Body composition and fat distribution were found to display differential effects on the incidence and mortality of chronic disease. However, it remained unclear whether there is an interaction between lifestyle factors and genetic susceptibility on body composition and fat distribution. This study investigated the associations of lifestyle and genetic factors with body composition and fat distribution among 121 664 women from the UK Biobank cohort study. Women with a favourable lifestyle had lower BMI (BMI, -7·72 % (95 % CI: -7·93 %, -7·51 %)), fat mass index (FMI, -15·70 % (95 % CI: -16·09 %, -15·30 %)), fat-free mass index (FFMI, -2·86 % (95 % CI: -2·98 %, -2·74 %)), arm fat ratio (AFR, -5·19 %, (95 % CI: -5·38 %, -5·00 %)) and trunk fat ratio (TFR, -0·73 %, (95 % CI: -0·84 %, -0·62 %)) but higher leg fat ratio (LFR, 2·30 % (95 % CI: 2·16 %, 2·44 %)) than those with an unfavourable lifestyle. Significant interactions between lifestyle factors and genetic susceptibility on BMI, FMI and AFR were observed (Pinteraction < 0·05). Among women with a high genetic susceptibility to body composition or fat distribution, those with a healthy lifestyle still had a lower BMI, FMI, FFMI, AFR and TFR and higher LFR (Ptrend < 0·001). Women who adhere to a favourable lifestyle tend to have healthy body composition and fat distribution, and this association is consistent across all strata of genetic risk.

Vascular endothelial dysfunction serves as a key pathological basis for diabetic vascular complications. Enhancing endothelial function and promoting angiogenesis are therefore critical strategies in the treatment of diabetic lower hindlimb ischemia (HLI). SETD2 is the primary methyltransferase for H3K36 trimethylation (H3K36me3) and is involved in vascular development, but its role in diabetes-associated endothelial dysfunction remains unknown. This study aimed to investigate the function and underlying mechanism of SETD2 in endothelial cells under diabetic conditions and in the context of diabetic HLI. A diabetic mouse model was established in endothelial-specific conditional SETD2 knockout (SETD2ECKO) mice using a high-fat diet combined with streptozotocin (HFD/STZ) injection. After a single ligation of the common femoral artery in these mice, we observed that endothelial-specific conditional deletion of SETD2 significantly impaired blood flow recovery and reduced capillary density in the ischemic gastrocnemius muscle. In vitro, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose and palmitate (HG/PA) to simulate a diabetic microenvironment. It was found that HG/PA treatment down-regulated the expression of SETD2 and H3K36me3 in HUVECs. Functional studies revealed that SETD2 over-expression alleviated, whereas SETD2 inhibition aggravated, HG/PA-induced impairments in endothelial proliferation, migration, and tube formation. Mechanistically, SETD2 was found to positively regulate the expression of ANGPT2. KEGG enrichment analysis and Western blot validation indicated that SETD2 modulates the PI3K-AKT signaling pathway. Notably, exogenous ANGPT2 supplementation partially rescued endothelial dysfunction and restored AKT phosphorylation in SETD2-inhibited cells under HG/PA conditions. In conclusion, SETD2 preserves endothelial function and promotes angiogenesis by up-regulating ANGPT2 and subsequently activating the PI3K-AKT signaling axis. The SETD2-ANGPT2-PI3K/AKT pathway may represent a promising therapeutic target for the treatment of diabetic vascular complications. This schematic illustrates the SETD2–ANGPT2–PI3K/AKT signaling axis and its role in enhancing endothelial function and angiogenesis in diabetic hindlimb ischemia.

