Search Results (73,758)

Mesothelioma is a rare and aggressive malignancy arising from mesothelial cells. Despite recent advances in systemic therapies, overall survival remains limited, underscoring the need for a deeper mechanistic understanding of disease pathogenesis and novel therapeutic strategies. In mesothelioma, chronic tissue injury induced by asbestos fibers leads to sustained activation of innate immune pathways and chronic inflammation that actively promote tumorigenesis. The release of Damage-Associated Molecular Patterns (DAMPs)—endogenous molecules that signal cellular stress and damage—contributes to establishing a self-sustaining inflammatory circuit within the pleural microenvironment that promotes tumor initiation and progression and immune evasion. Among DAMPs, High-Mobility Group ^{Box 1} (HMGB1) has emerged as a key regulator of mesothelioma pathogenesis. Several studies demonstrated that mesothelial cells actively secrete HMGB1 in response to asbestos exposure, driving macrophage recruitment, cytokine production, and chronic inflammation. Beyond HMGB1, additional DAMPs—including IL-33, extracellular ATP, cell-free nucleic acids, heat shock proteins, and calreticulin—contribute to inflammasome activation, stromal remodeling, and immune dysregulation. Recent evidence suggests that DAMP signaling in mesothelioma is dysregulated, resulting in chronic inflammation coupled with ineffective antitumor immunity. This review provides a comprehensive synthesis of DAMP biology in mesothelioma, highlighting the emerging therapeutic opportunities targeting DAMP-associated pathways. Full article

Dementia is one of the leading causes of disability and dependence among older adults and is increasingly encountered in patients undergoing surgery. As populations age and surgical interventions become more common, understanding the perioperative care of patients with pre-existing dementia has become an important clinical priority. Dementia is associated with reduced cognitive reserve, chronic neuroinflammation, synaptic dysfunction, blood–brain barrier impairment, neurotransmitter abnormalities, and cerebrovascular dysregulation, all of which may increase vulnerability to perioperative neurological injury. Surgical trauma and anaesthesia trigger systemic inflammatory, metabolic, and haemodynamic responses that may disrupt cerebral homeostasis and contribute to perioperative neurocognitive disorders, including postoperative delirium and delayed neurocognitive recovery. Postoperative delirium is consistently associated with accelerated cognitive and functional decline and may represent an important link between perioperative stress and adverse long-term outcomes. However, despite strong biological plausibility, current clinical evidence does not establish a direct causal relationship between anaesthesia, surgery, and accelerated dementia progression. Interpretation of the available literature is limited by methodological heterogeneity, residual confounding, and the frequent exclusion of patients with established cognitive impairment. This narrative review summarizes the neurobiological mechanisms underlying increased perioperative vulnerability in dementia, critically examines current evidence regarding the effects of anaesthesia and surgery on long-term cognitive and functional outcomes, and discusses practical strategies to reduce perioperative risk. A better understanding of these complex interactions is essential to optimize perioperative care and preserve cognitive function, functional independence, and quality of life in this highly vulnerable patient population. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) develops when hepatic lipid acquisition and synthesis exceed the capacity for oxidation and very-low-density lipoprotein export. Flavonoids act on several components of this network, yet their therapeutic development is constrained by poor aqueous solubility, extensive intestinal and first-pass metabolism, variable activity of circulating metabolites, and limited information on hepatic exposure. Experimental studies link representative flavonoids to AMPK–SREBP-1c and PPARα signaling, mitochondrial quality control, Nrf2-dependent redox defense, inflammatory pathways, and the gut–liver axis. By contrast, the available randomized trials of quercetin, hesperidin, anthocyanins, green-tea catechins, EGCG, and soy isoflavones show at most modest changes in liver fat or biochemical markers and do not demonstrate metabolic dysfunction-associated steatohepatitis (MASH) resolution or fibrosis regression. Liposomal, lipid-based, polymeric, and nanocrystal formulations have improved dissolution, systemic exposure, or liver distribution in preclinical models, but comparative pharmacokinetics, chronic safety, manufacturability, and clinical efficacy remain poorly defined. The evidence therefore supports viewing flavonoids as formulation-dependent investigational candidates rather than established MASLD therapies. Progress will depend on chemically standardized products, exposure–response studies, clinically relevant models, and adequately powered trials using validated imaging or histological endpoints. Full article

