👤 Hanting Xu

Retinal degenerative diseases (RDDs) cause irreversible vision loss with limited treatment options. Traditional Chinese medicine (TCM) formulas have demonstrated neuroprotective effects, yet their overall efficacy lacks comprehensive meta-evidence. The aim of this study was to exploratively evaluate the neuroprotective effects of TCM formulas in animal RDD models. A comprehensive literature search was conducted across eight electronic databases to identify animal studies that evaluated the neuroprotective effects of TCM formulas on RDDs. Pairwise meta-analysis and Bayesian network meta-analysis (NMA) were performed to synthesize evidence on key outcomes: neural growth, glial activation, oxidative stress, apoptosis factors, and ophthalmological parameters. Treatment rankings were assessed using the surface under the cumulative ranking curve (SUCRA). Twenty-four studies were included. The compositions and bioactive compounds of the TCM formulas have been defined and identified. Pairwise meta-analysis demonstrated that specific TCM formulas might exert neuroprotective effects on RDDs by regulating key biomarkers. Specifically, Zhen-Bao-Wan, Bu-Shen-Yi-Jing-Fang, and Qi-Shen-Yi-Qi pills modulated neural growth and glial activation by upregulating BDNF, CNTF, and reducing GFAP, respectively. Furthermore, Yi-Qi-Wen-Yang-Tong-Luo decoction, Zi-Yin-Ming-Mu decoction, and Yishi-Tablet suppressed oxidative stress and apoptosis by reducing SOD, retinal apoptotic cells and caspase-3, respectively. Additionally, Bu-Yang-Huan-Wu decoction improved retinal function by elevating ERG-a and ERG-b wave amplitudes. Subgroup analyses indicated that Bu-Yang-Huan-Wu decoction and Qu-Yu-Tong-Luo prescription exhibited superior efficacy in restoring retinal ganglion cell (RGC) counts and retinal thickness in specific RDD models. The NMA results indicated that the included TCM formulas exhibited target-specific and dose‒response trends, with different formulas showing preferential efficacy for distinct biomarkers. Given the limitations identified in this study, these findings should be interpreted as preliminary evidence to guide future research rather than as conclusive results. Future studies with rigorous experimental designs are needed to address these limitations and enhance translational relevance. This study provides preclinical and exploratory evidence that the included TCM formulas might exert neuroprotective effects on animal models of RDDs by modulating glial activation, promoting neuronal growth, and inhibiting oxidative stress and apoptosis. Additional high-quality preclinical studies are essential to validate these effects and inform future clinical translation. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251002491 identifier CRD420251002491. Show less

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focused on mild CP models (unilateral carotid artery occlusion [UCAO] model). This study explored the effect and mechanism of hUC-MSCs in a rat model of moderate-to-severe CP (bilateral carotid artery occlusion [BCAO] model). On postnatal Day 4 (P4), Wistar rat pups underwent BCAO induction. Subsequently, they received either a single intrathecal injection of hUC-MSCs on P21 or repeated injections on P21, P28, P35, and P42. Motor performance was assessed using the rotarod and front-limb suspension tests, while neuronal regeneration and inflammation were evaluated via biomarkers including neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and brain-derived neurotrophic factor (BDNF). P18 model screening confirmed that the BCAO model resulted in more severe brain damage and motor impairment than the UCAO model. After injection of lentivirally transfected hUC-MSCs, it was found that hUC-MSCs could nest in the damaged area and survive for at least 3 days. Administration of hUC-MSCs following BCAO modeling led to notable improvements in both behavioral performance and histological outcomes. Furthermore, repeated injections offered greater therapeutic benefits compared to single injection. It indicated that the efficacy of repeated injections of hUC-MSCs in the treatment of moderate-to-severe CP was superior to that of single injection. Its mechanism was related to the improvement of damaged myelin structure, reduced immunoinflammatory responses, and increased neurotrophic support. Show less