BackgroundBladder cancer, the most common malignancy of the urinary system, is associated with poor prognosis due to its metastatic potential, invasive behavior, and immune evasion. Intercellular adhesion molecule 5 (ICAM5), a member of the immunoglobulin superfamily, regulates cell adhesion and has been implicated in tumor progression. However, its biological function in bladder cancer remains unclear.MethodsIn this study, we analyzed data from The Cancer Genome Atlas (TCGA) and UCSC Xena databases to investigate ICAM5 expression, prognostic significance, genetic mutations, methylation, immune profiles, and regulatory functions in bladder cancer. Weighted Gene Coexpression Network Analysis (WGCNA) and Gene Set Cancer Analysis (GSCA) were employed to explore ICAM5-related pathways.ResultsOur findings demonstrated that ICAM5 expression was significantly upregulated in bladder cancer and associated with advanced disease features, including higher TNM stages, pathological grades, and aggressive molecular subtypes. Furthermore, ICAM5 influenced the immune microenvironment, regulated methylation, and modulated immune checkpoint expression, contributing to immunotherapy resistance. Mechanistically, ICAM5 promoted epithelial-mesenchymal transition (EMT), proliferation, and metastasis.ConclusionsICAM5 serves as a novel prognostic biomarker and potential therapeutic target in bladder cancer, orchestrating EMT progression, reshaping the immune microenvironment, and driving resistance to immunotherapy.

Long QT syndrome (LQTS) is an inherited life-threatening cardiac disorder characterized by delayed ventricular repolarization and increased risk of malignant arrhythmias. Among its subtypes, long QT syndrome type 2 (LQT2) is primarily caused by pathogenic variants in KCNH2, which encodes the human ether-à-go-go–related gene (hERG) potassium channel responsible for the rapid delayed rectifier current (IKr). However, the substantial functional heterogeneity among KCNH2 variants poses a major challenge for clinical interpretation and precision intervention. In this study, we sought to functionally characterize KCNH2 p.F68C variant (c.203T > G) identified in a Chinese LQT2 patient and to evaluate the feasibility of RNA interference–based modulation of its functional impact on the hERG channel. Using biochemical and electrophysiological analyses in HEK293T cells, we show that variant p.F68C causes a severe trafficking defect and exerts a dominant-negative effect on wild-type hERG channels, leading to markedly reduced rapid delayed rectifier potassium current (IKr). In contrast to several previously reported Per–Arnt–Sim (PAS) domain variants, the trafficking defect of p.F68C was resistant to reduced culture temperature, chemical chaperones, and pharmacological chaperones. Notably, allele-specific RNA interference selectively suppressed mutant hERG expression, alleviated dominant-negative interference, and partially restored hERG current density without detectable cytotoxicity. Together, these findings establish p.F68C as a loss-of-function KCNH2 variant and highlight allele-specific RNA interference as a variant-directed strategy that may serve as an alternative to suppression–replacement approaches, providing a basis for functional interpretation and precision therapeutic exploration of individual KCNH2 variants.

BACKGROUND:Alternative polyadenylation (APA) is a key post-transcriptional mechanism that regulates gene expression by modulating 3'UTR length, its dysregulation has been implicated in carcinogenesis. How genetic variants influence APA to affect hepatocellular carcinoma (HCC) prognosis remains unclear. METHODS:Prognosis-APA quantitative trait loci (apaQTL) were performed using genotype and APA profiling from TCGA data. A two-stage survival analysis in 848 Chinese and 369 TCGA LIHC patients and functional validation were used to identify prognostic apaQTL in HCC progression. RESULTS:A total of 2,025 and 817 significant APA events were identified in Chinese and TCGA cohort, respectively. Besides, 859 events were associated with poor prognosis in HCC and enriched in RNA splicing / metabolism pathways. We detected 32,034 significant apaQTLs, predominantly enriched in 3'UTRs and RBP-binding regions. CPEB3 was prioritized as a key APA regulator RBP; its low expression correlated with poor patient survival and promoted proliferation, migration, and invasion in HCC cells. Notably, a functional apaQTL variant rs2037547, located in GSK3B and mediated by CPEB3, demonstrated a poor survival of HCC patients in both cohort (pooled HR=1.29, p=0.016). Mechanistically, rs2037547 promoted aberrant APA at proximal poly(A) sites of GSK3B through CPEB3, leading to increased expression of short 3'UTR isoform. This regulatory alteration enhanced HCC cell proliferation, invasion, and migration, and contributed to HCC progression. CONCLUSION:These findings elucidated the distinct role of apaQTL-mediated APA dysregulation in HCC prognosis, providing insights for prognostic stratification and potential targets for personalized therapy in HCC.

