Sex-specific epigenetic signatures of circulating urate and its increase after BCG vaccination.

Background: Urate concentration and the physiological regulation of urate homeostasis exhibit clear sex differences. DNA methylation has been shown to explain a substantial proportion of serum urate variance, mediate the genetic effect on urate concentration, and co-regulate with cardiometabolic traits. However, whether urate concentration is associated with DNA methylation in a sex-dependent manner is unknown. Additionally, it is worth investigating if urate changes after perturbations, such as vaccination, are associated with DNA methylation in a sex-specific manner. Methods: We investigated the association between DNA methylation and serum urate concentrations in a Dutch cohort of 325 healthy individuals. Urate concentration and DNA methylation were measured before and after Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis. Validation of the identified CpG sites was conducted using three independent cohorts. Results: 215 CpG sites were associated with serum urate in males, while 5 CpG sites were associated with serum urate in females, indicating sex-specific associations. Circulating urate concentrations significantly increased after BCG vaccination, and baseline DNA methylation was associated with differences in urate concentration before and after vaccination in a sex-specific manner. The CpG sites associated with urate concentration in males were enriched in neuro-protection pathways, whereas in females, the urate change-associated CpG sites were related to lipid and glucose metabolism. Conclusion: Our study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights have significant implications for the diagnosis, prevention, and treatment of various urate-related diseases and highlight the importance of personalized and sex-specific approaches in medicine.

Implications of Physical Activity in Reducing Alcohol Use for Women Veterans: A Narrative Review.

Women veterans (WV) are a fast-growing population in the United States with concerning health disparities. Reports of increased risks of cardiovascular disease (CVD) and poorer health are evident in WV compared with their civilian counterparts. The transition from active duty to veteran poses additional life stressors, causing changes in health behaviors such as unhealthy alcohol consumption and decreased physical activity, which may explain health disparities in WV. The changes in these two health risk behaviors may be influenced by each other, and emerging evidence suggests that physical activity aids in managing alcohol consumption during alcohol use treatment. In this general narrative review, we summarized findings from studies involving WV on (1) the associations between alcohol consumption and physical activity and (2) the effect of physical activity on reducing alcohol use. We also discussed the clinical consideration of adding physical activity to alcohol use interventions for WV. Most of the literature included in this review has been based on predominantly veteran men populations. This knowledge gap highlights the importance of continued efforts and research studies targeting WV to eliminate health disparities among them.

Association between patent foramen ovale morphology and clinical outcomes following transcatheter closure.

BACKGROUND: Anatomic variations of the patent foramen ovale (PFO) are commonly observed, yet limited research has investigated their impact on clinical outcomes following transcatheter closure. We aimed to explore the association between PFO morphology and clinical outcomes. METHODS: Consecutive patients with cryptogenic stroke who underwent PFO closure were prospectively enrolled at a single center from September 2019 to April 2023. Patients were categorized into simple and complex groups based on PFO morphology. Composite events were compared between the two groups during a median follow-up of 24 months, including all-cause mortality, recurrent stroke, residual moderate or severe shunt, and symptomatic atrial fibrillation. RESULTS: A total of 247 patients were enrolled, with a mean age of 41.9 ± 13.0 years and 45.3% males. Ninety-one (36.8%) patients had complex PFO. These individuals were older (45.4 ± 12.5 years vs. 39.9 ± 12.9 years; P = 0.001), more males (56.0% vs. 39.1%; P = 0.010), had longer procedure times (54 ± 32 min vs 46 ± 29 min; P = 0.044), and had a higher rate of using delivery sheath-assisted crossing of the PFO (22.0% vs 12.8%; P = 0.040) than those with simple PFO. The estimated event rates were 27.9% and 11.3% (P = 0.006) in the complex and simple PFO groups, respectively (12.9 events and 5.2 events per 100 person-years; P = 0.001). After adjusting for age, sex, hypertension, diabetes, smoking, device type, and left atrial diameters, complex PFO remained independently associated with composite events (HR 2.10, 95%CI 1.06-4.17, P = 0.034). CONCLUSIONS: Patients with complex PFO may suffer from a higher risk of adverse events following transcatheter PFO closure.

Myeloid NCOA4 sequesters KEAP1 to reduce ferroptosis for protection against salmonellosis in mice.