ObjectivesThis study aimed to compare the effects of different exercise interventions on brain-derived neurotrophic factor (BDNF) levels in patients with neurodegenerative diseases and to explore regulatory factors.MethodsSearched PubMed, Scopus, Web of Science Core Collection, CNKI and Cochrane Library databases up to March 15, 2025. Bayesian network meta-analysis was conducted using R software, and meta-regression analyzed the moderating effects of training period and frequency.Results42 randomized controlled trials covering 1482 patients were included. The Surface Under the Cumulative Ranking (SUCRA) indicated that stretching training (SUCRA = 78.92) and high-intensity interval training (SUCRA = 69.73) were ranked higher than other exercise modalities and exhibited more favorable effect on BDNF enhancement, although neither demonstrated statistically significant superiority over the blank control. In contrast, combined training (SUCRA = 35.58), aerobic training (SUCRA = 35.17), and resistance training (SUCRA = 12.98) showed relatively lower potential for BDNF enhancement (blank control SUCRA = 67.62). Meta-regression analysis showed that the effect of combined training was significantly and positively correlated with intervention period ( Show less

Post-stroke cognitive impairment (PSCI) is a prevalent and disabling condition with limited effective treatment options. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential non-invasive neuromodulation therapy. This review synthesizes recent advances in rTMS for PSCI, focusing on its mechanisms, therapeutic effects across cognitive domains, and safety profile. We summarize evidence indicating that rTMS exerts its effects by modulating cortical excitability, promoting neuroplasticity via BDNF signaling, and regulating dysfunctional brain networks, particularly the central executive and default mode networks. Clinical studies demonstrate that high-frequency stimulation, primarily targeting the dorsolateral prefrontal cortex (DLPFC), can significantly improve memory, executive function, attention, and activities of daily living (ADLs) in patients with PSCI. A favorable safety profile is reported, with mild and transient adverse effects being most common. However, significant heterogeneity in stimulation parameters (e.g., frequency, intensity, pulses) exists across studies. Current evidence suggests that ensuring a sufficient number of stimulation pulses and duration may be necessary. rTMS represents a promising therapeutic tool for PSCI, demonstrating benefits in key cognitive and functional domains. Future research must prioritize large-scale, standardized randomized controlled trials to optimize stimulation protocols, confirm long-term efficacy, and explore synergistic combinations with other rehabilitation strategies. Show less

G protein-coupled receptors (GPCRs) are transmembrane receptors that regulate intracellular signaling by interacting with G proteins and other effectors, influencing various physiological processes. The Glucose-dependent Insulinotropic Polypeptide Receptor (GIPR), a class B1 GPCR family member activated by GIP, regulates postprandial glycaemia by augmenting glucose-dependent insulin secretion, delaying gastric emptying, and suppressing appetite. Recent studies highlight the transmembrane domain (TMD) as the primary interface for dimerization, allowing GPCR to form homodimers or heterodimers with distinct physiological roles. However, the transient nature of these dimers challenges structural analysis, hindering experimental exploration and drug development. Computational methods now offer powerful tools for predicting such interactions. This study employs a hybrid approach, combining multiple protein docking software and dynamic structural optimization, to generate potential homodimeric models of GIPR-TMD. In addition, Next, validated models will provide insights into dimer activation mechanisms and support novel therapeutic discoveries. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally, yet it lacks any approved pharmacological therapies. Dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have shown clinical promise, but their causal effect on MASLD remains unestablished. This study uses genetic evidence to evaluate the causal role of dual GLP-1R/GIPR agonists on MASLD and to explore its underlying mechanisms. Using a novel approach combining Mendelian randomization (MR) and Bayesian colocalization, we constructed a high-confidence genetic proxy for dual GLP-1R/GIPR agonists based on five genetic variants strongly associated with both mRNA expression and HbA1c levels. We then performed two-sample MR to assess the causal effect of this genetically proxied effect on MASLD and related metabolic risk abnormalities. Genetically proxied dual GLP-1R/GIPR agonists was causally associated with a substantially reduced risk of MASLD (OR: 0.24, 95 % CI: 0.08-0.75, P = 0.01). This protective effect was accompanied by significant improvements in systemic metabolic health, including increased high-density lipoprotein cholesterol (Beta: 0.39, 95 % CI: 0.13-0.66, P = 3.40 × 10 This study provides causal evidence that dual GLP-1R/GIPR agonists protects against MASLD. The mechanism likely involves broad improvements in lipid metabolism and insulin sensitivity. These findings offer strong genetic validation for this therapeutic strategy and provide a compelling rationale for its continued clinical development for the treatment of MASLD. Show less

