Cervical cancer remains one of the leading causes of cancer-related deaths among women globally, and there is still a need to research molecular targets that can be used for prognosis assessment and p Show more
Cervical cancer remains one of the leading causes of cancer-related deaths among women globally, and there is still a need to research molecular targets that can be used for prognosis assessment and personalized molecular therapies. Here, we investigate the role of potential molecular target ribosomal L22-like 1 (RPL22L1) on cervical cancer, identify its potential mechanisms, and explore its related applications in prognosis and molecular therapies. Multiple cervical cancer cohorts online, tissue microarrays and clinical tissue specimens were analyzed for the association between RPL22L1 expression and patient outcomes. Functional and molecular biology studies of cell and mice models were used to clarify the effects and potential mechanisms of RPL22L1 on cervical cancer. RPL22L1 is highly expressed in both cervical adenocarcinoma and squamous cell carcinoma, and its expression is significantly associated with histology grade, clinical stage, recurrence, vascular space involvement, tumor sizes and poor prognosis. In vitro and in vivo experiment revealed that RPL22L1 overexpression significantly promoted cervical cancer cell proliferation, migration, invasion, tumorigenicity and Sorafenib resistance, which were attenuated by RPL22L1 knockdown. Mechanistically, RPL22L1 competitively binds to ERK phosphatase DUSP6, leading to excessive activation of ERK. The combined application of ERK inhibitors can effectively inhibit RPL22L1 overexpressing cervical cancer cells both in vivo and in vitro. RPL22L1 promotes malignant biological behavior of cervical cancer cells by competitively binding with DUSP6, thereby activating the ERK pathway. The combined use of Sorafenib and an ERK inhibitor is a potentially effective molecular targeted therapy for RPL22L1-high cervical cancer. Show less
Liver and lung are the most common metastatic sites in colorectal cancer (CRC), where the tumor microenvironment (TME) plays a crucial role in the progression and metastasis of CRC. Understanding the Show more
Liver and lung are the most common metastatic sites in colorectal cancer (CRC), where the tumor microenvironment (TME) plays a crucial role in the progression and metastasis of CRC. Understanding the interactions between various types of cells in the TME can suggest innovative therapeutic strategies. Using single-cell RNA sequencing (scRNA-Seq) and clinical samples, fibroblast growth factor-19 (FGF19, rodent FGF15) is found to mediate a significant interaction between CRC cells and cancer-associated fibroblasts (CAFs), activating the hepatic stellate cells (HSCs)-to-CAFs differentiation. In various CRC metastatic mouse models, it is shown that FGF15 has a more pronounced effect on liver metastasis compared to pulmonary metastasis. More importantly, the differentially expressed genes (DEGs) are also identified from the RNA-Seq dataset upon the activation of HSCs by FGF19 and compared the DEGs in matched primary and metastatic mRNA samples from patients with CRC liver metastasis (CRCLM), it is found that the ANGPTL4 gene is significantly associated with HSCs activation. Different mouse models also demonstrated the impact of the FGF19/ANGPTL4 axis on the severity of CRCLM. Importantly, disruption of this axis significantly inhibits CRCLM in vivo. This study is among the first to demonstrate the impact of the FGF19/ANGPTL4 axis on CRCLM, offering a novel therapeutic strategy. Show less
Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborat Show more
Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients. Show less
G-protein coupled receptor 146 (GPR146)-deficient mice exhibit a moderate 21 % reduction in plasma cholesterol. This is associated with decreased phosphorylation of ERK1/2 and reduced SREBP2 activity Show more
G-protein coupled receptor 146 (GPR146)-deficient mice exhibit a moderate 21 % reduction in plasma cholesterol. This is associated with decreased phosphorylation of ERK1/2 and reduced SREBP2 activity in the liver, which leads to lower VLDL secretion. Insight into the role of GPR146 in humans is however limited. We therefore set out to study rare genetic variants in GPR146 to improve our understanding of this new player in lipid metabolism. We used whole genome sequencing data from UK Biobank participants to search for rare coding variants in GPR146. We first carried out gene-based burden tests (using SAIGE-GENE-framework) and examined the association of individual variants with plasma cholesterol levels. One of the variants (P62L) was also studied using the Global Lipids Genetics Consortium (GLGC) data set and in a knock-in mouse model. We found that the combination of rare genetic variants identified in