Search Results (578)

Per- and polyfluoroalkyl substances (PFASs) have gained significant attention due to their widespread distribution in the environment and potential adverse health effects. While ingestion, especially through contaminated drinking water, is considered the primary route of human exposure, recent research suggests that other pathways, such as inhalation and dermal absorption, also play a significant role. This review provides a concise overview of the toxicological impacts of both legacy and emerging PFASs, such as GenX and perfluorobutane sulfonic acid (PFBS), with a particular focus on their effects on the liver, kidneys, and immune and nervous systems, based on findings from recent in vivo, in vitro, and epidemiological studies. Despite the transition to PFAS alternatives, much of the existing toxicity data focus on a few legacy compounds, such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), which have been linked to adverse immune outcomes, particularly in children. However, evidence for carcinogenic risk remains limited to populations with extremely high exposure levels, and data on neurodevelopmental effects remain underexplored. While epidemiological and experimental animal studies supported these findings, significant knowledge gaps persist, especially regarding emerging PFASs. Therefore, this review examines the visceral, neural, and immunotoxicity data for emerging PFASs and mixtures from recent studies. Given the known risks from well-studied PFASs, a precautionary principle should be adopted to mitigate human health risks posed by this large and diverse group of chemicals. Full article

This study examines the impact of free trade zone (FTZ) establishment on regional economic resilience (RER) in China, using provincial-level panel data spanning from 2010 to 2022 and a multi-period difference-in-differences (DID) approach. The empirical results indicate that FTZ implementation significantly enhances regional economic resilience by 3.46%, with the development of green finance acting as a key moderating mechanism that amplifies this positive effect. Heterogeneity analysis uncovers notable disparities across policy cohorts and geographical regions: the first wave of FTZs demonstrates the most pronounced resilience-enhancing impact, whereas later cohorts exhibit weaker or even adverse effects. Coastal regions experience substantial benefits from FTZ policies, in contrast to statistically insignificant outcomes observed in inland areas. These findings suggest that strategically expanding the FTZ network, when paired with tailored implementation mechanisms and the integration of green finance, could serve as a powerful policy tool for post-COVID economic recovery. Importantly, by strengthening economic resilience through institutional openness and green investment, this study offers valuable insights into balancing economic growth with environmental sustainability. It provides empirical evidence to support the optimization of FTZ spatial governance and institutional innovation pathways, thereby contributing to the pursuit of sustainable regional development. Full article

Phthalate esters (PAEs), frequently detected in various environmental media, are associated with multiple health issues, particularly reproductive toxicity. This study employed molecular docking and molecular dynamics simulations to investigate the reproductive toxicity risk of 22 PAEs on the regulation of the hypothalamic–pituitary–gonadal (HPG) axis. Analysis revealed that when the carbon number of PAEs was the same, those with branched side chains exhibited more pronounced reproductive toxicity risks. In PAE molecules with branched side chains, reproductive toxicity risk was inversely proportional to the number of carbon atoms. Furthermore, five PAE molecules with unacceptable risk (DIPRP, DMEP, DMP, DPP, and DUP) and four key indicators were proposed. Key descriptors influencing PAEs’ reproductive toxicity risks were identified as Infrared and ATSC8e by machine learning analysis. Furthermore, carbonyl structure, substituent position, and electronegativity of PAE molecules are critical factors influencing PAE-induced reproductive toxicity risks via the HPG axis. This study provides a theoretical basis for further investigation of PAE-induced reproductive toxicity risk on the HPG axis, which facilitates the development of risk mitigation strategies for PAEs’ reproductive toxicity and provides novel perspectives and approaches for exploring the molecular mechanisms underlying the endocrine effects of emerging contaminants such as PAEs. Full article