In this study, to achieve more effective blood sugar lowering and weight-loss effects, eight glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic peptide (GIP)/glucagon (GCG) triple receptor agonists were designed and synthesized. Their sixteen related conjugates were obtained through Cys alkylation and Lys esterification modifications with two fatty acid side chains, respectively. After chemical structure confirmation using high-resolution mass spectrometry and peptide mapping, in vitro and in vivo biological effects of TRA01-24 were assessed. The structure-activity relationship (SAR) data on the amino acids, fatty acids, linkers and biological effects in vitro and in vivo of TRA01-24 have been summarized. Furthermore, peptide-protein molecular docking elucidated the structural basis for the biased agonist activity of TRA22 at GLP-1R, characterized by strong GLP-1R activation but weak GCGR and GIPR activation. In conclusion, a lead compound with excellent efficacy in vitro and in vivo, TRA24, was screened, which had better in vivo efficacy than tirzepatide in both normal and db/db mice. 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-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

Unimolecular multireceptor coagonists have emerged as a promising approach in the development of next-generation GLP-1 therapeutics. Herein, we describe the development of a long-acting and stapled GLP-1R/GIPR/GCGR triple agonist that exhibits balanced bioactivities comparable with those of their native ligands along with improved pharmacokinetic parameters. A robust and straightforward solid-phase Ugi macrocyclization strategy enables the facile synthesis of targeted peptides with a side-chain protractor attached on the exocyclic lactam bridge. In obese mice, the lead candidate UTG-4 demonstrates enhanced efficacy in promoting weight loss, suppressing food intake, and improving glucose tolerance and liver health compared to the clinically approved GLP-1R monoagonist semaglutide and GLP-1R/GIPR dual agonist tirzepatide. UTG-4 also exhibits remarkable antiatherosclerotic effects in the Show less

Angiogenesis, a meticulously regulated process essential for both normal development and pathological conditions, necessitates a comprehensive understanding of the endothelial mechanisms governing its progression. Leveraging the zebrafish model and NgAgo knockdown system to identify target genes influencing angiogenesis, our study highlights the significant role of gastric inhibitory polypeptide (GIP) and its receptor (GIPR) in this process. While GIP has been extensively studied for its insulinotropic and glucagonotropic effects, its role in angiogenesis remains unexplored. This study demonstrated that GIPR knockdown induced developmental delays, morphological abnormalities, and pronounced angiogenic impairments in zebrafish embryos. Conversely, exogenous D-Ala2-GIP administration enhanced blood vessel formation in the yolk sac membrane of chick embryos. Consistent with these findings, D-Ala2-GIP treatment promoted microvessel formation in the tube formation assays and rat aortic ring models. Further investigation revealed that D-Ala2-GIP facilitated human umbilical vein endothelial cell (HUVEC) migration, a key step in angiogenesis, through the cyclic adenosine monophosphate (cAMP)-mediated activation of the Epac/Rap1/Cdc42 signaling pathway. This study provides novel insights into the angiogenic functions of GIP and its potential implications for cardiovascular biology. Show less

Obesity is a global health challenge marked by substantial inter-individual differences in responses to dietary and lifestyle interventions. Traditional weight loss strategies often overlook critical biological variations in genetics, metabolic profiles, and gut microbiota composition, contributing to poor adherence and variable outcomes. Our primary aim is to identify key biological and behavioral effectors relevant to precision medicine for weight control, with a particular focus on nutrition, while also discussing their current and potential integration into digital health platforms. Thus, this review aligns more closely with the identification of influential factors within precision medicine (e.g., genetic, metabolic, and microbiome factors) but also explores how these factors are currently integrated into digital health tools. We synthesize recent advances in nutrigenomics, nutritional metabolomics, and microbiome-informed nutrition, highlighting how tailored dietary strategies-such as high-protein, low-glycemic, polyphenol-enriched, and fiber-based diets-can be aligned with specific genetic variants (e.g., FTO and MC4R), metabolic phenotypes (e.g., insulin resistance), and gut microbiota profiles (e.g., Show less

Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood. We performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response. We identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG-FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2-STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control. CD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL-PPARG-ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma. 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. 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