GPR146 is significantly associated with plasma cholesterol levels. Three rare variants, i.e. P62L, I129I, and A175T were individually associated with reduced plasma cholesterol. In the GLGC cohort, the P62L variant was associated with reductions in both HDL and LDL cholesterol. Follow-up experiments show lower plasma cholesterol levels in GPR146 This study shows that rare GPR146 gene variants are associated with lower plasma cholesterol levels in humans. One of these variants, P62L is associated with reductions of HDL cholesterol and LDL cholesterol in humans while the ortholog in mice confers a loss of GPR146 function leading to only reduced HDL cholesterol. How GPR146 affects HDL metabolism in humans and mice remains to be resolved. Show less
Polychlorinated biphenyls (PCBs) are environmental pollutants associated with various health issues, including breast cancer. This study investigates potential molecular mechanisms by which PCBs may i Show more
Polychlorinated biphenyls (PCBs) are environmental pollutants associated with various health issues, including breast cancer. This study investigates potential molecular mechanisms by which PCBs may influence breast cancer progression using computational and preliminary experimental approaches. We conducted a differential expression analysis using the TCGA-BRCA dataset. PCBs-related toxicological targets were collected from the Comparative Toxicogenomics Database (CTD). Enrichment and pathway analyses identified candidate biological processes and pathways. Protein-protein interaction (PPI) networks were constructed to identify hub genes. Single-cell expression levels of key targets were analyzed (GSE114727 dataset). Molecular docking predicted binding affinities of PCBs congeners with key targets. Cell experiments assessed gene expression changes upon PCBs exposure. We identified 52 upregulated and 24 downregulated PCBs-related toxicological targets in breast cancer. Enrichment analysis highlighted potential associations with pathways such as PI3K-Akt, MAPK, and HIF-1, including genes like BRCA1, FGFR1, IGF1, AKT1, and EGF. PPI network analysis identified key hub genes like EZH2, EGF, BRCA1, AKT1, IL6, and TNF. Single-cell analysis suggested variable expression of key targets across immune cell types. Molecular docking predicted strong binding affinities of PCB 105 with EZH2 and EGF Our integrated analysis proposes that PCBs exposure may perturb key molecular pathways in breast cancer. Computational findings implicate targets like EZH2 and EGF, while preliminary cell experiments support further investigation. These results highlight a need for mechanistic studies to confirm PCB-induced effects and their therapeutic relevance, underscoring environmental pollutants as potential risk factors in cancer. Show less
Pericytes regulate cerebral blood flow (CBF) and excess amyloid in the brain. Pericyte dysfunction may contribute to the pathology of Alzheimer's disease (AD). Acorus tatarinowii (AT), a Chinese medic Show more
Pericytes regulate cerebral blood flow (CBF) and excess amyloid in the brain. Pericyte dysfunction may contribute to the pathology of Alzheimer's disease (AD). Acorus tatarinowii (AT), a Chinese medicine commonly used to treat AD, protects the central nervous system. However, whether AT can regulate pericyte function and ameliorate cognitive dysfunction remains unclear. We employed a novel target recognition assay, quantitative measurement of CBF, hematoxylin and eosin staining, immunofluorescence staining, and Western blot to investigate the role of AT in improving cognitive function in patients with AD. Additionally, we investigated the therapeutic potential of β-Asarone, the primary active compound in AT, for treating AD by modulating pericyte function using transmission electron microscopy, silver staining, electrical impedance, and other methodologies. The results revealed that administration of AT effectively alleviated the cognitive impairments induced by D-galactose in mice, as evidenced by enhanced CBF, improved histological characteristics of damaged brain tissue cells, increased expression of platelet-derived growth factor-β (PDGF-β), decreased Aβ accumulation via enhanced lipoprotein receptor-related protein 1 (LRP1), and reduced beta-site APP-cleaving enzyme 1 (BACE1). β-Asarone treatment mitigated ROS release and BACE1 expression while elevating the cell index in Aβ1-40 injured mouse brain vascular pericytes (MBVP). These findings suggest that AT has the potential to enhance CBF and mitigate pericellular dysfunction, thereby ameliorating Aβ deposition in the brain and improving cognitive impairment in patients with AD. Show less
Endothelial cells (ECs) senescence has emerged as a critical factor in the pathogenesis of atherosclerosis, contributing to vascular aging and plaque formation. However, the molecular mechanisms under Show more