Primary aldosteronism (PA), the most common cause of secondary hypertension, is increasingly recognized as an independent driver of adverse cardiac remodeling, mediated through mechanisms beyond elevated blood pressure alone. Chronic aldosterone excess leads to myocardial fibrosis, left ventricular hypertrophy, and diastolic dysfunction via mineralocorticoid receptor activation, oxidative stress, inflammation, and extracellular matrix dysregulation. These changes culminate in a distinct cardiomyopathy phenotype, often underrecognized in early stages. Multimodality cardiac imaging, led primarily by conventional and speckle-tracking echocardiography, and complemented by exploratory cardiac magnetic resonance (CMR) techniques such as T1 mapping and late gadolinium enhancement, enables non-invasive assessment of structural, functional, and tissue-level changes in aldosterone-mediated myocardial damage. While numerous studies have established the diagnostic and prognostic relevance of imaging in PA, several gaps remain. Specifically, the relative sensitivity of different modalities in detecting subclinical myocardial changes, the long-term prognostic significance of imaging biomarkers, and the differential impact of adrenalectomy versus medical therapy on cardiac reverse remodeling require further clarification. Moreover, the lack of standardized imaging-based criteria for defining and monitoring PA-related cardiomyopathy hinders widespread clinical implementation. This narrative review aims to synthesize current knowledge on the pathophysiological mechanisms of aldosterone-induced cardiac remodeling, delineate the strengths and limitations of existing imaging modalities, and critically evaluate the comparative effects of surgical and pharmacologic interventions. Emphasis is placed on early detection strategies, identification of imaging biomarkers with prognostic utility, and integration of multimodal imaging into clinical decision-making pathways. By outlining current evidence and highlighting key unmet needs, this review provides a framework for future research aimed at advancing personalized care and improving cardiovascular outcomes in patients with PA. Full article

Gaultherin [methyl salicylate 2-O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside] is a natural salicylate found in some plant species belonging primarily to the Ericaceae and Rosaceae families. Biological studies conducted since the beginning of the 21st century have suggested the potential use of gaultherin in treating various diseases related to inflammation and oxidative stress, including rheumatoid arthritis, sciatica, neuralgia, and muscular pain. The accumulated results indicated a targeted range of biological effects, particularly anti-inflammatory, antipyretic, and anti-rheumatic properties associated with reduced adverse outcomes. The molecular mechanisms involve the influence on several signalling pathways, including NF-κB, MAPK, and potentially AMPK, as well as the inhibition of critical pro-inflammatory enzymes, such as COX-2. This inhibition is achieved without affecting the COX-1 isoform, thereby preventing side effects such as bleeding ulcers or intracranial haemorrhage. This overview summarises the current knowledge about pharmacokinetics, molecular mechanisms, pharmacology, and biocompatibility of gaultherin. Additionally, four methods for isolating gaultherin from plant material and its distribution within the plant kingdom were the focal points of review and discussion. The paper also describes significant differences between synthetic aspirin and natural gaultherin in their biological potential and side effects, resulting from their different mechanisms of action. As a prodrug of salicylic acid, gaultherin releases salicylic acid gradually through enzymatic hydrolysis in the gastrointestinal tract. This controlled release minimises direct gastric irritation and accounts for its superior gastrointestinal safety profile compared to aspirin. Unlike aspirin, which irreversibly inhibits COX-1 and can lead to serious side effects with chronic use, gaultherin selectively inhibits COX-2 while sparing COX-1. These properties position gaultherin as a compelling natural alternative for patients requiring long-term anti-inflammatory therapy with reduced risk of gastrointestinal or bleeding complications. Full article

