The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunc Show more
The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target. We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms-including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease-to dissect its tissue-specific pathophysiological impacts. The AMPK/SIRT1/PGC-1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC-1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease-specific mechanisms: promoting Aβ production via BACE1/γ-secretase in Alzheimer's; impairing α-synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF-β/Smad3 signaling. The AMPK/SIRT1/PGC-1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies-including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)-offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue-specific regulatory mechanisms, such as AMPK isoform diversity and PGC-1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders. Show less
Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understandin Show more
Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understanding of the genetic basis of HF and more specific NICM subtype in the East Asian populations and evaluate the biological pathways underlying subclinical left ventricular dysfunction. We conducted a meta-analysis of genome-wide association studies (GWAS) for all-cause HF in the East Asian populations (N cases ~ 13,385) and a more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (N cases~3,603). We identified a low-frequency East-Asian enriched coding variant near MYBPC3 and a NICM specific locus. Follow up analyses demonstrated male-specific HF association at the MYBPC3 locus, and highlighted SVIL as a candidate causal gene for NICM. Moreover, we demonstrated that SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. In addition, the gene expression level of B-type natriuretic peptide (BNP) which was deemed as a hallmark for HF was further elevated by SVIL silencing in PE-stimulated H9C2 cells. RNA-sequencing analysis of H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. These results enhance our understanding of the genetic architecture of HF in the East Asian populations, and provide important insight into the biological pathways underlying NICM and sex-specific relevance of the MYBPC3 locus that warrants further replication in another datasets. Show less
The contribution of glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling in brown adipose tissue (BAT) remains underexplored. We studied the acute effects of exogenous acyl-GIP (1 n Show more
The contribution of glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling in brown adipose tissue (BAT) remains underexplored. We studied the acute effects of exogenous acyl-GIP (1 nmol/kg) administration on whole-body lipid handling and fatty acid oxidation, using lipid tolerance tests (LTT) and indirect calorimetry, respectively. We demonstrate that in obese male mice, acute acyl-GIP administration improves lipid tolerance; however, pharmacological inhibition of GIPR, or genetic removal of GIPR globally or with the Myf5-Cre driver, completely abolishes GIP-mediated improvements in lipid tolerance, implicating GIPR in BAT. GIP-mediated improvements in lipid tolerance are associated with an increase in BAT lipid uptake, linked to increases in BAT lipoprotein lipase activity. Our data also reveal that BAT GIPR signalling is necessary for GIP-mediated increases in whole-body fatty acid oxidation, as Myf5-Cre: Gipr mice do not shift substrate oxidation upon GIP administration. Our findings suggest that BAT should be more closely considered in studies examining GIP's effects on whole-body metabolism in rodent models. Show less
Age-related Macular Degeneration (AMD) is widely acknowledged as a principal cause of vision loss in the elderly. Currently, the therapeutic interventions available in clinical practice fail to achiev Show more
Age-related Macular Degeneration (AMD) is widely acknowledged as a principal cause of vision loss in the elderly. Currently, the therapeutic interventions available in clinical practice fail to achieve satisfactory outcomes. Therefore, it is imperative that we approach the progress of AMD from novel perspectives in order to explore new therapeutic strategies. We obtained transcriptomic data from the macular and the peripheral retina from patients with AMD and a control group from the Gene Expression Omnibus (GEO) database. Through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we identified differentially expressed genes (DEGs) that were significantly enriched in functions associated with ferroptosis. Subsequent application of machine learning techniques enabled the identification of key hub genes, whose diagnostic potential was further validated. Additionally, the expression of these hub genes was corroborated in both animal and cellular models. Finally, we