Introduction:Obesity is a well-established risk factor for asthma pathogenesis. However, the underlying mechanisms remain incompletely understood, and effective therapeutic interventions are currently lacking, making asthma management in obese individuals particularly challenging. Asthma is characterized by chronic airway inflammation, eosinophilic infiltration, and airway hyperresponsiveness (AHR). In this study, we investigated the novel role of fibroblast growth factor 21 (FGF21), a stress-inducible hepatokine with pleiotropic metabolic regulatory functions, in obesity-associated AHR using a diet-induced obesity mouse model (n = 10). Material and Methods:Serum samples were collected from obese and lean asthma patients, along with relevant clinical indicators, including body mass index (BMI), forced expiratory volume in 1 second (FEV1%), and the FEV1/forced vital capacity (FVC) ratio, to facilitate the investigation. Moreover, diet-induced obese mice with innate AHR (male, n = 10) were employed to clarify the effects of FGF21 and FGF21-neutralizing antibody on obesity induced AHR. In vitro, LAD2 human mast cells and P815 murine mast cells activated by compound 48/80 were used to elucidate the underlying mechanisms. Results:Our findings demonstrate that serum FGF21 levels exhibit reportedly elevated in participants with obesity and are associated with impaired pulmonary function. In diet-induced obese (DIO) mice, FGF21 levels were increased in both serum and bronchoalveolar lavage fluid (BALF). In vivo investigations demonstrate that administration of recombinant FGF21 exacerbated AHR in DIO mice, whereas FGF21-neutralizing antibody treatment ameliorated obesity-induced AHR and suppressed mast cell infiltration. Mechanistically, FGF21 was found to potentiate mast cell activation through cholesterol biosynthesis modulation. Crucially, pharmacological inhibition of FGFR1 abrogated FGF21-induced mast cell hyperactivity and cholesterol synthesis, indicating FGFR1-dependent signaling in this process. Conclusion:These findings may represent the FGF21/FGFR1 axis as a potential therapeutic target for obesity-related AHR and asthma.

BACKGROUND:Retinal microvascular parameters are potential biomarkers for systemic vascular health. This study aimed to assess the interocular consistency of these parameters in patients with coronary atherosclerotic disease(CAD) using AI-based quantitative analysis. METHODS:We analysed 862 colour fundus photographs from 431 patients. Retinal vascular parameters-including fractal dimension (FD), vessel density (VD), and vessel diameters-were automatically measured using a ResNet 101-UNet deep learning model. Interocular symmetry was compared across groups stratified by Gensini score, CAD presence, and lesion location. Correlation was assessed using Pearson and intraclass correlation coefficients (ICC). RESULTS:Except for minor curvature variations in the overall population, no statistically significant interocular differences were found across any subgroups (Gensini scores, CAD vs. Non-CAD, or vessel location; all P > 0.05). All variables demonstrated good interocular consistency, with Pearson coefficients ranging from 0.387 to 0.833 and ICCs from 0.384 to 0.824. While linear regression suggested minor associations between gender and interocular differences in VD and mean branch angle, generalised linear mixed models-adjusting for age, gender, and clinical history-confirmed no significant interocular variance in fundus metrics across all subgroups (P > 0.05). CONCLUSION:Retinal vascular parameters exhibit high interocular symmetry in individuals regardless of their CAD status. These findings suggest that single-eye imaging may potentially represent retinal vascular status in cardiovascular risk assessment. This approach could help streamline screening protocols and provides a rationale for the standardised use of fundus examination as a non-invasive auxiliary tool for CAD evaluation.

