, and this correlation is linked to chemotherapy resistance. Together, our study reveals a novel mechanism for DNA damage-induced autophagy, involving K63-linked ubiquitination of RBM38c as a critical interactor with BECN1. Show less
Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims Show more
Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims to investigate its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in Chinese healthy volunteers. A randomized, double-blind, placebo-controlled and dose-escalation Phase I study was conducted as follows: a single dose (2.5 mg) and once-weekly administration for 2 weeks to reach target doses (5, 10 and 15 mg) by titration. A total of 40 volunteers received at least one dose of BGM0504 or placebo. The PK profile of BGM0504 was investigated over a wide dose range and supported once-weekly administration. It was observed that C BGM0504 was generally safe and well tolerated with favourable PK profile and potential role in weight loss was also confirmed. These findings support subsequent development of BGM0504 for type 2 diabetes mellitus (T2DM) and obesity. Show less
It remains controversial whether lipids affect osteoporosis (OP) or bone mineral density (BMD), and causality has not been established. This study aimed to investigate the genetic associations between Show more
It remains controversial whether lipids affect osteoporosis (OP) or bone mineral density (BMD), and causality has not been established. This study aimed to investigate the genetic associations between lipids, novel non-statin lipid-lowering drug target genes, and OP and BMD. Mendelian randomization (MR) method was used to explore the genetic associations between 179 lipid species and OP, BMD. Drug-target MR analysis was used to explore the causal associations between angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C3 (APOC3) inhibitors on BMD. The IVW results with Bonferroni correction indicated that triglyceride (TG) (51:3) (OR = 1.0029; 95% CI: 1.0014-1.0045; P = 0.0002) and TG (56:6) (OR = 1.0021; 95% CI: 1.0008-1.0033; P = 0.0011) were associated with an increased risk of OP; TG (51:2) (OR = 0.9543; 95% CI: 0.9148-0.9954; P = 0.0298) was associated with decreased BMD; and ANGPTL3 inhibitor (OR = 1.1342; 95% CI: 1.0393-1.2290; P = 0.0093) and APOC3 inhibitor (OR = 1.0506; 95% CI: 1.0155-1.0857; P = 0.0058) was associated with increased BMD. MR analysis indicated causal associations between genetically predicted TGs and OP and BMD. Drug-target MR analysis showed that ANGPTL3 and APOC3 have the potential to serve as novel non-statin lipid-lowering drug targets to treat or prevent OP. Show less
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANG Show more
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANGPTL4 levels are observed in diabetic and obese individuals. However, the potential link between ANGPTL4 and diabetes- or obesity-related complications remains uncertain. This study aimed to explore whether plasma ANGPTL4 level could serve as a predictor of cancer mortality, cardiovascular mortality, and all-cause mortality in a community-based cohort. A community-based cohort study was conducted, where fasting plasma ANGPTL4 concentrations were measured at baseline, and vital status was ascertained through linkage with the National Health Insurance Research Database in Taiwan. During a 10.46-year follow-up period, 29 (2.49%) of the 1163 participants died. Subjects within the highest tertile of plasma ANGPTL4 levels exhibited the lowest survival rate. In unadjusted models, plasma ANGPTL4 significantly predicted all-cause mortality, cancer mortality, and cardiovascular or cancer-related mortality. Upon adjustment for confounders including age, sex, smoking, body mass index (BMI), hypertension, diabetes mellitus (DM), and renal function, each standard deviation increase in plasma ANGPTL4 was associated with HRs of 1.35 (95% CI: 1.01-1.80, Plasma ANGPTL4 emerges as a promising biomarker capable of predicting 10-year mortality and enhancing risk prediction beyond established risk factors. 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
To identify the connections between lipid biomarkers and the anti-VEGF therapy response in patients with neovascular age-related macular degeneration (nAMD). A bidirectional and multivariable Mendelia Show more