BACKGROUND: Thoracic aortic dissection (TAD) is a highly lethal disease without effective drug therapy. Guidelines recommend control of risk factors, particularly of causal hypertension. Antihypertensive drugs are diverse in mechanisms of action, but no randomized controlled trials have been undertaken to evaluate their efficacy and safety, and guide rational drug selection for this disease. METHODS: Antihypertensive drugs were evaluated in a 3-aminopropionitrile-induced mouse model of TAD. Pharmacovigilance analysis using the FDA Adverse Events Reporting System and Medical Information Mart for Intensive Care databases, along with a systematic meta-analysis of 32 studies, was performed to assess drug-associated risks in aortic diseases. Signaling pathways related to smooth muscle cell contractility, adhesion, and cytoskeleton stabilization were examined in human and mouse tissues. A chemogenetic mouse strain with smooth muscle cell-specific expression of the pharmacologically selective actuator module 4-serotonin type 3 receptor channel was generated to modulate Ca 2+ signaling. RESULTS: Here, we assessed 8 classes of antihypertensives in a mouse TAD disease model but unexpectedly observed that hydrochlorothiazide and minoxidil exacerbated the disease. Pharmacovigilance analysis linked diuretic use to an increased TAD-associated risk in patients. TAD pathogenesis and the harmful drug effects are attributable to blunted Ca 2+ -dependent smooth muscle cell contractility and adhesion. To this therapeutic end, we leveraged a chemogenetic Ca 2+ -permeable cation channel (pharmacologically selective actuator module 4-serotonin type 3 receptor) exclusively activated by the clinical drug varenicline. The humanized chemogenetic device boosted smooth muscle cell Ca 2+ signaling, potentiated the Ca 2+ -dependent cellular processes, and protected against TAD and the aggravated phenotype induced by hydrochlorothiazide/minoxidil. CONCLUSIONS: This study calls for pharmacovigilance of certain antihypertensives in TAD, and suggests that pharmacologically selective actuator module 4-serotonin type 3 receptor, as a viable means of tuning Ca 2+ signaling, holds translational potential for TAD therapy.

BackgroundRenal cell carcinoma (RCC) is a common lethal malignancy of the urinary system with a complex pathogenesis. Among its subtypes, clear cell renal cell carcinoma (ccRCC) represents the predominant pathological type. Circular RNAs (circRNAs), a class of covalently closed RNA molecules, play critical roles in various cancers. CircCCDC66 has been reported to exhibit aberrant expression and participate in tumor progression in multiple malignancies; however, its functional role and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) remain unclear. This study aimed to investigate the role of circCCDC66 in ccRCC and its underlying regulatory mechanism.MethodsCircCCDC66, miR-1278, and HOXA13 expression levels in ccRCC tissues and cell lines were measured using quantitative real-time PCR (qPCR). Cell proliferation, migration, and invasion were assessed through colony formation, CCK-8, Transwell, and wound healing assays. Western blotting was conducted to evaluate the expression of epithelial-mesenchymal transition (EMT)-related markers, including E-cadherin, N-cadherin, Vimentin, and HOXA13. Bioinformatics tools, such as StarBase and CircInteractome, were utilized to predict the binding sites between circCCDC66 and miR-1278, as well as between miR-1278 and HOXA13; these predictions were further validated using dual-luciferase reporter assays. Additionally, a ccRCC xenograft tumor model was established to investigate the in vivo regulatory effect of circCCDC66 on tumor growth.ResultsCircCCDC66 and HOXA13 were significantly upregulated in ccRCC tissues and cell lines, whereas miR-1278 expression was markedly downregulated. Knockdown of circCCDC66 significantly inhibited ccRCC cell proliferation, migration, invasion, and EMT progression. In vivo, experiments further confirmed that circCCDC66 overexpression promoted tumor growth. Mechanistically, dual-luciferase reporter and RNA immunoprecipitation assays demonstrated that circCCDC66 directly binds to miR-1278, and inhibition of miR-1278 rescued the circCCDC66 knockdown-induced suppression of proliferation and metastasis. Furthermore, dual-luciferase reporter assays confirmed the binding between miR-1278 and HOXA13. Rescue experiments revealed that circCCDC66 functions as a competing endogenous RNA (ceRNA) by sponging miR-1278, thereby upregulating HOXA13 expression and facilitating ccRCC progression.ConclusionCircCCDC66 is upregulated in ccRCC and promotes tumorigenesis and progression by acting as a miR-1278 sponge to derepress HOXA13 expression.