Salmonellosis, caused by Salmonella enterica serovar Typhimurium, is a significant global threat. Host immunity limits bacterial replication by inducing hepcidin, which degrades ferroportin, reducing iron transfer. However, this boosts macrophage iron storage, aiding intracellular pathogens like Salmonella. Mice lacking ferritin heavy chain (FTH1) in myeloid cells suffer worsened Salmonella infection. Nuclear receptor co-activator 4 (NCOA4) regulates iron release via FTH1 degradation during low iron, but its role in salmonellosis is unclear. Here, we reveal that myeloid NCOA4 deficiency augments spleen iron levels and increases cellular iron accumulation, oxidative stress, and ferroptosis in bone marrow-derived macrophages. This deficiency also increases susceptibility to Salmonella-induced colitis in mice. Mechanistically, NCOA4 suppresses oxidative stress by directly binding to the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (KEAP1) and stabilizing the antioxidant transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2). Activation of NRF2 protects myeloid NCOA4 knockout mice from Salmonella-induced colitis. Antioxidant Tempol and myeloid cell-targeted curcumin offer protection against colitis in myeloid NCOA4-deficient mice. A low iron diet and ferroptosis inhibition also mitigate the heightened colitis in these mice. Overexpression of myeloid cell-specific NCOA4 confers protection against Salmonella-induced colitis via upregulating NRF2 signaling. Serum iron was reduced in myeloid NCOA4-overexpressing mice, but not in NCOA4-deficient mice. Targeted serum metabolomics analysis revealed that many lipids were decreased in myeloid NCOA4-deficient mice, while several of them were increased in myeloid NCOA4-overexpressing mice. Together, this study not only advances our understanding of NCOA4/KEAP1/NRF2/ferroptosis axis but also paves the way for novel myeloid cell-targeted therapies to combat salmonellosis.

Tuning Electron Delocalization of Redox-Active Porous Aromatic Framework for Low-Temperature Aqueous Zn-K Hybrid Batteries with Air Self-Chargeability.

Air self-charging aqueous batteries promise to integrate energy harvesting technology and battery systems, potentially overcoming a heavy reliance on energy and the spatiotemporal environment. However, the exploitation of multifunctional air self-charging battery systems using promising cathode materials and suitable charge carriers remains challenging. Herein, for the first time, we developed low-temperature self-charging aqueous Zn-K hybrid ion batteries (AZKHBs) using a fully conjugated hexaazanonaphthalene (HATN)-based porous aromatic framework as the cathode material, exhibiting redox chemistry using K+ as charge carriers, and regulating Zn-ion solvation chemistry to guide uniform Zn plating/stripping. The unique AZKHBs exhibit the exceptional electrochemical properties in all-climate conditions. Most importantly, the large potential difference causes the AZKHBs discharged cathode to be oxidized using oxygen, thereby initiating a self-charging process in the absence of an external power source. Impressively, the air self-charging AZKHBs can achieve a maximum voltage of 1.15 V, an impressive discharge capacity (466.3 mAh g-1), and exceptional self-charging performance even at -40 °C. Therefore, the development of self-charging AZKHBs offers a solution to the limitations imposed by the absence of a power grid in harsh environments or remote areas.

Combination of facial and nose features of Amur tigers to determine age.

We found that the area of black round or irregular-shaped spots on the tiger's nose increased with age, indicating a positive relationship between age and nose features. We used the deep learning model to train the facial and nose image features to identify the age of Amur tigers, using a combination of classification and prediction methods to achieve age determination with an accuracy of 87.81%.

Associations of online health information seeking with health behaviors of cancer survivors.

Objective: To examine the effects of online health information seeking (OHIS) behavior on five health behaviors (regular physical activity, less sedentary, calorie checking, no alcohol consumption, and no smoking) among adult cancer survivors in the United States. Methods: A cross-sectional analysis was conducted with adult cancer survivors (≥18 years old) from Cycles 2, 3, and 4 of the Health Information National Trends Survey (HINTS). The respondents self-reported OHIS, and the data on the five health behaviors were pooled to perform descriptive and multivariable logistic regression analyses using Stata 17.0. Results: Of the 1245 adult cancer survivors, approximately 74% reported OHIS behavior for themselves within the previous year of the survey. We found that OHIS was significantly and positively associated with the level of physical activity (odds ratio [OR] = 1.53, p = .002) and calorie checking (OR = 1.64, p = .001), but not with sedentary behavior, smoking, and alcohol consumption after adjusting for age, sex, race/ethnicity, education, income, body mass index (BMI), marital status, depression, and general health. Conclusions: Findings from this study suggest that most cancer survivors used various forms of digital tools and platforms to seek health information. The study also demonstrated an independent impact of OHIS behavior on physical activity and calorie checking. Healthcare professionals may need to encourage and guide cancer survivors to seek credible eHealth information and further utilize digital health tools as a platform for care delivery, promoting health behaviors and preventing adverse health outcomes among cancer survivors.