performed a functional enrichment analysis of these hub genes. In the macula of patients with AMD, 452 DEGs were identified, while in the peripheral retina, 222 DEGs were discovered. Within the macula, 19 genes were associated with ferroptosis, compared to 3 in the peripheral retina. Consequently, the macular was selected as the primary focus of the study. Subsequent screening of these 19 genes using LASSO regression, Support Vector Machine (SVM), and Random Forest algorithms identified four hub genes: FADS1, TFAP2A, AKR1C3, and TTPA. Consequently, we utilized cigarette smoke extract (CSE) to either stimulate retinal pigment epithelial (RPE) cells in vitro or administer it via intravitreal injection, thereby establishing in vitro and in vivo models of AMD. Results from RT-PCR and Western blot analyses revealed an upregulation of FADS1, AKR1C3, and TTPA, while TFAP2A exhibited decreased expression. Finally, we investigated the infiltration of immune cells within the macular and performed a functional enrichment analysis of the hub genes. We identified four key ferroptosis-related genes (FRGs)-FADS1, AKR1C3, TFAP2A, and TTPA-that possess diagnostic relevance for AMD and correlate with immune cell infiltration. Moreover, significant changes in both mRNA and protein expression levels of these genes have been observed in in vitro experiments and mice models. Show less
We have designed the first antigen-less pro-vaccine, named 8206, for treating autoimmune diseases. Composed of dexamethasone, rapamycin, and R848 at a mass ratio of 8:20:6, 8206 is a complete toleroge Show more
We have designed the first antigen-less pro-vaccine, named 8206, for treating autoimmune diseases. Composed of dexamethasone, rapamycin, and R848 at a mass ratio of 8:20:6, 8206 is a complete tolerogenic adjuvant that acts systemically to form an active vaccine in situ with endogenous pathogenic autoantigens. This active vaccine suppresses autoimmunity by expanding antigen-specific Treg cells in affected tissues. In a mouse model of atherosclerosis, 8206 successfully targeted all three analyzed pathogenic autoantigens (ApoB, HSP60, and HMGB1) and inhibited disease progression. These findings suggest that 8206 can potentially serve as a universal treatment vaccine for autoimmune diseases by eliminating the need for exogenous immunogens, with implications for broad applications in immunotherapy. Show less
In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a de Show more
In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a dearth of systematic research in this field. BEAS-2B cells were used to establish a cell model with continuous passaging after radiation exposure, which was subsequently subjected to in vivo tumorigenesis assays and in vitro malignant phenotype experiments. By scRNA-seq, we conducted copy number variation analysis, cell trajectory analysis, and cell communication analysis. Furthermore, we used FACS, molecular docking, multiplex immunohistochemistry, qRT-PCR, and co-immunoprecipitation to validate and further explore the molecular mechanisms driving tumor evolution. Long-term low dose-rate exposure is associated with a higher degree of malignancy, as evidenced by the induction of more CNV and EMT events, as well as the delayed activation of DNA repair pathways, which trigger increased genomic instability. The long-term low dose-rate specific ligand-receptor pair, ANGPTL4-SDC4, enhances cell malignancy by promoting angiogenesis in newly formed lung tumor cells. This study not only provides the first evidence and mechanistic explanation that long-term low dose-rate radiation leads to increased cellular malignancy but also offers valuable theoretical insights into the dynamic processes of early tumor evolution in lung cancer within the realm of tumor biology. Show less
By various assessments, the previous study has unequivocally concluded functional apoB and MTTP (microsomal triglyceride transfer protein) for VLDL production in chicken ovaries. The present study sou Show more
By various assessments, the previous study has unequivocally concluded functional apoB and MTTP (microsomal triglyceride transfer protein) for VLDL production in chicken ovaries. The present study sought to use whole tissue culture to define the role of VLDL secretion by small yellow follicles (SYFs) along their development under normal and heat stress (HS) conditions. Under thermoneutral conditions (39 °C), chicken SYFs increased MTTP activity, apoB expression and VLDL secretion, while underwent cell apoptosis along the time course. Despite relieved ER stress and protein ubiquitinylation, inhibition of VLDL secretion by Lomitapide and Mipomersen greatly increased triglyceride accumulation, impaired estradiol production and cell proliferation, and accelerated cell apoptosis in accordance with upregulated caspase 3/7 activity, JNK activation, protein carbonylation, and MDA