Background and Objectives: Adverse clinical outcomes are associated with malnutrition and frailty, which are highly prevalent among hospitalized older patients. This study aimed to evaluate their predictive value for the duration of hospitalization, short-term survival, and rehospitalization of patients admitted to internal medicine wards. Materials and Methods: This prospective cohort study included 134 acutely ill patients aged ≥50 years who were hospitalized in an internal medicine department and evaluated within the first 48 h of admission. Nutritional status was evaluated using the Mini nutritional assessment–short form (MNA-SF), Nutritional Risk Screening 2002 (NRS-2002), and Global Leadership Initiative on Malnutrition (GLIM) criteria. Frailty was evaluated using the FRAIL scale and Clinical Frailty Scale (CFS). The primary outcomes were prolonged hospitalization (>10 days), mortality, and rehospitalization at 3 and 6 months post-discharge. Results: According to MNA-SF, 33.6% of patients were malnourished; 44% had nutritional risk per NRS-2002, and 44.8% were malnourished per GLIM. Frailty prevalence was 53.7% (FRAIL) and 59% (CFS). Malnutrition defined by all three scales (MNA-SF, NRS-2002, GLIM) was significantly associated with prolonged hospitalization (p = 0.043, 0.014, and 0.023, respectively), increased rehospitalization at both 3 months (p < 0.001) and 6 months (p < 0.001). Mortality was also significantly higher among malnourished patients. Higher CFS scores and low handgrip strength were additional predictors of adverse outcomes (p < 0.05). In multivariable analysis, GLIM-defined malnutrition and CFS remained independent predictors of rehospitalization and mortality. Conclusions: Frailty and malnutrition are highly prevalent and independently associated with prolonged hospital stay, short-term rehospitalization and mortality. Routine screening at admission may facilitate early identification and guide timely interventions to improve patient outcomes. These findings might guide hospital protocols in aging health systems and support the development of standardized geriatric care pathways. Full article

Background and Objectives: A thorough comprehension of the essential molecules and related processes underlying the carcinogenesis, proliferation, and recurrence of acute myeloid leukemia (AML) is crucial. This study aimed to investigate the expression levels, diagnostic and prognostic significance and biological roles of Bcl-2-associated athanogene 4 (BAG4) in AML carcinogenesis. Materials and Methods: Gene expression profiles were analyzed using publicly available datasets, particularly GSE9476 and TCGA, using tools such as GEO2R, GEPIA2, UALCAN and TIMER2.0. The immune infiltration correlation was examined using the GSCA platform, while the function of BAG4 at the single-cell level was analyzed via CancerSEA. Protein–protein and gene–gene interaction networks were constructed using STRING and GeneMANIA, and enrichment analyses were performed using GO, KEGG and DAVID. Expression validation was performed using RT-qPCR in HL-60 (AML) and HaCaT (normal) cells, and ROC curve analysis evaluated the diagnostic accuracy. Results: BAG4 was significantly overexpressed in AML tissues and cell lines compared with healthy controls. High BAG4 expression was associated with poor overall survival and strong diagnostic power (AUC = 0.944). BAG4 was positively associated with immune cell infiltration and negatively associated with CD4+/CD8+ T and NK cells. At the single-cell level, BAG4 was associated with proliferation, invasion, and DNA repair functions. Functional network analysis showed that BAG4 interacted with apoptosis and necroptosis-related genes such as BCL2, BAG3 and TNFRSF1A and was enriched in pathways such as NF-κB, TNF signaling and apoptosis. Conclusions: BAG4 is overexpressed in AML and is associated with adverse clinical outcomes and immune modulation. It may play an important role in leukemogenesis by affecting apoptotic resistance and immune evasion. BAG4 has potential as a diagnostic biomarker and treatment target in AML, but further in vivo and clinical validation is needed. Full article

Background and Objectives: Preliminary studies indicate that dihydrogen (H₂) may affect molecular pathways involved in appetite regulation; however, its role in influencing patient-reported appetite outcomes in individuals with obesity remains uncertain. This randomized, placebo-controlled, double-blind trial aimed to evaluate the effects of H₂ supplementation on appetite, body composition, sleep quality, obesity-specific quality of life, and related biomarkers in obese men and women. Materials and Methods: The study included 36 participants (24 females; age 42.1 ± 13.2 years; BMI 30.8 ± 4.2 kg/m²) randomized to receive either 1.0 L of hydrogen-rich water (15 mg of H₂) or 1.0 L of control water (0 mg of H₂) daily for eight weeks. Results: The results demonstrated that hydrogen-rich water significantly mitigated cravings (p = 0.05), improved subjective sleep quality (p = 0.05), reduced total cholesterol (p = 0.02) and LDL cholesterol (p = 0.04), and increased plasma glucagon-like peptide-1 levels (p = 0.05) compared to the control. No severe adverse effects were reported throughout the trial. Conclusions: These findings suggest that hydrogen-rich water may serve as a safe and effective dietary strategy to address appetite regulation and related metabolic indices in individuals with obesity. The study is registered at ClinicalTrials.gov (NCT06722326). Full article

