ObjectiveTo study the efficacy and safety of upadacitinib in children with refractory inflammatory bowel disease (IBD).MethodsClinical data of eight children with refractory IBD treated with upadacitinib at the Children's Hospital, Zhejiang University School of Medicine, from December 1, 2023 to May 20, 2025 were retrospectively collected to evaluate efficacy and safety.ResultsEight children were included [Crohn's disease (CD), n=5; ulcerative colitis (UC), n=3]; seven were male and one was female. At baseline, six patients had mild disease activity (CD, n=4; UC, n=2) and two had severe activity (CD, n=1; UC, n=1). In UC, all three patients achieved clinical remission by week 2; the week-8 steroid-free clinical remission rate was 67% (2/3). In CD, after 4 weeks of upadacitinib, one patient achieved a clinical response and two switched to other drugs due to persistent activity; the week-12 clinical response rate was 20% (1/5). After 12 weeks, one additional patient switched therapy due to disease activity, and two received combination therapy with thalidomide and exclusive enteral nutrition, respectively. The median follow-up duration was 28 weeks. Overall, five patients achieved clinical remission; among CD, two achieved clinical remission at weeks 14 and 20, respectively. Among eight patients, one episode of norovirus infection occurred, complicated by hypovolemic shock.ConclusionsUpadacitinib can induce a rapid response in children with refractory UC. In refractory CD, combining upadacitinib with agents of different mechanisms may increase the clinical remission rate. Multicenter studies with larger samples are required for confirmation, and vigilance for infection during treatment is warranted.

Purpose:Prenatal hypoxia is a major environmental risk factor for neurodevelopmental disorders, yet effective prenatal therapeutic strategies remain lacking. This study aimed to develop a transferrin-modified lipid nanoparticle platform for targeted delivery of HIF-1α siRNA to the fetal brain and to evaluate its therapeutic efficacy and molecular mechanisms. Methods:Transferrin-modified lipid nanoparticles encapsulating HIF-1α siRNA were intravenously administered to pregnant rats prior to hypoxic exposure. Biodistribution, gene silencing efficiency, molecular signaling alterations, neuronal structural changes, and behavioral outcomes in offspring were systematically assessed. Results:In this study, we developed a transferrin-modified lipid nanoparticle system for non-invasive, transplacental delivery of HIF-1α small interfering RNA to the fetal brain, achieving a siRNA encapsulation efficiency of 84.18% and a loading capacity of 2.5%. Systemic administration to pregnant rats prior to hypoxic exposure resulted in preferential accumulation of nanoparticles in fetal brain tissue and effective suppression of HIF-1α expression in the fetal hippocampus without overt effects on offspring survival, as evidenced by comparable offspring survival rates across all groups (p > 0.05). Prenatal hypoxia induced sustained elevation of HIF-1α protein (p < 0.001), impaired phosphatase and tensin homolog (PTEN) activity through increased phosphorylation (p < 0.01), aberrant activation of the PI3K/AKT signaling pathway (p < 0.05), and deficits in hippocampal neuronal structural plasticity, including reduced dendritic spine density (p < 0.0001) and dendritic complexity (p < 0.0001), accompanied by autism-like behaviors in offspring, including impaired social preference (p < 0.01), prolonged self-grooming (p < 0.0001), and increased marble-burying (p < 0.001). Prenatal HIF-1α silencing restored PTEN functional status, normalized PI3K/AKT signaling, improved dendritic architecture to levels comparable to controls (p > 0.05 vs control), and significantly ameliorated behavioral abnormalities (social preference and stereotyped behaviors, p < 0.0001). Mechanistic analyses revealed that although HIF-1α binds to the PTEN promoter (ChIP-qPCR, p < 0.01), prenatal hypoxia did not alter PTEN transcript or total protein levels (p > 0.05), indicating that HIF-1α primarily regulates PTEN function at the post-transcriptional level in vivo. Conclusion:These findings identify a HIF-1α/PTEN/PI3K/AKT signaling axis as a key molecular pathway underlying hypoxia-associated neurodevelopmental impairment and demonstrate the feasibility of targeted prenatal gene modulation using transferrin-modified lipid nanoparticles. This work provides a nanomedicine-based framework linking environmental risk factors to early-life preventive strategies for neurodevelopmental disorders.

