Search Results (1,548)

Inflammatory diseases are caused by overactivation of the immune system and lead to tissue damage; their high incidence and complications seriously threaten human health. Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and immunosuppressants are the mainstay of clinical practice, but their long-term use can cause gastrointestinal damage, drug resistance, and other problems. In recent years, traditional Chinese medicine has become a research hotspot for the treatment of inflammatory diseases, among which Icariin (ICA), the main active ingredient of Epimedium, has demonstrated significant anti-inflammatory potential. In this review, a comprehensive literature search of PubMed and Web of Science was conducted, and original studies on the anti-inflammatory effects and mechanisms of ICA were included. The roles and mechanisms of ICA in inflammatory diseases in different systems are summarized. Specifically, ICA suppresses NF-κB and MAPK signaling, inhibits NLRP3 inflammasome activation, and activates the Nrf2/HO-1 antioxidant axis, thereby reducing the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. Overall, the current evidence indicates broad anti-inflammatory effects of ICA across multiple organ systems, particularly in atherosclerosis and myocardial infarction; however, clinical translation is limited by poor bioavailability and the lack of standardized dosage data. Future efforts should focus on pharmacokinetic optimization and well-designed clinical trials to facilitate its application in inflammatory diseases. Full article

Background: This study aimed to assess the effects of a combined vitamin D₃ (VD₃) and docosahexaenoic acid (DHA) intervention on cognitive function and blood pyroptotic biomarkers in older adults with mild cognitive impairment (MCI). Methods: In total, 360 participants with MCI were recruited, and randomly assigned into four groups: VD₃ (800 IU/day), DHA (1 g/day), VD₃+DHA (VD₃ 800 IU/day+DHA 1 g/day), and placebo. Cognitive function was evaluated by the Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC), and blood biomarkers were measured by ELISA and Western blot at baseline, 6 months and 12 months. Linear mixed-effects models (LMMs) were employed to analyze longitudinal interaction effects on cognitive function and blood biomarkers. Structural equation modeling (SEM) was conducted to evaluate the parallel mediation effects of blood biomarkers on cognitive improvements. Results: A total of 355 participants completed the trial. Over the 12-month intervention, all intervention groups demonstrated significant improvements in cognitive function and reductions in five blood biomarkers (IL-1β, IL-18, NLRP3, Gasdermin D (GSDMD), cleaved caspase-1) compared to the placebo group (p < 0.05). Compared to each single intervention, the combined VD₃ and DHA intervention yielded superior cognitive improvements in scores for full-scale IQ (FIQ), performance IQ (PIQ), verbal IQ (VIQ) and several subtests (information, comprehension, digit span, vocabulary, picture completion, block design, and picture arrangement), and significantly reduced five blood pyroptotic biomarkers (all p < 0.05). Path analysis revealed that longitudinal GSDMD reduction mediated the improvements in FIQ. Conclusions: A 12-month intervention with VD₃, DHA, or their combination significantly improves cognitive function and mitigates pyroptosis, and the combined intervention showed superior benefits, potentially mediated by downregulating the protein GSDMD. Full article

Chronic kidney disease (CKD) is sustained by a network of sterile inflammation, oxidative and metabolic stress, uremic toxin retention, gut barrier dysfunction, and maladaptive immune activation. These processes contribute to kidney fibrosis, cardiovascular injury, wasting, and excess mortality, but inflammatory biomarkers do not by themselves establish therapeutic causality. This narrative review integrates mechanistic and therapeutic evidence using an explicit three-layer translational hierarchy. Renin–angiotensin system inhibitors, sodium–glucose cotransporter-2 inhibitors, finerenone, and glucagon-like peptide-1 receptor agonists improve cardiorenal outcomes and have plausible anti-inflammatory actions, although inflammatory mediation remains unproven. Interleukin-1 blockade provides cardiovascular proof of principle and small dialysis feasibility data. Interleukin-6 ligand inhibition produces marked human target engagement; however, headline results from the completed phase 3 ZEUS trial showed no reduction in three-point major adverse cardiovascular events with ziltivekimab despite biomarker suppression, while serious infections were more frequent. POSIBIL6ESKD continues to test clazakizumab in inflamed dialysis patients. Direct NLRP3 inhibition has entered early human CKD development, whereas senescence-directed and microbiota-based approaches remain less mature. Future progress requires inflammatory endotyping, repeated biomarker assessment, mechanistically aligned outcomes, and rigorous infection surveillance. ZEUS underscores that pathway suppression must deliver clinical benefit beyond contemporary standard therapy. Full article

