BACKGROUND:Studies have confirmed that Pterocarya hupehensis skan total flavonoids(PHSTF)can improve the level of collagen-induced arthritis in rats,but there is still a lack of research on the regulation of Wnt/β-catenin signaling pathway in fibroblast-like synoviocytes and its effect on related cell functions.OBJECTIVE:To investigate the effect and mechanism of PHSTF on lipopolysaccharide-induced proliferation,migration and apoptosis of fibroblast-like synoviocytes based on the Wnt/β-catenin signaling pathwayMETHODS:Fibroblast-like synoviocytes were divided into control group,lipopolysaccharide group,lipopolysaccharide+low-,medium-,and high-dose PHSTF groups(10,20,and 40 μg/mL),lipopolysaccharide+Wnt pathway inhibitor DKK1 group,and lipopolysaccharide+Wnt pathway inhibitor DKK1+high-dose PHSTF group(40 μg/mL).The cell counting kit-8 method was used to detect the effect of PHSTF on the viability of fibroblast-like synoviocytes,and the final drug concentration and time were screened.Flow cytometry was used to detect the apoptosis of fibroblast-like synoviocytes.Cell scratch assay,EDU staining and cell cloning assay were used to detect the migration and proliferation of fibroblast-like synoviocytes.Western blot assay was used to detect the protein expression levels of Wnt3a,β-catenin,tumorigenic genes,matrix metalloproteinase 2,matrix metalloproteinase 9,Bax and Bcl-2 in fibroblast-like synoviocytes.RESULTS AND CONCLUSION:(1)Compared with the control group,the cell viability decreased significantly when the concentration of PHSTF was＞40 μg/mL(P＜0.01).Therefore,the drug concentration of≤40 μg/mL was selected for subsequent experiments.(2)Compared with the lipopolysaccharide group,the wound healing rate,cell clone formation rate and the number of EDU-positive cells in the low-,medium-and high-dose PHSTF groups were significantly reduced,while the apoptosis rate was significantly increased(P＜0.05-0.01).(3)Western blot results showed that compared with the lipopolysaccharide group,low-,medium-and high-dose PHSTF significantly inhibited cellular Wnt3a,β-catenin,cellular tumorigenic genes,matrix metalloproteinase 2,matrix metalloproteinase 9,and Bcl-2 protein expression,and promoted the expression of Bax protein(P＜0.01).(4)Compared with the DKK1 group,the combination of DKK1 and high-dose PHSTF significantly inhibited the protein expression of Wnt3a,β-catenin,matrix metalloproteinase 2,matrix metalloproteinase 9 and Bcl-2 protein expression and promoted the protein expression of Bax(P＜0.01).To conclude,PHSTF may inhibit the proliferation and migration of fibroblast-like synoviocytes and promote apoptosis by inhibiting the Wnt/β-catenin signaling pathway.

BACKGROUND:Rheumatoid arthritis is widely prevalent worldwide,with its high incidence and universality that considerably affects patients' quality of life.Previous studies have focused on a few immune cells or cytokines,whereas this study comprehensively provides a more complete view of the immune mechanisms in rheumatoid arthritis.OBJECTIVE:To explore the causal relationship between 731 immune cell phenotypes and rheumatoid arthritis using the Mendelian randomization method,thereby providing evidence of causality.METHODS:The 731 immune cell phenotypes used in this study were sourced from the GWAScatalog database,jointly developed by the National Human Genome Research Institute(NHGRI)and the European Bioinformatics Institute(EBI).The rheumatoid arthritis data were from the Finngen database,developed by the Finnish Institute for Molecular Medicine(FIMM).The inverse variance weighting method was employed as the primary analytical approach.Additionally,multiple analytical methods,including MR-Egger,weighted mode,simple mode,and weighted median,were concurrently utilized to complement the final results.Sensitivity analyses(Cochran's Q test,MR-Egger regression,and MR-presso analysis)were also conducted to verify the stability and feasibility of the data.RESULTS AND CONCLUSION:(1)After excluding results through heterogeneity testing,the inverse variance weighting analysis indicated that 10 absolute cell counts,15 median fluorescence intensities of surface antigen levels,1 morphological characteristic,and 9 relative cell counts had a causal relationship with the occurrence of rheumatoid arthritis.(2)According to cell classification,this study found that seven types of B cells,seven types of classical dendritic cells,six types of mature T cells,four types of monocytes,three types of myeloid cells,three types of TBNK cells(lymphocyte subset T cells,B cells and natural killer cells),and five types of Tregs had a causal association with the occurrence of rheumatoid arthritis.(3)Through comprehensive bidirectional two-sample MR analysis,we demonstrated the complex causal relationships between multiple immune phenotypes and rheumatoid arthritis,highlighting the intricate interaction patterns between the immune system and rheumatoid arthritis.These results provide new biomarkers for the early screening and diagnosis of rheumatoid arthritis in China,and help to improve the diagnostic accuracy and sensitivity.