Endothelial cells (ECs) senescence has emerged as a critical factor in the pathogenesis of atherosclerosis, contributing to vascular aging and plaque formation. However, the molecular mechanisms underlying endothelial senescence in atherosclerosis remain poorly understood. Single-cell RNA sequencing (scRNA-seq) data from atherosclerotic core plaques and adjacent normal tissues were analyzed using the Seurat package to identify cell subpopulations and senescence markers. RNA-seq data from early and late atherosclerotic plaques were used for differential gene expression analysis. Subsequently, the candidate gene was identified and validated in the atherosclerotic plaques of Single-cell analysis revealed elevated levels of senescence markers in ECs within atherosclerotic plaques. Combined with bulk RNA-seq analysis, This study highlights the critical role of endothelial senescence in atherosclerosis and identifies Show less
Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architect Show more
Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architecture remain undefined. We obtained genome-wide association study (GWAS) summary statistics for GERD (71 522 cases and 261 079 controls) and asthma (56 167 cases and 352 255 controls). Using linkage disequilibrium score regression (LDSC), we assessed genetic correlations between GERD and asthma. Bidirectional Mendelian randomization (MR) was performed to investigate potential causal relationships, followed by cross-trait GWAS meta-analysis and colocalization analysis to identify shared risk loci. Additionally, summary-data-based MR and transcriptome-wide association study were conducted to pinpoint common functional genes. Finally, we analyzed gene expression profiles in both healthy individuals and GERD patients using esophageal single-cell RNA sequencing (scRNA-seq) data. We identified a significant genetic correlation between GERD and asthma ( rg = 0.37, P = 6.19 × 10 -38 ) and a significant causal effect of GERD on asthma [odds ratio (OR) = 1.22, P = 1.54 × 10 -5 ]. Cross-trait meta-analyses revealed 56 shared risk loci between GERD and asthma, including 51 loci that were newly identified. Three loci (rs61937247, rs7960225, and rs769670) exhibited evidence of colocalization. Gene-level analyses pinpointed three novel shared genes ( RBM6, SUOX , and MPHOSPH9 ) between GERD and asthma. scRNA-seq analysis uncovered heightened expression of these genes in immune cells of patients diagnosed with GERD. Our study has discovered novel shared genetic loci and candidate genes between GERD and asthma, providing further insights into the genetic susceptibility of comorbidity and potential mechanisms of the two diseases. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hep Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression. Although there is an increased understanding of MASH pathogenesis and newly approved resmetirom, given its complexity and heterogeneous pathophysiology, there is a strong necessity to develop more drug candidates with better therapeutic efficacy and well-tolerated safety profile. With an increased list of pharmaceutical candidates in the pipeline, it is anticipated to witness successful approval of more potential candidates in this fast-evolving field, thereby offering different categories of medications for selective patient populations. In this review, we update the advances in MASH pharmacotherapeutics that have completed phase II or III clinical trials with potential application in clinical practice during the latest 2 years, focusing on effectiveness and safety issues. The overview of fast-evolving status of pharmacotherapeutic candidates for MASH treatment confers deep insights into the key issues, such as molecular targets, endpoint selection and validation, clinical trial design and execution, interaction with drug administration authority, real-world data feedback and further adjustment in clinical application. Show less
To explore the risk factors of post pancreatectomy diabetes mellitus (PPTDM)in pancreatic ductal carcinoma (PDAC) patients and the value of perioperative fasting blood glucose (FBG) level expression o Show more