Environmental persistent free radicals (EPFRs) represent a class of long-lived, redox-active species with half lives spanning minutes to months. Emerging as critical environmental pollutants, EPFRs pose significant risks due to their persistence, potential for bioaccumulation, and adverse effects on ecosystems and human health. This review critically synthesizes recent advancements in understanding EPFR formation mechanisms, analytical detection methodologies, environmental distribution patterns, and toxicological impacts. While progress has been made in characterization techniques, challenges persist—particularly in overcoming limitations of electron paramagnetic resonance (EPR) spectroscopy and spin-trapping methods in complex environmental matrices. Key knowledge gaps remain, including molecular-level dynamics of EPFR formation, long-term environmental fate under varying geochemical conditions, and quantitative relationships between chronic EPFR exposure and health outcomes. Future research priorities could focus on: (1) atomic-scale mechanistic investigations using advanced computational modeling to resolve formation pathways; (2) development of next-generation detection tools to improve sensitivity and spatial resolution; and (3) integration of EPFR data into region-specific air-quality indices to enhance risk assessment and inform mitigation strategies. Addressing these gaps will advance our capacity to mitigate EPFR persistence and safeguard environmental and public health. Full article

Background/Objectives: In this study, we aimed to evaluate probiotics’ clinical efficacy and safety in adults with chronic rhinosinusitis (CRS), and summarize mechanistic evidence related to mucosal immunity and microbiota modulation. Methods: We performed a systematic review and random-effects meta-analysis. MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched until May 2025. Eligibility: Randomized controlled trials (RCTs) and mechanistic studies investigating probiotics (any strain, dose, or administration route) in adults with CRS were eligible. Primary outcomes included changes in Sino-Nasal Outcome Test (SNOT-20/22) scores and CRS relapse rates. Secondary outcomes were adverse events and mechanistic endpoints. Results: Six studies (four RCTs, n = 337; two mechanistic studies) met the inclusion criteria. Probiotics did not significantly improve SNOT scores compared with the placebo, but trended in that direction (pooled mean difference—2.70; 95% CI −7.12 to 1.72; I² = 0%). Furthermore, probiotic use was associated with a non-significant trend towards fewer CRS relapses (risk ratio 0.41; 95% CI 0.16–1.04; p = 0.06; I² = 48%). Adverse events were mild and comparable to the placebo (risk ratio 0.87; 95% CI 0.33–2.34). Mechanistic data indicated that intranasal Lactococcus lactis W136 might downregulate type 1 inflammatory pathways and modestly increase microbiome diversity. Subgroup analyses (by route, duration, and CRS subtype) revealed no statistically significant effect modifiers, though mechanistic insights suggest possible differences in efficacy based on the CRS endotype and delivery method. Conclusions: Probiotics appear safe and may provide a small, non-significant improvement in CRS symptoms; emerging evidence of reduced relapse rates warrants further investigation through larger, endotype-stratified trials utilizing targeted probiotic strains and optimized delivery methods. Full article

The need to maximize aquaculture production while addressing environmental and food security challenges posed by climate change has driven research towards the development of functional aquafeeds that enhance performance and immunity in farmed species. However, exposure to dietary and environmental stressors affects marine organisms, altering key metabolic pathways best understood through high-throughput “omics” tools. This study assessed the effects of Asparagopsis taxiformis supplementation on central metabolic pathways by analyzing changes in primary metabolite levels in the liver of farmed Diplodus sargus under optimal and suboptimal temperature conditions. Results showed that seaweed supplementation had a beneficial effect on the fish’s primary metabolome; however, inclusion levels and rearing conditions played a crucial role in determining outcomes. While 1.5% supplementation maintained a balanced primary metabolome under optimal temperature conditions, 3.0% supplementation most effectively mitigated the adverse effects of acute thermal stress during a marine heatwave. These findings highlight the nutritive and functional potential of A. taxiformis supplementation in aquafeeds for marine omnivorous fish species and emphasize the importance of evaluating functional aquafeeds under suboptimal rearing conditions. Overall, our results demonstrate the value of metabolomics in elucidating the molecular basis underlying biological pathways in farmed marine fish and optimizing production through climate-smart dietary strategies. Full article

