👤 Jianrong Gu

Lewy body dementia (LBD) is the second common dementia, with unclear mechanisms and limited treatment options. Dyslipidemia has been implicated in LBD, but the role of lipid-lowering drugs remains underexplored. This study aims to investigate the association between lipid traits, drug targets, and LBD risk using Mendelian Randomization (MR) analysis. We performed univariable and multivariable MR analyses to evaluate the causal effects of lipid traits on the risk of LBD. Then, drug-target MR analysis and subtype analysis were conducted to evaluate the effects of lipid-lowering therapies on LBD. In univariable MR, genetically predicted low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC) levels were associated with an increased risk of LBD. Mediation analysis suggested a potential interaction between LDL-C and RC in influencing LBD risk. Drug-target MR analysis identified significant associations between genetically proxied inhibition of ANGPTL3, CETP, and HMGCR and LBD risk. This MR analysis provided evidence that elevated LDL-C and RC may increase the risk of LBD. Additionally, targeting ANGPTL3, CETP, and HMGCR may represent potential therapeutic strategies for the prevention or treatment of LBD. Show less

Chromatin accessibility and transcription levels during oocyte growth are important for oocyte maturation and subsequent development. However, chromatin accessibility changes in porcine oocytes during growth are unclear. The present study demonstrated that porcine oocytes derived from large follicles (LFO) exhibited higher developmental capacity than those derived from small follicles (SFO). Assay for transposase-accessible chromatin using sequencing (ATAC-seq) analysis identified 1117 and 1694 uniquely accessible chromatin peaks in LFO and SFO, respectively. Motif analysis of differential peaks revealed the top 10 significantly enriched transcription factor (TF)-binding motifs in LFO versus SFO, with only one increased peak (Spi1 binding site) and nine decreased peaks (NFYA, ATOH1, ZNF549, Foxn1, HAND2, THRB, NHLH2, FoxP1, and FoxP2 binding sites). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified key processes in the regulation of oocyte growth and maturation. Integration of ATAC-seq and RNA sequencing data revealed the top 10 hub genes involved in chromatin remodeling (MYSM1 and EZH2), histone modification (MYSM1, RNF2, USP1, EZH2, and MIER1), and transcription regulation (MYSM1, ASXL3, and MIER1), as well as those involved in metabolic processes and signal transduction (DOCK7, FGGY, DTL, and DNAJC6). All these genes exhibited increased expression levels in LFO versus SFO. In conclusion, the study demonstrated the dynamic nature of chromatin accessibility during porcine oocyte growth and revealed the TFs and genes closely associated with oocyte growth and maturation. These findings provide new insight into porcine oocyte growth and offer a potential strategy to enhance the in vitro developmental ability of SFO. Show less

Diabetic kidney disease (DKD) is a severe global complication of diabetes, yet its molecular mechanisms remain incompletely understood. This study aimed to investigate the role of protein glycosylation in DKD pathogenesis and its association with gene expression changes, with the goal of identifying diagnostic biomarkers and personalized therapeutic targets. Integrated bioinformatics and machine learning approaches were applied to analyze multiple gene expression datasets. Differentially expressed glycosylation-related genes were identified, followed by unsupervised clustering to define molecular subtypes. Functional enrichment, immune cell infiltration analysis, and machine learning algorithms (including feature selection for hub genes) were employed. qPCR validation was performed on clinical DKD and normal kidney tissues, and ROC curves were generated to assess diagnostic potential. Unsupervised clustering of glycosylation-related genes revealed two distinct DKD molecular subtypes with differential pathway activation (e.g., extracellular matrix remodeling) and immune infiltration patterns. Six hub genes (S100A12, EXT1, SBSPON, ADAMTS1, FMOD, SPTB) were identified as critical to DKD pathogenesis through machine learning. Immune infiltration analysis showed significant differences in macrophage and neutrophil activity between DKD and controls and Immunohistochemical results confirmed the occurrence of immune infiltration. qPCR validation confirmed dysregulation of hub genes in DKD tissues compared to normal samples. ROC analysis demonstrated high diagnostic accuracy for these genes. This study highlights abnormal protein glycosylation as a key player in DKD and identifies six hub genes with potential as diagnostic biomarkers. The molecular subtypes and immune infiltration patterns provide insights into disease heterogeneity, paving the way for personalized therapies. Future studies should validate these findings in larger cohorts with explicit sample sizes to strengthen clinical applicability. Show less