Osteoarthritis (OA) is increasingly recognized as a mechanically driven whole-joint disease in which abnormal mechanotransduction initiates a cascade of mitochondrial dysfunction, chronic inflammation, and progressive cartilage degeneration. Among the mechanosensitive molecules identified to date, Piezo1 has emerged as a key mechanosensitive regulator linking pathological mechanical loading to intracellular calcium signaling and downstream cellular responses. Growing evidence indicates that persistent Piezo1 activation promotes mitochondrial calcium overload, excessive reactive oxygen species production, ATP depletion, mitochondrial membrane depolarization, and impaired mitophagy, ultimately amplifying chondrocyte dysfunction and extracellular matrix degradation. In parallel, mitochondrial damage triggers immunometabolic reprogramming through activation of the cGAS–STING pathway and the NLRP3 inflammasome. It also promotes pro-inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α, and interleukin-6. Together, these responses may contribute to a self-perpetuating cycle of inflammation and tissue destruction. This review provides a comprehensive synthesis of recent advances regarding the role of Piezo1 in OA, focusing on the mechanistic links between mechanotransduction, mitochondrial dysfunction, mitophagy, and immunometabolic dysregulation. We further discuss the contribution of mitochondrial quality-control pathways, including PINK1/Parkin-, BNIP3-, and FUNDC1-mediated mitophagy, as well as alterations in mitochondrial dynamics involving DRP1, MFN1, MFN2, and OPA1. Emerging experimental models are discussed as valuable tools for accelerating therapeutic discovery. Finally, we critically evaluate current therapeutic strategies targeting the Piezo1–mitochondria axis, including mechanosensitive channel modulation, mitochondrial protection, mitophagy enhancement, gene therapy, biomaterial-assisted delivery, and nanomedicine. Collectively, current evidence supports the Piezo1–mitochondria–immune axis as an important mechanistic framework contributing to OA pathogenesis and as a potential therapeutic target. Integrating mechanobiology, mitochondrial medicine, and precision-engineered experimental models may facilitate the development of next-generation disease-modifying therapies capable of slowing or preventing osteoarthritis progression. Full article

Background: Elite HIV controllers exhibit persistent immune activation despite sustained viral suppression, a phenomenon that challenges the traditional view of immunological equilibrium. In parallel, autoimmune diseases are characterised by chronic inflammation driven by dysregulated immune responses. Objective: This study aimed to analyse the potential pathophysiological convergence between both conditions and to identify a shared inflammatory axis with possible translational implications. Methods: A critical narrative and integrative reflection was conducted using a purposive, concept-driven selection of evidence from PubMed/MEDLINE, Scopus, and Web of Science. A total of 43 sources were included: 28 studies informing mechanistic findings (14 on elite HIV controllers and 14 on autoimmune diseases), 12 addressing modulatory strategies (pharmacological and lifestyle-based), and 3 providing contextual frameworks. Results: Both conditions demonstrate sustained activation of innate immunity, characterised by elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF, type I interferons), increased inflammatory biomarkers (e.g., sCD14, IP-10), and activation of pathways such as NLRP3 inflammasome and NF-κB signalling. Collectively, these findings suggest convergence towards a potential shared inflammatory axis mediated by the inflammasome–interferon pathway, which may contribute to persistent systemic inflammation and tissue damage. Evidence from pharmacological and non-pharmacological interventions suggests that components of this axis may be susceptible to modulation. Conclusions: The observed convergence supports a conceptual model of shared innate inflammatory activation across both conditions. Rather than implying a unified therapeutic approach, the findings suggest a framework of convergent modulation targeting the inflammasome–interferon axis. This hypothesis warrants further investigation to determine its clinical and translational relevance. Full article

Skeletal muscle mitochondria possess the ability to autoregulate their health and functioning by the orchestration of mitochondrial quality control (MQC) pathways. This plasticity allows them to adapt to various stimuli, such as exercise. However, under pathological conditions, mitochondria can become dysfunctional, generating damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These DAMPs can launch an innate immune response, with consequences of widespread inflammation and atrophy. Integral to this is the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome results in maturation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18, as well as GSDMD. Consequently, the pore-forming GSDMD-N fragment induces pyroptosis, releasing mature IL-1β and IL-18. Exercise training is widely accepted as a potent mechanism to promote skeletal muscle health, particularly by remodeling the mitochondrial network and reducing the production of DAMPs. It has also been shown promote an anti-inflammatory milieu with the release of various myokines. Indeed, the potential of exercise to mitigate NLRP3 inflammasome-mediated inflammation and atrophy is promising. This review will examine the mechanisms underpinning inflammasome priming and activation, as well the effects of exercise, with an emphasis on the skeletal muscle. Full article