BACKGROUND:The optimal surgical strategy for treating chronic venous disease with concomitant deep and superficial reflux but without iliac/proximal obstruction remains unclear. This study aimed to compare clinical symptoms, health-related quality-of-life, and ulcer outcomes between superficial venous surgery alone and combined deep-superficial surgery (performed concurrently or in stages). METHODS:In this single-center retrospective cohort, 229 patients were grouped by treatment and received superficial-only (n = 138), concurrent deep + superficial (n = 49), or staged deep + superficial (n = 42) interventions. Outcomes were Venous Clinical Severity Score (VCSS), Chronic Venous Insufficiency Questionnaire-20 (CIVIQ-20) at baseline and follow-up (1, 3, and 6 months, and last follow-up), ulcer outcomes (n = 59) assessed by healing rates and Kaplan-Meier time-to-healing analysis, duplex valve competence after deep intervention, and complications. Analyses used Welch one-way analysis of variance with Games-Howell post hoc and log-rank testing. RESULTS:Baseline characteristics were comparable (baseline VCSS 8.6±3.3, 9.6±4.0, and 9.0±3.9; P = .32). Between-group differences in VCSS were significant at 1 month (P = .012), 6 months (P < .001), and last follow-up (P = .017). Staged treatment reduced VCSS vs superficial-only at 1 month (mean difference [MD], -1.47; Padj = .008); both concurrent and staged strategies showed lower VCSS vs superficial-only at 6 months (MD, -0.98 and -1.01; Padj = .003 and .001) and last follow-up (MD, -0.76 and -0.68; Padj = .025 and .033). The CIVIQ-20 at the last-follow-up was lower with concurrent and staged strategies vs superficial-only (MD, -2.83 [Padj < .001]; MD, -2.40 [Padj = .010]). Internal valvuloplasty (n = 77) demonstrated lower VCSS at 1 to 6 months and last follow-up vs superficial-only (all Padj ≤ .026) and a lower CIVIQ-20 score. Among 59 active ulcers, 89.8% healed overall; healing proportions did not differ (P = .310), but time to healing differed by Kaplan-Meier analysis (log-rank P = .038). Duplex after deep intervention showed reflux normalization (<0.5 seconds) in 94.5% to 98.9% at 1 to 6 months; complications were minor, with no symptomatic deep vein thrombosis/pulmonary embolism or major bleeding. CONCLUSIONS:In patients with chronic venous disease with concomitant deep and superficial reflux but no iliac obstruction, adding deep reflux correction (concurrent or staged) was associated with greater and more durable symptom relief and better quality of life than superficial-only surgery, with high duplex-confirmed competence and low complication rates; ulcer healing time may be accelerated.

OBJECTIVE:To evaluate the protective effect of Qingxin Jieyu Granule (QXJYG) on myocardial ischemia/reperfusion (I/R) injury by inhibiting cardiomyocyte pyroptosis via circulating exosomes. METHODS:Seventy-five Wistar rats were randomly assigned to 5 groups using a random number table (15 rats per group): sham-operated, model, low-, medium-, and high-dose QXJYG groups (L-QXJYG, M-QXJYG, and H-QXJYG). The L-QXJYG, M-QXJYG, and H-QXJYG groups were administered QXJYG at doses of 2.87, 5.73, and 11.46 g/kg, respectively, twice daily via intragastric administration for 28 consecutive days. The model group received an equal volume of normal saline following the same schedule. Following 28 days of administration, myocardial I/R injury was induced 1 h after the final dose. Myocardial infarction size, histopathological changes, and expression of key pyroptosis-related molecules in cardiac tissue were assessed. An oxygen-glucose deprivation/reperfusion model using H9c2 cardiomyocytes was established to investigate the cardioprotective mechanism of QXJYG, emphasizing the role of circulating exosomes in modulating pyroptosis through evaluations of cell viability, pyroptotic morphology, and associated molecular expression. RESULTS:In vivo experiments demonstrated that QXJYG significantly reduced myocardial infarction size, improved histopathological morphology, suppressed the inflammatory response, and inhibited myocardial pyroptosis (all P<0.05). In vitro, QXJYG was shown to enhance H9c2 cardiomyocyte viability, attenuate inflammation, and suppress pyroptosis by inhibiting the NLRP3/Caspase-1/GSDMD pathway via circulating exosomes (all P<0.05). CONCLUSION:QXJYG alleviates myocardial I/R injury by inhibiting cardiomyocyte pyroptosis through circulating exosomes, potentially via modulation of the NLRP3/ Caspase-1/GSDMD pathway.