BACKGROUND:Tissue-specific regulatory T cells (Tregs) accumulate in the heart after myocardial infarction (MI) and play a vital role in limiting inflammation and promoting tissue repair. However, the developmental trajectory of heart Tregs and the molecular cues that guide their recruitment to the heart remain poorly understood, impeding therapeutic strategies that leverage Treg-mediated cardiac protection. METHODS:We used single-cell and bulk RNA sequencing in a murine MI model to delineate the differentiation trajectory of Tregs from mediastinal lymph nodes to the heart. Functional validation was performed using Treg-specific Ccr8 (CC motif chemokine receptor 8) knockout mice (Ccr8flox/floxFoxp3Cre), Ccl1 (CC motif chemokine ligand 1) knockout mice (Ccl1-/-), macrophage-targeted Ccl1 knockdown mice, Ccl1-overexpressing mice, and DEREG mice. The CCL1-CCR8 axis was evaluated in cardiac tissues and circulating blood from patients with MI. RESULTS:Single-cell RNA sequencing revealed a stepwise differentiation of mediastinal lymph node-derived naive Tregs into heart Tregs, marked by the progressive acquisition of CCR8 expression and reparative capacity. CCR8+ Tregs in the heart exhibited enhanced immunosuppressive and tissue-repair signatures. Treg-specific Ccr8 deletion led to reduced Treg accumulation and worsened cardiac function after MI, along with increased proinflammatory macrophage features and number of CD8+ T cells and natural killer cells. In addition, Tregs promoted a shift of macrophages toward an anti-inflammatory phenotype by secreting IL-1R2 (interleukin 1 receptor, type 2). We identified cardiac macrophages as the main source of CCL1, which was essential for CCR8+ Treg recruitment. Ccl1 deficiency or macrophage-specific Ccl1 knockdown impaired Treg infiltration and aggravated ventricular remodeling; Ccl1 overexpression promoted Treg recruitment and improved cardiac outcomes. Moreover, the cardioprotective effects of CCL1 were abolished in DEREG mice upon Treg depletion and Ccr8flox/floxFoxp3Cre mice, establishing a CCR8+ Treg-dependent mechanism. Furthermore, circulating CCR8+ Tregs and cardiac CCL1 were elevated in humans with MI, and the presence of CCR8+ Tregs and CCL1-expressing macrophages was confirmed in the hearts of patients with MI, suggesting important clinical relevance. CONCLUSIONS:Our findings reveal a 2-phase Treg specialization process and establish the CCL1-CCR8 axis as a crucial pathway for Treg recruitment and function in the infarcted heart. Therapeutic targeting of this axis may improve immune-regulated cardiac repair after MI.

Background:Malnutrition and immune status significantly influence the prognosis of diabetic kidney disease (DKD). However, the correlations between two novel nutritional-immune indices-geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI)-and the risk of all-cause mortality (ACM) and cardiovascular mortality (CVM) in patients with DKD remain unclear. Our investigation was, therefore, designed to explore these associations. Methods:This study analyzed data from 2038 DKD individuals in the National Health and Nutrition Examination Survey (NHANES) (1999-2018). Multivariate weighted Cox regression, Kaplan-Meier survival curves (K-M curves), subgroup analysis, and interaction analysis were employed to clarify the associations of GNRI and PNI with ACM and CVM. We also applied restricted cubic splines (RCS) and threshold analysis to evaluate potential nonlinear correlations and inflection points. Subsequently, time-dependent receiver operating characteristic (ROC) curves were utilized to explore and compare the prognostic performance of GNRI and PNI for survival outcomes over time. Results:Throughout the median follow-up period of 68 months, 1006 (49.36%) of 2038 patients with DKD died, including 374 (37.18%) cardiovascular disease (CVD) deaths. Multivariate weighted Cox regression analysis and K-M curves illustrated that high levels of GNRI and PNI are independent protective factors against ACM and CVM in DKD patients. RCS analysis and threshold analysis revealed a nonlinear correlation of PNI with ACM and CVM, and the inflection points were identified at 51.24 and 49.63, respectively. What's more, ROC curves demonstrated that GNRI and PNI exhibit significant predictive potential in both the short and long terms, with similar predictive performance. Conclusions:As novel nutritional-immune markers, GNRI and PNI could independently forecast the ACM and CVM in DKD patients, aiding in risk stratification and timely intervention for this disease.