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disease. Genetic linkage analyses have identified that mutations in the exostosin glycosyltransferase (EXT)1 and EXT2 genes are linked to HME pathogenesis, with EXT1 mutation being the most frequent. The aim of this study was to generate a mice model with Ext1 gene editing to simulate human EXT1 mutation and investigate the genetic pathogenicity of Ext1 through phenotypic analyses. We designed a pair of dual sgRNAs targeting exon 1 of the mice Ext1 gene for precise deletion of a 46 bp DNA fragment, resulting in frameshift mutation of the Ext1 gene. The designed dual sgRNAs and Cas9 proteins were injected into mice zygotes cytoplasm. A total of 14 mice were obtained via embryo transfer, among which two genotypic chimera mice had a deletion of the 46 bp DNA fragment in exon 1 of the Ext1 gene. By hybridization and breeding, we successfully generated heterozygous mice with edited Ext1 gene (Ext Show less

Drug resistance severely hinders the clinical application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC). Notably, resistance caused by rare target mutations (with a mutation incidence rate below 5 %) accounts for approximately 15 % of total resistance cases in NSCLC. Due to the diversity and complexity of these mutations, targeted therapies against them are currently very limited. To address the challenge of multi-driver resistance in NSCLC, this study aimed to explore a novel therapeutic strategy that can simultaneously inhibit multiple resistance drivers and enhance drug resensitization to EGFR-TKIs, overcoming the limitations of conventional single-protein inhibitors. Established gefitinib-resistant HCC827 cell models driven by rare co-activation of two EGFR-independent membrane proteins. Developed a strategy targeting lipid raft cholesterol to destabilize raft integrity, leveraging the cholesterol-modulating properties of ginsenosides. Evaluated the synergistic effect of co-administering ginsenoside Rg3 with gefitinib in both in vitro and in vivo models. Explored the mechanism of Rg3 action, including its binding to lipid raft cholesterol, disruption of membrane anchoring of resistance-associated receptor tyrosine kinases, and acceleration of their endocytic degradation. Co-administration of ginsenoside Rg3 with gefitinib synergistically restored antitumor efficacy in both in vitro and in vivo models, outperforming conventional single-protein inhibitors. Mechanistically, Rg3 specifically binds to lipid raft cholesterol, disrupting the membrane anchoring of resistance-associated receptor tyrosine kinases (e.g., FGFR1 and VEGFR2) and accelerating their endocytic degradation. Structural-activity relationship analyses revealed that the cholesterol-binding capacity of ginsenosides-critical for resistance reversal-is modulated by the stereochemical configuration of sugar moieties at C3, C6, and C20 positions. This study elucidates a novel membrane-centric paradigm for overcoming multi-driver resistance in NSCLC, where pharmacological perturbation of cholesterol-lipid raft interactions by natural compounds like Rg3 enables broad-spectrum suppression of coexisting resistance mechanisms. It not only provides novel insights into the mechanisms underlying resistance in NSCLC but also presents a promising clinical strategy that could significantly improve treatment outcomes for patients. Show less

The high mortality rate of severe heat stroke is mainly related to multiple organ dysfunction syndrome (MODS), and respiratory failure caused by acute lung injury (ALI) is a significant factor in the development of MODS during the course of severe heat stroke. Previous research has demonstrated that severe heat stroke-induced acute lung injury (sHS-ALI) is associated with an increase in reactive oxygen species (ROS) in vascular endothelial cells (VECs), but the specific initiating factors and intermediate mechanisms involved are unclear. In this study, the mRNA profiles of mouse lung tissues were analysed using high-throughput sequencing. Genome-wide knockout was performed using CRISPR-Cas9 technology to identify a cohort of differentially expressed genes that promote human umbilical vein endothelial cells survival after heat stress. The expression of key proteins [fibroblast growth factor 23 (FGF23), phosphorylated fibroblast growth factor receptor-1 (p-FGFR-1), FGFR-1, phosphorylated phospholipase C-γ2 (p-PLC-γ2), PLC-γ2, p-p47 In this study, we first screened sHS-ALI target genes by cross-comparison This study confirmed that FGF23/FGFR1 signalling, as an upstream priming factor, mediated NOX2-ROS activation in VECs after heat stress, thus participating in the sHS-ALI process. FGFR-1 Y766 phosphorylation is essential for FGF23/FGFR-1 signalling activation in VECs, which is involved in sHS-ALI. These findings further clarify the mechanism underlying sHS-ALI and contribute to reducing the mortality and morbidity of severe heat stroke. Show less

A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, specifically mediated by melatonin (MEL) receptor 1a (MT1). T2DM mice with SF intervention displayed several deleterious phenotypes such as apoptosis, deregulated lipid metabolism, and impaired testicular function. Unexpectedly, sleep recovery (SR) for 2 consecutive weeks could not completely abrogate SF's detrimental effects on lipid deposition and testicular function. Interestingly, MEL and MT1 agonist 2-iodomelatonin (2IM) effectively improved lipid homeostasis, highlighting MEL/2IM as a promising therapeutic drug for SF-trigged testicular damage. Mechanistically, MEL and 2IM activated FGFR1 and sequentially restrained the crosstalk and physical interaction between TAB1 and TAK1, which ultimately suppressed the phosphorylation of TAK1 to block lipid deposition and cell apoptosis caused by SF. The ameliorating effect of MEL/2IM was overtly nullified in Show less

Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders appear progressively more severe after ADR-based chemotherapy in the obese state, and the specific molecular mechanism needs to be further clarified. This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high-fat diet (HFD). We engineered Fgf21 KO mice and used long-term (4 months) and short-term (0.5 months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce an in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on the regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology, and in vitro approaches. Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF receptor-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor 4 alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy. Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy. Show less

This study aims to investigate how Bifidobacterium breve BBr60 improves obesity-related metabolic disorders by modulating the gut microbiota-SCFAs axis, thereby affecting inflammatory factors and metabolic hormones. A randomized, double-blind, placebo-controlled trial was conducted. A total of 75 individuals with obesity subjects (BMI ≥ 28) were enrolled and randomly assigned to either the BBr60 intervention group (10 billion CFU daily) and the placebo group. After the 12-week intervention, 65 participants (BBr60: n = 33; placebo: n = 32) completed the study and were included in the primary analysis. All participants received standardized nutritional counseling aimed at a moderate energy intake (~ 1800 kcal/day, including a daily intake of 25 g of dietary fiber.). Every week, we call participants at a fixed time to inquire about their weekly diet and weight changes, and provide dietary suggestions for the following week based on the inquiry results. Participants were instructed to maintain their usual physical activity levels throughout the study. The composition of the gut microbiota was analyzed by 16 S sequencing, fecal SCFAs were detected by GC-MS, and serum levels of IL-27, IL-1β, and metabolic hormones were measured using ELISA technology. Metabolic indicators such as body weight, body fat percentage, and HOMA-IR were also assessed. The BBr60 intervention significantly increased fecal butyrate levels (p < 0.001), accompanied by a decrease in IL-1β levels (p < 0.05) and an upregulation of IL-27 (p < 0.01). In terms of metabolic hormones, leptin (LEP), adiponectin (ADPN), connecting peptide (C-P), pancreatic polypeptide (PP), peptide YY (PYY), Glucose-dependent insulinotropic polypeptide (GIP), and Glucagon-Like Peptide-1 (GLP-1) were all significantly elevated (p < 0.05), while Homeostasis Model Assessment for Insulin Resistance(HOMA-IR) was significantly reduced in the BBr60 group (p < 0.05). In the control group, C-P, PP, and GIP were significantly increased (p < 0.05), whereas LEP, ADPN, PYY, GLP-1, and HOMA-IR showed no difference before and after the 12-week period. Correlation analysis indicated that butyrate levels were significantly positively correlated with GLP-1 and IL-27, and negatively correlated with IL-1β. Bifidobacterium breve BBr60, by remodeling the gut microbiota-SCFAs axis, inhibits the pro-inflammatory factor IL-1β, activates the anti-inflammatory signal IL-27, and synergistically regulates the metabolic hormone network (such as GLP-1, ADPN), significantly improving obesity-related metabolic disorders. This study provides a theoretical basis and intervention targets for the clinical application of probiotics targeting the "microbiota-SCFAs-inflammation/hormone axis," and future research can explore precise probiotic treatment regimens based on individual microbiota characteristics. Show less

To explore the latent categories of volume management behaviors in patients with chronic heart failure (CHF) and analyze their relationship with symptom distress. This cross-sectional study utilized a convenience sampling method to select 552 CHF patients from the cardiology departments of Nantong Sixth People's Hospital and Nantong Fourth People's Hospital. Volume management behaviors were assessed using the Volume Management Behavior Scale, and symptom distress was evaluated using the Symptom Distress Questionnaire (SDQ), which measures the severity of eight core symptoms. Latent Profile Analysis (LPA) was employed to identify behavioral categories. Multivariate Analysis of Variance (MANOVA) and multiple linear regression were used to analyze differences in symptom distress across behavioral categories and to examine the independent predictive effect of behavioral classification on symptom distress. The volume management behaviors of CHF patients were classified into three latent categories: active management type (43.1%), selective adherence type (27.7%), and passive dependence type (29.2%). Symptom distress scores showed a significant increasing trend across the three categories (active type: 10.5 ± 3.8; selective type: 13.2 ± 4.1; passive type: 16.3 ± 5.2, CHF patients exhibit three distinct clinical patterns of volume management behaviors, with the passive dependence type associated with the highest symptom burden. Behavioral category is a significant predictor of symptom distress. These findings provide an empirical basis for developing precise intervention strategies tailored to different behavioral phenotypes. Show less

