Heart failure (HF) represents the terminal stage of many cardiovascular diseases. Doxorubicin (DOX) can induce HF through oxidative stress (OS), inflammation, and apoptosis. Ginkgetin (GK) has potential cardioprotective effects, but its underlying mechanisms remain unclear. This study investigated the protective effects of GK against DOX-induced HF and explored its mechanisms, focusing on mitochondrial function and related signaling pathways. In vivo and in vitro experimental models. HF was induced by DOX in mice and H9c2 cardiomyocytes. Cardiac function, myocardial injury, OS, inflammation, and apoptosis were assessed using echocardiography, biochemical assays, enzyme-linked immunosorbent assay, histopathology, immunofluorescence, and Western blot. Mitochondrial function was evaluated via transmission electron microscopy, RT-qPCR, and Seahorse analysis. Compound C was applied to verify the involvement of the adenosine monophosphate-activated protein kinase (AMPK)/Sirt1/nuclear factor-κB (NF-κB) pathway. GK markedly improved DOX-induced cardiac dysfunction and myocardial injury, reduced cardiac injury markers and inflammatory cytokines, and alleviated fibrosis, hypertrophy, apoptosis, and reactive oxygen species accumulation. GK restored superoxide dismutase activity, decreased malondialdehyde levels, increased glutathione and ATP, and preserved mitochondrial structure and respiratory function. GK upregulated AMPK and Sirt1, inhibited NF-κB activation, and regulated apoptosis-related proteins, whereas Compound C reversed these effects. GK protects against DOX-induced HF by activating AMPK/Sirt1 and inhibiting NF-κB signaling, thereby mitigating OS, inflammation, apoptosis, and mitochondrial dysfunction.

Renal ischemia-reperfusion (I/R) injury is a major cause of graft dysfunction and failure, driving inflammation and tissue damage. Mesenchymal stem cells (MSCs) possess therapeutic potential due to their immunomodulatory properties. Notably, neutrophils express the inhibitory receptor CD32b, which is a specific target of the immunosuppressive molecule soluble fibrinogen-like protein 2 (sFgl2). This study aimed to investigate the therapeutic efficacy and underlying mechanisms of genetically engineered MSCs expressing sFgl2 (sFgl2-MSCs) in treating renal I/R injury, with a focus on neutrophil regulation. An in vivo renal I/R injury mouse model. Following imaging to localize MSCs, mice were randomly allocated into four treatment groups. Treatments were administered according to group assignments. Renal function was assessed using serum creatinine and blood urea nitrogen levels, while systemic inflammation was evaluated by measuring serum interleukin-1 beta (IL-1β), interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and IL-10 via enzyme-linked immunosorbent assay (ELISA). Neutrophil proportions in the blood and kidney were analyzed by flow cytometry. At 24 h, surface expression of CD95 and CD206 was assessed; CD206 was used to define neutrophils with N2-like (CD206+) and N1-like (CD95+) phenotypic features. Histopathological scoring of renal tissue was performed at 24 h. Infiltration of Ly6G+ neutrophils and citrullinated histone H3 (CitH3) as well as myeloperoxidase/CitH3 co-localization (an indicator of neutrophil extracellular traps, NETs) were detected by immunohistochemistry and immunofluorescence. Circulating free DNA (cf-DNA) in plasma was quantified using PicoGreen dye. Furthermore, the impact of sFgl2-MSCs on bone marrow-derived neutrophil polarization and function was evaluated in vivo using flow cytometry, ELISA, and a co-culture system. While unmodified MSCs exhibited a moderate therapeutic effect, sFgl2-MSCs treatment was significantly more effective. sFgl2-MSCs markedly improved renal function, reduced histopathological damage (e.g., tubular necrosis), and modulated systemic cytokine levels by decreasing pro-inflammatory (IL-1β, IL-6, TNF-α) and increasing anti-inflammatory (IL-10) cytokines. Crucially, sFgl2-MSCs regulated neutrophil responses in the kidney: they increased the proportion of N2-like neutrophils and decreased N1-like neutrophils, concurrently reducing NET-related markers, as evidenced by decreased CitH3 and cf-DNA. Mechanistically, sFgl2-MSCs enhanced neutrophil immunoregulatory function via the TGFβ-Smad2/3 signaling pathway. Genetically modified sFgl2-MSCs alleviate renal I/R injury. This protective effect is associated with engagement of neutrophil CD32b receptors, activation of the TGFβ-Smad2/3 pathway, promotion of a protective N2-like neutrophil phenotype, and suppression of N1-like and NET-related markers.