To explore the risk factors of post pancreatectomy diabetes mellitus (PPTDM)in pancreatic ductal carcinoma (PDAC) patients and the value of perioperative fasting blood glucose (FBG) level expression on the long-term survival after surgery. Between December 2015 and December 2019, a cohort of 509 patients diagnosed with PDAC and undergoing resection at our hospital was analyzed. They were stratified into two groups, Control group (Control) and study group (PPTDM), depending on the onset of postoperative diabetes mellitus. We analyzed the survival rates at 6 months, 12 months and 24 months post-operation in the two groups. We use univariate and logostic multivariate regressions to analyze the risk factors for PPTDM. ROC curve analysis was conducted to assess the diagnostic significance of perioperative FBG levels regarding patients' long-term survival rates. The Kaplan-Meier method was employed to assess the impact of both preoperative and postoperative FBG levels on the survival rates within 24 months for each patient group. The comparison of general clinical data between the two groups shows marginal differences without statistical significance(P > 0.05); Patients in PPTDM group had significantly higher BMI, preoperative jaundice proportion, larger tumor diameter, higher TNM stage and higher proportion of distal pancreatectomy (DP), with P values of 0.023, 0.010, 0.040, 0.012 and 0.005, respectively. The levels of preoperative FBG and postoperative FBG in PPTDM patients exhibited statistically significant elevation compared to the control group (P < 0.05). There were no significant differences in surgery-related indicators between the two groups in operative time, number of dissected positive lymph nodes, total number of dissected lymph nodes, intraoperative blood loss and other related data (P > 0.05). Hospitalization duration of PPTDM patients was longer than control group (P = 0.047). PPTDM group had significantly higher expression concentrations of BUN, Cr, TG, LDL and Apo-B factors (P = 0.023, 0.024, 0.013, 0.045 and 0.017). 17 patients (5.03%) died in the PPTDM group and 4 patients (2.35%) in control group which had significantly difference (P = 0.020). In univariate and logostic multivariate regression analysis indicated tumor size, jaundice, BUN, Cr, TG, LDL, Apo-B concentrations and DP approach were significantly correlated to the risk for PPTDM (P < 0.05). ROC curve analysis results showed combining of preoperative and postoperation FBG showed the highest diagnostic efficacy, followed by postoperation FBG and preoperative FBG. The AUC areas of the three groups were 0.745, 0.623 and 0.588, respectively, and the critical values of the three groups were 9.81/9.95 mmol/L, 10.18 mmol/L and 10.23 mmol/L, respectively, with statistical significance (P < 0.05). Results were considered statistically significant if the p-value was less than 0.05. PPTDM stands as a significant postoperative complication following pancreatic cancer surgery, characterized by a high incidence and severity. Several risk factors have garnered considerable attention among clinical surgeon. PPTDM may be an influential factor in postoperative prognosis of pancreatic cancer. The expression levels of preoperative and postoperative blood glucose hold diagnostic value for the long-term prognosis of pancreatic cancer patients. Early regulation and intervention by surgeons concerning perioperative FBG could potentially mitigate the risk of PPTDM. Show less
At present, there is no consensus on the relationship between selenium (Se) exposure and human serum lipid metabolism. The etiological role of high-Se exposure in lipid markers, dyslipidemia, and nona Show more
At present, there is no consensus on the relationship between selenium (Se) exposure and human serum lipid metabolism. The etiological role of high-Se exposure in lipid markers, dyslipidemia, and nonalcoholic fatty liver (NAFLD) remains unclear. We used serum untargeted metabolomics analysis to evaluate whether high-Se exposure is cross-sectionally associated with lipid metabolism in adults from high-Se exposure area (n = 112) and control area (n = 101) in Hubei Province, China. An untargeted liquid chromatography/mass spectrometry (LC/MS)-based metabolomic analysis identified 144 differential pathways and yielded 204 differentially abundant metabolites, including 32 lipid metabolites associated with lipids profiles. To further explore the correlation between Se exposure and serum lipid metabolism, we measured serum levels of lipid profiles among all the people, including serum cholesterol (CHOL), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (APOB). The average serum Se level of the high-Se exposure group was 537.18 μg/L, significantly higher than 72.98 μg/L in the control group (p < 0.0001). The measurement levels of serum TG, LDL-C, HDL-C, and APOB in the high-Se exposure group were 1.03 (0.76, 1.34) mmol/L, 2.25 ± 0.48 mmol/L, 1.12 ± 0.24 mmol/L, and 0.77 ± 0.15 g/L, respectively, while the control group were 1.13 (0.84, 1.80) mmol/L, 2.56 ± 0.61 mmol/L, 1.02 ± 0.22 mmol/L, and 0.83 ± 0.16 g/L, respectively (all p values <0.05). Correlation analysis showed a significant negative correlation between serum Se and CHOL (r = -0.201, p < 0.01), serum Se is also associated with metabolomics markers, the negative correlation includes glyceric acid and ect., the positive correlation includes phosphorylcholine and ect. Our study suggests that high-Se exposure is negatively associated with serum lipid profiles and decreases the risk of high-TC and HDL-C dyslipidemia. Show less