Background/Objectives: Psoriasis is a chronic inflammatory skin disease driven by Th17/Treg imbalance. Colquhounia Root Tablet (CRT), derived from Tripterygium hypoglaucum, has shown clinical potential for psoriasis, but its mechanisms remain unclear. This study aimed to evaluate the anti-psoriatic effects of CRT and elucidate its underlying mechanisms. Methods: Anti-psoriatic activity was evaluated in an IMQ-induced psoriasis-like mouse model. Mice received oral CRT at 0.085, 0.17, or 0.35 g/kg daily from days 2 to 8. Immune-cell populations were analyzed by flow cytometry. Bone marrow-derived dendritic cells (BMDCs) were used for in vitro studies. Network pharmacology, transcriptomics, molecular docking, and experimental validation were integrated to explore the mechanisms. Results: CRT dose-dependently ameliorated psoriasiform dermatitis and reduced Th17/Treg ratio while inhibiting CD11c⁺MHC II⁺ DC activation in vivo. In vitro, CRT suppressed R848-induced BMDC maturation and inhibited p65/IκBα phosphorylation. Transcriptomic analysis revealed modulation of TNF, NF-κB, IL-17, and JAK-STAT pathways. Molecular docking predicted the strong binding of multiple CRT compounds to RELA. Conclusions: CRT exerts anti-psoriatic effects in a murine model with concurrent modulation of NF-κB-related DC maturation and Th17/Treg correction, suggesting a potential immunomodulatory mechanism requiring further causal validation. Full article

Cystic kidney disease is characterized by progressive structural remodeling of renal parenchyma and altered cellular signaling. Inflammatory mediators may contribute to disease biology; however, data on interleukin-15 (IL-15) in pediatric cystic kidney disorders remain limited. The aim of this study was to assess serum and urinary IL-15 concentrations in children with cystic kidney disease and to evaluate their association with renal function. Methods: This study included 47 children with cystic kidney disease and 41 controls without renal cystic disease or other systemic, inflammatory, or immunological disorders. Serum and urinary IL-15 concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Renal function was assessed using the estimated glomerular filtration rate (eGFR). Statistical analyses included non-parametric comparisons, logistic regression, and receiver operating characteristic (ROC) curve analysis. Results: Children with cystic kidney disease demonstrated significantly elevated serum and urinary IL-15 concentrations compared with controls. IL-15 levels were not associated with eGFR and did not differ between cystic disease subtypes. In logistic regression analysis, IL-15 remained significantly associated with disease status. ROC analysis suggested high diagnostic ability of serum and urinary IL-15. Conclusions: IL-15 concentrations are increased in children with cystic kidney disease independently of current renal function. These findings suggest that IL-15 may reflect early inflammatory or epithelial signaling rather than established functional impairment. Full article

Immune dysregulation characterized by persistent myeloid activation and associated impairment of regulatory T cell (Treg) function contributes to inflammatory signaling across peripheral and central compartments in neurodegenerative diseases. We evaluated whether combining a glucagon-like peptide-1 receptor agonist (GLP-1RA; semaglutide) with low-dose interleukin-2 (LD-IL2) could modulate myeloid-associated transcript expression and enhance Treg-associated regulatory transcripts in a subacute lipopolysaccharide (LPS)-induced model of systemic and CNS inflammation. Mice received LPS once daily for 5 days, while GLP-1RA, LD-IL2, or combination treatment was initiated 24 h after LPS onset and continued daily. Splenic immune populations were quantified, and transcript expressions were assessed in magnetically enriched CD11b⁺ myeloid cells and CD4⁺CD25⁺ Tregs, as well as in cortex and hippocampus. As monotherapies, GLP-1RA reduced myeloid expansion with modest modulation of pro-inflammatory and anti-inflammatory myeloid transcripts, whereas LD-IL2 selectively enhanced Treg numbers and increased transcripts associated with Treg stability and suppressive regulation, including Il2ra (CD25), Foxp3, Ctla4, Ikzf2 (HELIOS), Entpd1 (CD39), and Nt5e (CD73). Combination treatment significantly reduced LPS-induced myeloid Il6, Il1b, and Tnf expression and increased Arg1 expression. Combination treatment further enhanced Treg-associated Il2ra (CD25), Tgfb1, and Ctla4 expression relative to monotherapies. In cortical and hippocampal tissues, combination treatment produced more robust modulation of inflammatory transcripts compared with effects observed with monotherapies, including reductions in Il6 and Il1b and increases in Cd163 and Mrc1 (CD206) expression. Together, these findings demonstrate coordinated and complementary changes in peripheral immune-cell populations and myeloid inflammatory and Treg-associated regulatory transcripts and warrant further evaluation of this combination in inflammation-driven neurodegenerative disease. Full article