The longitudinal relationship between antihypertensive medication patterns and depression risk remains controversial. This study aimed to identify distinct long-term medication trajectories among Chinese middle-aged and older adults with hypertension and prospectively examine their association with incident depression. Using data from the China Health and Retirement Longitudinal Study (CHARLS), we constructed two independent cohorts. A primary analysis cohort included 4304 participants aged ≥45 years without baseline depression. Latent Class Growth Modeling was applied to individuals with baseline hypertension (n = 2477) to identify medication use trajectories across three survey waves (2011-2015). An independent validation cohort comprised individuals with new-onset hypertension and a persistently normotensive control group (total n = 1625). Incident depression was assessed using the CESD-10 scale. Associations were examined using Kaplan-Meier analysis and multivariable Cox proportional hazards models, with robustness assessed through multiple sensitivity analyses. In the primary analysis cohort, four medication trajectories were identified. The transition from non-use to use had the highest cumulative incidence of depression (39.3%) and was the only trajectory significantly associated with increased depression risk after full adjustment (Hazard Ratio [HR]=1.389, 95% Confidence Interval [CI]: 1.180-1.635). This association was confirmed in the validation cohort (HR=1.761, 95% CI: 1.159-2.676) and remained consistent across all sensitivity analyses. These findings indicate that the transition from medication non-use to use represents a significant risk factor for incident depression, identifying a critical behavioral window for targeted monitoring and integrated mental health intervention in hypertension management.

The combined effects of metabolic status and genetic predisposition on healthy ageing remain unclear. We aimed to investigate the association of metabolic status and genetic predisposition with healthy ageing and life expectancy across obesity levels in the context of predictive, preventive, and personalized medicine (PPPM). Cox regression models were used to examine the relationships of metabolic status and polygenic risk score (PRS) with healthy ageing across obesity levels using data from the UK Biobank. Multistate life tables were used to evaluate life expectancy with and without major chronic diseases, cognitive dysfunction, physical impairment, and mental impairment. Compared with individuals with metabolically unhealthy obesity (MUO) and a low PRS for healthy ageing, those with metabolically healthy obesity (MHO) and a high PRS had a significantly increased likelihood of healthy ageing (hazard ratio [HR]: 1.10; 95

IntroductionChenpi (Citrus reticulata) has both medicinal and dietary applications, while Banxia (Pinellia ternata) is frequently combined with Chenpi to treat inflammatory diseases. This study aimed to investigate the potential therapeutic targets and pharmacological mechanisms of the Chenpi-Banxia (CB) herbal combination in rheumatoid arthritis (RA).MethodsA collagen-induced arthritis (CIA) rat model was used to evaluate the effects of CB on arthritis symptoms, histopathology, and serum cytokine levels. Network pharmacology was applied to identify active compounds and potential targets. Key components were analyzed by high-performance liquid chromatography, and molecular docking and molecular dynamics simulations were performed to assess their interactions with JNK proteins. The regulatory effects of CB on the JNK/AP-1 pathway were further examined in leptin-induced fibroblast-like synoviocytes (FLSs) and CIA rats.ResultsCB significantly reduced paw swelling and arthritis scores, ameliorated joint pathological damage, and decreased TNF-α and IL-6 levels in the serum and synovial tissues of CIA rats. Network pharmacology identified the JNK pathway as a key target. Among five candidate compounds detected in CB-containing serum, nobiletin showed the largest chromatographic peak area. Molecular docking and dynamics simulations supported stable interactions between nobiletin and JNK1/JNK2. In vitro, nobiletin and CB-containing serum inhibited leptin-induced FLS proliferation, migration, inflammatory factor release, JNK phosphorylation, and downstream c-Jun and c-Fos expression. In vivo, CB also suppressed JNK/AP-1 activation in synovial tissue.DiscussionThese findings suggest that CB alleviates experimental arthritis and synovial inflammation, at least partly by suppressing leptin-mediated JNK/AP-1 signaling and abnormal FLS activation, thereby supporting its potential therapeutic relevance in RA.