accumulation. Exposure to HS at 44 °C boosted cell apoptosis in a duration-dependent manner. Acute HS for 3 h enhanced VLDL secretion, impaired estradiol production and cell proliferation, and promoted IL-1b production, oxidative damages, and cell apoptosis, whereas except MDA content and cell proliferation, the detrimental effects were halted after 13 h recovery. Lomitapide and Mipomersen augmented lipid accumulation, oxidative stress, inflammatory response, and exacerbated transient impairment of estradiol secretion and cell proliferation in SYFs under 3 h HS and after recovery, but failed to rescue cell viability despite relieved ER and proteostatic stress. In conclusion, routine secretion of VLDL by SYFs serves as an intrinsic mechanism to sustain cell viability and functions to support the whole program required for follicle development, while under HS, this mechanism provisionally rescues steroidogenesis and cell proliferation. Show less
Atherosclerosis, a progressive inflammatory disease and the leading cause of cardiovascular disease (CVD), remains a global health burden due to the lack of effective early therapeutic interventions. Show more
Atherosclerosis, a progressive inflammatory disease and the leading cause of cardiovascular disease (CVD), remains a global health burden due to the lack of effective early therapeutic interventions. Although growing evidence highlights the involvement of plasma proteins in atherogenesis, their causal contributions to disease pathogenesis are poorly understood. To address this gap, we conducted a proteome-wide Mendelian randomization (MR) analysis using cis-pQTLs (cis-protein quantitative trait loci) from the deCODE and UKB-PPP cohorts (~90,000 individuals) as instrumental variables. We integrated colocalization analysis, summary-data-based MR (SMR), and HEIDI tests to systematically prioritize causal plasma proteins. Key findings were replicated in the CARDIOGRAMplusC4D (coronary artery disease, CAD) and FinnGen (CVD) cohorts. Functional validation was performed through phenome-wide association studies (PheWAS), single-cell transcriptomics, histological staining, and ELISA assays to characterize protein expression patterns in specific cell types and tissues. Among 2,711 plasma proteins analyzed, 28 showed strong genetic associations with atherosclerosis. Of these, five proteins (ADK, ANGPTL4, CD4, MGAT1, SYT11) met strict validation criteria through colocalization (posterior probability of colocalization, PP.H4 > 0.8) and SMR. Subsequent replication using MR and PheWAS further confirmed the causal roles of ADK, CALB2, and COMT in CAD and other CVD outcomes. Notably, CALB2 was specifically enriched in mast cells within atherosclerotic plaques and adipose tissue, and plasma levels were significantly elevated in patients with severe carotid artery stenosis (CAS). This study identifies 28 novel therapeutic targets for atherosclerosis using a rigorous multi-omics approach. Our findings establish CALB2 as a promising biomarker and therapeutic target, particularly in severe CAS, by linking genetic evidence to cell-type-specific expression and clinical phenotypes. These insights pave the way for precision medicine approaches in the prevention and treatment of CVD. The online version contains supplementary material available at 10.1186/s12967-025-07269-6. Show less
Colorectal cancer (CRC) metastasis remains a major cause of mortality, driven by epithelial-to-mesenchymal transition (EMT) and invasion. Programmed cell death 4 (Pdcd4), a tumor suppressor, is known Show more
Colorectal cancer (CRC) metastasis remains a major cause of mortality, driven by epithelial-to-mesenchymal transition (EMT) and invasion. Programmed cell death 4 (Pdcd4), a tumor suppressor, is known to inhibit translation via interaction with eukaryotic initiation factor 4A (eIF4A). Previous studies have established that Pdcd4 suppresses stress-activated protein kinase 1-interacting protein 1 (Sin1) translation through the mTORC2-Akt axis, thereby downregulating Snail expression and EMT in CRC cells. However, whether Pdcd4 directly regulates Slug, another critical EMT transcription factor, remains unexplored. PDCD4 shRNA and SLUG siRNA were used to knock down Pdcd4 and Slug in colorectal cancer cells, respectively. The sucrose gradient fractionation was performed to determine SLUG translation. A luciferase reporter assay was used to determine the role of the SLUG 5' untranslated region (5'UTR) on Pdcd4 inhibition. The effect of Slug on promoting invasion was determined by Matrigel invasion assays. Knockdown of Pdcd4 in colorectal cancer cells increased Slug protein levels without altering SLUG mRNA abundance. Sucrose gradient fractionation revealed that Pdcd4 knockdown elevated the proportion of SLUG mRNA in polysome fractions, demonstrating Pdcd4-mediated suppression of SLUG translation. To validate the mechanism, the SLUG 5'UTR was