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
Apolipoprotein B (apoB) can be measured directly and accurately, and better predicts atherogenic risk than conventional lipid profiles. We aimed to investigate whether total and regional (trunk or leg Show more
Apolipoprotein B (apoB) can be measured directly and accurately, and better predicts atherogenic risk than conventional lipid profiles. We aimed to investigate whether total and regional (trunk or leg) fat deposits are associated with apoB levels in general US adults. 4585 participants were enrolled from the US National Health and Nutritional Surveys from 2011 to 2016. Overall and regional body fat were measured using dual-energy X-ray absorptiometry. The associations of total and regional fat with apoB levels were evaluated using linear regression models. Following adjustment for demographic, lifestyle, and clinical risk factors, whole-body fat percentage was positively associated with apoB levels. Additionally, percent trunk fat was positively associated (highest vs. lowest tertile beta = 17.73 for men and 14.89 for women, respectively), whereas percent leg fat was inversely associated (highest vs. lowest tertile beta = - 4.84 for men and - 6.55 for women, respectively) with apoB levels in both sexes. The association for trunk fat and leg fat remained significant after further adjustment for body mass index or waist circumference. Higher percent trunk fat combined with lower percent leg fat was associated with particularly higher apoB. In conclusion, among general US adults, both elevated trunk fat and reduced leg fat are associated with higher levels of apoB. Further research is required to elucidate the underlying pathophysiological mechanisms. 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
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
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
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
(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
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
D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in Show more
D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in breast cancer remains largely unexplored. We applied an advanced biosensor approach to detect the D-2HG levels in breast cancer samples. We then investigated the biological functions of D-2HG through multiple in vitro and in vivo assays. A joint MeRIP-seq and RNA-seq strategy was used to identify the target genes regulated by D-2HG-mediated N6-methyladenosine (m We found that D-2HG accumulated in triple-negative breast cancer (TNBC), exerting oncogenic effects both in vitro and in vivo by promoting TNBC cell growth and metastasis. Mechanistically, D-2HG enhanced global m Our study unveils a previously unrecognized role for D-2HG-mediated RNA modification in TNBC progression and targeting the D-2HG/FTO/m 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
Roshni Jaffery, Yuhang Zhao, Sarfraz Ahmed+11 more · 2025 · bioRxiv : the preprint server for biology · Cold Spring Harbor Laboratory · added 2026-04-24
Mutations in the Leucine-rich repeat kinase 2 ( We investigated the levels of soluble immune regulators in the serum (n=651) and cerebrospinal fluid (CSF, n=129) of In this extensive discovery cohort, Show more
Mutations in the Leucine-rich repeat kinase 2 ( We investigated the levels of soluble immune regulators in the serum (n=651) and cerebrospinal fluid (CSF, n=129) of In this extensive discovery cohort, we identified several elevated serum immune regulatory factors associated with This study highlights distinct immune profiles associated with LRRK2 mutations and PD in the periphery and CNS. Serum levels of SDF-1alpha and TNF-RII were elevated in LRRK2 mutation carriers, while CSF immune markers were reduced. In PD, irrespective of LRRK2 status, reduced CSF inflammatory analytes and weak serum signals were observed. These results provide insight into immune dysregulation linked to LRRK2 mutations. If replicable in independent datasets, they offer potential avenues for biomarker and therapeutic exploration. Show less
The balance between adipogenic and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is essential for maintaining bone homeostasis. This study aimed to investigate the role of r Show more
The balance between adipogenic and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is essential for maintaining bone homeostasis. This study aimed to investigate the role of retinoid-related orphan receptor α (RORα) in the adipogenic differentiation of BMSCs. Stable BMSC lines with RORα overexpression or knockdown were established. Adipogenic differentiation was evaluated using Oil Red O staining and by measuring the expression of adipogenic markers, including PPARγ2, LPL, LEP, FABP4, and ADIPOQ. Treatment with the RORα inhibitor SR3335 significantly promoted adipogenic differentiation, whereas the RORα agonist SR1078 exerted the opposite effect. Similarly, RORα-overexpressing (OE-RORα) BMSCs showed reduced adipogenic differentiation, while RORα knockdown BMSCs exhibited enhanced differentiation at 14 days after induction. During adipogenesis, PPARγ2 expression increased significantly, peaking at day 6 before gradually declining. Overexpression and knockdown of RORα accentuated this downregulation and upregulation, respectively, at days 6 and 12. The adipogenic marker genes lipoprotein lipase (LPL), leptin (LEP), fatty acid binding protein 4 (FABP4), and adiponectin C1Q and collagen domain containing (ADIPOQ) were markedly downregulated in RORα-overexpressing BMSCs at day 12. Moreover, RORα overexpression enhanced β-catenin nuclear translocation at day 1 post-induction and upregulated downstream WNT/β-catenin signaling molecules (Axin2, c-Myc, CD44) at day 6. Inhibition of WNT/β-catenin signaling with XAV-939 effectively reversed the suppressive effect of RORα overexpression on adipogenic differentiation and restored the expression of adipogenesis-related genes. RORα suppresses adipogenic differentiation of BMSCs, at least in part, by activating WNT/β-catenin signaling. Show less
Amyloid deposition of human islet amyloid polypeptide (hIAPP) is closely linked to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Developing effective inhibitors to suppress hIAP Show more