Infectious diseases can cause lasting immune disturbances, but whether they contribute to later inflammatory bowel disease (IBD) is unclear. Hospital-treated infections may be especially informative because they reflect substantial immune challenge, yet their relation to IBD risk and the role of host genetics remain poorly defined. It examines hospital-treated infections and incident IBD in a prospective cohort and integrates gene-environment interaction analyses to identify susceptibility pathways and develop a post-infection risk score. Hospital-treated infections of multiple pathogen types and sites were associated with higher subsequent IBD risk. This association is stronger in carriers of immune-related risk variants, with Crohn's disease linked mainly to innate immune and autophagy pathways and ulcerative colitis to JAK-STAT, T-cell differentiation, and chemokine signaling. An Infection IBD Score based on 44 immune-related genes stratified post-infection risk. These findings support infections as triggers of IBD in genetically susceptible individuals and highlight a potential tool for risk stratification.

Osteoclasts and osteoblasts play critical roles in bone remodeling, and their dysregulation leads to pathological bone loss. However, the precise mechanisms underlying the regulation of differentiation remain unclear. This study investigated the role of the transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and bone resorption. Mechanistically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis.

Objective: To examine how socioeconomic status (SES) affects diabetes incidence in prediabetic adults, quantifying the mediating role of modifiable lifestyle factors in SES-related disparities to guide interventions. Methods: A prospective cohort of 34,669 adults with prediabetes from UK Biobank (2006-2010) with follow-up through 31 October 2022. From 27 SES indicators based on the social determinants of health framework, education, employment, and income were selected for latent class analysis. Lifestyle was assessed using a composite score (0-5) including smoking, diet, sleep duration, body mass index (BMI), and sedentary behavior. Cox models estimated associations; mediation analysis quantified the proportion mediated by lifestyle, and population-attributable fractions estimated preventable burden. Results: Over a median 13.22-year follow-up, 6904 incident diabetes cases were identified. Compared with the high SES group, the hazard ratios for incident diabetes were 1.36 (95% confidence interval (CI): 1.25, 1.48) and 1.91 (95% CI: 1.75, 2.09) for medium and low SES, respectively. Lifestyle factors mediated 33.71% and 31.44% of the SES-diabetes association in the medium and low SES, respectively. The population-attributable fractions were 24.05% for lifestyle and 34.50% for SES. Conclusions: Lower SES is associated with elevated diabetes progression risk, with about one-third mediated by lifestyle factors, particularly BMI.

[Objective] : This study aimed to investigate the correlation between plaque viscoelastic parameters and systemic biochemical markers in individuals at high cardiovascular risk, and to evaluate their predictive value for cardiovascular risk. [Methods] : A total of 38 patients were enrolled and divided into a high-risk group (n = 23) and an intermediate-risk group (n = 15). Six viscoelastic parameters were measured, including the stiffness, D-dispersion coefficient, and V-viscosity coefficient of the whole plaque and its proximal shoulder, respectively. Twenty-four systemic biochemical indices were also examined. Statistical tests were used to compare intergroup differences, while correlation analysis, random forest models, and receiver operating characteristic (ROC) curves were applied to evaluate the correlations and predictive efficacy of these indicators. [Result] : Fasting blood glucose (Glu) and glycated hemoglobin (HbA1c) were significantly higher in the high-risk group than in the intermediate-risk group (P < 0.05), and BNP also showed an increasing trend (P = 0.033). Correlation analysis revealed high internal consistency among viscoelastic parameters. Platelet count (PLT) was significantly negatively correlated with whole-plaque D-dispersion coefficient (WP-DDC), and alanine aminotransferase (ALT) was negatively correlated with whole-plaque stiffness (WP-kPa). ROC analysis indicated that proximal shoulder V-viscosity coefficient (PSh-VC) and whole-plaque V-viscosity coefficient (WP-VC) exhibited certain value for risk screening and diagnosis, with area under the curve (AUC) values of 0.543 and 0.551, respectively. The random forest model further demonstrated that total cholesterol (TC), platelet count (PLT), NT-proBNP, and ALT were core driving factors for viscoelastic parameters, with the coefficient of determination (R²) of each prediction model ranging from 0.779 to 0.830. [Conclusion] : Viscoelastic parameters are closely correlated with various biochemical indicators, and their combined application can provide a new basis for the early identification and individualized intervention of cardiovascular risk.