Osteoporotic bone defects pose significant clinical challenges. While icariin (ICA) exhibits pro-osteogenic effects in vitro, its capacity to repair osteoporosis (OP)-related bone defects remains unverified. This study investigates ICA' s therapeutic role in bone regeneration and elucidates its molecular mechanisms via the Hippo pathway in bone marrow mesenchymal stem cells (BMSCs) and OP rats. Rat BMSCs were isolated and characterized by flow cytometry (CD29+/CD34-/CD45-). BMSCs were induced under osteogenic conditions with ICA at 25 and 50 mg/L. Osteogenic differentiation and mineralization were assessed by ALP and Alizarin Red staining and by measuring mRNA and protein levels of ALP, Runx2, and OCN. The Hippo/TAZ pathway was evaluated by Western blot and qPCR for MST1, p-MST1, TAZ, and p-TAZ. A rescue experiment employed the Hippo pathway agonist lysophosphatidic acid (LPA). An ovariectomized (OVX) rat model of osteoporosis was established to validate ICA's effects in vivo, examined by micro-CT, histology, and tibial expression analyses of osteogenic markers and Hippo/TAZ signaling components. ICA promoted osteogenic differentiation and mineralization of BMSCs. Mechanistically, ICA did not alter MST1 or TAZ transcripts but markedly reduced MST1 and TAZ phosphorylation, thereby stabilizing total TAZ and enhancing downstream osteogenesis. Co-treatment with LPA abrogated ICA-induced osteogenesis, confirming Hippo/TAZ pathway dependence. In OVX rats, ICA mitigated bone loss, improved trabecular microarchitecture (BMD, BV/TV, Tb.N), and upregulated tibial expression of ALP, Runx2, and OCN. Consistently, ICA reduced p-MST1 and p-TAZ levels and increased total TAZ in bone tissues. ICA promotes bone formation both in vitro and in vivo by inhibiting Hippo kinase activity and stabilizing TAZ, thereby enhancing osteogenic differentiation. Our findings identify the Hippo/TAZ axis as a potential therapeutic target for OP and support further translational exploration of ICA as an anti-osteoporotic agent. Show less

We conducted a systematic review on cardiac metabolomic alterations in type 2 diabetes and the interplay with lipoprotein lipase (LPL). To synthesize evidence on LPL activity, cardiac metabolomics, and cardiovascular outcomes in type 2 diabetes. EMBASE, PsycINFO, AMED, LILACS, and Web of Science were searched from January 2000 to August 2025; last searches: EMBASE [22 August 2025], PsycINFO [22 August 2025], AMED [22 August 2025], LILACS [22 August 2025], Web of Science [22 August 2025]. Original human studies in type 2 diabetes reporting cardiac metabolomics and LPL activity; no language restrictions. Two reviewers independently screened records/reports and extracted data; risk of bias was assessed with RoB 2 (randomized trials), ROBINS-I (nonrandomized studies), and the Newcastle-Ottawa Scale (observational). We planned random-effects meta-analyses using mean difference/standardized mean difference or risk ratio, quantified heterogeneity with I2 and τ2, examined small-study effects with funnel plots/Egger's test, and rated certainty with GRADE. We included 11 studies ( Show less

The current trial sought to assess the impact of fermented chicory root waste (FCRW) dietary administration on growth, lipid metabolism, chemical composition, and intestinal barrier pathway in common carp ( Show less

Wenchang chicken, renowned for its high-quality meat, is the economic meat breed in Hainan Province, China. This study compared cage-rearing (CR) and free-range (FR) groups in terms of growth performance, slaughter performance, meat quality, IMP (inosine monophosphate) content, AAs, FAs, serum lipid metabolites, and transcriptomic and metabolomic analyses. The CR group showed increased body weight, live weight, and abdominal fat but lower leg muscle percentage and breast muscle redness, suggesting flavor differences. CR chickens had higher IMP, threonine (Thr), and pentadecanoic, oleic, and linoleic acids, while glutamate (Glu) and alpha-linolenic acid were lower compared to FR. Glycine was elevated, but histidine, myristic, and tricosanoic acids were lower in CR leg muscle. Serum analysis revealed higher total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), fatty acid synthase (FAS), thyroid-stimulating hormone (TSH), leptin (LEP), and adiponectin (ADP) in the CR group. Transcriptomic and metabolomic studies identified 252 differentially expressed genes and 34 metabolites linked to metabolic pathways. In summary, CR system can improve production performance, FR system is considered more flavorful. The results can act as a theoretical basis for selecting a suitable rearing method for this unique breed. Show less