Ulcerative colitis （UC）， a chronic relapsing inflammatory bowel disease， involves multifaceted pathological mechanisms such as intestinal barrier dysfunction， immune dysregulation， and oxidative stress. Current therapeutic strategies remain limited in efficacy and safety. In recent years， the adenosine monophosphate-activated protein kinase （AMPK） signaling pathway has emerged as a pivotal therapeutic target for UC due to its central role in energy metabolism， inflammatory regulation， and intestinal homeostasis. This article systematically reviewed the mechanisms by which traditional Chinese medicine （TCM） prevented and treated UC through the regulation of the AMPK signaling pathway， with a focus on elucidating AMPK's multidimensional regulatory network in inflammatory signaling crosstalk， alleviating oxidative stress， restoring intestinal immune balance， repairing the intestinal barrier， and modulating gut microbiota. Leveraging its unique advantages of multi-target engagement and low toxicity， TCM demonstrates promising potential in UC treatment and has become a focal area of research. By systematically summarizing and synthesizing the existing literature on TCM-mediated AMPK pathway modulation in UC， this review aims to provide a theoretical foundation for advancing mechanistic research and clinical interventions in UC.

BACKGROUND:Studies have confirmed that Pterocarya hupehensis skan total flavonoids(PHSTF)can improve the level of collagen-induced arthritis in rats,but there is still a lack of research on the regulation of Wnt/β-catenin signaling pathway in fibroblast-like synoviocytes and its effect on related cell functions.OBJECTIVE:To investigate the effect and mechanism of PHSTF on lipopolysaccharide-induced proliferation,migration and apoptosis of fibroblast-like synoviocytes based on the Wnt/β-catenin signaling pathwayMETHODS:Fibroblast-like synoviocytes were divided into control group,lipopolysaccharide group,lipopolysaccharide+low-,medium-,and high-dose PHSTF groups(10,20,and 40 μg/mL),lipopolysaccharide+Wnt pathway inhibitor DKK1 group,and lipopolysaccharide+Wnt pathway inhibitor DKK1+high-dose PHSTF group(40 μg/mL).The cell counting kit-8 method was used to detect the effect of PHSTF on the viability of fibroblast-like synoviocytes,and the final drug concentration and time were screened.Flow cytometry was used to detect the apoptosis of fibroblast-like synoviocytes.Cell scratch assay,EDU staining and cell cloning assay were used to detect the migration and proliferation of fibroblast-like synoviocytes.Western blot assay was used to detect the protein expression levels of Wnt3a,β-catenin,tumorigenic genes,matrix metalloproteinase 2,matrix metalloproteinase 9,Bax and Bcl-2 in fibroblast-like synoviocytes.RESULTS AND CONCLUSION:(1)Compared with the control group,the cell viability decreased significantly when the concentration of PHSTF was＞40 μg/mL(P＜0.01).Therefore,the drug concentration of≤40 μg/mL was selected for subsequent experiments.(2)Compared with the lipopolysaccharide group,the wound healing rate,cell clone formation rate and the number of EDU-positive cells in the low-,medium-and high-dose PHSTF groups were significantly reduced,while the apoptosis rate was significantly increased(P＜0.05-0.01).(3)Western blot results showed that compared with the lipopolysaccharide group,low-,medium-and high-dose PHSTF significantly inhibited cellular Wnt3a,β-catenin,cellular tumorigenic genes,matrix metalloproteinase 2,matrix metalloproteinase 9,and Bcl-2 protein expression,and promoted the expression of Bax protein(P＜0.01).(4)Compared with the DKK1 group,the combination of DKK1 and high-dose PHSTF significantly inhibited the protein expression of Wnt3a,β-catenin,matrix metalloproteinase 2,matrix metalloproteinase 9 and Bcl-2 protein expression and promoted the protein expression of Bax(P＜0.01).To conclude,PHSTF may inhibit the proliferation and migration of fibroblast-like synoviocytes and promote apoptosis by inhibiting the Wnt/β-catenin signaling pathway.