The association between early life exposure to smoking and the risk of inflammatory bowel disease (IBD) needs to be further verified, and the potential role of DNA methylation in the association is unclear. Through an integrated study design, this study demonstrates that maternal smoking during pregnancy (MSDP) is potentially associated with increased risk of IBD, Crohn's disease (CD), and ulcerative colitis (UC) in offspring. In addition, individuals who started smoking in adolescence have a higher risk of developing CD and IBD. Mechanistically, MSDP-associated DNA methylation alterations in ADCY7 (newborn), AKAP8L (newborn), TIGD7 (newborn), and TNF/LTA (across life stages) are significantly correlated with increased risk of CD in offspring; MSDP-induced DNA methylation changes in PRRT1 (newborn), AHRR (across life stages), and MYO1G (across life stages) show significant associations with UC risk in offspring. Notably, the alterations of DNA methylation status within AHRR, MYO1G, and TNF/LTA loci associated with smoking exposure are present throughout the life course. Collectively, MSDP may serve as an independent risk factor for IBD in offspring, and active smoking during adolescence may cause increased risk of developing CD and IBD. MSDP may contribute to IBD susceptibility by inducing persistent DNA methylation alterations at multiple developmental stages.

Increased intake of ultra-processed food (UPF) links to higher risk of inflammatory bowel disease (IBD)1, while its biological mechanism remains unclear. Our previous work implied gene-diet interaction modulates the risk of IBD, especially in those with higher IBD susceptibility2,3. This study is to unveil UPF’s effect on IBD via circulating metabolites, localize key component, and explore its mechanism linking UPF to IBD. We aim to find the mechanism of UPF on incident IBD through key metabolite and related gene. Analyses involved two parts: a. construct UPF metabolic signature in UK Biobank (UKB) discovery cohort (n = 10,229), with internal (n = 91,306) and external validation (Whitehall II [WHII], n = 7,893); b. identify and validate key metabolite in UPF-IBD association and its mechanism in Western and Eastern (n = 752) cohorts. UPF metabolic signature was developed by elastic net regression of metabolites (assayed by high-throughput metabolomic platforms) on UPF intake (measured by repeated dietary recalls). We applied Cox regression to assess the metabolic signature on IBD risk. Weighted gene co-expression network analysis (WGCNA) was used to identify metabolite clusters in the signature. We combined linear model, elastic net regression, survival analysis, mediation analysis, and WGCNA to identify key metabolites. Further validation was performed in an Eastern multi-center cohort, ONE-IBD. Mendelian randomisation (MR), colocalization, and gene-environment (G-E) interaction analyses were used to address potential causality and genetic locus (Fig 1). A UPF metabolic signature of 73 metabolites was constructed (Fig 2A) and validated in UKB and WHII (Spearman ρ: 0.20-0.25). More pronounced UPF metabolic signature was associated with higher risk of IBD and CD (IBD: HRper SD=1.72, 95% CI 1.32-2.24; CD: HRper SD=2.65, 95% CI 1.57-4.48 Fig 2B). WGCNA revealed a cluster rich in fatty acids inversely associated with CD (HRper SD=0.66, 95% CI 0.45-0.98, Fig 2C), in which docosahexaenoic acid (DHA) was pinpointed as key metabolite (mediated proportion=12.5%, Fig 2D-E). External validation in ONE-IBD supported DHA as the metabolite most strongly associated with UPF and CD (Fig 2F). MR and colocalization revealed rs174546 in FADS1 gene as a shared variant linking DHA with CD (Fig 2G-H). G-E analysis showed UPF’s effect on CD was pronounced in individuals with FADS1 variant (T allele carriers, linking to lower DHA), while metabolic signature’s effect on CD was weakened, stressing the central role of metabolites (Fig 2I). Our study reveals the critical role of metabolites linking UPF and IBD risk, especially in CD, with consistent evidence identifying DHA and FADS1 gene as personalised targets in IBD precision prevention. References: 1.Chen J, Wellens J, Kalla R, Fu T, Deng M, Zhang H, Yuan S, Wang X, Theodoratou E, Li X, Satsangi J. Intake of Ultra-processed Foods Is Associated with an Increased Risk of Crohn’s Disease: A Cross-sectional and Prospective Analysis of 187 154 Participants in the UK Biobank. J Crohns Colitis. 