Nickel exposure increases the risk of lung cancer; however, the mechanisms underlying nickel-induced oncogenic cell death remain unclear. While ferroptosis is linked to lung cancer, its role in nickel-induced malignant transformation is not well understood. We simulated long-term exposure of human bronchial epithelial cells (Beas-2B cells) to nickel-refining fumes (NiRF) from a smelter and found that NiRF exposure induced their malignant transformation. Ferroptosis was inhibited in these transformed cells (2B-NiRF cells), a phenomenon also observed in NiRF-exposed mouse lung tissue. Treatment of 2B-NiRF cells with ferroptosis inducers and inhibitors indicated that ferroptosis suppresses their malignant phenotype. Transcriptome analysis of 2B-NiRF cells revealed enrichment in hypoxia and HIF-1 signaling pathways. Mechanistically, the NiRF-induced hypoxic microenvironment inactivates prolyl hydroxylase domain protein 1 (PHD1), stabilizing hypoxia-inducible factor-1α (HIF-1α), which coordinates the transcriptional program to maintain 2B-NiRF cells in a ferroptosis-resistant state. Overexpression of PHD1 inhibits HIF-1α and its downstream angiopoietin-like protein 4 (ANGPTL4)/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, thereby restoring sensitivity to ferroptosis in 2B-NiRF cells; knockdown of ANGPTL4 similarly modulates sensitivity to ferroptosis. This underscores the crucial role of the PHD1/HIF-1α/ANGPTL4/JAK2/STAT3 axis in ferroptosis-mediated NiRF-induced malignant transformation. The NiRF-exposed mouse model further confirms that in vivo expression of the PHD1/HIF-1α/ANGPTL4/JAK2/STAT3 axis is dysregulated. In conclusion, this study reveals a novel regulatory cascade in which NiRF inhibits cellular ferroptosis via the PHD1/HIF-1α/ANGPTL4/JAK2/STAT3 axis, thereby inducing malignant transformation of cells, providing potential targets for occupational lung cancer risk management against ferroptosis. Show less

Angiogenesis is a critical pathological process in vascular dementia (VD), yet current therapeutic strategies targeting this mechanism remain limited. Identifying novel molecular pathways involved in angiogenesis holds significant promise for advancing both diagnostic and therapeutic approaches for VD. We first applied weighted gene coexpression network analysis (WGCNA) and differentially expressed gene (DEG) analysis, combined with phenotypic gene database mining, to identify angiogenesis-associated genes in VD. We then used the Least Absolute Shrinkage and Selection Operator (LASSO) regression to select key diagnostic genes. The diagnostic efficacy of these genes was evaluated using receiver operating characteristic (ROC) curve analysis, while their association with immune cell infiltration was assessed via xCell immunoinfiltration. Using single-nucleus RNA sequencing (snRNA-seq), we determined the cellular distribution of key genes and applied Gene Set Enrichment Analysis (GSEA) to analyze functional pathways in the differentially expressed cell clusters. Finally, we validated gene expression changes in the hippocampus of bilateral common carotid artery occlusion (BCCAO)-induced VD rats using quantitative polymerase chain reaction (qPCR) and Western blot (WB). Ultimately, we screened five key genes, namely, These five key genes might be used as angiogenesis diagnostic genes for VD and might be novel potential targets for diagnosis, treatment, and prevention. Show less

Angiopoietin-like 4 (ANGPTL4) expression is increased in wound tissue and contributes to wound healing. However, the underlying mechanisms are not fully understood. Here, we demonstrate that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during wound healing in mice. Increased Angptl4 expression is positively correlated with increased expressions of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1. Each of these molecules induces Angptl4 expression in mouse EpSCs. RNA sequencing of EpSCs derived from wild-type and Angptl4 knockout (Angptl4 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 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

To investigate the role of adipokines in primary open angle glaucoma (POAG) by comparing the levels of these molecules in the aqueous humor among POAG patients and cataract patients with or without metabolic disorders. In this cross-sectional study, aqueous humor samples of 22 eyes of POAG patients (POAG group), 24 eyes of cataract patients without metabolic disorders (cataract group), and 24 eyes of cataract patients with metabolic disorders (cataract+metabolic disorders group) were assessed for 15 adipokines by Luminex bead-based multiplex array. The correlation between aqueous humor adipokines and clinical indicators of POAG was analyzed and compared across the groups. The analysis revealed that the levels of adiponectin, leptin, adipsin, retinol-binding protein 4 (RBP4), angiopoietin-2, angiopoietin-like protein 4 (ANGPTL4), chemokine (C-C motif) ligand 2 (CCL2), interleukin-8 (IL-8), and interleukin-18 (IL-18) in the aqueous humor of the POAG group were significantly higher than those in the cataract group. Additionally, the level of angiopoietin-2 in the POAG group was higher than in the cataract+metabolic disorders group. However, no significant correlation was found between the levels of adipokines in the POAG group and intraocular pressure (IOP), severity of POAG, or the use of glaucoma medications. This study demonstrates significant differences in aqueous humor adipokine levels between POAG and cataract patients. The findings suggest that the levels of aqueous humor adipokines may reflect the inflammatory states in POAG and systemic metabolic abnormalities. Show less