Metabolism alteration is a common complication of rheumatic arthritis (RA). This work investigated the reason behind RA-caused triglyceride (TG) changes. Fresh RA patients' whole blood was transfused into NOD-SCID mice. Metabolism-regulatory tissues were examined after sacrifice. To verify the findings, tissues of the rats with long-lasting adjuvant-induced arthritis (AIA) were analyzed. Some rats were injected with human plasma and GPIHBP1, and their blood TG was monitored. Various cells were stimulated by cytokines or rheumatic subjects' serum. Some pre-adipocytes were cultured by human serum or in the presence of HUVEC cells and GPIHBP1. TG decrease occurred in blood and white adipose tissues (WAT) of the RA blood-transfused NOD-SCID mice and chronic AIA rats. Fatty acids (FA) oxidation in muscles was accelerated a bit, while TG catabolism status in their livers was varied. TNF-α, IL-1β, IL-6 and RA/AIA serum promoted expression of TG utilization-related enzymes and FA uptake transporters in pre-adipocytes, but barely affected LPL. Mild IL-6 stimulus promoted GPIHBP1 release of HUVEC cells. GPIHBP1 was increased in RA serum. This change can decrease blood TG in rats, which was overshadowed by an injection of excessive GPIHBP1. RA serum slightly inhibited LPL secretion in pre-adipocytes. Both HUVEC cells co-culture and GPIHBP1 supplement reduced LPL distribution on pre-adipocytes, and eliminated LPL activity difference between normal and RA serum-treated cells. No TG uptake difference was observed in these circumstances. RA-associated inflammation induces GPIHBP1 secretion of endothelial cells, which facilitates blood TG hydrolysis and uptake to compensate the loss in WAT. Show less

Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs. Show less

Mesenchymal cells constitute the primary structural support elements within endometriotic lesions, yet their pivotal roles in endometriotic pathogenesis remain largely uncharted. This study aimed to construct a single-cell atlas of endometriosis using samples from three ovarian tissues affected by endometriosis and three normal ovarian tissues. Through the utilization of scRNA-seq, we have unveiled six distinct mesenchymal subclusters in normal and endometriosis-afflicted ovaries, elucidating the diverse functions of mesenchymal populations in endometriosis. Our comprehensive analysis has revealed that mesenchymal cells predominantly engage in three key functions: ribosome-mediated protein synthesis and processing, cell adhesion facilitating intercellular support and communication, and a range of metabolic processes. Furthermore, our findings have identified several pivotal differentially expressed genes (e.g. C3, FN1, COL3A1, COL1A1, NRXN3), primarily associated with the complement and coagulation cascades, extracellular matrix (ECM) regulation, ECM receptor interactions, and cell adhesion molecules. In essence, our study provides a comprehensive transcriptomic dataset and novel insights into adhesive molecule and integrin networks within mesenchymal subclusters in endometriosis. This, in effect, has deepened the understanding of the pathomechanisms governing this condition. Show less

An increasing number of studies have demonstrated a strong correlation between metabolism, inflammation, and chronic obstructive pulmonary disease (COPD). However, it remains unclear if there is a causal relationship between these factors. This study employed the Mendelian randomization (MR) approach to investigate the associations between these factors and explore the mediating roles of key inflammatory proteins. MR was used to assess the causal associations between plasma metabolites, inflammatory proteins, and COPD. Sensitivity analyses were performed to verify the robustness of the findings. Mediation analysis was conducted to explore the roles of inflammatory proteins in the metabolism-COPD pathway. We constructed protein-protein interaction (PPI) network and explored the potential mechanism through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Single-cell sequencing and transcriptome datasets were used for auxiliary validation. Finally, experimental validation was performed using human lung tissue. This study identified 63 metabolites, 10 metabolite ratios, and 48 inflammatory proteins that were associated with COPD, all of which exhibited potential causal relationships. Furthermore, three proteins were identified as mediators in the metabolite-to-COPD pathway. PPI network, GO and KEGG enrichment analysis revealed the biological pathways in which they were involved. Validation of the expression of these three intermediary proteins in lung tissue demonstrated that NRXN3 was expressed in pulmonary endothelial cells and exerted a protective effect against COPD development. The MR analysis revealed causal associations among metabolism, inflammation, and COPD. These findings offer novel insights into metabolism-inflammation-COPD mechanisms, suggesting that interventions targeting metabolic processes may represent a promising strategy for preventing the onset or progression of COPD. Show less