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic condition characterized by hepatic lipid deposits, insulin resistance, and inflammation which may progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Protein kinases play an important role in NAFLD development by regulating metabolic and inflammatory pathways. Mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K)/AKT, and mechanistic target of rapamycin (mTOR) are all involved in NAFLD and NASH progression. Emerging evidence indicates that Farnesoid X Receptor (FXR) agonists have therapeutic potential by modulating bile acid metabolism, lipid balance, and inflammatory responses. This review examines the mechanistic interplay between FXR agonists and important protein kinases in NAFLD and NASH. FXR agonists activate AMPK, which promotes fatty acid oxidation and reduces hepatic steatosis. They also regulate MAPK signaling, which reduces c-Jun NH2-terminal kinase (JNK)- and p38 MAPK-mediated inflammation. Furthermore, FXR agonists activate the PI3K/AKT pathway, enhancing insulin sensitivity and modulating mTOR signaling to reduce hepatic fibrosis. Clinical studies in NAFLD/NASH indicate that FXR agonists confer metabolic and anti-inflammatory benefits, although optimizing efficacy and minimizing adverse effects remain challenging. Future studies should focus on combination therapies targeting FXR alongside specific kinases to improve therapeutic outcomes. This review highlights the potential of FXR agonists to modulate protein kinase signaling, opening new avenues for targeted NAFLD/NASH therapy. Full article

Peripheral artery disease (PAD) is associated with an elevated risk of major adverse cardiovascular events (MACE). Despite this, few reliable biomarkers exist to identify patients at heightened risk of MACE. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine implicated in inflammation, atherosclerosis, and thrombosis, has been broadly studied in cardiovascular disease but remains underexplored in PAD. This study aimed to evaluate the prognostic utility of GDF15 for predicting 2-year MACE in PAD patients using explainable statistical and machine learning approaches. We conducted a prospective analysis of 1192 individuals (454 with PAD and 738 without PAD). At study entry, patient plasma GDF15 concentrations were measured using a validated multiplex immunoassay. The cohort was followed for two years to monitor the occurrence of MACE, defined as stroke, myocardial infarction, or death. Baseline GDF15 levels were compared between PAD and non-PAD participants using the Mann–Whitney U test. A machine learning model based on extreme gradient boosting (XGBoost) was trained to predict 2-year MACE using 10-fold cross-validation, incorporating GDF15 and clinical variables including age, sex, comorbidities (hypertension, diabetes, dyslipidemia, congestive heart failure, coronary artery disease, and previous stroke or transient ischemic attack), smoking history, and cardioprotective medication use. The model’s primary evaluation metric was the F1 score, a validated measurement of the harmonic mean of the precision and recall values of the prediction model. Secondary model performance metrics included precision, recall, positive likelihood ratio (LR+), and negative likelihood ratio (LR-). A prediction probability histogram and Shapley additive explanations (SHAP) analysis were used to assess model discrimination and interpretability. The mean participant age was 70 ± SD 11 years, with 32% (n = 386) female representation. Median plasma GDF15 levels were significantly higher in PAD patients compared to the levels in non-PAD patients (1.29 [IQR 0.77–2.22] vs. 0.99 [IQR 0.61–1.63] pg/mL; p < 0.001). During the 2-year follow-up period, 219 individuals (18.4%) experienced MACE. The XGBoost model demonstrated strong predictive performance for 2-year MACE (F1 score = 0.83; precision = 82.0%; recall = 83.7%; LR+ = 1.88; LR− = 0.83). The prediction histogram revealed distinct stratification between those who did vs. did not experience 2-year MACE. SHAP analysis identified GDF15 as the most influential predictive feature, surpassing traditional clinical predictors such as age, cardiovascular history, and smoking status. This study highlights GDF15 as a strong prognostic biomarker for 2-year MACE in patients with PAD. When combined with clinical variables in an interpretable machine learning model, GDF15 supports the early identification of patients at high risk for systemic cardiovascular events, facilitating personalized treatment strategies including multidisciplinary specialist referrals and aggressive cardiovascular risk reduction therapy. This biomarker-guided approach offers a promising pathway for improving cardiovascular outcomes in the PAD population through precision risk stratification. Full article