2023 Apr 19;17(4):535-552. 2.Sun Y, Yuan S, Chen X, Sun J, Kalla R, Yu L, Wang L, Zhou X, Kong X, Hesketh T, Ho GT, Ding K, Dunlop M, Larsson SC, Satsangi J, Chen J, Wang X, Li X, Theodoratou E, Giovannucci EL. The Contribution of Genetic Risk and Lifestyle Factors in the Development of Adult-Onset Inflammatory Bowel Disease: A Prospective Cohort Study. Am J Gastroenterol. 2023 Mar 1;118(3):511-522. 3.Chen J, Dan L, Yuan S, Fu T, Sun J, Wolk A, Ludvigsson JF, Li X, Wang X, Larsson SC. Dietary Antioxidant Capacity, Genetic Susceptibility and Polymorphism, and Inflammatory Bowel Disease Risk in a Prospective Cohort. Clin Gastroenterol Hepatol. 2025 Aug;23(9):1623-1632.e16. Conflict of interest: Wang, Sidan: No conflict of interest Dan, Lintao: No conflict of interest Ruan, Xixian: No conflict of interest Wellens, Judith: No conflict of interest Sun, Yuhao: No conflict of interest Yao, Jialu: No conflict of interest Tian, Li: No conflict of interest Kalla, Rahul: No conflict of interest Theodoratou, Evropi: No conflict of interest Yuan, Shuai: No conflict of interest Larsson, Susanna C: No conflict of interest Jonas, Ludvigsson: Dr Ludvigsson has received financial support from Merck/MSD for a study on inflammatory bowel disease and fibrosis and for developing a paper reviewing national healthcare registers in China. Dr Ludvigsson also has an ongoing research collaboration on celiac disease with Takeda. Earlier support includes a grant from Janssen for an unrelated study on behalf of the Swedish IBD quality register (SWIBREG). Peyrin-Biroulet, Laurent: No conflict of interest Satsangi, Jack: No conflict of interest Magro, Fernando: Fernando Magro served as speaker and received honoraria from Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, Vifor. Li, Xue: No conflict of interest Wang, Xiaoyan: No conflict of interest Dr. Chen, Jie: No conflict of interest

Background:The elevated risk of cardiovascular disease (CVD) in inflammatory bowel disease (IBD) has been increasingly recognized. Although inflammation is implicated in both IBD and CVD, the IBD-CVD association through the mediation of systemic inflammation remains underexplored. Objective:To evaluate the associations between IBD and incident CVD and examine the mediating role of inflammatory biomarkers. Design:A sex- and age-matched cohort study. Methods:Using data from the UK Biobank, the study included 1494 participants with a first-ever diagnosis of IBD from 1999 to the recruitment date (2006-2010), and 14,940 matched reference individuals. The primary outcome was any CVD, whereas secondary outcomes included 7 major CVD categories and 19 specific CVD entities. Fifteen inflammatory biomarkers and indices measured at recruitment were included, serving as proxies of underlying inflammatory status. Cox proportional hazard model estimated the adjusted hazard ratios (HRs) and 95% confidence intervals (CI) of associations between IBD and CVD and between inflammatory biomarkers and CVD. Model-based mediation analyses were conducted to explore the potential mediating role of inflammatory biomarkers in IBD-CVD associations. Results:Compared with reference individuals, patients with IBD had an increased risk of any CVD (HR = 1.34, 95%CI 1.20, 1.49), ischemic heart disease (HR = 1.20, 95%CI 1.02, 1.41), heart failure (HR = 1.61, 95%CI 1.28, 2.02), arrhythmias (HR = 1.34, 95%CI 1.13, 1.59), atrial fibrillation (HR = 1.34, 95%CI 1.11, 1.62), other supraventricular arrhythmia (HR = 1.83, 95%CI 1.12, 2.99), and venous thromboembolism (HR = 1.74, 95%CI 1.38, 2.21). The mediation proportion was generally higher in Crohn's disease and in CVD subtypes (ischemic heart disease, heart failure, and arrhythmias) than in venous thromboembolism. Conclusion:IBD is associated with various CVD outcomes, and inflammatory biomarkers mediate their associations, suggesting that reducing inflammation may help alleviate cardiac burden in patients with IBD.