The integration of serum biomarkers and gene polymorphisms may enhance early prognostic assessment in sepsis. Early and accurate prediction of outcomes is crucial for optimizing treatment strategies a Show more
The integration of serum biomarkers and gene polymorphisms may enhance early prognostic assessment in sepsis. Early and accurate prediction of outcomes is crucial for optimizing treatment strategies and improving survival. However, the clinical utility of combining genetic markers with conventional inflammatory indicators remains insufficiently validated. In this retrospective cohort ( 6 predictors were retained - PCT, CRP, lactate (LAC), lactate clearance rate (LCR), TLR4 rs4986790, and PPARγ rs1801282. The nomogram achieved AUC 0.885 (95% CI 0.812-0.943) with sensitivity 88.6% and specificity 73.9%; calibration was good (H - L χ This integrative biomarker-genotype model demonstrated strong internal performance and potential clinical utility for individualized risk stratification in sepsis. The results support combining genetic susceptibility and inflammatory biomarkers for enhanced prognostic precision, although external and multi-ethnic validation remains warranted before widespread adoption. Show less
This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × L Show more
This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × Large, body weight = 2.58 ± 0.05 kg) were divided into three treatment groups based on similar body weights and equal numbers of males and females: the blank control group (CON group), the PEDV infection group (PEDV group), and the NG intervention + PEDV infection group (NG + PEDV group) ( Show less
Dysregulation of the fibroblast growth factor receptor 1 (FGFR1) signaling has prompted efforts to develop therapeutic agents, which is a carcinogenic driver of many cancers, including breast, prostat Show more
Dysregulation of the fibroblast growth factor receptor 1 (FGFR1) signaling has prompted efforts to develop therapeutic agents, which is a carcinogenic driver of many cancers, including breast, prostate, bladder, and chronic myeloid leukemia. Despite significant progress in the development of potent and selective FGFR inhibitors, the long-term efficacy of these drugs in cancer therapy has been hampered by the rapid onset of acquired resistance. Therefore, more drug discovery strategies are needed to promote the development of FGFR-targeted drugs. Here, we discovered compound S2h, a compound that selectively and effectively degrades FGFR1 at nanomolar concentrations in KG1a cells (IC Show less
Alpha-enolase (ENO1), the enzyme catalyzing 2-phosphoglycerate conversion to phosphoenolpyruvate, is highly expressed in diffuse large B-cell lymphoma (DLBCL) and correlates with adverse clinical outc Show more
Alpha-enolase (ENO1), the enzyme catalyzing 2-phosphoglycerate conversion to phosphoenolpyruvate, is highly expressed in diffuse large B-cell lymphoma (DLBCL) and correlates with adverse clinical outcomes. Thus, understanding the relationship between ENO1-related gene (ERG) network and DLBCL is imperative. Here, we integrated multi-omics profiling (RIP-seq, RNA-seq, and protein interactome analysis) to identify ERGs and established a prognostic model by machine learning algorithms. We identified eleven hub genes (CHERP, SYNE2, INTS1, FAP, MMP9, LRP5, RBM8A, PRMT5, SLC25A6, PABPC4, PSTPIP2) using RNA sequencing, RNA immunoprecipitation sequencing, and protein interaction profiling. A prognostic model was constructed using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression in the GSE10846 dataset and validated in two independent cohorts. DLBCL patients were stratified into high- and low-risk groups based on the model, and clinical characteristics were compared. The tumor immune microenvironment (TIME) was analyzed using CIBERSORT and xCell algorithms to explore correlations with the ERG score. Drug sensitivity assays in DLBCL cell lines were performed to validate the model's predictive capacity for chemotherapy response. Furthermore, the functional role of PABPC4, a key gene in the scoring system, was investigated through A prognostic model including 11 hub genes was established. Patients in the high-risk group exhibited worse clinical outcomes and an immunosuppressive TIME, characterized by altered expression of immune checkpoint-related proteins. This group demonstrated increased sensitivity to vincristine, etoposide, and oxaliplatin. Knockdown of PABPC4 significantly inhibited cell proliferation, reduced colony formation, and delayed tumor growth The ERG scoring system offers a robust and precise tool for predicting survival and guiding personalized treatment in DLBCL patients. Show less
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiolo Show more