While spermatogenesis has been extensively characterized in mammals, its molecular underpinnings in avian species remain largely unexplored. To address this knowledge gap, we performed single-cell transcriptomic profiling of duck testes across developmental stages (10-week immature vs. 23-week mature). Our analysis generated a comprehensive cellular atlas comprising 54,702 cells, resolving eight germ cell clusters (three spermatogonia [SPG], three spermatocytes [SPC], two spermatozoa [SPT]) and nine somatic populations, including peritubular myoid cells, immune subsets (T cells, macrophages, granulocytes), endothelial cells, Leydig cells, and three Sertoli cell subtypes, each defined by unique marker gene signatures. Furthermore, novel marker genes were identified, including EXFABP for granulocyte, ARHGAP15 for T cell regulation, FDX1 specific to Leydig cells (LC), and TSSK3/TSSK2 linked to elongated spermatid formation (SPT). Notably, we identified some novel molecular markers distinguishing these populations. Pseudotemporal trajectory reconstruction of germline development revealed stage-specific enrichment of ribosome, endoplasmic reticulum protein processing, and autophagy pathways. Core regulators MRPL13, MRPL2, MRPL22, MRPS14, MRPS7 (ribosome), HSPA5 (ER stress response), and PIK3C3 (autophagy) emerged as molecular hubs showing progressive downregulation during differentiation. Comparative transcriptomic analysis of germ cells and Sertoli cells between immature (IMT) and mature (MT) testes revealed significant enrichment of the spliceosome pathway in both germ and Sertoli cells. Critical spliceosome components SNRPG, SF3B3, and SNRPF exhibited coordinated downregulation during testicular maturation, suggesting their role as negative regulators of spermatogenic progression. This study establishes the first high-resolution cellular blueprint of avian spermatogenesis, delineating regulatory networks of duck testis cell development. Our findings provide valuable datasets and mechanistic insights into the evolutionary specialization of reproductive strategies in poultry. Show less

Endothelial-to-mesenchymal transition (EndMT) induced by dysfunctional pulmonary artery endothelial cells (PAECs) is regarded as an initiating and pivotal factor in pulmonary hypertension (PH). This study focuses on identifying a novel therapeutic target for regulating EndMT in PH. A comprehensive analysis of 2 hypoxic PAECs datasets yielded 310 overlapping upregulated and 229 downregulated differentially expressed genes (DEGs). These upregulated DEGs were primarily enriched in HIF-1 signalling pathway and glycolysis/gluconeogenesis, while downregulated only in spliceosome, as indicated by KEGG. Through PPI network analysis and the application of MCC algorithms, 5 hub genes were identified among these upregulated DEGs: GAPDH, LDHA, ALDOA, PFKL, and PFKP. Their enrichment in the 2 aforementioned pathways was confirmed by cross-pathway DEGs analysis and ClueGo. Among the hub genes, LDHA was chosen as the key gene based upon expression and correlation analysis of the validation set from PH patients. Subsequent GSEA also revealed the enrichment of LDHA in these 2 pathways. Additionally, the increased expression of LDHA protein in tissues and cells was confirmed, and the elevated enzymatic activity of LDHA in clinical serum samples was also verified. From 2 online databases, 4 LDHA inhibitors were filtered out, and the stable binding between the inhibitors and the LDHA protein was confirmed through molecular docking and molecular dynamics simulation. Finally, the experimental results indicated that one of the inhibitors FX11 reversed EndMT by inhibiting the lactate-SNAI1 axis, thereby alleviating hypoxia-induced PH. The potential of LDHA as a therapeutic target for PH by modulating EndMT was proposed in this study. Show less

Preventing the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the AKI-to-CKD transition and its underlying mechanisms. Renal biopsies from patients with AKI showed marked upregulation of WNT5A and its receptor, CD146, in proximal tubules, with higher expression in patients with CKD progression. In murine AKI models, Wnt5a knockdown attenuated CKD progression. Conversely, proximal tubular overexpression of Wnt5a exacerbated renal fibrosis in ischemia-reperfusion injury (IRI) mice, which was alleviated by Box5, a specific WNT5A antagonist. In vitro, WNT5A overexpression in transforming growth factor β (TGF-β)-stimulated HK-2 cells promoted CD146 upregulation, activated JNK phosphorylation, and enhanced SNAI1 expression. The genetic silencing of WNT5A/CD146 and JNK inhibition suppresses SNAI1 expression and attenuates fibrotic responses. Mechanistically, JNK-mediated c-JUN phosphorylation promoted its interaction with KLF5 at the SNAI1 promoter, driving renal fibrosis. Elevated serum levels of soluble CD146 correlated with renal function in patients with AKI and were higher in patients exhibiting CKD progression. Inhibition of WNT5A could serve as a therapeutic target for delaying renal fibrosis in AKI progression. Show less

Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progression of hepatocellular carcinoma (HCC) are yet largely unexplored. Here, we demonstrated that VRK1 expression is elevated in HCC tumor tissues, which is associated with high tumor stage and poor prognosis in HCC patients. In vitro and in vivo experiments manifested that VRK1 overexpression significantly promotes cell proliferation, colony formation, migration and tumor growth of HCC by inducing epithelial-mesenchymal transition (EMT) program. Mechanistically, immunoprecipitation combined with mass spectrometry analysis determined that VRK1 interacts with CHD1L, which mediates the phosphorylation of CHD1L at serine 122 site. RNA-seq revealed that one of the key downstream target genes of VRK1 is SNAI1, by which VRK1 promotes EMT process and HCC progression. Furthermore, VRK1 upregulates SNAI1 expression through phosphorylating CHD1L. In conclusion, these findings suggested that VRK1/CHD1L/SNAI1 axis acts as a cancer-driving pathway to promote the proliferation and EMT of HCC, indicating that targeting VRK1 may be an attractive therapeutic strategy of HCC. Show less