Ulcerative colitis is a chronic inflammatory bowel disease characterized by mucosal barrier disruption, dysregulated immune responses, and gut microbial imbalance. However, limitations of current therapies highlight the need for safe probiotic interventions. This study evaluated the preventive effects of fermented yak milk-derived Lacticaseibacillus paracasei CD12-1 on dextran sulfate sodium (DSS)-induced colitis in mice. The results showed that DSS caused body weight loss, an increased disease activity index, colon shortening, and severe histopathological injury. CD12-1 alleviated these abnormalities with differential effects across doses. The low-dose treatment produced the most comprehensive improvements in histopathological damage, goblet cell abundance, tight junction integrity, inflammatory cytokines, and short-chain fatty acids, whereas the high dose more effectively attenuated body weight loss. CD12-1 increased colonic ZO-1 and Occludin expression, reduced IL-1β, IL-6, and TNF-α levels, and increased IL-10. The low dose also elevated acetate and butyrate levels. Gut microbiota analysis showed that CD12-1 was associated with changes in the relative abundances of Lactobacillus, Bifidobacterium, Allobaculum, Akkermansia, and several inflammation-associated taxa. Correlation analysis associated Lactobacillus and Allobaculum with milder disease and improved barrier-related indicators, whereas Bacteroides and Sutterella were associated with greater disease severity and inflammation. Overall, CD12-1 alleviated DSS-induced colitis by improving intestinal barrier integrity and inflammatory homeostasis, accompanied by changes in microbial composition and short-chain fatty acid production. Full article

Background/Objectives: Maternal obesogenic diets may produce persistent developmental alterations in offspring, with response patterns that may differ between males and females. We investigated whether propolis supplementation from preconception through lactation modified metabolic and hepatic outcomes in offspring exposed to a maternal cafeteria diet. Methods: Thirty-two Wistar rat dams received a control diet (CON), cafeteria diet (CAF), or either diet with propolis in drinking water (CONP and CAFP; target exposure, 200 mg/kg/day). One male and one female per litter (n = 8/sex/group) received standard chow after weaning. This design isolated maternal exposure because offspring received no propolis after weaning. At 18 weeks, metabolic and inflammatory biomarkers, liver histopathology, and hepatic lipid-metabolism gene expression were evaluated using groupwise tests and two-way ANOVA. Results: Final body weights were comparable across groups. In males, maternal diet affected glucose (p = 0.034) and HOMA-IR (p = 0.023), with a diet × propolis interaction for glucose (p = 0.042). CAF males had higher TNF-α than CAFP and CONP males. In females, diet × propolis interactions were detected for insulin, total cholesterol, triglycerides, and leptin (all p ≤ 0.049); CAF females had higher triglycerides than CON and CAFP females. Hydropic degeneration was greater in CAF dams than all other groups and in CAF than CONP male offspring; female histopathology did not differ. Male hepatic gene expression did not differ among groups, whereas female PPAR-β and FADS2 showed propolis main effects (p = 0.046 and p = 0.009, respectively). Conclusions: Maternal cafeteria-diet exposure was associated with persistent metabolic and hepatic alterations despite comparable offspring body weights, with different response patterns observed in the separate male and female analyses. Maternal propolis supplementation selectively modified some inflammatory, lipid-related, and histopathological outcomes; however, these effects were heterogeneous and did not consistently normalize the cafeteria-associated phenotype. Overall, the findings support partial, endpoint-specific, and context-dependent modulation rather than uniform metabolic or hepatic protection. Full article