Background The effect of alcohol consumption on IBD remains inconclusive, potentially due to the overlooked role of alcohol metabolism. Objective We aimed to investigate the potential modifying role of alcohol metabolic capacity in the associations. Design A prospective cohort study (n=455 417) was used for association analysis between alcohol consumption and IBD risk using Cox proportional hazards regression. An acetaldehyde burden score, using genetic variants of alcohol dehydrogenase and aldehyde dehydrogenase validated by expression quantitative trait loci and proteomic data, was constructed to test effect modification. Genetic and metabolomic analyses, along with mice and human-derived colonic organoid experiments, were conducted to strengthen causal inference. Results The inverse association between alcohol and IBD risk was mainly attributable to red wine. Among individuals with low burden, reflecting low acetaldehyde generation and high acetaldehyde metabolism, per SD increase in red wine consumption (equivalent to 59.4 g/week of pure alcohol intake) was associated with a 20% (95% CI 7% to 31%) reduced Crohn’s disease risk, whereas a 38% (95% CI 13% to 70%) increased risk among those with high burden. Genetic and metabolomic analyses further revealed harmful effects of acetaldehyde and protective effects of acetate. In vivo and in vitro experiments further confirmed these effects and showed that modulation of aldehyde dehydrogenase activity significantly altered colitis outcomes. Conclusion Acetaldehyde metabolism burden modifies susceptibility to alcohol-related IBD and emphasises the importance of considering individual differences in alcohol metabolism when developing precision prevention strategies for IBD.

INTRODUCTION:The global prevalence of diabetes continues to rise, and long-term use of anti-diabetic drugs has thus become a cornerstone of clinical management for most patients. OBJECTIVES:This study aimed to explore the impact of antidiabetic drug use, combination therapy, and medication sequence on the risk of gastrointestinal disorders. METHODS:This study included 27,784 type 2 diabetes patients at baseline in the UK Biobank. Multivariate Cox models were employed to explore the associations between antidiabetic drugs (metformin, sulfonylureas, thiazolidinediones, alpha glucosidase inhibitors (AGI), glucagon-like peptide-1 receptor agonists (GLP-1RA), and insulin) and the incidence of gastrointestinal disorders. We leveraged the summary statistics from the FinnGen study and genome-wide association studies to perform drug-target Mendelian randomization (MR) analyses, validating the observed associations. RESULTS:During a median follow-up period of 15.2 years, sulfonylurea users had a lower risk of colorectal cancer (CRC) (HR: 0.76, 95% CI: 0.62-0.94) than nonsulfonylurea users. Insulin users had a decreased risk of diverticular disease (HR: 0.75, 95% CI: 0.68-0.83) compared with noninsulin users. In addition, metformin combined with sulfonylureas was associated with decreased CRC risk (HR: 0.61, 95% CI: 0.46-0.82), while postmetformin use of DPP-4i with sulfonylureas or GLP-1RA was related to higher acute pancreatitis risk. In two-sample MR, genetically predicted sulfonylureas targeting INS were associated with a reduced risk of CRC (OR: 0.56, 95% CI: 0.35-0.88), and insulin targeting LRP2 was associated with a reduced risk of diverticular disease (OR: 0.89, 95% CI: 0.80-0.98). CONCLUSION:Our study indicates that antidiabetic regimens, including combination therapies and treatment sequences, are clinically important for preventing gastrointestinal morbidity in type 2 diabetes patients. This underscores the need for personalized treatment to prevent gastrointestinal comorbidities.