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. To comprehensively identify the metabolic causal factors and potential drug targets for PCOS. This genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. The PCOS cohort included 10,074 PCOS cases (mean age 28 to 45 years) and 103,164 controls (mean age 27 to 60 years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95 % CI, 2.65-4.36]), triglyceride (TG) (OR = 1.54 [95 % CI, 1.17-2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95 % CI, 1.07-1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95 % CI, 1.09-1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95 % CI, 0.47-0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactions among these metabolic factors, identifying BMI and HDL-c as the most prominent causal factors. Notably, drug-target MR analysis identified incretin-based therapeutics, PCSK9 inhibitors, LPL gene therapy, sulfonylureas, and thiazolidinediones as potential therapeutics for PCOS. All these findings were validated in an independent dataset. This study offered insights into the roles of obesity, diabetes, and dyslipidemia in PCOS etiology and therapeutics, underscoring the necessity for managing metabolic health in women and paving the way for tailored therapeutic strategies for PCOS based on its metabolic underpinnings. Show less
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases Show more
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases such as obesity. Several randomized controlled trials (RCTs) targeting obese or overweight populations have found that individuals with different genotypes exhibit varying responses to the same lifestyle intervention (gene-lifestyle intervention interactions). To date, more than 20 genes, including Show less
Microcystin-LR (MC-LR) is a toxin that causes hepatic steatosis. Our previous study found that exposure to 60 μg/L MC-LR for 9 months resulted in liver lipid accumulation, but the underlying mechanism Show more
Microcystin-LR (MC-LR) is a toxin that causes hepatic steatosis. Our previous study found that exposure to 60 μg/L MC-LR for 9 months resulted in liver lipid accumulation, but the underlying mechanisms remain elusive. Herein, for the first time, fatty acid-targeted metabolome and RNA-seq were combined to probe the effect and mechanism of chronic (12-month) MC-LR treatment on mice lipid metabolism at environmental-related levels (1, 60, and 120 μg/L). It was found that MC-LR dose-dependently raised serum and liver lipid levels. The total cholesterol (TC) levels in the liver were significantly increased following treatment with 1 μg/L MC-LR (equivalent to 0.004 μ/L in human). Treatment with 60 and 120 μg/L MC-LR significantly elevated TC and triglyceride (TG) levels in both serum and liver. Serum fatty acid-targeted metabolome analysis demonstrated that exposure to 1, 60, and 120 μg/L MC-LR caused significant alterations in the fatty acid profile. Chronic 1, 60, and 120 μg/L MC-LR treatment significantly increased serum polyunsaturated fatty acids (PUFAs), including conjugated linoleic acid and eicosapentaenoic acid, which positively correlated with serum or liver TG levels. Chronic exposure to 120 μg/L MC-LR led to a significant decrease in the accumulation of saturated fatty acids, including citramalic acid, pentadecanoic acid, and docosanoic acid, which were negatively correlated with serum or liver lipid levels. These findings suggested that 1 μg/L MC-LR exposure caused mild lipid metabolism disruption, while 60 and 120 μg/L MC-LR treatment resulted in pronounced hepatic steatosis in mice. Transcriptome analysis revealed that chronic environmental MC-LR treatment regulated the expression of genes involved in the phosphatidylinositol 3-kinase (PI3K) complex and fatty acid metabolism. Western blotting and RT-qPCR confirmed that chronic environmental MC-LR exposure activated the PI3K/AKT/mTOR signaling pathway, the downstream of Show less
Based on the Caco-2 cell heat stress model, the study explored the heat stress preventive regulatory mechanisms of key polyphenol fractions in mung bean by metabolomics and transcriptomics association Show more
Based on the Caco-2 cell heat stress model, the study explored the heat stress preventive regulatory mechanisms of key polyphenol fractions in mung bean by metabolomics and transcriptomics association analysis. Results Mung bean polyphenol intervention before heat stress significantly reduced the elevated expression level of heat shock protein 70 (HSP70) caused by 39 °C temperature. At the metabolic level, mung bean polyphenols could play a role in heat stress regulation by alleviating oxidative stress damage. At the gene level, mung bean polyphenols showed regulation of cell proliferation, differentiation, and DNA damage, with DUSP6 and NEURL3 as key regulatory genes. The correlation analysis showed that nucleotide metabolism, and oxidative phosphorylation metabolism were the key pathways in the regulation of mung bean polyphenols by heat stress. Then mung bean polyphenols can exert heat stress preventive activity through the regulation of cellular oxidative damage and energy metabolism. This study provides a good idea for the research and development of dietary intervention products for heat stress. 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 im Show more
