Search Results (4,398)

Background: Subjective well-being (SWB) is an important outcome in healthcare. Identifying correlates of SWB among economically vulnerable populations can inform healthcare delivery and policy decisions. Objective: This study examines whether social capital is more strongly associated with evaluative SWB than mental health among financially insecure households in the U.S. South. Methods: Data were drawn from the SR-Stat Baseline Survey 2024. Multiple regression analysis was used to examine the relative associations of interpersonal trust, institutional trust, and mental health with evaluative SWB, while controlling for socioeconomic-demographic characteristics. Results: Interpersonal trust, institutional trust, and mental health were each significantly associated with evaluative SWB. Institutional trust exhibited the largest standardized association, followed closely by mental health and interpersonal trust, with differences in magnitude remaining modest across variables. Several control variables, particularly age, income, and health insurance coverage, were also independently associated with SWB. Healthcare systems and policymakers may benefit from incorporating trust-building practices, such as transparent communication and equitable service delivery, alongside mental health screening and support, to address multiple dimensions of well-being in economically vulnerable populations. Conclusions: Evaluative SWB among financially insecure households is associated with mental health and trust-based social capital at both interpersonal and institutional levels. These findings highlight the importance of addressing individual functioning and broader institutional contexts when designing interventions aimed at improving well-being. Full article

Introduction: Ball velocity is a critical determinant of shot effectiveness in football, yet its influence on advanced post-shot metrics, such as expected shot impact timing (xSIT) and expected goals on target (xGOT), remains poorly understood, particularly in the context of sex-specific differences. This study examined the relationship between ball velocity and these metrics in men’s and women’s elite European tournaments. Methods: A total of 2174 shots were analyzed from all matches of the 2024 UEFA Men’s EURO (n = 1305) and 2025 UEFA Women’s EURO (n = 869), classified as goal shots on target, non-goal shots on target, and shots off target. Ball velocity was measured for each shot, and its associations with xSIT, our own xGOT model and the StatsBomb xGOT model were quantified using correlation coefficients. Results: Ball velocity differed significantly between sexes (p < 0.001), with higher values in men, and goal shots on target exhibited lower velocities than non-goal or off-target shots, indicating a speed–accuracy trade-off. Only xSIT and our own xGOT model were sensitive to ball velocity, reflecting sex-specific differences (p < 0.001). When comparing shot types across advanced metrics, a consistent trend was observed in both tournaments: xSIT showed no significant differences between goal and non-goal shots, whereas both xGOT models were higher for goal shots on target. Correlations indicated a moderate positive relationship between xSIT and ball velocity, and moderate negative correlations for both xGOT models, slightly stronger in men. Conclusions: Ball velocity is a critical factor influencing shot performance and advanced post-shot metrics, with notable sex-specific differences. Full article

Colorectal cancer (CRC) remains one of the most common malignancies worldwide with relatively high levels of morbidity and mortality. Current data demonstrate the significant role of adipokines, in particular leptin and adiponectin, in CRC pathogenesis and progression. Both adipokines exert pleiotropic activities and often possess opposing physiological effects. The main goal of this study was to provide a comprehensive overview of current knowledge regarding the complex relationship between leptin and adiponectin signaling and tumorigenesis with a specific focus on CRC. The pro-tumorigenic role of leptin in CRC has been highly emphasized by recent reports, primarily by activation of JAK2/STAT3 and PI3K/Akt/mTOR signaling pathways. In contrast, adiponectin has been shown to demonstrate an anti-tumorigenic role mainly because of activation of AMPK and PPARα signaling cascades. Focusing on the current advances in the field of adipokines’ signaling, we highlighted the latest achievements in understanding their role in colorectal malignancy. Full article

Background/Objectives: Cancer cachexia is a wasting syndrome with significant loss of body weight and muscle mass caused by inflammation and abnormal metabolism in advanced cancers. Despite its detrimental effects on patients, no standard treatment has been established for this syndrome. Thus, finding new treatments will broaden the remedy for cancer cachexia, resulting in increased survival in patients with terminal cancer. Methods: In this study, we assessed the therapeutic effects of the natural compound polydatin on cancer cachexia in vitro and in vivo using C2C12 myoblasts and CT26-bearing mice to elucidate the mechanisms of how it ameliorates muscle atrophy. At the same time, molecular docking analysis of polydatin with the IL6/STAT3 signaling pathway was conducted to demonstrate their interaction. Results: Our data showed that polydatin treatment at 100 mg/kg could attenuate symptoms of cancer cachexia including body weight loss, muscle strength and severe inflammation. Muscle mass reduction—with the shrinking of muscle fibers, an increase in the expression levels of two E3 ubiquitin ligases (MuRF1 and Atrogin-1) and interleukin-6, and a downregulation of MyHC—observed in CT26-bearing mice was reversed by polydatin at 100 mg/kg. On C2C12 myotubes, polydatin also ameliorated muscle atrophy induced by the CT26 conditioned medium and suppressed STAT3 phosphorylation at the concentration of 200 µM. Structural features of polydatin in the proteins in the STAT3 pathway were identified through molecular docking simulations. Conclusions: Taken together, polydatin significantly attenuated muscle atrophy in a cancer cachexia model by inhibiting the STAT3 signaling pathway; thus, it might be a promising compound in the development of drug candidates for cancer cachexia therapy. Full article