Objective:To evaluate the gender-specific predictive performance of 12 anthropometric indices for metabolic syndrome (MetS) among Lahu ethnic adults with dyslipidemia. Methods:This cross-sectional study employed stratified cluster sampling in two Lahu communities in southwest China. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) criteria. Twelve indices were assessed: body mass index (BMI), waist circumference (WC), lipid accumulation product (LAP), visceral adiposity index (VAI), a body shape index (ABSI), body adiposity index (BAI), body roundness index (BRI), relative fat mass (RFM), uric acid-to-HDL-C ratio (UHR), triglyceride-glucose index (TyG), cardiometabolic index (CMI), and Chinese visceral adiposity index (CVAI). Receiver operating characteristic (ROC) curve analysis evaluated predictive performance, and binary logistic regression assessed associations with MetS and its components. Results:This study of 1257 Lahu adults with dyslipidemia (48.5% male) revealed a 23.4% MetS prevalence, significantly higher in females (29.2% vs 17.2%, p<0.001). The TyG index emerged as the strongest MetS predictor in both sexes (AUC: males 0.828, females 0.784), followed by CMI, VAI, LAP and CVAI with moderate predictive ability (AUC range: 0.678-0.779). Other indices showed limited predictive value, while ABSI was not significant. For MetS components, BRI showed strong associations with elevated BP in both genders (males: 1.666[1.228-2.261]; females: 1.804[1.388-2.344]) and with elevated TG (1.644[1.248-2.166]) in males. Female‑specific associations included VAI with reduced HDL‑C, and BMI/CVAI with elevated FPG. Conclusion:Among dyslipidemic Lahu adults, all indices except ABSI demonstrated predictive efficacy for MetS, with the TyG index outperforming all others. These simple, low-cost indices could be applied for early MetS screening or risk stratification in this population, particularly in rural or resource-limited settings. Notably, gender-specific differences should be considered in clinical applications.

Regulation of enhancer activity plays a pivotal role in governing gene expression and cellular behaviors. However, the precise mechanisms underlying dynamic control of active enhancers remain incompletely defined. Here, we demonstrate that the nuclear receptor estrogen-related receptor α (ERRα) forms a functional complex with the H3K4me3-specific demethylase KDM5C to co-occupy a large set of active enhancers, including the locus of STING. In breast cancer cells, ERRα depletion induces STING enhancer hyperactivation, evidenced by H3K4me3 deposition, decreased H3K4me1, and increased enhancer RNA (eRNA) transcription. Accordingly, depletion of ERRα leads to further activation of STING gene transcription and TBK1-IRF3 pathway, accompanied by increased type I interferon (IFN) and IFN-stimulated gene (ISG) expression, as confirmed by transcriptomic analysis. Notably, depleting ERRα markedly attenuates breast tumor cell growth in vitro and in vivo, and our in vitro evidence indicates this occurs in part through activating STING signaling. These findings establish that the ERRα-KDM5C serves as a critical checkpoint for STING enhancer activity, revealing a regulatory mechanism of STING enhancer activity in breast tumor progression.

IntroductionKeloids are fibroproliferative skin scars characterized by excessive extracellular matrix deposition and a high rate of recurrence. Despite extensive research, their pathogenesis remains incompletely understood and effective curative therapies are lacking.MethodsRNA sequencing (RNA-seq) and metabolomics were performed to compare gene expression and metabolite profiles between human keloid tissues and normal skin. Single-cell RNA sequencing, immunohistochemistry, and immunofluorescence were used to determine the cellular localization of key genes. In vitro, human fibroblasts were stimulated with glutamate, followed by RNA-seq, quantitative RT-PCR, and ELISA to evaluate inflammatory gene expression and cytokine secretion.ResultsTranscriptomic analysis revealed significant enrichment of the neuroactive ligand-receptor interaction pathway in keloid tissue, with marked upregulation of the glutamate receptor subunit GRIN2D. Single-cell and histological analyses demonstrated that GRIN2D is predominantly expressed in fibroblasts. Metabolomic profiling showed significantly increased levels of glutamate and glutamine in keloid tissues. Glutamate stimulation of fibroblasts significantly enhanced the expression and secretion of inflammatory cytokines IL-6 and IL-11, as well as chemokines CXCL2, CXCL3, and CXCL8 (IL-8).DiscussionThese results underscore the crucial role of glutamate metabolism in promoting the infammatory functions of fbroblasts. They suggest that glutamate contributes to keloid progression and provides a theoretical basis for targeting glutamte signaling pathway in keloid treatment.