BackgroundChronic venous disease (CVD) arises from venous obstruction, reflux, or both. Iliac vein stenting is standard for obstructive lesions, but the incremental benefit of concurrently treating deep venous reflux remains uncertain. We evaluated the efficacy of combining iliac vein stent placement with deep venous valve reconstruction in CVD patients presenting with both iliac obstruction and reflux.MethodsFrom October 2015 to May 2025, we retrospectively analyzed a prospectively maintained cohort of 74 patients with lower-limb CVD and iliac vein stenosis and stratified them by reflux pattern: Group 1 (n = 14), iliac obstruction + superficial venous reflux; Group 2 (n = 16), iliac obstruction + deep venous reflux; Group 3 (n = 44), iliac obstruction + both deep and superficial venous reflux. Outcomes included Venous Clinical Severity Score (VCSS), ulcer healing, and complications.ResultsAll groups showed symptomatic improvement with significant VCSS reductions. Patients in Group 3, who received comprehensive management for iliac obstruction and both deep and superficial reflux, showed numerically more favorable outcomes than the other groups. Among 27 patients with active ulcers, the overall healing rate was 85.2%; those undergoing deep venous valve reconstruction had higher healing rates and shorter time to closure. Primary patency of iliac stents was 98.3%, and no major complications were observed.ConclusionsIn CVD with coexisting iliac obstruction and venous reflux, a combined strategy-iliac stenting plus deep venous valve reconstruction-was associated with greater clinical improvement and a shorter time to complete ulcer healing compared with treating obstruction alone. This approach appears safe, maintains high stent patency, and may optimize outcomes in complex CVD.

Chronic deep venous insufficiency (CVI) of the lower extremities results from structural or functional abnormalities of the venous valves, leading to blood reflux and increased venous pressure. Common clinical manifestations include edema, varicose veins, skin hyperpigmentation, and ulcers. The primary etiologies of CVI include congenital valve defects and secondary damage from venous thrombosis, both of which significantly impair quality of life. Surgical treatments for CVI include valve repair, valve transposition, and valve transplantation. Valve repair is effective when the valve structure is relatively intact, as it restores function and improves venous return. However, its efficacy diminishes in cases of severe valve damage, and long-term follow-up is necessary. Valve transposition, which involves relocating a functional segment of the valve to a non-functional area, is technically challenging and carries a higher risk of complications. Valve transplantation, in which veins from other parts of the body are used, is indicated for extensive valve damage but is constrained by the limited availability of donor veins and the technical complexity of the procedure. The selection of an appropriate surgical method should be based on a comprehensive assessment of the patient’s condition.This manuscript presents a unique case of successful femoral vein valve repair combined with deep femoral vein ligation in a patient with CVI and aneurysmal dilation, highlighting an effective treatment approach for femoral and deep femoral vein reflux. The case offers valuable insights into the management of CVI, particularly in complex cases where conventional treatments may be less effective.