NDRG1, a cell differentiation-associated factor, has recently emerged as a regulator ferroptosis. Nevertheless, its role in modulating ferroptosis within hepatocellular carcinoma (HCC) remains uncharacterized. The differential expression of NDRG1 and its prognostic value were analyzed in HCC using data from TCGA and GEO. Ferroptosis in HepG2 and Huh7 cells was assessed using flow cytometry, transmission electron microscopy, and propidium iodide staining following NDRG1 knockdown using shRNA. RNA-seq was performed to characterize the mRNA expression profiles in HepG2 cells, identifying differentially expressed mRNAs (DE-mRNAs) and NDRG1-related hub genes. NDRG1 was overexpressed in multiple malignant tumors, including HCC, and was associated with a significantly poor prognosis in HCC patients. A nomogram model integrating NDRG1 expression and clinical parameters demonstrated robust prognostic accuracy. NDRG1 knockdown potentiated erastin-induced alterations in Fe NDRG1 exhibits strong predictive value for HCC, and accelerates tumor progression by suppressing ferroptosis. Show less

Lipoprotein lipase (LPL) participates in the development of obesity by regulating triglyceride hydrolysis and fat storage or oxidation. In this study, the anti-obesity effects of lotus seed skin catechins and its mechanisms associated with LPL modulation were demonstrated. In vivo, catechins reduced body weight in high-fat diet-induced obese mice, improved lipid metabolism and antioxidant indices, and modulated LPL activity in adipose and skeletal muscle tissues. The expression of peroxisome proliferator-activated receptor γ (PPARγ) and (angiopoietin-like 4 proteins) ANGPTL4 mRNA and protein was significantly upregulated in epididymal fat depot but downregulated in skeletal muscle tissue. In vitro cell experiments and chromatin immunoprecipitation (ChIP) assays further revealed that the binding sites of PPARγ protein in the ANGPTL4 promoter region were enriched in adipocytes or reduced in skeletal muscle cells in response to catechin treatment. Therefore, lotus seed skin catechins exhibit anti-obesity activity in vivo and in vitro by specifically regulating the activity and expression of LPL in target tissues. Show less

Calcific aortic valve disease (CAVD) is characterized by progressive leaflet thickening and calcification, with no available pharmacological treatments. Plasma proteins play a pivotal role in disease regulation. This study aimed to uncover novel therapeutic targets for CAVD using Mendelian randomization (MR) integrated with transcriptomic analysis. Protein quantitative trait loci (pQTL) from the deCODE and UK Biobank Pharma Proteomics Project (UKB-PPP) plasma protein databases were used as exposure data. The FinnGen cohort (9870 cases, 402,311 controls) served as the discovery set, while the TARGET cohort (13,765 cases, 640,102 controls) provided validation. MR and summary data-based Mendelian randomization (SMR) were employed to screen for potential causal targets of CAVD. Colocalization analysis was conducted to assess whether CAVD and target proteins shared common causal SNPs. Additional analyses included trancriptomic profiling at multiple RNA levels. Protein-level validation was conducted via Western blot and immunostaining. Six proteins (ANGPTL4, PCSK9, ITGAV, CTSB, GNPTG, and FURIN) with strong genetic colocalization were identified by MR and SMR analysis. Among these, cellular trancriptomic analysis revealed ANGPTL4 and ITGAV with significantly greater expression in osteogenic group, which was further validated in calcified aortic valves and osteogenic valvular interstitial cells in protein level. This study identified six causal proteins with strong genetic colocalization for CAVD, with ANGPTL4 and ITGAV emerging as the most promising targets for further investigation. Show less