Background: Hypoxia-induced oxidative stress and ferroptosis contribute to blood–brain barrier dysfunction and neurovascular injury associated with ischemic stroke and neurodegenerative diseases. Luteolin, a naturally occurring flavonoid with potent antioxidant and anti-inflammatory activities, has emerged as a potential neuroprotective agent; however, its effects on hypoxia-induced ferroptosis in brain microvascular endothelial cells remain unclear. This study investigated the protective effects of luteolin and its association with changes in the PPARγ/FABP5/ALOX15 signaling pathway during hypoxia-induced ferroptotic injury. Methods: Human brain microvascular endothelial cells (HBEC-5i) were exposed to cobalt chloride (CoCl₂) to establish an in vitro hypoxia model and subsequently treated with luteolin. Cell viability was assessed using the MTT assay. Intracellular Fe²⁺ accumulation, reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH/GSSG) levels were determined using biochemical assays. The expression of ferroptosis- and hypoxia-related proteins, including GPX4, ALOX15, FABP5, PPARγ, HIF-1α, and VEGF, was evaluated by Western blotting. Results: CoCl₂-induced hypoxia significantly reduced cell viability and increased intracellular Fe²⁺ accumulation, ROS generation, lipid peroxidation, and ferroptosis-associated signaling in HBEC-5i cells. Hypoxic conditions upregulated ALOX15 and FABP5 expression while suppressing GPX4 and PPARγ levels. Luteolin treatment markedly attenuated these effects by restoring GSH/GSSG homeostasis, enhancing GPX4 expression, reducing ALOX15-mediated lipid peroxidation, and suppressing HIF-1α and VEGF expression. In addition, luteolin modulated the PPARγ/FABP5 signaling pathway, suggesting its involvement in the regulation of hypoxia-induced ferroptosis. Conclusions: Luteolin attenuates hypoxia-induced ferroptosis-associated changes in human brain microvascular endothelial cells by restoring redox homeostasis and is associated with coordinated modulation of the PPARγ/FABP5/ALOX15 pathway. These findings extend previous reports of the anti-ferroptotic effects of luteolin by providing evidence in brain microvascular endothelial cells under hypoxia-mimetic stress. Full article

Adipotoxicity is a major contributor to insulin resistance and type 2 diabetes, and increasing evidence highlights the gut–adipose axis as a promising therapeutic target. Soursop (Annona muricata) is rich in phytochemicals that can be biotransformed by the gut microbiota into bioactive metabolites with metabolic benefits. The present study investigated whether metabolites generated by in vitro fecal fermentation of soursop fruit (SWSF) and peel (SWSFP) protect against fructose-induced adipotoxicity. SWSF and SWSFP were fermented with rat fecal microbiota, and the resulting metabolites were evaluated in an ex vivo fructose-induced adipotoxicity model using perigonadal white adipose tissue. Activities of enzymes involved in glucose metabolism, the polyol pathway, glutathione metabolism, glyoxalase-1 activity, purinergic signaling, and inflammatory lipid metabolism were determined. GC–MS-based metabolomics and pathway enrichment analyses were performed on fecal and adipose tissues. Soursop fermentation significantly remodeled the fecal metabolome, enriching metabolites associated with fatty acid metabolism, glycerolipid metabolism, β-oxidation, sterol metabolism, and arachidonic acid metabolism. Fructose-induced adipotoxicity disrupted glucose metabolism, activated the polyol pathway, impaired glutathione metabolism and glyoxalase-1 activity, suppressed ATPase and ENTPDase activities, and elevated 5-LOX and 12/15-LOX activities. Treatment with soursop-enriched fecal metabolites significantly reversed these alterations in a dose-dependent manner. Adipose metabolomics further demonstrated restoration of pathways associated with fatty acid biosynthesis, mitochondrial β-oxidation, glycerolipid metabolism, steroid biosynthesis, and polyunsaturated fatty acid metabolism, indicating improved lipid homeostasis and reduced inflammatory lipid signaling. SWSF and SWSFP generally exhibited greater metabolic protection than the reference antioxidant compound, gallic acid. Soursop-derived gut metabolites attenuate fructose-induced adipotoxicity by coordinately restoring glucose metabolism, redox homeostasis, carbonyl detoxification, purinergic signaling, and lipid metabolism through the gut–adipose axis. These results suggest soursop as a potential functional food for preventing and managing adipose tissue dysfunction and metabolic disorders. Full article