Background:Long COVID, a persistent condition following SARS-CoV-2 infection, exhibits diverse symptoms across multiple organ systems. This study aims to summarize the existing clustering and classification approaches to support the management of Long COVID. Methods:Following PRISMA guidelines, we systematically searched PubMed, Embase, Web of Science, and Google Scholar from their inception to January 21, 2025, and updated the search on October 1, 2025, to identify studies that presented a way to categorize Long COVID patients or symptoms. Data extraction and quality assessment were conducted for eligible studies. We presented symptom co-occurrence networks, and performed meta-analysis to estimate the percentage of different organ system-based symptom clusters. In addition, we conducted an exploratory analysis of the determinants of different symptom clusters. The protocol was registered in OSF (https://doi.org/10.17605/OSF.IO/J483F). Findings:Forty-seven cohort studies and 17 cross-sectional studies categorizing Long COVID subtypes or symptoms were included, encompassing 2.43 million participants across 20 countries. The methodological quality of the cohort studies was on average high (mean Newcastle-Ottawa scale score: 7.5/9), and of the 17 cross-sectional studies moderate (mean Joanna Briggs Institute tool score: 0.61/1.00). Patients or symptoms were categorized either according to the co-occurrence of symptoms (n = 30 studies, 46.9%); by the affected organ system (n = 16, 25.0%); by severity stratification (n = 9, 14.1%); by clinical indicators (n = 3, 4.7%); or by using other ways of classification (n = 6, 9.4%). Among the 30 studies defining patient clusters by the co-occurrence of symptoms, fatigue was the most frequently used descriptor for a cluster, either alone or together with other symptoms (n = 15 studies). Pairwise co-occurrence analysis revealed some commonly used symptom dyads, including olfactory-gustatory dysfunction (n = 10 times), anxiety-depression (n = 10) and joint pain/swelling-muscle pain (n = 9). Fatigue was a recurrent core symptom, frequently co-occurring with joint pain/swelling (n = 9 times) or muscle pain (n = 7), cognitive symptoms (n = 7), and dyspnea (n = 7). Meta-analysis of the organ system-based subtypes showed that respiratory symptom cluster had the highest pooled percentage (47% [95% CI: 29%-65%]), followed by neurological (31% [95% CI: 3%-60%]) and gastrointestinal clusters (28% [95% CI: 0%-57%]). These percentages represent the proportion of Long COVID patients with each symptom cluster within the 16 included organ system-based subtyping studies, not population-level prevalence of Long COVID. Exploratory analysis indicated that symptom subtypes were influenced by factors such as sex, age, virus variant, and comorbidities. Interpretation:This review identified four major approaches for categorizing Long COVID patients and their symptoms. Symptom co-occurrence and organ system were the most commonly used subtypes used in categorization. Fatigue and olfactory-gustatory dysfunction emerged as recurrent core symptoms across multiple subtypes of Long COVID. Funding:This work was supported by the K. C. Wong Education Foundation, Hong Kong, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2024-I2M-ZD-011), the Beijing Nova Program (20240484523), the Elite Medical Professionals Project of China-Japan Friendship Hospital (NO. ZRJY2024-GG03), and the National High Level Hospital Clinical Research Funding.

Background Airway mucus hypersecretion is a key pathophysiological feature in many respiratory diseases and could lead to airway obstruction and repeated infections, consequently accelerating disease progression, which impacts on pulmonary function and quality of life (QoL), highlighting the importance of mucolytic therapy targeting airway mucus hypersecretion.Objectives To investigate the safety and efficacy of inhalable ambroxol hydrochloride aerosol for adult patients with respiratory diseases.Design An open-label, single-arm, multicentre postmarketing surveillance study.Methods Adult patients with acute or chronic respiratory diseases were eligible to receive aerosol inhalation of ambroxol hydrochloride (3 mL and 7.5 mg/mL) using a nebuliser two times per day given at least 6 hours apart between doses. The treatment lasted for a maximum of 7 days. The primary safety outcome was the frequency and severity of adverse events (AEs), and the primary efficacy outcome was changes in sputum scale scores.Results Among 1201 eligible patients, 1192 received study medication and were included in the full analysis set and the safety set. Any grade AEs occurred in 16.3% of the patients, including serious AEs in four (0.3%) patients. The three most frequent AEs were respiratory symptoms and signs (1.5%), nausea and vomiting (0.8%) and digestive tract symptoms and signs (0.7%). In the full analysis set, the patients showed a mean reduction of 77.6% (95% CI, 75.9% to 79.3%) in the sputum scale score at the end of treatment, with a mean difference of −1.7±0.7 from baseline (p<0.001).Conclusion Inhalable ambroxol hydrochloride aerosol is well tolerated and effective in easing expectoration and alleviating cough, reducing sputum and improving the QoL of adult patients with acute and chronic respiratory diseases.Trial registration number ChiCTR2100043736.