Diabetic retinopathy (DR) is the main cause of blindness worldwide, and its prevalence rate is constantly rising. More in-depth exploration of its risk factors and pathogenic mechanisms is needed. This study systematically identified potential therapeutic targets for DR by evaluating causal effects of 16,989 genes and 2,923 proteins on DR/subtypes via two-sample Mendelian randomization (MR), validated with colocalization/Summary-data-based Mendelian randomization (SMR). National Health and Nutrition Examination Survey (NHANES) 1999-2010 cross-sectional data (weighted logistic/Restricted cubic spline (RCS)) pinpointed key risk factors; MR explored their links to DR subtypes. Bioinformatics (bulk and single-cell transcriptomics) analyzed molecular mechanisms of shared targets (gene expression, immune infiltration, pathway enrichment). Machine learning selected key targets for models. Finally, two-step mediation MR examined how targets regulate DR via risk factors. This study identified 64 core targets with causal links to DR. Subtype analysis revealed 2,128 causal genes and subtype-specific targets (e.g. 52 for background DR, 66 for proliferative DR). SMR validated these findings. NHANES data highlighted body mass index (BMI), stroke, hypertension (HBP), and C-reactive protein (CRP) as key DR risk factors, confirmed by MR. Transcriptomics identified 29 differentially expressed genes associated with both risk factors and DR, linked to immune cell regulation. Machine learning selected core targets (LY9, WWP2, etc.) and built a nomogram for DR risk prediction. Functional enrichment showed these targets enriched in chemokine/cytokine and immune-inflammatory pathways. Two-step mediation MR further revealed LY9, ARHGAP1, and WWP2 influence DR subtypes via regulating BMI, CRP, and HBP. This study systematically elucidates the key risk factors, potential molecular mechanisms, and core regulatory targets of DR through multi-omics integration, causal inference, and bioinformatics approaches. The results indicate that inflammation, immune dysregulation, and metabolic disorders play crucial roles in the pathogenesis of DR. Key genes such as LY9, ARHGAP1, and WWP2 could serve as potential intervention targets, offering theoretical foundations and strategic support for early warning and precision treatment of DR. Show less

Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulates cell proliferation and differentiation. Whether WWP2 plays a regulatory role in AKI remains to be elucidated. We aimed to investigate the implication of WWP2 in AKI and its underlying mechanism in the present study. We utilized renal tissues from patients with AKI and established AKI models in global or tubule-specific knockout (cKO) mice strains to study WWP2's implication in AKI. We also systemically analyzed ubiquitylation omics and proteomics to decipher the underlying mechanism. In the present study, we found that WWP2 expression significantly increased in the tubules of kidneys with AKI. Global or tubule-specific knockout of WWP2 significantly aggravated renal dysfunction and tubular injury in AKI kidneys, whereas WWP2 overexpression significantly protected tubular epithelial cells against cisplatin. WWP2 deficiency profoundly affected autophagy in AKI kidneys. Further analysis with ubiquitylation omics, quantitative proteomics and experimental validation suggested that WWP2 mediated poly-ubiquitylation of CDC20, a negative regulator of autophagy. CDC20 was significantly decreased in AKI kidneys, and selective inhibiting CDC20 with apcin profoundly alleviated renal dysfunction and tubular injury in the cisplatin model with or without WWP2 cKO, indicating that CDC20 may serve as a downstream target of WWP2 in AKI. Inhibiting autophagy with 3-methyladenine blocked apcin's protection against cisplatin-induced renal tubular cell injury. Activating autophagy by rapamycin significantly protected against cisplatin-induced AKI in WWP2 cKO mice, whereas inhibiting autophagy by 3-methyladenine further aggravated apoptosis in cisplatin-exposed WWP2 KO cells. Taken together, our data indicated that the WWP2/CDC20/autophagy may be an essential intrinsic protective mechanism against AKI. Further activating WWP2 or inhibiting CDC20 may be novel therapeutic strategies for AKI. Show less