Chronic inflammation is a well-established driving force in tumor initiation and progression, accounting for a substantial proportion of inflammation-associated malignancies. Persistent inflammatory stimulation creates a pathological microenvironment characterized by sustained inflammatory signaling, oxidative stress, immune dysregulation, and epigenetic reprogramming, which collectively promote genomic instability, malignant transformation, and tumor progression. Understanding the biological basis of inflammation–cancer transformation is therefore essential for the development of effective preventive and therapeutic strategies. Plant-derived bioactive compounds have attracted increasing attention as promising modulators of inflammation-driven carcinogenesis due to their structural diversity, multi-target regulatory capacity, and relatively low toxicity. Specifically, this review focuses on four major classes of these compounds: flavonoids, alkaloids, terpenoids, and curcuminoids. Accumulating evidence demonstrates that these compounds can effectively interrupt the inflammation–cancer continuum by simultaneously targeting multiple pathogenic processes rather than single molecular pathways. In particular, these plant-derived agents suppress inflammation-driven signaling cascades, including NF-κB, MAPK, and JAK/STAT pathways; attenuate oxidative stress and inflammation-induced DNA damage; reprogram the immune microenvironment to restore anti-tumor immunity; and modulate epigenetic and transcriptional programs that stabilize pro-tumorigenic phenotypes. Accordingly, this review synthesizes the shared pathological drivers of inflammation–cancer transformation and summarizes how plant-derived compounds collectively target these mechanisms to interrupt disease progression. In addition, emerging translational strategies, including combination therapy and nanocarrier-based delivery systems, are discussed to highlight the clinical potential of plant-derived interventions. Collectively, this review offers an integrated mechanistic framework for understanding and exploiting plant-derived bioactive compounds in the prevention and treatment of inflammation-related cancers. Full article

Background/Objectives: Human papillomavirus (HPV) oncoproteins early (E)6 and E7 cause upregulation of the IL-6 and IL-23 cytokines in HPV16+ cancers, contributing to tumor progression through enhanced tumor cell proliferation and suppression of the tumor specific adaptive CD8 T-cell response. The IL-6 and IL-23 receptors signal through signal transducer and activator of transcription 3 (STAT3) in the tumor microenvironment. Methods: To better understand how HPV-induced STAT3 signaling contributes to tumor progression and explore its therapeutic potential, we used the platinum (IV) compound CPA-7, a specific STAT3 inhibitor. CPA-7 was tested in vitro for its ability to inhibit STAT3 signaling, alter proliferation, and cause cell death in HPV16+ C3.43 tumor cells. In vivo, CPA-7 was tested for its ability to affect the HPV specific T-cell response, tumor growth, and survival in C3.43 tumor bearing mice. Results: In vitro, CPA-7 inhibited STAT3 signaling, reduced proliferation, and caused significant cell death to HPV16+ C3.43 cells. In vivo, CPA-7 eradicated early-stage HPV16+ tumors, while therapeutic treatment of late-stage tumors led to a systemically increased presence of tumor-specific CD8 T-cells and halted tumor progression. Conclusions: These results suggest that targeting STAT3 signaling downregulates tumor cell proliferation and induces tumor cell death. In addition, targeting STAT3 increases the HPV-specific anti-tumor adaptive immune response. Combined, this results in significantly reduced late-stage HPV16+ tumor progression. Full article