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
Cholesterol metabolism (CM) plays essential roles in human disease. Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with significant morbidity and healthcare burden. However Show more
Cholesterol metabolism (CM) plays essential roles in human disease. Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with significant morbidity and healthcare burden. However, the role of CM in UC remains unclear. Gene expression data of UC patients and control samples were retrieved and merged from GSE75214, GSE92415, GSE16879, and GSE48958. Differential analysis was performed for the identification of cholesterol homeostasis-related differentially expressed genes (DEGs), followed by machine learning for cholesterol homeostasis-related hub DEGs. Five cholesterol homeostasis related genes were identified. We further assessed the related pathways of 5 hub genes. Five overlapped cholesterol homeostasis related genes were identified by DEGs analysis. LIPC, LIPG, CETP, ABCB11, and APOH were identified as hub genes. The current study identified 5 cholesterol homeostasis related genes, LIPC, LIPG, CETP, ABCB11, and APOH, that might play key roles in the development of UC. These findings offer new insights for further exploring UC and its underlying mechanisms. Show less
This study aimed to investigate the role of SIRT4 in retinal protection, specifically its ability to mitigate excitotoxic damage to Müller glial cells through the regulation of mitochondrial dynamics Show more
This study aimed to investigate the role of SIRT4 in retinal protection, specifically its ability to mitigate excitotoxic damage to Müller glial cells through the regulation of mitochondrial dynamics and glutamate transporters (GLASTs). A model of retinal excitatory neurotoxicity was established in mice. Proteins related to mitochondrial dynamics, GLAST, and SIRT4 were analyzed on days 0, 1, 3, and 5 following toxic injury. The influence of SIRT4 on mitochondrial dynamics-related proteins and GLAST was examined by inducing SIRT4 overexpression through intraperitoneal injection of resveratrol or by using SIRT4 knockout (KO) mice. Additionally, the effects of upregulating and downregulating SIRT4 expression in rat Müller glial cell lines (rMC-1) were explored via lentiviral vector transfection to assess changes in mitochondrial morphology and GLAST expression. After excitotoxic injury to the mouse retina, the retinal thickness and structure were disrupted, the number of retinal ganglion cells (RGCs) decreased, and Müller glial cells were activated by day 1. The levels of OPA1, GLAST, and SIRT4 proteins peaked on the first day after injury and then gradually decreased, indicating a synchronized dynamic trend. The upregulation of SIRT4 expression promoted OPA1 and GLAST protein expression, thereby alleviating retinal excitotoxic injury. Furthermore, the upregulation of SIRT4 expression promoted mitochondrial fusion and increased GLAST expression in rMC-1 cells, reducing cellular excitotoxic damage. Conversely, downregulation of SIRT4 had the opposite effect. SIRT4 plays a significant role in mitigating excitotoxic damage in the retina, modulating Müller glial cell injury by regulating mitochondrial dynamics and glutamate transporter expression, ultimately influencing retinal health. Show less
Yuemei Zhang, Yuxin Cao, Yongxin Sun+12 more · 2025 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
The activation of blood monocytes and the infiltration of monocyte-derived macrophages into the vessel walls are the central part of atherosclerosis. However, the mechanisms underlying the processes r Show more
The activation of blood monocytes and the infiltration of monocyte-derived macrophages into the vessel walls are the central part of atherosclerosis. However, the mechanisms underlying the processes remain unclear. Here, we report that G-protein signaling modulator 1 (GPSM1) plays a critical role in atherogenesis. We found that GPSM1 expression in lesional macrophages was increased during atherosclerosis development both in mice and humans. Myeloid-specific GPSM1 ablation protects mice against atherosclerosis and reduces aortic inflammation in both Show less
Problematic smartphone use (PSU) has become a growing concern among young populations, raising significant issues for their physical and psychological well-being. Guided by Compensatory Internet Use T Show more