cloned and fused to a luciferase reporter and named SLUG-5'UTR-Luc. Pdcd4 knockdown markedly enhanced SLUG-5'UTR-Luc activity; whereas, ectopic Pdcd4 expression suppressed it, indicating that the SLUG 5'UTR is critical for Pdcd4-mediated translational repression. Treatment with the eIF4A inhibitor silvestrol substantially reduced Slug protein levels and SLUG-5'UTR-Luc activity. In addition, Pdcd4 overexpression decreased Slug protein abundance and restored E-cadherin expression. Notably, Slug knockdown in Pdcd4-deficient cells rescued E-cadherin expression and abrogated the invasive phenotype. These findings suggest that up-regulation of Slug translation by Pdcd4 knockdown contributes to enhanced invasion. Pdcd4 suppresses colorectal cancer invasion by translationally downregulating Slug expression. Show less
To investigate the role and mechanism of the SREBP1/SNAI1 signalling pathway in the effect of brexpiprazole on the EMT and metastasis of CRC. The effects of different concentrations of brexpiprazole o Show more
To investigate the role and mechanism of the SREBP1/SNAI1 signalling pathway in the effect of brexpiprazole on the EMT and metastasis of CRC. The effects of different concentrations of brexpiprazole on cell migration, cell invasion and protein expression Brexpiprazole significantly inhibited the migration and invasion of CRC cells; downregulated the expression of SREBP1(m), SNAI1 and MMP9; upregulated the expression of E-Cad and ZO1; and decreased the levels of secreted ICAM-1 and VEGF in the supernatant of CRC cells. Western blotting and dual-luciferase assays revealed that SREBP1 could directly regulate the expression of SANI1. On the other hand, Brexpiprazole inhibits the migration, invasion and metastasis of CRC cells by inhibiting the SREBP1/SNAI1 signalling pathway and downregulating the expression of EMT-related factors. Show less
Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctori Show more
Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctorius exhibit multi-target anti-AS potential, yet their compositional complexity limits clinical translation. This study aimed to systematically identify core anti-AS components from these herbs and enhance their anti-AS efficacy via machine learning-aided screening and nanotechnology-driven codelivery. We initially pioneered a machine learning-aided hybrid strategy integrating network pharmacology and quantitative activity relationship (QSAR) modeling to identify four core anti-AS polyphenols (i.e., salvianic acid A, salvianolic acid B, protocatechuic acid, and hydroxysafflor yellow A). Subsequently, a quaternary metal-phenolic network (SSPH-MPN) was engineered for plaque-targeted codelivery, optimized via the median-effect principle for achieving a synergistic effect based on ROS scavenging efficacy. The optimized SSPH-MPN was characterized by a series of studies, including molecular dynamics simulations, UV, DLS, TEM, FTIR, XPS, and ICP-MS. The anti-AS effect of the optimized SSPH-MPN was evaluated by monitoring oxidative status (ROS levels, antioxidant enzymes SOD, GSH-Px, MDA, T-AOC), inflammatory markers (IL-1β, IL-6, TNF-α), lipid metabolism (DiI-oxLDL uptake, cholesterol efflux, blood lipid levels, lipid accumulation), and plaque areas. The results demonstrated that the optimized SSPH-MPN showed great efficiency in inhibiting lipid uptake and accumulation, and mediating cholesterol efflux in RAW 264.7 cells, and exhibited improved lipid metabolism, attenuated oxidative stress and inflammation, thus acquired diminished plaque area in apoE Show less
We report a diagnostically challenging case of acute myeloid leukemia (AML) in a 2-year-9-month-old boy, presenting with diarrhea and pancytopenia. Bone marrow aspiration revealed 90% blasts exhibitin Show more
We report a diagnostically challenging case of acute myeloid leukemia (AML) in a 2-year-9-month-old boy, presenting with diarrhea and pancytopenia. Bone marrow aspiration revealed 90% blasts exhibiting cup-like nuclei and azurophilic granules, morphologically mimicking acute promyelocytic leukemia (APL).However, immunophenotyping was inconsistent with classic APL, showing positivity for CD33 and cytoplasmic myeloperoxidase (cMPO) but negativity for CD34 and HLA-DR. Molecular analysis was negative for the canonical PML::RARA fusion but identified a rare Show less
This study aims to elucidate the effects of arecaidine on oral mucosa through RNA sequencing (RNA-Seq) combined with in vivo and in vitro experimental validation. Based on transcriptomic analysis, we Show more