Introduction: Stroke remains the second leading cause of death worldwide and a major cause of long-term disability. Approximately 87% of strokes are ischemic, and 30% of these are large vessel occlusions (LVOs). Early recognition of LVOs and rapid transport to a comprehensive stroke center (CSC) capable of MT are critical to improving outcomes. Accurately predicting LVOs in prehospital settings remains chall29enging. Several triage scales have been developed to aid early detection, but their diagnostic accuracy varies across studies. This study compares the performance of commonly used prehospital LVO scales by pooling published data to identify which tools best support emergency medical services (EMS) in optimizing triage and improving outcomes. Methods: A systematic search, following the Cochrane Library, of PubMed, Scopus, and Web of Science identified studies evaluating prehospital LVO triage scales using standardized search terms. Diagnostic accuracy measurements were extracted, and a pooled analysis was completed to compare scores. Results: From 743 unique articles, 15 studies evaluating prehospital large vessel occlusion (LVO) triage scales were included. Pooled log diagnostic odds ratios (DORs) indicated that RACE demonstrated the highest discriminative performance (2.367 [1.943–2.792]), followed by LAMS (2.228 [1.987–2.470]). The lowest scores were from the PASS (1.992 [1.758–2.227]) and C-STAT (1.886 [1.652–2.119]) scales. Conclusions: Among prehospital triage scales, RACE demonstrated the highest accuracy for LVO detection, followed by LAMS and G-FAST. Variation in scores may indicate inconsistency in performing the tests or the complexity of the questions. These findings support a personalized approach to choosing an LVO identification scale based on the resources available. Full article

Mitochondria, the cell’s powerhouses, generate ATP to sustain essential biological functions. Dysfunctional mitochondria can lead to cell death and subsequent tissue damage. Mitochondrial impairment is a key driver of cellular dysfunction in cardiomyocytes, endothelial cells, and macrophages, contributing to cardiovascular diseases such as atherosclerosis, myocardial ischemia–reperfusion injury, and cardiac hypertrophy. The signal transducer and activator of transcription (STAT) family regulates immune responses, apoptosis, and cell proliferation. Despite evidence suggesting that STATs influence mitochondrial pathways in various cardiovascular conditions, their roles are often contradictory and context-dependent. This review examines the structural and functional dynamics of STATs, their upstream and downstream signaling networks, and therapeutic strategies targeting STAT3 (the most extensively studied isoform), with a particular focus on natural compounds and pharmacological inhibitors. By synthesizing current findings, this review offers valuable insights into STATs as potential therapeutic targets for mitochondrial dysfunction in cardiovascular diseases, while also highlighting directions for future research. Full article

Gliomas are among the most challenging brain tumors to treat, owing to their marked heterogeneity and the aberrant signaling networks that sustain tumor growth and resistance to therapy. Quercetin, a dietary flavonoid widely found in fruit and vegetables, exhibits documented anticancer activity, prompting the development of optimized derivatives with improved biological potency. In earlier work, we synthesized and evaluated a series of quercetin derivatives and identified the acylated compound 3-O-decanoylquercetin (Q-3-Dec) as particularly effective in reducing glioma cell viability. In this study, we explored Q-3-Dec as a multi-target agent, which concomitantly impairs NF-κB/STAT3-dependent survival signaling, mitochondrial function, and O6-Methylguanine-DNA Methyltransferase (MGMT) expression, a DNA repair enzyme closely associated with chemoresistance, in glioma cells. In U373-MG glioma cells, treatment with 50 μM Q-3-Dec triggered pronounced, time-dependent morphological changes and an early loss of mitochondrial membrane potential after 3 h. With prolonged exposure, Q-3-Dec markedly decreased NF-κB and STAT3 phosphorylation and reduced the expression of the anti-apoptotic proteins Bcl-2 and survivin, alongside a significant decrease in MGMT levels. These combined effects culminated in a progressive increase in cell death, reaching approximately 30% after 48 h. Together, these findings position Q-3-Dec as a multi-node modulator of glioma survival, supporting its potential for further preclinical development to improve future therapeutic strategies against glioma. Full article