Senile osteoporosis (SOP) is an age-related metabolic bone disease characterized by reduced bone quality and increased fracture risk, closely associated with immune senescence. Among immune components in the bone marrow niche, macrophages undergo age-associated phenotypic and functional changes that may impair bone homeostasis; however, whether these changes reflect bona fide senescence, inflammatory activation, or polarization remains unclear. This review summarizes the biological characteristics of senescent macrophages, including alterations in senescence markers, senescence-associated secretory phenotype (SASP), epigenetic modifications, and telomere dynamics. It then outlines their functional changes, focusing on oxidative stress, autophagy, and metabolic dysregulation. Importantly, we discuss how senescent or senescence-like macrophage states may regulate macrophage–bone marrow mesenchymal stem cell (BMSC) crosstalk through SASP-related factors, the grancalcin–plexin-B2 axis, mitochondrial transfer, exosome-mediated signaling, and metabolic reprogramming, while distinguishing direct ageing-related evidence from indirect mechanistic evidence.

Background Despite interest in the health effects of IgG N-glycosylation, the mediating role of IgG N-glycosylation in the effects of adiposity and tobacco use on cardiovascular diseases (CVDs) has not been systematically studied. Objective This study aimed to investigate the causal effects of adiposity and tobacco use on CVDs and the potential mediating role of 23 traits of IgG N-glycosylation using Mendelian randomization (MR). Methods Summary statistics from GWAS were used. Two-sample MR assessed the causal links between adiposity, tobacco use, and CVDs, while two-step MR examined whether IgG N-glycosylation traits mediate these associations. Random-effects inverse-variance weighted analyses, along with MR-Egger, weighted median, simple, and weighted model approaches, were conducted. Results We observed genetically predicted body mass index (OR = 1.48, 95% CI: 1.40, 1.56), fat mass index (OR = 1.68, 95% CI: 1.37, 2.06), fat-free mass index (OR = 1.55, 95% CI: 1.27, 1.89), lifetime smoking index (OR = 1.75, 95% CI: 1.43, 2.14), and smoking initiation (OR = 1.15, 95% CI: 1.06, 1.25) were positively associated with CVDs. Moreover, IGP5 mediated 5.4% of the effect of BMI on pulmonary embolism, whereas IGP7 mediated 2.8% of the effect of BMI on coronary artery disease. Conclusion Our findings illustrated the causal associations of adiposity and tobacco use with CVDs, with IgG N-glycosylation traits potentially acting as mediators, and thereby highlighting possible mechanistic targets for further investigation.

Fat distribution patterns are increasingly linked to obesity-related cancers; however, their shared genetic determinants remain unclear. To identify shared genetic architecture between adiposity measures and obesity-related cancers. Utilizing large-scale summary statistics from genome-wide association study, we conducted genome-wide cross trait analyses of nine adiposity measures [body mass index (BMI), waist-to-hip (WTH) ratio, waist-to-hip ratio adjusted for BMI, arm fat ratio, trunk fat ratio, leg fat ratio, abdominal subcutaneous adipose tissue, gluteofemoral adipose tissue, and visceral adipose tissue] in five obesity-related cancers (colorectal cancer, esophageal adenocarcinoma, breast cancer, endometrial cancer, and ovarian cancer) to characterize their shared genetic architecture, biological pathways, and causal relationships. Cross-trait analyses revealed extensive genomic correlations between adiposity measures and obesity-related cancers. Pleiotropic analysis identified 464 pleiotropic loci and 409 unique candidate pleiotropic genes, 128 of which replicated in the transcriptome-wide association studies analysis. Gene-level analysis revealed potential shared biological mechanisms involving the brain-derived neurotrophic factor signaling pathway, WNT/β-catenin signaling, and adipogenesis, whereas TWAS revealed their predominant expression in the digestive, nervous, and adipose tissues. Mendelian randomization analysis showed stronger associations between genetically increased BMI, WTH, and obesity-related cancers than other body fat distributions. Our study demonstrates that pleiotropic genetic determinants between adiposity and obesity-related cancers are widely distributed across the genome, reinforcing the hypothesis that adiposity increases cancer risk and revealing potential molecular pathways that may contribute to both adiposity and cancer development.