Considered a global public health priority, sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. Its heterogeneous clinical presentation arises, in part, from pre-existing chronic conditions such as hypertension, metabolic syndrome, diabetes, alcohol exposure, psychosocial stress, and periodontitis, which induce persistent systemic changes even before the infectious event. This narrative review synthesizes evidence from experimental models and clinical studies to clarify the molecular and immunological mechanisms by which chronic conditions influence the septic state. We discuss how these conditions converge on common pathophysiological mechanisms, including low-grade chronic inflammation, oxidative stress, endothelial and mitochondrial dysfunction, and changes in the microbiota and neuroimmune regulation. Pathways such as TLR-NF-κB signaling and the NLRP3 inflammasome are maintained in a basal state of activation, lowering the threshold for hyperinflammatory responses and increasing the risk of multiple organ dysfunction syndrome. In conclusion, understanding these phenotypes can guide the identification of biomarkers and the development of personalized therapeutic strategies, thereby moving beyond one-size-fits-all approaches to the management of sepsis and septic shock. Full article

Uterine fibroids, the most common tumors in reproductive-age women, remain without a defined precursor tissue state. Unlike cervical dysplasia preceding cervical cancer, or colonic polyps preceding colorectal malignancy, no equivalent “at-risk” tissue marker exists for fibroids, and diagnosis relies on radiological imaging only after tumors are already well-established and often symptomatic including excessive menstrual bleeding, pelvic pain, infertility and obstetric complications. In this narrative review, we propose that a subset of women with unexplained AUB may harbor a chronic, non-infectious inflammatory condition of the myometrium, which we term Chronic Aseptic Myometritis (CAM). We synthesize mechanistic and human tissue evidence suggesting that sterile inflammation driven by damage-associated molecular patterns, NLRP3 inflammasome activation, oxidative DNA damage, and TGF-β–mediated extracellular-matrix remodeling may underlie the transition from normal myometrium (MyoN) to a pre-fibroid, inflamed and stiffened state (MyoF), and may contribute both to abnormal uterine bleeding (AUB) and to fibroid initiation. We propose a preliminary framework for future CAM research, including the identification of candidate biomarker categories and imaging correlates. We also discuss whether early mechanism-based interventions, such as vitamin D and epigallocatechin gallate (EGCG), may offer a potential pathway toward primary prevention. Because the components of this model derive largely from experimental and cross-sectional human studies, CAM is presented as a hypothesis-generating, myometrium-centered framework rather than a validated clinical entity, and prospective validation is required. Full article

Introduction: IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. Given the significant adverse effects and inconsistent long-term efficacy of conventional immunosuppressive strategies, there is an unmet need for safer adjunctive therapies. Omega-3 polyunsaturated fatty acids (PUFAs) have been proposed as potential candidates to address this therapeutic gap. Purpose: This narrative review summarizes the proposed mechanisms of action of omega-3 PUFAs in IgAN and critically evaluates the current clinical evidence regarding their therapeutic potential and limitations. Mechanisms: Emerging experimental data suggest that omega-3 PUFAs may modulate inflammatory and fibrotic pathways relevant to kidney injury. Proposed mechanisms include modulation of eicosanoid metabolism, attenuation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, and generation of specialized pro-resolving mediators. In experimental studies, omega-3 PUFAs may also suppress nuclear factor kappa B (NF-κB)-driven transcription and attenuate mesangial cell proliferation, IgA immune-complex deposition, and transforming growth factor beta 1 (TGF-β1)/Smad3-mediated fibrotic signaling. Clinical Evidence: Conclusions: Omega-3 PUFAs have biological plausibility as adjunctive therapy in IgAN, but their clinical benefit remains uncertain. Available randomized trials and meta-analyses suggest possible modest effects on proteinuria in some settings, whereas evidence for preservation of kidney function or prevention of kidney failure is inconsistent and of low certainty. Future well-designed trials incorporating guideline-directed background therapy and biomarker-guided patient selection are essential to determine optimal dosing, formulation, biological exposure, and whether any patient subgroups derive clinically meaningful benefit. Full article