Background and Objectives: The volume–outcome relationship in congenital heart surgery (CHS) has been widely reported internationally, but systematic nationwide evidence from Korea remains limited. Given the concentration of high-volume centers in the Seoul Capital Area (SCA), we aimed to examine whether hospital surgical volume was associated with short-term mortality and to what extent regional disparities could be explained by differences in surgical volume. Materials and Methods: We conducted a nationwide retrospective cohort study of 31,150 patients who underwent CHS in 91 hospitals in Korea between 2002 and 2021 using National Health Insurance claims data. Hospitals were classified by location (SCA vs. non-SCA). Annual surgical volume was defined using two approaches, (i) above vs. below the overall mean annual volume (17.1 cases per hospital), and (ii) three categories (≤20, 21–40, and >40 cases/year). The primary outcome was 30-day mortality. Multivariable logistic regression adjusted for case mix, including J-STAT category, sex, hospital type, age, prematurity, and low birth weight. Hospital-level variation was further evaluated using generalized linear mixed models with random hospital intercepts, and intraclass correlation coefficients (ICCs) were estimated to quantify between-hospital variation and the explanatory contribution of surgical volume. Results: Overall 30-day mortality was 1.99%, with higher mortality observed in non-SCA hospitals compared with SCA hospitals (3.19% vs. 1.57%). After adjustment, lower annual surgical volume was strongly associated with higher 30-day mortality. Compared with hospitals performing >40 cases/year, the adjusted odds ratios were 4.13 (95% CI, 3.30–5.17) for hospitals performing 21–40 cases/year and 4.95 (95% CI, 3.98–5.95) for those performing ≤20 cases/year. In multilevel analyses, annual surgical volume accounted for 54% of the between-hospital variation in 30-day mortality. Adjustment for surgical volume substantially attenuated the regional disparity, with the odds ratio for non-SCA versus SCA hospitals decreasing from 2.12 (95% CI, 1.80–2.49) to 1.14 (95% CI, 0.95–1.37). Conclusions: A strong volume–outcome relationship exists in congenital heart surgery in Korea, with excess mortality concentrated in low-volume hospitals rather than regional location itself. Regional disparities in outcomes appear largely attributable to the uneven distribution of surgical volume. Strategies focused on service consolidation and strengthened referral to high-volume centers may be effective in reducing inter-hospital variation and improving national outcomes in pediatric cardiac surgery. Full article

Background/Objectives: Obesity is characterized by dysregulated hypothalamic energy homeostasis and reduced central responsiveness to the anorexigenic hormones leptin and insulin. β-Hydroxybutyrate (β-HB), a major ketone body, has recently garnered attention as a signaling metabolite. However, its effects on hypothalamic leptin and insulin responsiveness remain unclear. This study aimed to investigate the effects of β-HB on hypothalamic hormone responsiveness and the associated molecular mechanisms, primarily using a high-fat diet (HFD)-induced obese mouse model. Methods: Male mice were fed an HFD to induce obesity and treated with β-HB via oral or intracerebroventricular (ICV) administration. Feeding behavior following leptin and insulin administration was evaluated, and activation of hypothalamic leptin-induced STAT3 signaling and insulin-induced Akt signaling was analyzed. In addition, mRNA expression of inflammation-related and appetite-regulating genes was assessed by quantitative PCR. Normal mice also received chronic ICV administration of β-HB from the onset of HFD feeding, and changes in body weight and cumulative food intake were measured. Results: Both oral and ICV administration of β-HB significantly enhanced the anorexigenic responses to leptin and insulin in HFD-induced obese mice. At the molecular level, leptin-induced STAT3 phosphorylation and insulin-induced Akt phosphorylation were enhanced in the hypothalamus. Gene expression analysis revealed reduced SOCS3 and TNFα expression and increased POMC expression. Furthermore, chronic ICV administration of β-HB from the onset of HFD feeding significantly suppressed body weight gain and the increase in cumulative food intake. Conclusions: This study demonstrates that β-HB improves hypothalamic leptin and insulin responsiveness in obese mice and modulates the associated molecular environment. These findings suggest that β-HB acts as a metabolically responsive signaling molecule regulating hypothalamic function, providing a basis for novel metabolic intervention strategies against obesity. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with an extremely poor prognosis, and current clinical treatment options are limited. Natural products, due to their multi-target and low-toxicity characteristics, have emerged as an important direction for the development of anti-tumor drugs. Palmaturbine (Pal), an isoquinoline alkaloid derived from Coptis chinensis and Berberis species, has shown anti-inflammatory and anti-tumor potential in preliminary studies; however, its mechanism of action in PDAC remains unclear. This study systematically evaluated the anti-tumor effects and molecular mechanisms of Pal on PDAC through in vitro and in vivo experiments. In vitro, Pal significantly inhibited PDAC cell proliferation, migration, and invasion, induced G2/M phase cell cycle arrest, and promoted apoptosis. Transcriptomic sequencing and Western blot analysis revealed that Pal suppressed the JAK2/STAT3 signaling pathway by inhibiting the phosphorylation of JAK2 and STAT3. Animal experiments further indicated that Pal significantly inhibited the growth of subcutaneous xenograft tumors in nude mice without causing obvious toxicity. In summary, Pal, as a natural JAK/STAT pathway inhibitor, exhibits favorable anti-tumor activity and safety in PDAC treatment, holding potential as a novel candidate drug for PDAC. Full article