Early prediction and diagnosis of systemic inflammatory response syndrome (SIRS) following percutaneous nephrolithotomy (PCNL) are critical. This study aimed to investigate differences in clinical characteristics and the renal pelvis urobiome between patients with and without post-PCNL SIRS to identify potential predictive biomarkers. Patients undergoing unilateral PCNL were categorized into SIRS(+) and SIRS(-) groups based on postoperative SIRS status. Renal pelvis urine samples were collected for 2bRAD-M sequencing to profile the urobiome. Clinical data and urobiome composition were compared between the groups. Logistic regression identified preoperative serum albumin-globulin ratio (AGR) as an independent protective factor and operative time as an independent risk factor for post-PCNL SIRS, with an area under the receiver operating characteristic curve (AUC) of 0.76. Diversity analysis revealed distinctive microbial differences between the two groups. Through differential analysis and random forest, we screened six species, including Sphingomonas paucimobilis, Ralstonia sp000620465, Ralstonia pickettii, Pelomonas puraquae, Comamonas tsuruhatensis, and Lawsonella clevelandensis_A, to build the microbial prediction model, which achieved an AUC of 0.81. The combination of microbial data and clinical factors further improved predictive accuracy, achieving an AUC of 0.94. Functional profiling of the urobiome also demonstrated significant intergroup differences. This is the first study to explore renal pelvis urobiome dysbiosis in post-PCNL SIRS. Both clinical and microbial factors showed strong predictive value, with their combination offering the greatest discriminatory power. This research could pave the way for the early prediction of post-PCNL SIRS.IMPORTANCEGiven the significant morbidity associated with postoperative percutaneous nephrolithotomy (PCNL) systemic inflammatory response syndrome (SIRS), early prediction and diagnosis are crucial for preventing severe complications like sepsis, which can lead to multiple organ dysfunction or death. Our study uniquely explores how renal pelvis urobiome dysbiosis contributes to post-PCNL SIRS. By utilizing the novel 2bRAD-M sequencing, the research identifies key microbial species in the renal pelvis and integrates them with clinical factors like albumin-globulin ratio and operative time. The resulting prediction model, with an impressive area under the curve, significantly outperforms traditional clinical models. This offers a more precise approach to stratify patients at high risk of developing SIRS. This work suggests that microbial imbalances may actively drive SIRS, pointing to the potential to revolutionize the predictive strategies for post-PCNL SIRS.

This study aims to investigate the roles of gut microbiota and plasma metabolites in salt sensitivity (SS) of blood pressure (SSBP) and hypertension. A 23-day, multicenter, dietary salt intervention trial (the MetaSalt study) recruited 528 participants who underwent a baseline observation, low-salt, and high-salt interventions. SSBP was assessed and used as the primary outcome, and fecal shotgun metagenome and plasma targeted metabolome were measured. We found that high salt significantly altered 85 gut-microbial species (p < 9.42 × 10−5) and 70 metabolites (p < 2.26 × 10−4). Among them, the changes in 22 species and 8 metabolites were associated with SSBP (p < 0.05), and a gut microbiota-acylcarnitine network implicated in SSBP was identified, with a gut microbiota-derived metabolite, isovalerylcarnitine, as the core metabolite. Isovalerylcarnitine was also inversely associated with SSBP in the GenSalt study (p = 0.0102). Importantly, increased isovalerylcarnitine attenuated SS hypertension and improved endothelial function in rats, and was associated with reduced risk (ranging from 13