To identify the connections between lipid biomarkers and the anti-VEGF therapy response in patients with neovascular age-related macular degeneration (nAMD). A bidirectional and multivariable Mendelian randomization study. The summary statistics for anti-VEGF nAMD treatment response included a total of 128 responders, 51 nonresponders, and 6 908 005 genetic variants available for analysis. The sample size of lipid biomarkers is 441 016 and 12 321 875 genetic variants available for analysis. Two-sample Mendelian randomization (MR) method was conducted to exhaustively appraise the causalities among 13 lipid biomarkers and the risk of different anti-VEGF treatment responses (including visual acuity [VA] and central retinal thickness [CRT]) for nAMD subtypes. Thirteen lipid biomarkers, VA, and CRT. A positive causal relationship was identified between triglycerides (TGs), apolipoproteins (Apos) E2, ApoE3, total cholesterol (TC), and VA response to anti-VEGF therapy in patients with nAMD, as confirmed by MR-Egger, weighted median, and weighted mode models. The MR-Egger model yielded statistically significant results for TC, ApoA-I, ApoB, and ApoA-V in relation to the CRT response to anti-VEGF treatment in patients with nAMD. In the reverse MR, the MR-Egger model identified significant causal relationships between ApoA-I, low-density lipoprotein cholesterol (LDL-c), ApoE3, and ApoF and the VA response. However, this was not the case in the weighted median and weighted mode models. In the MR-Egger model, ApoB, LDL-c, ApoE3, and ApoM were identified as significantly influencing the CRT response. In the multisample MR analysis, TC, high-density lipoprotein cholesterol, LDL-c, and TG were found to be causally related to VA response, and TC was also identified as being causally related to the CRT response to anti-VEGF therapy in patients with nAMD. This MR study suggests unidirectional causality between TG and ApoE3 and the response to anti-VEGF treatment in patients with nAMD. The author(s) have no proprietary or commercial interest in any materials discussed in this article. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, yet efficient therapeutic approaches are lacking. The advent of glucagon-li Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, yet efficient therapeutic approaches are lacking. The advent of glucagon-like peptide-1 receptor (GLP-1R)-based multi-target agonists generated renewed optimism for MASLD. Building on preclinical and clinical data suggesting synergistic metabolic benefits, we hypothesized that combining glucose-dependent insulinotropic polypeptide receptor (GIPR) or glucagon receptor (GCGR) agonism with GLP-1R agonism would confer superior protective effects against MASLD and its complications. We identified genetic proxies of the effect of GLP-1R, GIPR, and GCGR by combining Mendelian randomization (MR), Bayesian colocalization, and linkage disequilibrium (LD) analyses. We then performed two-sample MR and colocalization analyses to estimate the causal effect of GLP-1R-based agonists on MASLD, its metabolic risk factors, and multi-organ complications. The MR analyses suggested genetically proxied GLP-1R-based agonists were causally associated with a reduced risk of MASLD (GIPR/GLP-1R agonist: OR: 0.17, 95%CI: 0.05-0.52, P = 2.07 × 10 We identified the causal role of GLP-1R-based agonists in reducing the risk of MASLD and its complications, probably by improving systemic metabolic disorders and partly independent of their weight-loss effect. Show less
Ovarian cancer (OC), a common fatal malignancy in women, has a poor prognosis. RNA modifications are associated with the development of OC. In this study, we aimed to identify and verify RNA modificat Show more
Ovarian cancer (OC), a common fatal malignancy in women, has a poor prognosis. RNA modifications are associated with the development of OC. In this study, we aimed to identify and verify RNA modifications-related prognostic genes in OC by integrating bulk and single-cell RNA sequencing (scRNA-seq) data. Transcriptome data came from public databases and RNA modifications-related genes (RMRGs) were obtained from literature. Candidate genes were identified by intersecting RMRGs with differentially expressed genes (DEGs) in OC patients. Prognostic genes were gained via machine learning techniques, particularly LASSO regression. A risk model was built to predict the prognosis. OC patients were divided into high-risk and low-risk groups according to risk score. Subsequent analyses covered enrichment analysis, immune microenvironment, mutation analysis, and chemotherapeutic drug sensitivity. In addition, scRNA-seq data was assessed for key cells and gene expression in them. Finally, RT-qPCR was applied to identify the expression of prognostic genes. We constructed an RNA modifications-related prognostic signature that can effectively predict clinical outcomes and therapeutic responses in patients with OC. 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