The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies. Show less

Osteoarthritis is recognized as a common geriatric condition characterized by irregular chronic pain. Its prevalence is steadily increasing, posing significant challenges to global public health, while some studies indicate a trend towards younger individuals being affected. This condition severely impacts patients' quality of life. Using the Gene Expression Omnibus (GEO) database, we downloaded datasets GSE114007, GSE169077, and GSE206848. We utilized R software to screen and confirm differentially expressed genes (DEGs) related to the development of osteoarthritis. A cross-analysis of the three datasets was conducted, with the least overlapping dataset, GSE206848, selected as the validation set. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the DEGs from GSE114007 and GSE169077. Weighted Gene Co-Expression Network Analysis (WGCNA) was employed to identify modules closely associated with osteoarthritis, and genes from these intersecting modules were entered into the STRING database to construct Protein-Protein Interaction Networks. The top ten genes by connectivity were identified and validated using GSE206848. Key genes were identified and preliminarily validated using Quantitative Real-Time PCR (QPCR). Subsequent validation of related genes was carried out through Western Blot (WB) analysis. Differentially expressed genes were identified from the GSE114007 and GSE169077 datasets and validated in the GSE206848 dataset, with ANGPTL4 selected as the key gene. QPCR results indicated a significant difference in ANGPTL4 expression levels between normal and osteoarthritic chondrocytes. Western Blot analysis confirmed a significant difference in ANGPTL4 protein expression between normal and osteoarthritic chondrocytes. Based on the experimental findings, ANGPTL4 appears to be a potential key gene in osteoarthritis. Show less

Increasing evidence suggests that metabolic disorders such as obesity are implicated in the development of Alzheimer's disease (AD). The pathological buildup of lipids in microglia is regarded as a key indicator in brain aging and the progression of AD, yet the mechanisms behind this process remain uncertain. The adipokine ANGPTL4 is strongly associated with obesity and is thought to play a role in the advancement of neurodegenerative diseases. This study utilized RNA sequencing to identify differential expression in lipid-accumulating BV2 microglia and investigated the potential mechanism through ANGPTL4 overexpression in BV2. Subsequently, animal models and clinical data were employed to further explore alterations in circulating ANGPTL4 levels in AD. RNA sequencing results indicated a correlation between ANGPTL4 and microglial lipid accumulation. The overexpression of ANGPTL4 in microglia resulted in increased secretion of inflammatory factors, elevated oxidative stress levels, and diminished antiviral capacity. Furthermore, when simulating the coexistence of AD and obesity through combined treatment with Amyloid-Beta 1-42 peptide (Aβ) and Free Fatty Acids (FFA) in vitro, we observed a notable upregulation of ANGPTL4 expression, highlighting its potential role in the interplay between AD and obesity. In vivo experiments, we also observed a significant increase in ANGPTL4 expression in the hippocampus and plasma of APP/PS1 mice compared to wild-type controls. This was accompanied by heightened microglial activation and reduced expression of longevity-related genes in the hippocampus. Clinical data from the UK Biobank indicated that plasma ANGPTL4 levels are elevated in patients with AD when compared to healthy controls. Moreover, significantly higher ANGPTL4 levels were observed in obese AD patients relative to their non-obese counterparts. Our findings suggest that ANGPTL4-mediated microglial aging may serve as a crucial link between AD and obesity, proposing ANGPTL4 as a potential biomarker for AD. Show less

Although progress has been made in the treatment of LAUD, the survival rate for patients remains poor. An in-depth grasp of the molecular pathways implicated in LUAD progression is vital for improving diagnosis and treatment strategies. This study aims to explore novel molecular mechanisms driving LUAD progression and identify new potential prognostic biomarkers for LAUD patients. Based on mass spectrometry analysis of human LUAD tissues, HNRNPD and MAD2L2 were identified as potential key proteins involved in LUAD progression. Subsequently, the interplay between HNRNPD and MAD2L2 was examined through dual-luciferase reporter assays, RNA-seq analysis, and various molecular biology techniques. Ultimately, the role of the HNRNPD/MAD2L2 axis in LUAD advancement and its potential as a prognostic indicator were investigated utilizing LUAD specimens, cell lines, and xenograft mouse models. In human LAUD tissues and cell lines, elevated levels of HNRNPD and MAD2L2 proteins were discovered. It was determined that HNRNPD binds to the MAD2L2 promoter, forming a regulatory axis at the transcriptional level. Subsequently, both in vitro and in vivo data demonstrated that the downregulation of the HNRNPD/MAD2L2 axis inhibited LUAD progression, while this effect could be rescued by MAD2L2 upregulation. Conversely, the upregulation of the HNRNPD/MAD2L2 axis facilitated LUAD progression, and this outcome could be reversed by MAD2L2 knockdown. Mechanistically, the downregulation of HNRNPD suppressed the promoter activity and transcription of MAD2L2, thus inhibiting the PI3K/HIF1α/ANGPTL4 pathway and tumor angiogenesis. Finally, it was confirmed that LUAD patients with high levels of both HNRNPD and MAD2L2 exhibited the poorest prognosis. Therefore, the HNRNPD/MAD2L2 axis has been identified as a potential predictive indicator for LUAD patients. The HNRNPD/MAD2L2 axis facilitates LUAD progression and serves as a potential prognostic biomarker. Show less