Regulatory T cells (Tregs) have been documented to accumulate in damaged myocardial tissue, where they play a pivotal role in attenuating excessive inflammatory responses during myocardial ischemia/reperfusion (I/R) injury. Concurrently, soluble receptor for advanced glycation end-products (sRAGE) has been demonstrated to alleviate myocardial I/R injury by suppressing inflammation, suggesting a potential involvement of Tregs in the inhibitory effects of sRAGE on myocardial I/R injury. I/R surgery or glucose deprivation/reoxygenation was employed to explore myocardial injury and the related mechanisms by using cardiomyocyte-specific sRAGE knock-in mice or cultured cardiomyocytes. Potential molecular mechanisms were analyzed via western blotting, immunohistochemistry, and flow cytometric analysis. The findings revealed that sRAGE overexpression significantly increased the numbers of Tregs. Depletion of Tregs abrogated the protective effects of sRAGE against I/R-induced cardiac dysfunction, myocardial fibrosis, and inflammatory response in cardiac-specific sRAGE transgenic mice. Mechanistically, sRAGE was found to enhance the expression of programmed cell death ligand 1 (PD-L1) and its upstream JAK2/STAT3 signaling axis, thereby facilitating CD4+ T cells differentiation into Tregs within myocardial tissue during I/R. The study demonstrated that sRAGE protected against myocardial I/R injury by modulating the differentiation of Tregs through upregulation of the JAK2/STAT3-PD-L1 signaling pathway.

Bone marrow-derived macrophages (BMMs) exhibit dynamic behavior and functional capabilities in response to specific microenvironmental stimuli. Recent investigations have proved that BMMs play crucial roles in promoting necrotic lesion resolution. Despite substantial advancements in understanding their activation and interaction with injured livers, researchers face challenges to develop effective treatments based on manipulating BMMs function. Caveolin-1 (Cav-1) is the major structural protein on the plasma membrane. We previously reported that Cav-1 knockout (KO) mice exhibited less functional damage and necrosis in carbon tetrachloride (CCl4)-induced liver injury. We hypothesize that the activation and recruitment of BMMs are involved in the resolution of necrotic lesions in Cav-1 KO mice. Wild-type (WT) and Cav-1 KO mice were injected with CCl4 (10% v/v) to induce acute liver injury model. Blood samples and hepatic tissues were harvested for serum alanine transaminase (ALT) activity assessment, histopathological examination through hematoxylin-eosin (H&E) staining, and BMMs subpopulation analysis via flow cytometry. Then, primary BMMs were isolated and cultured to investigate the effect of Cav-1 on BMMs polarization, migration, and activation of STAT3 signal pathway. Validation of hepatic macrophage depletion was induced by administrating clodronate liposomes (CLs), and BMMs reconstitution was evaluated by EGFP labelled BMMs. Following this, hepatic macrophages were depleted by CLs, BMMs were isolated from Cav-1 KO, and WT mice were cultured and administrated to evaluate the protective role of Cav-1-deleted BMMs on the resolution of hepatocellular necrosis and apoptosis in acute liver injury. The BMMs ratio significantly increased from 2.12% (1D), 4.38% (1W), and 5.38% (2W) in oil control mice to 7.17%, 14.90%, and 19.30% in CCl4-treated mice (p < 0.01 or p < 0.001). Concurrently, Cav-1 positive BMMs exhibited a marked elevation from 6.41% at 1D to 24.90% by 2W (p = 0.0228). Cav-1 KO exerted protective effects by reducing serum ALT by 26% (p = 0.0265) and necrotic areas by 28% (p = 0.0220) and enhancing BMMs infiltration by 60% (p = 0.0059). In vitro, Cav-1 KO BMMs showed a decrease in CD206 fluorescence intensity (p < 0.001), a time-dependent upregulation of arginase-1 mRNA (p < 0.05 or p < 0.01), a 1.22-fold increase in phosphorylated STAT3 (p = 0.0036), and impaired wound healing from 12 to 24 h (p < 0.001). The macrophage-depleting action in livers by CL injection persists for a minimum of 48 h. Administrated EGFP+ BMMs emerged as the predominant population following CL injection for a duration of 48 h. Following clodronate liposome-mediated hepatic macrophage depletion, the adoptive transfer of Cav-1 KO BMMs demonstrated therapeutic efficacy in CCl4-induced acute liver injury. In CCl4-induced acute liver injury, the adoptive transfer of Cav-1 KO BMMs reduced necrosis by 12.8% (p = 0.0105), apoptosis by 25.2% (p = 0.0127), doubled macrophages infiltration (p = 0.0269), and suppressed CXCL9/10 mRNA expression (p = 0.0044 or p = 0.0385). BMMs play a key role in the resolution of liver necrotic lesions in CCl4-induced acute liver injury. Cav-1 depletion attenuates hepatocellular necrosis and apoptosis by accelerating BMMs recruitment and M2 polarization. Cav-1 in macrophages may represent a potential therapeutic target for acute liver injury.