Problematic smartphone use (PSU) has become a growing concern among young populations, raising significant issues for their physical and psychological well-being. Guided by Compensatory Internet Use Theory and the Interaction of Person-Affect-Cognition-Execution (I-PACE) model, this study examined the associations between different forms of childhood trauma and PSU. Participants were 2717 college students (661 males, 22.49%; Mage = 19.81 years). Two chain mediation models were tested, and latent profile analysis (LPA) was employed to capture individual differences from a person-centred perspective. LPA revealed three distinct trauma profiles: low childhood trauma, moderate childhood abuse, and high childhood abuse. Across both variable-centred and person-centred ap-proaches, rumination and social anxiety were identified as mediators linking childhood trauma to PSU. These findings advance understanding of the pathways through which childhood trauma contributes to PSU in college students. By integrating variable- and person-centred approaches, the study highlights the importance of cognitive-emotional mechanisms and provides implications for targeted prevention and intervention strategies. Show less
DHAV-3 is one of the main causative agents of duck viral hepatitis (DVH), an acute and highly lethal infectious disease in duck industry. However, the understanding of the pathogenesis of this virus i Show more
DHAV-3 is one of the main causative agents of duck viral hepatitis (DVH), an acute and highly lethal infectious disease in duck industry. However, the understanding of the pathogenesis of this virus in ducklings is limited. To dissect the molecular characteristics associated with pathobiology of ducklings to DHAV-3, we applied single-cell RNA-sequencing approach to profile the transcriptome of 1.4 million cells from 14 livers of DHAV-3 susceptible (S) and resistant (R) ducklings during viral infection and 4 uninfected healthy controls. We found that infected S ducks exhibited the activation of type I and II interferon pathways with elevated expression of interferon-stimulated genes (ISGs) compared to infected R ducks and healthy controls. DHAV-3 promoted proinflammatory phenotype and inhibited the cell apoptosis pathway of Kupffer cells of S ducks. Furthermore, we observed the elevated expression of host factor PLAC8 in S ducks and validated its ability to facilitate the infection of DHAV-3. We identified significant dysregulation of various genes in complement and coagulation cascades in hepatocytes2 exclusive to S ducks, together with over-secretion of ANGPTL4 from endothelial cells in S ducks which is confirmed to promote cellular migration, suggesting etiology of coagulopathic complications in ducks with severe DVH. Collectively, this study provides a rich resource for understanding the inflammatory immune signatures and cell communications underlying the pathogenesis of DHAV-3 infection, which may accelerate the development of better diagnostic methods and strategies for controlling this disease. Show less
Vascular calcification (VC) significantly increases the incidence and mortality of many diseases. The causal relationships of dyslipidaemia and lipid-lowering drug use with VC severity remain unclear. Show more
Vascular calcification (VC) significantly increases the incidence and mortality of many diseases. The causal relationships of dyslipidaemia and lipid-lowering drug use with VC severity remain unclear. This study explores the genetic causal associations of different circulating lipids and lipid-lowering drug targets with coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC). We obtained single-nucleotide polymorphisms (SNPs) and expression quantitative trait loci (eQTLs) associated with seven circulating lipids and 13 lipid-lowering drug targets from publicly available genome-wide association studies and eQTL databases. Causal associations were investigated by univariable, multivariable, drug-target, and summary data-based Mendelian randomization (MR) analyses. Potential mediation effects of metabolic risk factors were evaluated. MR analysis revealed that genetic proxies for low-density lipoprotein cholesterol (LDL-C), triglycerides (TC) and Lipoprotein (a) (Lp(a)) were causally associated with CAC severity, and apolipoprotein B (apoB) level was causally associated with AAC severity. A significant association was detected between hepatic Lipoprotein(A) (LPA) gene expression and CAC severity. Colocalisation analysis supported the hypothesis that the association between LPA expression and CAC quantity is driven by different causal variant sites within the ±1 Mb flanking region of LPA. Serum calcium and phosphorus had causal associations with CAC severity. Inhibitors targeting LPA might represent CAC drug candidates. Moreover, T2DM, hypercalcemia, and hyperphosphatemia are positively causally associated with CAC severity, while chronic kidney disease and estimated glomerular filtration rate are not. Show less