This study aims to elucidate the effects of arecaidine on oral mucosa through RNA sequencing (RNA-Seq) combined with in vivo and in vitro experimental validation. Based on transcriptomic analysis, we preliminarily explored the molecular targets and mechanisms by which arecaidine influences oral mucosa. Subsequent validation was performed using arecaidine-treated human primary oral mucosal fibroblasts. In vivo experiments revealed that the arecaidine-treated group exhibited significantly restricted oral cavity opening compared to the control group, with markedly reduced mouth-opening values. Histopathological analysis via HE staining and Masson staining demonstrated fibrotic lesions in the arecaidine-treated group. RNA-Seq libraries constructed from oral mucosal tissues identified 100 significantly differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that arecaidine influenced multiple pathways, including autoimmune thyroid disease, allograft rejection, type I diabetes, graft-versus-host disease, and the PPAR-γ signaling pathway. Notably, arecaidine significantly downregulated PPAR-γ, PCK1, pdk4, plin5, Hmgcs2, UCP3, and Angptl4, while upregulating TGF-β1, FOS, and other genes associated with the PPAR pathway. In vitro experiments confirmed that arecaidine induced substantial damage to fibroblasts, suppressing proliferation and promoting the secretion of inflammatory cytokines (e.g., IL-6, TGF-β, TNF-α) after 48 h exposure to high concentrations. Furthermore, arecaidine significantly altered the expression of molecules linked to the PPAR-γ signaling pathway. This study delineates the transcriptomic response of oral mucosa to arecaidine through integrated in vivo and in vitro experiments, confirming its role in inducing submucosal fibrosis. The underlying mechanism is associated with dysregulation of the PPAR-γ signaling pathway. Show less
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from Show more
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies. Show less
Scatophagus argus is a highly valuable aquaculture fish. Its artificial breeding faces problems in the induction of high quality eggs, thus necessitating studies on the regulation of ovarian developme Show more
Scatophagus argus is a highly valuable aquaculture fish. Its artificial breeding faces problems in the induction of high quality eggs, thus necessitating studies on the regulation of ovarian development. As the centre of nutrient metabolism in fish, the liver provides the material basis for ovarian development. However, the molecular mechanism of the liver in ovarian development in S. argus is still unclear. In this study, a transcriptome analysis of adult S. argus livers at different stages of ovarian development (stages II, III and IV) was performed. 410, 1025 and 1867 differentially expressed genes (DEGs) were obtained between stages II and III, stages II and IV and stages III and IV, respectively. In GO and KEGG analyses, DEGs were mostly involved in vitellogenesis and egg envelope formation (e.g., erα, erβ1, vtga, vtgb, vtgc, zp3, zp4a and zp4b), lipid metabolism and energy metabolism (e.g., dagt1, dagt2, lpl, apob, hk1, acly, ogdh, pc, and fbp1), and hormone signaling (e.g., lepa and igfbp1). Additionally, genes that were significantly upregulated in the liver at stage IV of ovarian development, compared to stages II and III, were markedly enriched in steroid biosynthesis and metabolism pathways. These findings provide clues to understanding the mechanisms of liver action in teleost ovarian development. Show less
Atherosclerosis (AS) is a chronic inflammatory disorder driven by dysregulated lipid metabolism and remains a leading cause of cardiovascular morbidity. The Shen-Hong-Tong-Luo (SHTL) preparation has d Show more
Atherosclerosis (AS) is a chronic inflammatory disorder driven by dysregulated lipid metabolism and remains a leading cause of cardiovascular morbidity. The Shen-Hong-Tong-Luo (SHTL) preparation has demonstrated clinical benefit in stabilizing atherosclerotic plaques, yet its molecular mechanisms are not fully defined. This research sought to elucidate the protective effects exerted by SHTL on AS progression. To investigate the impact of SHTL on macrophage function and plaque stability, we utilized ApoE SHTL markedly attenuated the progression of AS, demonstrated by reduced plaque formation within both the aortic root and aorta, diminished plasma lipid concentrations, and suppressed inflammatory responses. SHTL demonstrates significant anti-inflammatory and lipid-regulatory effects, attenuating AS progression through the PPARγ/Mfge8 pathway, thereby enhancing macrophage efferocytosis. These findings highlight a novel mechanism by which SHTL may contribute to preventing and treating atherosclerotic diseases. Show less
Acute respiratory distress syndrome (ARDS) is a lung inflammatory condition associated with the accumulation of fluid edema and cell infiltrates into the alveolar space along with dysregulation of the Show more