Glucose transporter 4 (GLUT4)-mediated glucose metabolism is a promising therapeutic target facilitating cardiomyocyte survival during myocardial ischemia/reperfusion (I/R) injury. Soluble receptor for advanced glycation end-products (sRAGE) has been proven to attenuate I/R injury via inhibiting AGE-RAGE mediated signaling pathways, but its role in regulating glucose metabolism remains unclear. Recently, AGEs were reported to hamper the GLUT4 translocation by interfering with the insulin signaling pathway in granulosa cells. Thus, it was speculated that sRAGE might inhibit myocardial I/R injury by enhancing the GLUT4-mediated glucose metabolism. Cardiomyocyte-specific sRAGE knock-in mice were constructed and underwent I/R surgery. H9c2 cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R). The overexpression of sRAGE in cardiomyocytes improved cardiac function, decreased infarct size, and inhibited apoptosis during myocardial I/R injury. sRAGE did not affect the expression of total GLUT4 but increased the translocation of GLUT4 to the plasma membrane, which enhanced the glucose uptake in cardiomyocytes. Meanwhile, sRAGE increased the production of lactate, NADH/NAD+, and adenosine triphosphate levels in cardiomyocytes during OGD/R. sRAGE activated the AMP-activated protein kinase (AMPK)/Akt substrate of 160 kDa (AS160) signaling pathway, and the application of AMPK inhibitor or AS160 mutant abolished the effect of sRAGE on facilitating plasma membrane GLUT4 localization and glucose metabolism. Moreover, the AMPK inhibitor or silenced GLUT4 depleted the anti-apoptotic effect of sRAGE during OGD/R in cardiomyocytes. Therefore, it was suggested that sRAGE inhibited I/R-induced apoptosis via enhancing the GLUT4 translocation to the plasma membrane and glucose metabolism through the AMPK/AS160 signaling pathway.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder, with some studies suggesting that obesity may increase the risk of developing RA. However, the relationship between obesity and RA is complex, involving both epidemiological associations and, paradoxically, protective effects. The exact role of obesity in RA pathophysiology remains controversial. In this study, we investigated the impact of obesity on RA progression, focusing on the molecular mechanisms of immune regulation mediated by the adipokine leptin. We examined obese RA patients and employed high-fat diet (HFD)-induced obesity models along with leptin gene-deficient (ob) mice to explore the influence of obesity on RA progression. Our findings revealed elevated serum leptin levels in obese RA patients, which were positively correlated with disease severity. Furthermore, HFD-induced obesity exacerbated arthritis severity in collagen-induced arthritis (CIA) mice, leading to increased joint pathology and bone destruction. To further assess the role of leptin, we utilized ob mice and exogenous leptin supplementation models to investigate its effects on CIA and Th17 polarization. Our results emphasize that leptin, rather than obesity per se, plays a critical role in RA progression by interacting with peroxisome proliferator-activated receptor gamma (PPARγ), thereby promoting Th17 cell differentiation. These findings provide valuable insights into the role of leptin in RA pathogenesis and suggest that leptin may serve as a potential therapeutic target for managing RA in obese individuals.