It is well known that the burden of inflammatory bowel disease (IBD) has surged amid profound societal shifts, including industrialization and westernization of lifestyles in modern societies. However, how contemporary occupations, as a key social linkage connecting industrialization and profoundly shaping individual lives, modulate individual susceptibility to IBD remains largely understudied. This study aims to (1) systematically delineate the landscape of associations between occupations and IBD risk, and (2) elucidate the factors through which occupations influence individual susceptibility to IBD. We used robust Poisson regression to assess IBD risk across 353 occupations (coded by SOC2000) in the UK Biobank cohort, with validation in an independent Chinese cohort derived from the Hunan Medical Insurance Database. To further clarify the potential mechanisms behind the identified risk occupations, we employed Cox proportional hazards models to evaluate associations between IBD risk and occupation-related factors, including pollutants (airborne, dust-related, and complex chemical contaminants), occupation-specific behaviors (work-related physical activity, sedentary time, work stress, and night shifts), and occupation-related socioeconomic status. Among 120,290 participants, including 9,748 diagnosed with IBD, 10 occupations were identified as associated with an increased risk of IBD, with subgroup analyses revealing 16 and 6 occupations linked to Crohn’s disease (CD) and ulcerative colitis (UC), respectively. The excess risk observed for the skilled trades occupational category was further confirmed in the independent Hunan Medical Insurance Cohort (Figure 2A). High-level exposures to diesel (HR 1.56, 95% CI: 1.14-2.13) and mists (HR 1.31, 95% CI: 1.04-1.66) were associated with an increased risk of IBD, with similar patterns observed for both CD and UC (Figure 2B). Further analyses of behavioral and socioeconomic dimensions showed that lifelong exposure to high levels of occupational physical activity was associated with an elevated IBD risk (HR 1.18, 95% CI: 1.05-1.32), whereas higher occupational social status exerted a protective effect (HR 0.73, 95% CI: 0.66-0.90) with consistent risk reductions observed for CD and UC (Figure 2C). This study systematically presents the occupational landscape of IBD risk, highlighting the impact of high-pollution and high physical activity occupations on individual IBD susceptibility, while further linking industrialization-driven work patterns and social stratification to disease risk. These findings expand the environmental framework of IBD etiology and underscore the importance of integrating occupational factors into future etiologic and preventive research. Conflict of interest Zhou, Yuying: Have no conflict of interest. Dan, Lintao: I have no COI related to submitted program Ruan, Xixian: I disclose no relevant conflict of interest. Deng, Minzi: No conflict of interest Chen, Jie: No conflict of interest Wang, Xiaoyan: No conflict of interest

Cryptococcus neoformans meningitis (CM), a severe AIDS-defining illness with high mortality, remains refractory to effective therapies. This study investigated the mechanisms underlying Cryptococcus neoformans (Cn)-induced disruption of the blood-brain barrier (BBB). Using in vitro models of cerebral microvascular endothelial cells, we demonstrated that Cn disrupted the BBB via adhesion and invasion, leading to pyroptosis in these cells. Furthermore, our findings revealed that Cn induced upregulation of the α7 nicotinic acetylcholine receptor (α7nAChR). Importantly, inhibition of α7nAChR alleviated pyroptosis caused by Cn. Interestingly, the CHRFAM7A gene product, a duplicated α7nAChR subunit, negatively regulated its activity, thereby mitigating Cn-induced pyroptosis in cerebral microvascular endothelial cells. Fungal ergosterol, a key virulence factor, plays a critical role in this process. It slowed the wound healing in cell scratch assays and induced pyroptosis in cerebral microvascular endothelial cells. Consistent with in vitro findings, in vivo experiments using immunosuppressed mouse models demonstrated that Cn increased BBB permeability, as evidenced by enhanced Evans blue leakage and reduced ZO-1 expression in the cerebral cortex. Additionally, Cn reduced vascular activity and regulated pyroptosis-related proteins in the mouse cerebral cortex. Notably, both pharmacological inhibition of α7nAChR with MLA and its genetic modulation via CHRFAM7A overexpression conferred significant survival benefits and alleviated Cn-induced pathological damage in mice. These findings provide novel insights and potential therapeutic targets for the prevention and treatment of CM.