Association between triglyceride-glucose index and endothelial dysfunction.

BACKGROUND: Triglyceride-glucose (TyG) index, a simple surrogate marker for insulin resistance (IR), has been reported as an independent predictor of arterial structural damage and future cardiovascular events. The association between TyG index and endothelial dysfunction remains uncertain. OBJECTIVE: The purpose of this study was to investigate the association between TyG index and endothelial dysfunction. METHODS: Endothelial dysfunction was measured using flow-mediated dilation (FMD). A total of 840 subjects, who voluntarily accepted FMD measurement at the Health Management Department of Xuanwu Hospital from October 2016 to January 2020, were included in this study. TyG index was calculated as Ln [fasting triglyceride (TG)(mg/dL) × fasting plasma glucose (FPG) (mg/dL)/2]. RESULTS: The mean age was 59.92 ± 10.28 years and 559 (66.55%) participants were male. The TyG index was correlated with FMD values (P = 0.022). Each unit increment in TyG index was associated with lower FMD values (ß = -0.330, 95%CI -0.609 to -0.052, P = 0.020) after adjusting for covariates. Age (ß = -0.069, 95%CI -0.088 to -0.051, P < 0.001), female (ß = 0.592, 95%CI 0.172 to1.012, P = 0.006), smoking (ß = -0.430, 95%CI -0.859 to -0.002, P = 0.049) and hypertension (ß = -0.741, 95%CI -1.117 to -0.365, P < 0.001) were also independent predictors for endothelial dysfunction. A significant association between the TyG index and endothelial dysfunction was found only in populations younger than 60 years (ß = -0.843, 95%CI -1.371 to -0.316, P = 0.002), females (ß = -0.612, 95%CI -1.147 to -0.077, P = 0.025), and populations without diabetes mellitus (DM) (ß = -0.594, 95%CI -1.042 to -0.147, P = 0.009). CONCLUSIONS: Subjects with an elevated TyG index are more likely to have endothelial dysfunction, particularly in populations without DM.

Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells.

OBJECTIVE: Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24h with varying concentrations of soluble urate, followed by 24h restimulation with lipopolysaccharides (LPS)±monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation. RESULTS: PBMCs pre-treated with urate produced more interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate. CONCLUSION: In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.

Glutathione peroxidase 4 suppresses manganese-dependent oxidative stress to reduce colorectal tumorigenesis.

The role of glutathione peroxidase 4 (GPX4) in ferroptosis and various cancers is well-established; however, its specific contribution to colorectal cancer has been unclear. Surprisingly, in a genetic mouse model of colon tumors, the deletion of GPX4 specifically in colon epithelial cells increased tumor burden but decreased oxidized glutathione. Notably, this specific GPX4 deletion did not enhance susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice with varied iron diets but showed vulnerability in mice with a vitamin E-deficient diet. Additionally, a high manganese diet heightened susceptibility, while a low manganese diet reduced DSS-induced colitis in colon epithelial-specific GPX4-deficient mice. Strikingly, the low manganese diet also significantly reduced colorectal cancer formation in both colon epithelial-specific GPX4-deficient and wildtype mice. Mechanistically, antioxidant proteins, especially manganese-dependent superoxide dismutase (MnSOD or SOD2), correlated with disease severity. Treatment with tempol, a superoxide dismutase mimetic radical scavenger, suppressed GPX4 deficiency-induced colorectal tumors. In conclusion, the study elucidates the critical role of GPX4 in inhibiting colorectal cancer progression by regulating oxidative stress in a manganese-dependent manner. The findings underscore the intricate interactions between GPX4, dietary factors, and their collective influence on colorectal cancer development, providing potential insights for personalized therapeutic strategies.