Stroke has been a topic of extensive research due to its debilitating consequences and high mortality. New findings offer a deeper understanding of specific factors that affect post-stroke recovery and identify therapies that may facilitate this process. One such factor is post-stroke neuroinflammation, a complex and time-dependent process in which acute immune responses can cause significant secondary inflammatory damage if the process is prolonged. Microglia are neuronal immune cells that are highly reactive to cytokines in the neuroenvironment and can, in turn, affect the inflammatory cascades that originate after stroke, making them ideal candidates for immunomodulation in the brain. Many FDA-approved immunotherapies have been found to target distinct inflammatory signaling molecules and responders, including IL-6 inhibitors, IL-13 inhibitors, IL-12/IL-23 inhibitors, B-cell modulators, type I interferon inhibitors, CAR T-cell therapy, calcineurin inhibitors, complement inhibitors, and JAK-STAT pathway inhibitors. The FDA-approved immunotherapies discussed in this review demonstrate potential in modulating the immune response after stroke by targeting key inflammatory pathways involved in secondary brain injury. Future research should focus on defining optimal therapeutic windows, identifying suitable patient populations, determining the most appropriate timing of therapy, and targeting specific immune mechanisms to balance the attenuation of harmful inflammation with the preservation of reparative processes. Full article

Cold-inducible RNA-binding protein (CIRP) is a critical molecule in the central nervous system (CNS) with functions that depend on its subcellular localization, exhibiting biphasic regulatory roles in both physiological and pathological processes. Under physiological conditions, intracellular cold-inducible RNA-binding protein (iCIRP) contributes to the maintenance of circadian rhythms by regulating the stability of core clock gene mRNAs and exerts neuroprotective effects during mild hypothermia by preserving the blood–brain barrier and inhibiting apoptosis. Pathologically, extracellular cold-inducible RNA-binding protein (eCIRP) functions as a damage-associated molecular pattern (DAMP) that drives neuroinflammation and brain injury. In ischemic stroke (IS), eCIRP promotes neutrophil extracellular trap (NET) formation and increases microglial activity via the Toll-like receptor 4 (TLR4) pathway. In cerebral ischemia–reperfusion (I/R) injury, eCIRP activates oxidative stress and the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome through the TLR4 axis, exacerbating mitochondrial damage. In intracerebral hemorrhage (ICH), eCIRP further amplifies inflammation via the interleukin-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. In traumatic brain injury (TBI), eCIRP activates the endoplasmic reticulum stress pathway, intensifying apoptosis. In Alzheimer’s disease (AD), eCIRP regulates tau phosphorylation and β-amyloid (Aβ) metabolism and may mediate the link between alcohol exposure and AD pathology. Preclinical studies indicate that serum eCIRP levels correlate with IS and ICH severity, highlighting its potential as a biomarker. This systematic review elucidates the mechanisms of CIRP in CNS diseases, providing insights for understanding and preventing conditions such as IS, cerebral I/R injury, ICH, TBI, and AD. Full article

Background/Objectives: Radiation-induced jaw bone injury is a severe and refractory complication following radiotherapy, and the key to treatment is promoting osteogenic differentiation and alleviating oxidative stress injury in irradiated BMSCs. Cerium oxide nanoparticles (CeONPs) exhibit considerable research potential in various oxidative stress injury-related diseases due to their excellent reactive oxygen species (ROS) scavenging capacity; however, its biosafety risk makes direct application in disease treatment a matter of controversy. Methods: Recent evidence suggests that treating cells with nanoparticles can regulate the content of exosomes, enhancing the regenerative potential of exosomes. Accordingly, this study was designed to explore the therapeutic effects and underlying mechanism of exosomes derived from BMSCs treated with CeONPs (BMSC-Ce-exos) in radiation-induced jaw bone injury. Results: In vitro, 25 μg/mL CeONPs were identified as the optimal treatment concentration; BMSC-Ce-exos significantly promoted the osteogenic differentiation and reduced the ROS levels of irradiated BMSCs. In vivo, BMSC-Ce-exos notably promoted bone formation and decreased the ROS levels in rats with radiation-induced jaw bone injury. miRNA sequencing revealed that BMSC-Ce-exos were highly enriched with miR-21-5p, which promoted the osteogenic differentiation and reduced the ROS levels of irradiated BMSCs through targeting STAT3. Conclusions: Collectively, these results suggest that BMSC-Ce-exos provided a potential therapeutic approach for radiation-induced jaw bone injury. Full article