Amyloid deposition of human islet amyloid polypeptide (hIAPP) is closely linked to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Developing effective inhibitors to suppress hIAPP aggregation holds significant therapeutic potential for the prevention and treatment of T2DM. Recent researches indicate that both heme and lithospermic acid (LPA) can inhibit hIAPP aggregation. However, heme is prone to induce protein damage under oxidative stress, while LPA exhibits limited inhibitory efficacy despite its antioxidant properties. To overcome these limitations, we aimed to develop a dual-component inhibitor comprising heme and LPA. thioflavin T (ThT) fluorescence, transmission electron microscopy (TEM), circular dichroism (CD) and gel electrophoresis were combined to observe the inhibitory efficacy of heme-LPA co-formulation on hIAPP aggregation. The results demonstrate that LPA and heme can synergistically inhibit hIAPP aggregation. The inhibitory effect of heme-LPA co-formulation on hIAPP aggregation is significantly stronger than that of either component alone. The heme-LPA not only prevents the complete conversion of hIAPP into β-sheet fibrillar structures but also maintains its active monomeric conformation for extended periods. Furthermore, peroxidase activity assays revealed that the presence of LPA significantly reduces the peroxidase activity of heme in a concentration-dependent manner and attenuates peptide nitration damage under H₂O₂-NO₂ 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
Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were appr Show more
Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were approximately 20 million new cancer cases and 10 million cancer deaths worldwide. Amidst this global health concern, branched chain amino acids have emerged as key players, playing an important role in the occurrence and development of cancer. In certain malignancies like colorectal cancer, the average level of BCAA in tumor tissues is twice that in normal tissues. BCAA metabolism is intricately associated with the progression of multiple tumors and is modulated by diverse enzymes, including BCAT, BCKDH, and BCKDK. The metabolism of BCAA involves multiple enzymes and biochemical processes via signaling pathways such as PI3K/AKT/mTOR and AMPK/mTOR, etc. In addition, mTOR inhibitors show potential value in cancer treatment by regulating the metabolism and signaling pathways of tumor cells, which provides a new direction for anticancer efforts. Simultaneously, BCAAs are closely associated with tumor immunity, including NK cells, CD4 Show less
A crucial aspect of the association involving inflammation and the development of cancer is the ability of cancer cells to undergo a transition into mesenchymal cells. The process is referred to as ep Show more
A crucial aspect of the association involving inflammation and the development of cancer is the ability of cancer cells to undergo a transition into mesenchymal cells. The process is referred to as epithelial-mesenchymal transition (EMT). Cytokines and chemokines, which are inflammatory agents found in the carcinoma microenvironment, induce epithelial-mesenchymal transition (EMT) changes in malignant cells. Evaluating the role of cytokines in EMT in breast carcinoma and investigating their potential therapeutic implications is the objective of this comprehensive research report. The following search criteria were applied to the Cochrane, Embase, PubMed, and Web of Science databases: "cytokines," "the cytokines," "chemokines," "EMT," "epithelial-mesenchymal transition or transformation," "breast tumor," "breast carcinoma," and "breast cancer." A body of research comprising 54 articles has demonstrated that a number of cytokines, including TNF-α, TGF-β, and IL-6, contribute to the promotion of EMT alterations in breast tumors. The epithelial markers E-cadherin and β-catenin were downregulated as a consequence of morphological changes induced by EMT; conversely, the mesenchymal markers N-cadherin, vimentin, and fibronectin were upregulated. The EMT transforming factors (EMT-TF) TWIST/ZEB/SNAI1/SNAI2 were upregulated. Pharmaceuticals with the capacity to specifically target cytokines or their epithelial-mesenchymal transition (EMT) signalling pathways have the potential to significantly reduce treatment resistance, impede the progression of cancer, and prevent the recurrence of breast cancer. Epithelial-mesenchymal transition (EMT) induced by cytokines is a factor in breast cancer progression and metastasis. 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
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
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
To establish the reference interval for the serum lipid index in pregnant women and to explore the relationship between lipid metabolism levels and pregnancy outcomes. Data were derived from 446 pregn Show more
To establish the reference interval for the serum lipid index in pregnant women and to explore the relationship between lipid metabolism levels and pregnancy outcomes. Data were derived from 446 pregnancy women and 317 healthy non-pregnant women. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein (a) [Lp(a)], and hypersensitive C-reactive protein (hs-CRP) were measured in both groups. The mean and standard deviation of each index were calculated to establish the reference range of normal serum lipid levels in pregnant women in mid-to-late pregnancy. The associations between serum lipid levels and perinatal outcomes were assessed statistically. There were no significant differences in age, pregnancy, or parity between the adverse outcome and normal delivery groups, but the caesarean section rate was significantly higher in the adverse outcome group. The levels of hs-CRP, TG, TC, HDL-C, LDL-C, and ApoA1 were significantly higher in the adverse outcome group. Elevated hs-CRP, TG, and HDL-C levels were risk factors for adverse pregnancy outcomes. According to the receiver operating characteristic curve, the optimal threshold of the combined diagnosis of these three indicators to predict adverse pregnancy outcomes was 0.534, and the area under the curve was 0.822. The establishment of lipid reference intervals in the second and third trimesters of pregnancy can effectively evaluate lipid metabolism in pregnant women, and the measurement of lipid metabolism in pregnant women is helpful in predicting adverse pregnancy outcomes. 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