Pork serves as a significant meat commodity, with intramuscular fat (IMF) content being a critical determinant of its quality. However, the epigenetic mechanism of porcine IMF deposition is still unclear. This study integrated proteomics and lactylation profiles from the longissimus thoracis (LT) muscles of pigs with extremely high (IMF_H) and extremely low (IMF_L) IMF content to clarify the association between lactylation and porcine fat deposition. Furthermore, an intramuscular preadipocyte induction and differentiation model was conducted to elucidate the changes in lactylation during adipocyte differentiation. Finally, the regulatory role of lactylation in adipocyte differentiation was explored by modulating lactate production during the induction and differentiation of preadipocytes. Proteomic analysis revealed significantly increased expression of key lipid metabolism related proteins (FASN, APOA4, FABP4, ACLY, PLIN1) in IMF_H pig muscle tissues compared with IMF_L tissues, along with substantial activation of lipid metabolism pathways. Lactylation profiling identified 95 differential lysine sites across 56 proteins, with most showing lower lactylation levels in the IMF_H group. The integrative omics analysis revealed differences in lactylation profiles in porcine LT tissues with varying efficiencies of IMF deposition, highlighted PGK1, PKM, and PYGM as central lactylation-modified proteins in porcine fat deposition regulation. Further in vitro study proved that lactate-mediated lactylation inhibited adipogenic differentiation of porcine intramuscular preadipocytes through PPARγ signaling pathway. This study clarified the changes in the lactylation profile in porcine LT tissues with varying efficiencies of IMF deposition, and demonstrated that lactate-mediated lactylation inhibits the PPARγ signaling pathway and the adipogenic differentiation of porcine intramuscular preadipocyte. This study provided a new insight to understanding the epigenetic regulation mechanisms of lipid deposition in pigs. Show less

Lipopolysaccharide (LPS) from gram-negative bacteria initially induces the pro-inflammatory cytokines storm and causes inflammatory cascade responses. However, the LPS with higher dosage induced duodenal, cecal, hepatic, and cardiac inflammation remains elusive. Specific pathogen-free chicken embryos (n = 72) were allocated to the control, LPS groups (10 μg, 24 μg, 50 μg, 100 μg, 170 μg/egg, respectively). Fifteen day old embryonated eggs were injected abovementioned solutions via the allantoic cavity by disposable syringes. On embryonic day 19, the tissues of the embryos were collected for histopathology, RNA extraction, real-time PCR, and immunohistochemistry investigation. The results demonstrated that there was inflammatory responses (heterophils infiltration or macrophages accumulation) presented in the duodena, ceca, livers, and hearts after LPS induction. The duodenal mRNA expressions of inflammatory-associated mediators (TLR4, IFNγ, IL-1β, IL-6, IL-8, MMP9, MMP3, p38, or NF-κB1) were significantly upregulated after LPS induction (10 μg, 24 μg, 50 μg, 100 μg, or 170 μg /egg) when compared with the control group, respectively. Duodenal immunopositivity of TLR4, MMP9, and MMP3 significantly increased following LPS induction (24 μg or 50 μg) compared to the control group. Meanwhile, the hepatic mRNA expressions of inflammatory-associated factors (IFNγ, MMP3, IL-1β, IL-10, TNFα, IL-8, or NF-κB1) significantly increased after LPS induction (10 μg, 24 μg, 50 μg, 100 μg, or 170 μg /egg) when compared with the control group, respectively. Additionally, cardiac mRNA expression of TLR4, IFNγ, IL-1β, IL-8, IL-10, MMP3, MMP9, and TNFα was significantly increased in all five LPS groups compared to the control group. Cardiac protein expressions of TLR4 or IFNγ significantly increased when compared 100 μg LPS group with the control group. Duodenal and cecal mRNA expressions of programmed cell death-related factors presented irregular. The mRNA expression of hepatic pyroptosis-associated gene AMPKα2, Beclin-1, Bcl-2, CASP1, or CASP12 after LPS induction (10 μg, 24 μg, or 50 μg/egg) increased when compared with the control group. Furthermore, the cardiac mRNA expressions of pyroptosis-related gene CASP1 and CASP12 in five LPS groups increased when compared with the control group. Cardiac autophagy-related gene Bcl-2, ATG5, or LC3B enhanced in LPS groups (10 μg, 50 μg, or 100 μg/egg) when compared with the control group, whereas LC3A, CASP1, or Drp1 mRNA expression in five LPS groups reduced when compared with the control group, respectively. The mRNA expressions of duodenal mucosal barrier function-associated mediators Claudin 1 and PEPT1 were upregulated after LPS induction (10 μg or 50 μg/egg) when compared five LPS groups with the control group, respectively; nevertheless, duodenal Mucin 2 and SGLT1 mRNA expression reduced in four groups (24 μg, 50 μg, 100 μg, or 170μg /egg) when compared with the control group, as well as cecal mRNA expressions of Mucin 2, occludin, SGLT1.The mRNA expressions of liver permeability-related gene (claudin 1 and occludin) increased in the five groups when compared with the control group, as well as cardiac permeability and energy metabolism-related gene (AMPKα2, APOA4, PPARα, SGLT, and claudin1). In conclusion, LPS can induce duodenal, hepatic and cardiac inflammation, initiate energy deficiency, autophagy, programmed cell death, enhanced intestinal mucous barrier function, tight junction, and permeability in chicken embryos. Show less