AIM:Chronic kidney disease (CKD) is highly prevalent among individuals with abnormal glucose metabolism. However, limited research has specifically investigated CKD-associated proteins within this high-risk population. To address this gap, our study aimed to identify proteins associated with CKD in participants with abnormal glucose metabolism, potentially informing early detection and targeted therapeutic strategies. METHODS:We first employed orthogonal partial least squares discriminant analysis (OPLS-DA) to select important proteins and further used Cox proportional hazards models using proteomic data from the UK Biobank to identify candidate proteins associated with CKD in participants with abnormal glucose metabolism. Subsequently, we performed one-sample Mendelian randomization (MR) using individual-level genomic data from the UK Biobank and pQTL summary statistics from the UKB-PPP, applying a two-stage least squares approach. For two-sample MR, we utilized pQTL data from deCODE and CKD GWAS summary statistics derived from the UK Biobank, applying either the Wald ratio or inverse variance weighted (IVW) method. Proteins supported by both observational analyses and at least one MR approach were further evaluated using publicly available databases to determine their novelty. Finally, for proteins consistently identified across all approaches, we assessed tissue specificity, gene expression, and conducted sensitivity analyses to strengthen the robustness of our findings. RESULTS:Through integrated observational and MR analyses, we identified a total of 45 proteins significantly associated with CKD in participants with abnormal glucose metabolism, among which 11 represent novel discoveries: CD300C, CD300LG, CDNF, CDSN, CHRDL1, ENPP6, LEFTY2, MOG, RSPO3, TNFRSF13B, and MYLPF. Notably, ENPP6 emerged with consistent evidence across all analytic approaches. Observational analyses demonstrated a hazard ratio (HR) of 0.75 (95% CI: 0.63-0.89), while one-sample MR revealed an odds ratio (OR) of 0.32 (95% CI: 0.14-0.73), and two-sample MR produced an OR of 0.60 (95% CI: 0.37-0.98), supporting a protective role of ENPP6 in CKD development. Furthermore, ENPP6 displayed kidney-specific expression, particularly within peritubular and proximal tubular cells. These findings were robustly validated through comprehensive sensitivity analyses. CONCLUSION:In conclusion, we identified 11 novel proteins associated with CKD in individuals with abnormal glucose metabolism, with ENPP6 emerging as a particularly compelling candidate due to its consistent protective association across multiple analytical approaches. These findings offer promising insights into CKD pathophysiology and highlight ENPP6 as a potential biomarker or therapeutic target. Further research is warranted to elucidate the mechanistic roles of these novel proteins in CKD development and progression.

A considerable number of patients with deep vein thrombosis of the lower extremities will develop post-thrombotic syndrome even after receiving standardized anticoagulation therapy. Damage to the femoral vein valves caused by post-thrombotic syndrome can lead to severe chronic lower limb venous insufficiency and currently there is a lack of effective treatment. We present a patient with pigmentation and itching due to post-thrombotic syndrome, where the anterior leaflet of the first set of valves in the superficial femoral vein was completely destroyed, while the posterior leaflet, although structurally intact, was adhered to the vessel wall. By reconstructing the posterior leaflet of the femoral vein valve and simultaneously narrowing the lumen where the anterior leaflet was located through suture ligation, we restored the valve’s function to prevent venous reflux. During a 12-month follow-up period, the patient’s quality of life significantly improved. Single-leaflet reconstruction surgery may serve as a potential treatment option for patients with post-thrombotic syndrome.

Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.