Nitrogen-containing bisphosphonates (N-BPs) are commonly used drugs in the treatment of bone diseases due to their potent inhibition of the mevalonate pathway, leading to disrupted protein prenylation and reduced osteoclast activity. Although N-BPs are effective in reducing bone resorption, increasing evidence indicates their side effects on various non-skeletal cells. The aim of this review is to synthesize the current knowledge on the cellular and molecular effects of N-BPs outside the skeletal system, with particular emphasis on their impact on mitochondrial function and energy metabolism. At the cellular level, N-BPs may reduce viability, modulate inflammatory responses, trigger apoptosis, disrupt cytoskeletal organization, and influence signaling and energy metabolism. N-BPs may also impair the prenylation of proteins essential for mitochondrial dynamics and quality control, and may disrupt Ca²⁺ homeostasis. As we have shown in endothelial cells, by inhibiting the mevalonate pathway, N-BPs may lead to a reduction in key components of the mitochondrial respiratory chain, such as coenzyme Q (CoQ) and a-heme. These effects can contribute to impaired mitochondrial respiratory function, increased oxidative stress, and mitochondria-dependent apoptosis, affecting cellular energy metabolism and viability. These findings underscore the multifaceted impact of N-BPs beyond bone, emphasizing the importance of mitochondrial health and energy metabolism in understanding their broader biological effects and potential adverse outcomes. Full article

Background: Prehabilitation programs improve postoperative outcomes in vulnerable patients undergoing major surgery. However, current screening tools such as the Malnutrition Universal Screening Tool (MUST) may lack the sensitivity needed to identify those who would benefit most. Muscle quality assessed by Computed Tomography (CT), specifically muscle radiodensity in Hounsfield Units (HUs), has emerged as a promising alternative for risk stratification. Objective: To evaluate the prognostic performance of CT-derived muscle radiodensity in predicting adverse postoperative outcomes in colorectal cancer patients, and to compare it with the performance of the MUST score. Methods: This single-center cross-sectional study included 201 patients with non-metastatic colon cancer undergoing elective laparoscopic resection. Patients were stratified based on enrollment in a multimodal prehabilitation program, either within an Enhanced Recovery After Surgery (ERAS) protocol or a non-ERAS pathway. Nutritional status was assessed using MUST, SARC-F questionnaire (strength, assistance with walking, rise from a chair, climb stairs, and falls), and the Global Leadership Initiative on Malnutrition (GLIM) criteria. CT scans at the L3 level were analyzed using automated segmentation to extract muscle area and radiodensity. Postoperative complications and hospital stay were compared across nutritional screening tools and CT-derived metrics. Results: MUST shows limited sensitivity (<27%) for predicting complications and prolonged hospitalization. In contrast, CT-derived muscle radiodensity demonstrates higher discriminative power (AUC 0.62–0.69), especially using a 37 HU threshold. In the non-ERAS group, patients with HU ≤ 37 had significantly more complications (33% vs. 15%, p = 0.036), longer surgeries, and more severe events (Clavien–Dindo ≥ 3). Conclusions: Opportunistic CT-based assessment of muscle radiodensity outperforms traditional screening tools in identifying patients at risk of poor postoperative outcomes, and may enhance patient selection for prehabilitation strategies like the ERAS program. Full article