Background:Whether physical activity and restricted sedentary behaviour can maintain pancreas health remains inconclusive. We aimed to comprehensively investigate the associations of physical activity and sedentary behaviour with exocrine and endocrine pancreatic diseases in a prospective cohort study and further verify these associations by using Mendelian randomization (MR). Methods:The prospective study included 437,131 UK Biobank participants free of pancreatic diseases at baseline. We used moderate-to-vigorous physical activity (MVPA) to indicate physical activity and leisure screen time (LST) to indicate sedentary behaviour. Outcomes included five diseases related to pancreatic secretory functions. We conducted Cox proportional hazards regression and mediation analyses to examine the mediating role of body mass index (BMI). MR analysis was used to assess the robustness of the observational findings. Results:During a mean follow-up of 14 years, we identified 2,548 acute pancreatitis (AP), 638 chronic pancreatitis (CP), 1,711 pancreatic cancer (PC), 1,705 type 1 diabetes mellitus (T1DM), and 19,371 type 2 diabetes mellitus (T2DM) cases. Increasing MVPA was associated with AP, CP, T1DM, and T2DM risk in a U-shaped manner, with the lowest risk at ∼3,000 metabolic equivalent tasks-minutes/week (all P-nonlinearity < 0.05). BMI partially mediated associations of MVPA with AP, T1DM, and T2DM. LST was associated with an increased risk of AP, CP, PC, T1DM, and T2DM, with significant linear trends for CP, PC, and T1DM (all P-nonlinearity > 0.05). BMI partially mediated the associations of LST with AP, PC, T1DM, and T2DM. MR confirmed the associations of MVPA with AP and CP and of LST with AP, CP, and T2DM. Conclusion:Moderate MVPA and strict restriction of LST can serve as effective and practical strategies for preventing AP, CP, and T2DM.

OBJECTIVES:This study aimed to investigate the association between dietary total antioxidant capacity (TAC) and the risks of clinical outcomes, including surgery, gastrointestinal cancer, and mortality, among middle-aged and older individuals with IBD. DESIGN:Nationwide prospective cohort study. SETTING AND PARTICIPANTS:We included middle-aged and older participants with IBD when recruited in the UK Biobank. MEASUREMENTS:Dietary TAC was calculated by the oxygen radical absorbance capacity from the food by repeated dietary recalls. The outcomes representing IBD prognosis include IBD-related surgery, gastrointestinal cancer, and death events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. Polymorphism of antioxidant-related enzymes genes was ascertained via genotype data. RESULTS:With a median follow-up period of 10.9 years, we documented 174 cases of IBD-related surgery, 52 gastrointestinal cancer, and 189 death events among 2487 IBD participants. Compared to the lowest quartile of dietary TAC, participants in the highest quartile presented lower risks of IBD-related surgery (HR 0.53; 95% CI 0.34-0.84; P-trend = 0.005) and all-cause mortality (HR 0.61; 95% CI 0.39-0.96; P-trend = 0.014). Compared to the lowest decile, participants in the higher deciles of dietary TAC had a lower risk of gastrointestinal cancer (HR 0.39; 95% CI 0.19-0.83; P = 0.014). We also found genetic variants in catalase gene CAT and antioxidant transporter gene SLC2A14 modified the association between dietary TAC and IBD prognosis. CONCLUSIONS:Higher dietary TAC was associated with better prognosis of middle-aged and older individuals with IBD, including lower risk of related surgery, gastrointestinal cancer, and all-cause mortality, suggesting the importance of adherence to high-TAC diet in IBD management.