Background: Human ischemic stroke thrombi are increasingly recognized as biologically active immunothrombotic structures. While the NLRP3 inflammasome contributes to experimental stroke pathology, its role within human cerebral thrombi remains poorly understood. Methods: Thrombi retrieved by mechanical thrombectomy from 34 patients with acute ischemic stroke caused by large vessel occlusion were analyzed by immunofluorescence for NLRP3, ASC, neutrophils (CD66B), NETosis (H3CIT), HMGB1, and Gasdermin D. Results: NLRP3 was detected in all thrombi and correlated with neutrophil abundance, NETosis, HMGB1, and GSDMD independently of fibrin content. A majority of CD66B-positive neutrophils exhibited ASC immunoreactivity. Neither NLRP3 nor the inflammatory thrombus signature was associated with stroke severity, infarct extent, or functional outcome. Conclusions: Human ischemic stroke thrombi contain an NLRP3-associated neutrophil inflammatory network with histological evidence consistent with inflammasome assembly. This signature appears to reflect local thrombus biology rather than clinical disease severity. Full article

Peripheral neuropathy (PN) is a debilitating condition characterized by chronic pain, numbness, and motor dysfunction, with limited treatment options. Ischemic stroke can cause central neuropathy, which may also induce PN. Human mesenchymal stem cells (hMSCs) have shown promise in therapeutic applications, but limitations in cell viability, immune response, and efficacy persist. Extracellular vesicles (EVs), which facilitate cell-free intercellular communication, offer a promising alternative for nerve regeneration. Electrical stimulation (ES) has emerged as a method to enhance EV secretion, and this study investigates its potential for promoting EV production from human adipose tissue-derived mesenchymal stem cells (hASCs) and human Schwann cells (hSCs). In this study, hASCs, hSCs, and lipopolysaccharide (LPS)-induced inflamed hSCs were subjected to one hour of low-frequency direct current (DC) electrical stimulation (100 mV/mL) for 7 days. EVs were isolated using differential ultracentrifugation and characterized through nanoparticle tracking analysis (NTA). Gene expression was analyzed via qRT-PCR to evaluate markers associated with EV biogenesis as well as pro- and anti-inflammatory cytokines. Our results demonstrate that ES significantly increases EV secretion from both hASCs and hSCs, with a notable upregulation of genes involved in both the endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways of EV biogenesis. Additionally, ES modulates inflammation-related markers, promoting anti-inflammatory gene expression and reducing pro-inflammatory gene levels. Notably, LPS-induced hSCs exhibited a phenotype shift from myelinating to non-myelinating cells, producing EVs capable of modulating the inflammatory microenvironment. However, prolonged exposure to ES led to a decrease in EV secretion and changes in EV size distribution, suggesting potential cellular adaptation or membrane stress. This study highlights the potential of ES as a scalable, cell-free strategy to enhance EV production, offering new insights into its therapeutic applications for peripheral neuropathy and nerve regeneration. Full article

Chronic pain, sleep disturbances, and mental health disorders such as anxiety and depression disorders frequently co-occur, forming a self-reinforcing cycle that impairs daily functioning and quality of life. Chronic pain is driven by peripheral and central sensitization, the latter sustained by reciprocal microglial–astrocytic crosstalk and maladaptive neuroplasticity. Poor sleep amplifies pain through inflammation and circadian disruption. Imbalances in serotonin, dopamine, and norepinephrine, together with limbic alterations and HPA axis dysregulation, contribute to comorbid anxiety and depression. Elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), NF-κB-driven neuroinflammation, and mitochondrial oxidative stress serve as key molecular links. Building on previous evidence, this review presents an updated triadic, mechanism-based framework describing the reciprocal reinforcement among chronic pain, sleep disturbances, and anxiety and depressive disorders. Consequently, therapeutic strategies targeting inflammatory cytokines, microglial and astrocytic activation, neurotransmitter imbalance, and psychological dysfunction may help address these shared neuroimmune and neuroplastic mechanisms underlying these interconnected disorders. Full article