Acute respiratory distress syndrome (ARDS) is a lung inflammatory condition associated with the accumulation of fluid edema and cell infiltrates into the alveolar space along with dysregulation of the immune response. Current therapeutics are limited to palliative care, i.e., mechanical ventilators, thus highlighting the need to develop targeted therapeutic for ARDS. Interleukin-27 (IL-27) is a multifunctional cytokine with the capability for immune modulation. Our interest lies in exploring the properties of IL-27, particularly as an anti-inflammatory cytokine that functions as an antagonist of IL-6 signaling, as an inducer of anti-viral genes, as a promoter of tissue repair, and as a regulator of both the innate and adaptive immune responses, possessing promising potential as a therapeutic for ARDS. To overcome the challenge of repeated administration due to the short half-life of cytokines, we utilized a cell-based gene therapy approach. An IL-27-expressing plasmid was transfected into adipose mesenchymal stromal cells (ASC) that serve as the gene therapy carriers. For in vitro studies, we treated mono- and co-culture lung lipopolysaccharide (LPS)-induced lung epithelial and monocytes/macrophages cell line with IL-27-expressing ASC (IL-27 ASC) conditioned media (CM) to determine the effects on pro-inflammatory gene expression. For in vivo studies, male C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) and treated either PBS, ASC, or IL-27 ASC (5 × 10 IL-27 ASC CM reduced pro-inflammatory gene expression of lung epithelial and macrophages cultured in both mono- and co-culture systems. Additionally, IL-27 ASC were able to reduce pro-inflammatory markers, decrease cell infiltration into the lungs, promote genes and immune cells involved in tissue repair, and rebalance innate and adaptive immunity in an LPS-induced in vivo model. Collectively, our in vitro and in vivo results show promising potential for IL-27 cell-based gene therapy as a treatment for ARDS. Show less
Ttraumatic brain injury (TBI) induces oxidative stress, which contributes to neuronal damage and cognitive impairment. Apolipoprotein E (ApoE) plays a key role in neural repair and may modulate oxidat Show more
Ttraumatic brain injury (TBI) induces oxidative stress, which contributes to neuronal damage and cognitive impairment. Apolipoprotein E (ApoE) plays a key role in neural repair and may modulate oxidative stress responses. However, the relationship between ApoE expression at different stages after TBI and oxidative stress markers, as well as its association with cognitive outcomes, remains unclear. A total of 126 patients with TBI were prospectively enrolled and stratified according to the Glasgow Coma Scale (GCS) score on admission into mild ( Serum ApoE levels peaked at 24 h and slightly decreased thereafter, with overall levels increasing in proportion to TBI severity ( ApoE exhibits an injury-severity-dependent increase during the early stage of TBI, and its levels are closely associated with oxidative stress imbalance and cognitive impairment. These findings suggest that ApoE may play a critical role in both the pathological progression and neural repair following TBI. Show less
Angiopoietin-like proteins (ANGPTLs) represent a family of secreted glycoproteins that are extensively expressed in vivo and are integral to various pathophysiological processes, including glucose and Show more
Angiopoietin-like proteins (ANGPTLs) represent a family of secreted glycoproteins that are extensively expressed in vivo and are integral to various pathophysiological processes, including glucose and lipid metabolism, stem cell proliferation, local inflammation, vascular permeability, and angiogenesis. Particularly interesting is ANGPTL4, which has been identified as a significant factor in the development and progression of diabetic retinopathy (DR), thus becoming a central focus of DR research. ANGPTLs modulate metabolic pathways, enhance vascular permeability, and facilitate pathological angiogenesis, in addition to causing intraocular inflammation. As promising molecular targets, ANGPTLs not only serve as biomarkers for predicting the onset and progression of DR but also present therapeutic potential through antibody-based interventions. This paper discusses the pathogenesis of DR and the potential applications of ANGPTLs in early diagnosis and targeted therapy. It provides references for advancing precision diagnosis and personalized treatment strategies through more profound ANGPTLs research in the future. 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
This study aims to establish a hypoxia-immune-related gene signature within the tumor microenvironment (TME) to reliably predict prognosis in non-small cell lung cancer (NSCLC). Transcriptomic profile Show more