Despite the known impacts of weaning on animal health, the underlying molecular mechanisms remain unclear, particularly how psychological and nutritional stress differentially affect gut health and immune function over time. This study hypothesized that early weaning exerts distinct short- and long-term effects on lamb stress physiology, immunity, and gut health, mediated by specific molecular pathways. Twelve pairs of full-sibling male Hu sheep lambs were assigned to control (CON) or early-weaned (EW) groups. Plasma stress/immune markers were dynamically monitored, and intestinal morphology, antioxidant capacity, apoptosis, and transcriptomic profiles were analyzed at 5 and 28 days post-weaning. Early weaning triggered transient psychological stress, elevating hypothalamic-pituitary-adrenal (HPA) axis hormones (cortisol, catecholamines) and inflammatory cytokines (TNF-α) within 1 day ( Show less

The dysregulation of hepatic lipid metabolism is closely associated with dyslipidemia. Previous research suggested that Hepatic Data regarding circulating lipid traits and hepatic Hepatic This study identifies Show less

The quality of eggshells holds substantial economic significance and serves as a critical selection criterion in poultry breeding. Eggshell translucency significantly impairs their aesthetic quality, which is structurally attributed to the thinning of the eggshell membrane or reduced tensile strength. In this study, 836 dwarf white hens were selected, with 45 hens each assigned to the opaque group and the translucent group. Grading for eggshell translucency was conducted at 75, 80, and 85 weeks of age. Based on the results from these three gradings, 35 hens that consistently produced translucent eggs and 35 hens that consistently produced opaque eggs were reclassified into the translucent group and the opaque group, respectively. The thickness of the eggshell membrane, latitudinal and longitudinal tensile force and length, and other indicators related to eggshell membrane quality were measured. Correlation analysis was performed using RNA-seq genomics and DIA proteomics based on the relationships among these indicators. Transcriptome analysis revealed 179 significantly differentially expressed genes, indicating that the causes of translucent eggshells are associated with metabolism, signal transduction, the immune system, molecular binding, transport, and catabolism. Seven potential candidate genes, including Show less

Cardiovascular diseases from abnormal lipid metabolism significantly increase mortality in systemic lupus erythematosus (SLE). The causal link between dyslipidemia and SLE is unclear. Lipid metabolism in patients with SLE was evaluated based on clinical data from 511 patients with SLE and 706 healthy individuals. Bidirectional Mendelian randomization (MR) was employed to assess causal links between 179 plasma lipid metabolites, lipid-lowering drug targets, and SLE risk. Genetic instruments from GWAS and eQTL data were used to evaluate CETP and APOA4 effects. Peripheral blood CETP and apolipoprotein levels in SLE patients were validated via ELISA. SLE patients exhibited reduced HDL-C (P < 0.0001), APOA1 (P < 0.0001), and APOA4 (P < 0.0001), alongside elevated triglycerides (TG, P < 0.0001), APOC3, APOD, and APOF. MR identified three lipid metabolites-PC(18:2₂₀:4), TG(56:6), and TG(58:7)-as causal factors for SLE (P < 2.79E-5). CETP inhibition significantly reduced SLE risk via HDL-C modulation (OR = 0.72, P = 3.38E-08) and influenced LDL-C, TG, and apolipoproteins. Clinical validation confirmed elevated CETP and reduced APOA4 in SLE, correlating with disease activity. APOA4 activation showed protective effects, while PCSK9 inhibition lacked relevance. Bidirectional Mendelian randomization analyses confirmed dyslipidemia as a causal antecedent to SLE, with no evidence of reverse causation. A variety of MR analyses and clinical validation indicated that targeting HDL-C regulation offers significant advantages for managing dyslipidemia in patients with SLE, with CETP identified as the optimal pharmacological target. Show less