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
Sleep Deprivation (SD) severely disrupts emotional regulation, predisposing individuals to mood disturbances and anxiety. However, the precise mechanisms underlying anxiety triggered by sleep loss rem Show more
Sleep Deprivation (SD) severely disrupts emotional regulation, predisposing individuals to mood disturbances and anxiety. However, the precise mechanisms underlying anxiety triggered by sleep loss remain elusive. In this study, a mouse model of chronic SD was established using a continuously running treadmill paradigm for 28 days. SD induced anxiety-like behaviors and hippocampal ApoE downregulation. Furthermore, SD downregulated the expression of the autophagy-related protein ATG5 and upregulated p62. In addition, SD inhibited AMPK phosphorylation and induced mTOR phosphorylation. Levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-18, were markedly increased. Immunofluorescence staining revealed a notable increase in the activation of microglia and astrocytes in the hippocampi of SD mice. Either hippocampal overexpression of ApoE via bilateral AAV injection or rapamycin treatment significantly alleviated anxiety-like behaviors, enhanced autophagy, and reduced neuroinflammation in SD mice. Thus, SD induces anxiety by suppressing autophagy level. This effect is mediated through the inhibition of ApoE-dependent AMPK phosphorylation and the concomitant promotion of mTOR phosphorylation, revealing a potential therapeutic target. Show less
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our gen Show more
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV Show less
Patients with schizophrenia (SCZ) face multiple health challenges due to the complication of chronic diseases and psychiatric disorders. Among these, cardiovascular comorbidities are the leading cause Show more
Patients with schizophrenia (SCZ) face multiple health challenges due to the complication of chronic diseases and psychiatric disorders. Among these, cardiovascular comorbidities are the leading cause of their life expectancy being 15-20 years shorter than that of the general population. Identifying comorbidity patterns and uncovering differences in immune and metabolic function are crucial steps toward improving prevention and management strategies. A retrospective cross-sectional study was conducted using electronic medical records of inpatients discharged between 2015 and 2024 from a municipal psychiatric hospital in China. The study included patients diagnosed with Schizophrenia, Schizotypal, and Delusional Disorders (SSDs) (ICD-10: F20-F29). Comorbidity patterns were identified through latent class analysis (LCA) based on the 20 most common comorbid conditions among SSD patients. To investigate differences in peripheral blood metabolic and immune function, linear regression or generalized linear models were applied to 44 laboratory test indicators collected during the acute episode. The Benjamini-Hochberg method was used for p-value correction, and the false discovery rate (FDR) was calculated, with statistical significance set at FDR < 0.05. Among 3,697 inpatients with SSDs, four distinct comorbidity clusters were identified: SSDs only (Class 1), High-Risk Metabolic Multisystem Disorders (Class 2, n = 39), Low-Risk Metabolic Multisystem Disorders (Class 3, n = 573), and Sleep Disorders (Class 4, n = 205). Compared to Class 1, Class 2 exhibited significantly elevated levels of apolipoprotein A (ApoA; β = 90.62), apolipoprotein B (ApoB; β = 0.181), mean platelet volume (MPV; β = 0.994), red cell distribution width-coefficient of variation (RDW-CV; β = 1.182), antistreptolysin O (ASO; β = 276.80), and absolute lymphocyte count (ALC; β = 0.306), along with reduced apolipoprotein AI (ApoAI; β = -0.173) and hematocrit (HCT; β = -35.13). Class 3 showed moderate increases in low-density lipoprotein cholesterol (LDL-C; β = 0.113), MPV (β = 0.267), white blood cell count (WBC; β = 0.476), and absolute neutrophil count (ANC; β = 0.272), with decreased HCT (β = -9.81). Class 4 was characterized by elevated aggregate index of systemic inflammation (AISI; β = 81.07), neutrophil-to-lymphocyte ratio (NLR; β = 0.465), and systemic inflammation response index (SIRI; β = 0.346), indicating a heightened inflammatory state. The comorbidity patterns of patients with SCZ can be distinctly classified. During the acute episode, those with comorbid metabolic disorders exhibit a higher risk of cardiovascular diseases and immune system abnormalities, while patients with comorbid sleep disorders present a pronounced systemic inflammatory state and immune dysfunction. This study provides a basis for the chronic disease management and anti-inflammatory treatment, while also offering objective biomarker insights for transdiagnostic research. Show less
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
ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL Show more
ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate, and both cleavages generate similar C-terminal domain-containing (CD)-ANGPTL4 fragments. Whereas several studies have investigated associations of free ANGPTL proteins with cardiovascular risk, there are no data describing associations of the complexes and CD-ANGPTL4 with outcomes or describing the effects of the complexes on LPL bound to GPIHBP1 (glycosylphosphatidylinositol HDL-binding protein 1). Recombinant protein assays were used to study ANGPTL protein and complex effects on GPIHBP1-LPL activity. ANGPTL3/8, ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 were measured with dedicated immunoassays in 2394 LURIC (Ludwigshafen Risk and Cardiovascular Health) study participants undergoing coronary angiography and 6188 getABI study (German Epidemiological Trial on Ankle Brachial Index) participants undergoing ankle brachial index measurement. There was a follow-up for cardiovascular death with a median (interquartile range) duration of 9.80 (8.75-10.40) years in the LURIC study and 7.06 (7.00-7.14) years in the getABI study. ANGPTL3/8 potently inhibited GPIHBP1-LPL activity and showed positive associations with LDL-C (low-density lipoprotein cholesterol) and triglycerides (both ANGPTL3/8 potently inhibited GPIHBP1-LPL enzymatic activity, consistent with its positive association with serum lipids. However, ANGPTL3/8, LDL-C, and triglyceride levels were not associated with cardiovascular death in the LURIC and getABI cohorts. In contrast, concentrations of ANGPTL4/8 and particularly CD-ANGPTL4 were positively associated with inflammation, the prevalence of diabetes, and cardiovascular mortality. 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
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup Show more
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup (KSS) significantly attenuated hepatic steatosis in rats. This study explored the main components of KSS and the mechanisms by which it exerts its protective effects against NAFLD. Twenty-four 6-week-old male Sprague-Dowley (SD) rats were randomly assigned to three treatments: feeding a normal standard diet, a high-fat diet, or a high-fat diet plus gavage KSS. The effects of KSS treatment on hepatic lipid accumulation were assessed using biochemical, histological, and molecular experiments. The amounts of KSS ingredients were measured using biochemical assays. Network pharmacology analyses were performed to identify the hub genes of KSS targets and enriched pathways. CCK-8 assay was used to determine the effect of free fatty acids (FFA), lycopene, and estrogen on HepG2 viability. Quantitative Real-Time polymerase chain reaction (qRT-PCR) and Western blot assays were performed to determine the effect of KSS or lycopene on estrogen signaling and expression of lipid metabolism-related molecules. Statistical analyses were performed using GraphPad Prism and SPSS. KSS alleviated fat deposition in rat liver tissue and affected the expression of hepatic lipid synthesis, catabolism, and oxidative molecules. Lycopene was identified as the ingredient with the highest amount in KSS. Network pharmacology analyses showed that the hub genes were enriched in the estrogen signaling pathway. Cellular experiments showed that lycopene increased the expression of Estrogen Receptor α (ERα), Carnitine palmitoyltransferase 1 A ( KSS ameliorated abnormal lipid metabolism in patients with NAFLD. Lycopene was the major component of KSS, and it affected estrogen signaling and the expression of lipid metabolism molecules. In short, both KSS and LYC could change lipid metabolism by lowering lipid accumulation and raising lipolysis. Show less