This study aims to establish a hypoxia-immune-related gene signature within the tumor microenvironment (TME) to reliably predict prognosis in non-small cell lung cancer (NSCLC). Transcriptomic profiles and clinical data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases (GSE74777, GSE68465). Hypoxia- and immune-related genes were curated from MSigDB, ImmPort, and INATDB. Prognostic genes were identified via Cox and LASSO regression analyses, and a risk model was constructed. Model validity was assessed through Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, and external validation. An eight-gene prognostic signature (AKAP12, MT2A, SERPINE1, CD1E, CD79A, CXCL13, XCL2, ANGPTL4) was established. The model demonstrated significant predictive accuracy for NSCLC survival (AUC: 0.643/0.649/0.620 at 1/3/5 years in TCGA cohort). Patients with high immune activity exhibited superior survival outcomes compared to those with low-immune counterparts (log-rank P < 0.001). Multivariate Cox regression confirmed the risk score as an independent prognostic factor (HR = 1.82, 95% CI: 1.44-2.30, P < 0.001). The hypoxia-immune microenvironment signature serves as a robust prognostic classifier for NSCLC, providing a quantitative framework for personalized risk stratification and clinical decision support. Show less
Given the lack of evidence, we cannot definitively determine the relationship between attachment networks and problematic mobile phone use, hindering effective intervention strategies. Therefore, a th Show more
Given the lack of evidence, we cannot definitively determine the relationship between attachment networks and problematic mobile phone use, hindering effective intervention strategies. Therefore, a three-wave longitudinal study was designed to explore the heterogeneity of parent-child attachment networks using latent profile analysis (LPA) and random intercept latent transition analysis (RI-LTA). Participants included 2116 adolescents (ages 14-21; 53.8% girls). Results identified five stable parent-child attachment network profiles, each showing moderate but decreasing stability. Notably, adolescents who were grouped into an attachment network characterized by secure maternal attachment but insecure paternal attachment, similar to those in attachment networks with both insecure maternal and paternal attachment, scored higher levels of problematic mobile phone use than those who were grouped into attachment networks with both secure maternal and paternal attachment. Our findings fill empirical gaps and provide strong evidence supporting attachment-based interventions to reduce problematic mobile phone use. Show less
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathologic Show more
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV) or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits. Show less
Cardiac hypertrophy as one of the major predisposing factors for chronic heart failure lacks effective interventions. It has been shown that protein ubiquitination plays an important role in cardiac h Show more
Cardiac hypertrophy as one of the major predisposing factors for chronic heart failure lacks effective interventions. It has been shown that protein ubiquitination plays an important role in cardiac hypertrophy. SMURF2 (SMAD-specific E3 ubiquitin ligase 2) is an important member of NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) family of HECT E3 ubiquitin ligases. In this study we investigated the regulatory role of SMURF2 in cardiac hypertrophy. Experiment models were established in mice by transverse aortic constriction (TAC) in vivo, as well as in neonatal rat cardiomyocytes (NRCMs) by treatment with angiotensin II (Ang II, 1 μM) in vitro. We showed that the expression levels of SMURF2 were significantly elevated in cardiac tissues from patients with cardiac hypertrophy and the two experiment models. In NRCMs, SMURF2 knockdown or treatment with a specific SMURF2 inhibitor heclin (8 μM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, evidenced by reduced mRNA levels of Anp, Bnp and β-Mhc as well as cell surface. Prophylactic or therapeutic administration of heclin (10 mg·kg 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
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompl Show more
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less
The feeding rhythm is a major temporal regulator of metabolic physiology, yet its impact on microbiome-derived functional traits relevant to cardiometabolic disease remains insufficiently understood. Show more
The feeding rhythm is a major temporal regulator of metabolic physiology, yet its impact on microbiome-derived functional traits relevant to cardiometabolic disease remains insufficiently understood. Our previous work demonstrated that ad libitum, daytime-restricted, and nighttime-restricted feeding produce markedly different atherosclerotic outcomes in Apoe 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
Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion Show more
Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion (I/R) injury, and the related mechanisms are unclear. Our previous study has shown that adipose stem cell-derived exosomes (ADSC-Exos) contain high levels of Show less