Background: Uterine fibroids (UFs) are the most common benign tumors in women of reproductive age and are associated with abnormal uterine bleeding, infertility, and impaired implantation and endometrial receptivity. However, the contribution of the myometrial microbiome (MM) to fibroid biology and the broader uterine environment remains poorly understood. Materials and Methods: We characterized the paired MM of UF tissue and adjacent healthy myometrium (HM) from 21 women undergoing surgery and integrated serum free fatty acid (FFA) and cytokine profiling. Results: Taxonomic composition and microbial diversity were highly similar between tissues, with no differentially abundant taxa after multiple-testing correction. In contrast, PICRUSt2-based functional prediction indicated tissue-specific differences in microbial metabolic potential: UF tissue showed higher predicted representation of pathways related to L-tyrosine biosynthesis and aromatic amine degradation, whereas HM showed higher predicted representation of coenzyme A and arginine biosynthesis pathways. Patients also exhibited distinct circulating FFA profiles compared with healthy women, and integrative analyses identified phenotype-specific associations among microbial taxa, FFAs, and inflammatory mediators, particularly in women with heavy menstrual bleeding or specific fibroid localizations. Conclusions: These findings suggest that UFs are associated with potential functional remodeling of the MM rather than major taxonomic alterations, which may contribute to changes in the uterine environment relevant to implantation, endometrial receptivity, and reproductive health. Full article

Elymus repens (L.) Gould has a long history of use in traditional medicine across the British Isles, particularly among Gaelic and Anglo-Saxon communities, where it has been employed as a diuretic and anti-inflammatory agent. Despite its ethnopharmacological significance, comprehensive insights into its phytochemical composition and biological activities remain limited. The present study aimed to provide an integrated characterization of E. repens through macro- and microscopic analyses, advanced phytochemical profiling, and evaluation of the biological activities of the rhizome part. Microscopic examination revealed distinct anatomical features differentiating rhizome and stem, leaf tissues, supporting accurate identification and pharmacognostic standardization. Chemical profiling using Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (LC-QToF-MS) enabled the tentative identification of 93 metabolites, including amino acids, in aerial and rhizome extracts. These compounds were primarily classified into polyamines (e.g., feruloylputrescine, hydroxycoumaroylagmatine), phenolic acids (gallic, vanillic, and ferulic acids), flavonoids (apigenin, tricin, saponarin analogues), amino acids (arginine, tyrosine, tryptophan), organic acids (malic, succinic acids), nucleosides (adenosine, thymidine), and phospholipids. Biological evaluation demonstrated that the hydroethanolic rhizome extract exhibited notable antifungal activity against Aspergillus fumigatus (IC₅₀ = 34.9 µg/mL). Additionally, hydroethanolic extracts of both the aerial and rhizome parts showed no cytotoxicity in the Artemia salina lethality assay at concentrations up to 10 mg/mL, indicating a favorable preliminary safety profile. Of particular interest is tricin, which possesses anti-inflammatory, antioxidant, antimicrobial, and potential nephroprotective therapeutic effects; its mechanism of action is associated with the suppression of oxidative stress, the inhibition of pro-inflammatory mediators, and the disruption of metabolic processes in microbial cells. Overall, this study provides a comprehensive phytochemical and pharmacognostic characterization of E. repens, highlighting its potential as a source of bioactive compounds. The metabolite profile obtained directly from the biologically active extract, combined with its proven antifungal activity, serves as direct confirmation of the antimicrobial aspect of this plant’s traditional use, while its broader applications in ethnomedicine require targeted pharmacological testing. These findings contribute valuable data for chemotaxonomic classification and future pharmacological investigations. Full article