Vaccinium macrocarpon (American Cranberry) fruit is processed to make juice, supplements, and other edible products, leaving pomace as a sidestream that contains secondary metabolites with potential anti-inflammatory and anti-proliferative activities. Ultrasound-assisted extraction and chromatographic methods were developed to prepare an extract (POM-ACE) and fractions rich in pentacyclic triterpenoids and phytosterols for bioactivity evaluation. These were characterized using UPLC-MS and GC-MS. Anti-inflammatory effects were assessed in a human monocyte (THP-1) model, identifying several fractions containing triterpenoids and sitosterol that significantly inhibited IL-1β expression. Molecular docking indicated favorable interactions of these components with NLRP3, suggesting a possible modulation of inflammasome. Fractions rich in ursolic acid (UA) and oleanolic acid (OA) and their p-hydroxycinnamic acid (HCA) esters also showed mild concentration-dependent inhibition of lipoxygenase (LOX) activity. Pearson correlation analysis identified strong positive correlations between UA, OA, and their trans-HCA esters with LOX inhibition. Anti-proliferative activity was assessed in HT-29 colon adenocarcinoma cells using MTT, with several fractions exhibiting moderate concentration-dependent activity (IC₅₀ = 12–17 µg/mL). PLS regression analysis supported significant contributions by UA, OA, and their HCA esters. Flow cytometry experiments demonstrated that cell death occurs in part through apoptosis; the role of apoptosis was further supported by favorable molecular docking interactions between pomace triterpenoids and caspases-3 and -9. These findings suggest that cranberry pomace is a promising source of triterpenoids and phytosterols with anti-inflammatory and anti-proliferative properties. Full article

Immunosenescence is a major contributor to age-associated morbidity, yet microbiota-directed strategies capable of restoring immune homeostasis remain insufficiently validated. Medicinal plant polysaccharides (MPPs) are structurally diverse macromolecules that often resist host digestion and undergo microbial transformation in the colon, but their effects cannot be interpreted as those of a homogeneous intervention class. In this structured narrative review, we critically synthesize evidence across structural carbohydrate biology, microbial ecology, metabolite signaling, and immune aging and propose a structure–microbiota–metabolite–immunity framework for evaluating how MPPs may influence immunosenescence. Monosaccharide composition, glycosidic linkages, molecular-weight distribution, branching, uronic acid content, chemical substitutions, and higher-order conformation can shape microbial carbohydrate-active enzyme activity, polysaccharide utilization, and ecological cross-feeding. The resulting changes in short-chain fatty acids, secondary bile acids, tryptophan-derived indoles, and other metabolites may affect epithelial barrier integrity, regulatory T-cell/T helper 17-cell (Treg/Th17) balance, macrophage polarization, nuclear factor-κB (NF-κB) signaling, NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, and systemic inflammatory tone. However, evidence from in vitro systems and young disease models primarily supports mechanistic plausibility and should not be treated as direct evidence of immunosenescence modification. Translation will require structurally defined preparations, causal validation in aging-relevant models, comparison with established fermentable fibers, identification of responder phenotypes, and adequately powered trials in older adults. Full article

Kaempferol is a natural flavonol compound widely present in various single-herb remedies and compound formulations used for the treatment of ocular diseases. Despite its inherent pharmaceutical limitations, accumulating evidence indicates that kaempferol exerts broad protective effects against diverse ocular disorders through multiple biological pathways, highlighting its potential as a multi-target therapeutic candidate in ophthalmology. However, current evidence regarding kaempferol-based ophthalmic applications remains fragmented across different ocular diseases and mechanistic investigations, and a comprehensive evaluation of its therapeutic potential, translational challenges, and existing limitations is still lacking. This review systematically summarizes the research progress on kaempferol in the treatment of eye diseases, encompassing its source distribution, structural characteristics, ocular delivery strategies, disease spectrum coverage, molecular mechanisms, and safety profile. By critically evaluating currently available evidence, this review further identifies unresolved issues and translational barriers that hinder the clinical application of kaempferol in ophthalmology. Regarding delivery strategies, carriers such as gelatin nanoparticles, porous bovine serum albumin membranes, platelet-derived extracellular vesicles, and polyvinylpyrrolidone-based nanocomposites have preliminarily improved ocular surface retention and corneal permeability of kaempferol in models of corneal neovascularization and alkali burns. In terms of therapeutic indications, kaempferol has demonstrated protective effects in diverse experimental models, including age-related macular degeneration (AMD), diabetic retinopathy, diabetic cataract, dry eye disease, fungal keratitis, corneal transplant rejection, acute glaucoma, and retinoblastoma. At the mechanistic level, kaempferol exerts comprehensive pharmacological actions—anti-inflammatory, antioxidant, metabolic regulation, anti-angiogenic, and immunomodulatory—by modulating multiple signaling pathways, including MAPK, NF-κB, STAT1/IRF7, Nrf2/HO-1, VEGF/PI3K/Src/Akt/ERK, aldose reductase, estrogen-related receptor alpha (ERRα), and the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Available safety assessments suggest that kaempferol exhibits a generally favorable safety profile across ocular, cellular, systemic, and genetic evaluations. Despite these advances, the clinical translation of kaempferol in ophthalmology remains limited by insufficient clinical and pharmacokinetic evidence, underdeveloped targeted delivery strategies, and a lack of integrated understanding of its molecular basis in ocular protection. By systematically integrating evidence from ocular disease models, molecular mechanisms, delivery strategies, and safety evaluations, this review bridges fragmented knowledge regarding kaempferol-based ophthalmic applications and provides an integrated framework for understanding its therapeutic potential and translational prospects. Overall, this review highlights kaempferol as a promising multi-target therapeutic candidate for ocular diseases and provides insights into its future translational development. Full article