BACKGROUND:Rheumatoid arthritis is widely prevalent worldwide,with its high incidence and universality that considerably affects patients' quality of life.Previous studies have focused on a few immune cells or cytokines,whereas this study comprehensively provides a more complete view of the immune mechanisms in rheumatoid arthritis.OBJECTIVE:To explore the causal relationship between 731 immune cell phenotypes and rheumatoid arthritis using the Mendelian randomization method,thereby providing evidence of causality.METHODS:The 731 immune cell phenotypes used in this study were sourced from the GWAScatalog database,jointly developed by the National Human Genome Research Institute(NHGRI)and the European Bioinformatics Institute(EBI).The rheumatoid arthritis data were from the Finngen database,developed by the Finnish Institute for Molecular Medicine(FIMM).The inverse variance weighting method was employed as the primary analytical approach.Additionally,multiple analytical methods,including MR-Egger,weighted mode,simple mode,and weighted median,were concurrently utilized to complement the final results.Sensitivity analyses(Cochran's Q test,MR-Egger regression,and MR-presso analysis)were also conducted to verify the stability and feasibility of the data.RESULTS AND CONCLUSION:(1)After excluding results through heterogeneity testing,the inverse variance weighting analysis indicated that 10 absolute cell counts,15 median fluorescence intensities of surface antigen levels,1 morphological characteristic,and 9 relative cell counts had a causal relationship with the occurrence of rheumatoid arthritis.(2)According to cell classification,this study found that seven types of B cells,seven types of classical dendritic cells,six types of mature T cells,four types of monocytes,three types of myeloid cells,three types of TBNK cells(lymphocyte subset T cells,B cells and natural killer cells),and five types of Tregs had a causal association with the occurrence of rheumatoid arthritis.(3)Through comprehensive bidirectional two-sample MR analysis,we demonstrated the complex causal relationships between multiple immune phenotypes and rheumatoid arthritis,highlighting the intricate interaction patterns between the immune system and rheumatoid arthritis.These results provide new biomarkers for the early screening and diagnosis of rheumatoid arthritis in China,and help to improve the diagnostic accuracy and sensitivity.

With the rising incidence of colon cancer, several studies have indicated that aquaporin 1 (AQP1) expression is associated with the development of colon cancer. This study aims to elucidate the potential molecular mechanisms between them. Methods: We screened data from The Cancer Genome Atlas (TCGA) database and retrospectively examined AQP1 protein expression in 127 colon cancer patients to analyze the relationship between AQP1 expression and pathological stages, prognosis. We created stable colon cancer cell lines with differential AQP1 expression, the effect of AQP1 expression on the proliferation and migration of colon cancer cells was assessed by in vitro and in vivo studies, and explored potential molecular mechanisms through Western blotting. Results: High AQP1 expression was associated with poorer survival (overall survival [OS], p = .028) in colon cancer patients from the TCGA database. Similarly, retrospective clinical data indicated that high AQP1 expression was associated with reduced disease-free survival and OS (p = .036 and p = .017, respectively). The low-expressing AQP1 colon cancer cells exhibited a decrease in proliferation and migration ability of colon cancer cells compared to the overexpressing AQP1 group (p < .05) in vitro and in vivo. Immunohistochemistry and western blotting experiments validated heightened expression of N-cadherin, vimentin, and claudin- 1 in the tumor tissues of the overexpressing AQP1 group. Conversely, reduced AQP1 expression resulted in decreased expression of claudin- 1. Conclusions: AQP1 correlates with unfavorable prognosis in colon cancer and potentially enhances the proliferation and migration of colon cancer by up-regulating claudin-1 expression.