Restorative proctocolectomy with ileal pouch-anal anastomosis restores intestinal continuity and generally provides excellent long-term functional outcomes. However, 5-15% of patients experience pouch failure, most commonly due to septic, mechanical, or inflammatory complications. Surgical management of pouch failure is technically demanding and requires a multidisciplinary approach in high-volume, specialized centers. This narrative review synthesizes contemporary evidence on the transabdominal surgical management of pouch failure, with an emphasis on standardized preoperative evaluation, nomenclature. Key topics include predictors of failure, differentiation of Crohn's-like disease from mechanical etiologies, and technical considerations for pouch reconstruction. The review also emphasizes the importance of a unified team for revisional pouch surgery, involving specialized colorectal surgeons, gastroenterologists, radiologists, physician assistants, dietitians, IBD-specialized psychologists, wound-ostomy nurses, and patient support personnel.

Hyperuricemia and gout are common metabolic disorders that show substantial disparities in prevalence and management across different socioeconomic status. To investigate the association between social determinants of health (SDOH) and mortality risk in adults with hyperuricemia and/or gout, to assess whether the interaction between SDOH and gout/hyperuricemia status influences mortality risk. A retrospective cohort study. We analyzed 6,560 United States (US) adults (mean age 58 years, 60.02% men) with hyperuricemia and/or gout from the 1999-2018 National Health and Nutrition Examination Survey. The primary study outcomes were all-cause and cardiovascular mortality. A control group of 6,560 adults without hyperuricemia or gout was measured using propensity-score matching based on age, sex, and race. SDOH was measured using a composite score (range 0-8) created from eight socioeconomic indicators: education, employment, food security, family income-to-poverty ratio, marital status, health insurance coverage, insurance type, and home ownership. Over a median follow-up of 101 months, 1,335 (14.76%) deaths occurred among participants with hyperuricemia and/or gout, including 496 (5.33%) cardiovascular deaths. Relative to adults with hyperuricemia and/or gout who had an SDOH score of 7-8, the hazard ratios (95% confidence intervals) for those with SDOH scores of 5-6, 3-4, and ≤ 2 were 1.48 (1.21-1.81), 1.85 (1.49-2.28), and 2.38 (1.82-3.11), respectively, for all-cause mortality, and 1.62 (1.16-2.25), 1.65 (1.18-2.31), and 2.10 (1.24-3.54), respectively, for cardiovascular mortality. Restricted cubic spline analyses demonstrated an inverse relationship between SDOH and both mortality outcomes. Subgroup analysis indicated that the association between SDOH and mortality risk was stronger among participants younger than 60 years. Interaction analyses showed that hyperuricemia/gout status did not significantly modify the association between SDOH and mortality. Cumulative social disadvantage, indicated by a lower SDOH score, independently predicted higher mortality risk in US adults with hyperuricemia and/or gout, with the most pronounced effects observed in individuals under 60 years. Notably, the unfavorable cardiovascular effects associated with SDOH appeared more evident in adults without hyperuricemia or gout than in those with these conditions.

Aberrations in cadherin-related 23 (CDH23) account for a significant proportion of familial autosomal recessive non-syndromic hearing loss (DFNB12), a common subtype of hereditary hearing loss worldwide. This study aimed to elucidate the molecular basis and pathogenic mechanism of DFNB12 in an affected girl from a nine-member pedigree. Family-based genetic study with pedigree analysis. Clinical whole-exome sequencing combined with pedigree analysis was used to identify disease-causing mutations. The potential functional consequences of these mutations were investigated using structural bioinformatic approaches, including homology modeling, molecular dynamics simulations, and other relevant tools. The proband carried compound heterozygous variants: a known pathogenic maternal variant (c.6049G > A) and a paternal haplotype comprising two linked variants (c.3262G > A and c.6911G > A), each individually classified as benign. Pedigree segregation analysis demonstrated that the paternal haplotype acts as a single pathogenic allele. Two individually benign variants can combine to form a novel pathogenic haplotype (c.3262A-c.6911A). This mechanism may be under-recognized in routine variant interpretation pipelines. Our findings underscore the importance of evaluating the combined effects of linked benign variants to ensure accurate genetic counseling.