Background Previous research has shown a correlation between high visceral fat levels and hyperuricemia incidence. The Chinese Visceral Adiposity Index (CVAI) assessed visceral fat status in the Chinese population. Our study investigates the correlation between CVAI and asymptomatic hyperuricemia in type 2 diabetes patients. Methods This cross-sectional study analyzed 1,588 hospitalized type 2 diabetes patients to investigate the association between CVAI and hyperuricemia. CVAI was included in the logistic regression analysis as both a continuous and categorical variable, and restricted cubic splines were used to assess the dose-response relationship. Additionally, subgroup analyses were performed to investigate potential interactions among variables. The predictive capability of CVAI was assessed using the receiver operating characteristic (ROC) curve based on the basic model. Results The CVAI quartile group analysis revealed a higher prevalence of hyperuricemia with increasing CVAI levels. CVAI is significantly associated with hyperuricemia, as identified through multifactorial logistic regression analysis. After adjusting for all covariates, the odds ratios for CVAI in the second, third, and fourth quartiles were significantly higher than in the lowest quartile, with values of 2.688 (95% CI [1.301–5.554], p = 0.008), 2.752 (95% CI [1.320–5.739], p = 0.007), and 4.990 (95% CI [2.392–10.409], p < 0.001), respectively. No significant interactions were observed in the subgroup analysis. Incorporating CVAI into the basic model increased the ROC curve’s area under the curve to 0.714. Conclusion This study found a positive correlation between CVAI and hyperuricemia incidence in type 2 diabetes patients. Consequently, CVAI may reliably indicate hyperuricemia in this patient population.

Psoriasis is a prevalent chronic skin disease. Cycloastragenol (CAG) has been shown to activate autophagy and alleviate epidermal keratinocyte hyperproliferation in psoriasis. This study aimed to clarify the mechanism of CAG-mediated autophagy in psoriasis-like models. We treated C57BL/6 mice with imiquimod cream and stimulated HaCaT cells with a cytokine mixture (C-mix) to establish mouse and cell models. Psoriasis area and severity index scores were used to evaluate pathological changes. Autophagy flux was monitored using a monomeric red fluorescent protein-green fluorescent protein-microtubule-associated protein 1 light chain 3 assay. The interaction between sirtuin 1 (SIRT1) and zinc finger containing Krüppel-associated box and SCAN domain 3 (ZKSCAN3), as well as ZKSCAN3 acetylation, was examined using co-immunoprecipitation. Our results found that CAG alleviated autophagy inhibition in the imiquimod-induced psoriasis-like mouse model and enhanced autophagy by upregulating SIRT1 expression. ZKSCAN3 inhibited autophagy in the C-mix-stimulated psoriasis-like cellular model, while SIRT1 reduced the nuclear localization of ZKSCAN3 through deacetylation. ZKSCAN3 overexpression reversed SIRT1-mediated autophagy enhancement, whereas CAG promoted autophagy by regulating the nuclear localization of ZKSCAN3. In conclusion, our findings demonstrate that CAG ameliorates autophagy inhibition by modulating the SIRT1/ZKSCAN3 axis in psoriasis.

The protective effects of autophagy-mediated microglial inflammatory regulation on diseases of the central nervous system (CNS) has been a recent field of interest. The canonical signaling pathway activated by Wnt1, the Wnt/β-catenin signaling cascade, also plays a crucial protective role in neurodegenerative diseases. However, the relationship between Wnt1/β-catenin signaling and microglial activation remains unclear. Our study focused on understanding the impact and mechanism of Wnt1 on microglial activation. To simulate neuroinflammatory conditions in vitro, BV2 cells were exposed to 1 μg/mL lipopolysaccharide. CD86- and CD206-positive cells were identified by flow cytometry and immunofluorescence assays. Inflammatory and anti-inflammatory factors were measured using enzyme-linked immunosorbent assays. Autophagy was analyzed by expression of LC3B puncta, LC3, P62, and beclin1 expression. The inflammatory activation suppressed by rhWnt1 was restricted by DKK1, siRNA-β-catenin and siRNA-LKB1, respectively, with concomitant changes in β-catenin expression and phosphorylation of NFκB-p65, LKB1, and AMPK. Although the anti-inflammatory effect of Wnt1/LKB1 pathway was independent of β-catenin, Wnt1/LKB1 regulated β-catenin. The reduced inflammation caused by rhWnt1 is linked to its enhancement of autophagy, a process blocked by siRNA-LKB1 and 3-MA partially. The anti-inflammatory effects of Wnt1 on BV2 cells improved autophagy, a mechanism partly dependent on the β-catenin pathway or the phosphorylation of LKB1. Furthermore, the Wnt1/LKB1 pathway was activated independently of β-catenin and participated in regulating its expression. Our research unveils a previously unknown method through which Wnt1 exerts its anti-inflammatory effects, which may have a potential protective role against CNS diseases.