Diabetic sarcopenia (DS) is a common but often ignored skeletal muscle complication in individuals with diabetes mellitus. It is characterized by progressive loss of skeletal muscle mass, reduced muscle strength, and impaired physical performance, which may further increase the risk of falls, disabilities, metabolic disorders, and adverse clinical outcomes. Traditionally, DS has been attributed mainly to hyperglycemia, insulin resistance, aging-related muscle decline, and chronic complications of diabetes. However, increasing evidence suggests that lipid metabolic disturbance and pathological lipid metabolic reprogramming are not merely secondary consequences of diabetes, but may actively participate in the initiation and progression of DS. Under diabetic conditions, impaired fatty acid uptake, transport, oxidation, and storage disrupt skeletal muscle metabolic homeostasis, leading to ectopic lipid deposition and accumulation of lipotoxic intermediates. These lipid-derived metabolites can aggravate insulin resistance, impair mitochondrial energy production, enhance oxidative stress, activate chronic low-grade inflammation, and disturb protein synthesis and degradation balance, thereby accelerating skeletal muscle atrophy and functional decline. Lipid metabolic dysregulation may also interact with multiple pathological processes involved in DS, including mitochondrial dysfunction, inflammatory signaling, oxidative damage, impaired autophagy, and gut microbiota imbalance. These mechanisms do not occur independently; instead, they form a complex bidirectional vicious cycle with diabetes-related metabolic disorders. Specifically, mitochondrial dysfunction reduces fatty acid oxidative capacity, which further promotes lipid accumulation and lipotoxicity. Inflammatory activation can impair insulin signaling and muscle protein metabolism, while lipid overload may in turn amplify inflammatory responses. Similarly, gut microbiota dysbiosis and altered microbial metabolites may influence systemic inflammation, lipid metabolism, and skeletal muscle homeostasis. Therefore, lipid metabolic reprogramming provides an important mechanistic perspective for understanding the progression of DS from metabolic disturbance to structural and functional muscle impairment. Exercise intervention is an effective and clinically feasible non-pharmacological strategy for the prevention and management of DS. Both aerobic exercise and resistance training have been shown to improve insulin sensitivity, enhance fatty acid oxidation, increase mitochondrial biogenesis, reduce ectopic lipid deposition, and attenuate lipotoxic metabolite accumulation. These adaptations not only improved glucose and lipid metabolism, but also increased the preservation of muscle mass, muscle strength, and physical function. Moreover, combined exercise strategies may provide complementary benefits by integrating the metabolic advantages of aerobic exercise with the anabolic and functional effects of resistance training. Based on analyses of publicly available datasets and literature evidences, this review systematically summarizes the role of lipid metabolic disorders in the pathogenesis of DS, with particular attention to the molecular mechanisms linking lipid dysregulation to insulin resistance, chronic inflammation, oxidative stress, mitochondrial dysfunction, and gut microbiota disturbance. Furthermore, this review discusses the potential mechanisms by which exercise intervention improves DS through the regulation of lipid metabolic reprogramming, and outlines exercise prescription strategies in terms of modality, intensity, frequency, and duration. Understanding the interaction between lipid metabolism and skeletal muscle dysfunction may provide new theoretical evidence for early identification, mechanistic research, and precision exercise therapy in DS. Overall, targeting pathological lipid metabolic reprogramming through exercise intervention represents a promising and clinically actionable approach for improving muscle health and prognosis in individuals with DS.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Magnetic resonance imaging(MRI),as a non-invasive neuroimaging technique,has been widely employed to investi-gate changes in functional brain regions.In recent years,the application of MRI in the study of lifelong premature ejaculation(LPE)has progressively uncovered the pathological mechanisms underlying abnormalities in LPE-associated brain regions.These mechanisms involve brain areas associated with higher-order cognitive and decision-making regulation,sensory and perceptual processing,as well as emotional regulation and reward systems.The application and findings of MRI in the study of LPE mechanisms will be introduced in this review,with the goal of deepening our understanding of the neuroimaging-based mechanisms of LPE.