Acute kidney injury (AKI) is a critical clinical syndrome with limited effective therapies, in which renal tubular epithelial cell (RTEC) pyroptosis mediated by the NLRP3 inflammasome represents an important pathological contributor. Stress granules (SGs), dynamic membrane-less condensates, enable cells to adapt to various stress conditions, yet their role and regulatory mechanism in AKI remain unclear. Here, we identify SG persistence as a protective mechanism against AKI and show that poly(ADP-ribosyl)ation (PARylation)-mediated regulation of SG dynamics alleviates pyroptosis during renal injury. We found that SGs were prominently formed in RTECs from AKI patients, cisplatin-induced AKI mice, and cisplatin-stimulated HK-2 cells. Poly(ADP-ribose) glycohydrolase (PARG), the key enzyme for reversing PARylation, was significantly upregulated in injured renal tissues and cells. Genetic or pharmacological inhibition of PARG delayed SG disassembly, enhanced SG persistence, and mitigated renal injury. Mechanistically, persistent SGs regulated DDX3X availability and reduced DDX3X-NLRP3 inflammasome activation, thereby attenuating RTEC pyroptosis. These findings uncover a novel mechanism of SG-mediated renoprotection and highlight SG dynamics as a potential therapeutic target in AKI. Full article

Perirenal adipose tissue (PRAT) has emerged as a clinically relevant endocrine organ connecting obesity to cardiovascular disease (CVD), chronic kidney disease, and certain malignancies. Its unique anatomical location, surrounding the kidneys, accounts for PRAT’s role in altering intrarenal haemodynamics and hydrostatic pressure. Accordingly, PRAT’s expansion is associated with the activation of the renin–angiotensin–aldosterone system (RAAS), further increasing blood pressure. Adipokine dysregulation, together with overexpression of miR-24-3p, miR-155, miR-146a, and miR-21 in PRAT, modulates inflammation and oxidative stress, leading to endothelial dysfunction and increased risk of atherosclerosis and hypertension in obesity. Imaging assessment of PRAT thickness through computed tomography, magnetic resonance, or ultrasound has also emerged as a complementary measure for the evaluation of CVD risk. Potential therapeutic strategies targeting PRAT include lifestyle interventions, antidiabetic agents, RAAS inhibitors, adipose tissue browning agents, NOD-like receptor protein 3 (NLRP3) inflammasome inhibitors, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, and surgery. Currently, novel therapeutic interventions targeting PRAT activity in CVD, such as senotherapeutic strategies, bioengineering approaches aimed at enhancing adipose-derived mesenchymal stem cell (ADMSC) function, gut microbiota modulation, and colchicine and bone morphogenetic protein 4 (BMP4) administration, are also being explored. In light of these findings, PRAT’s clinical relevance extends beyond its energy storage role, highlighting it as a metabolically active fat depot. Its assessment and therapeutic modulation may complement existing cardiovascular prevention strategies, particularly in patients with obesity. Full article

Gout is a crystal-induced inflammatory arthritis driven by hyperuricemia and monosodium urate (MSU) crystal deposition, yet urate burden alone does not explain why only a subset of hyperuricemic individuals develops clinical disease, why acute flares are usually self-limited, or why gout clusters with renal and cardiometabolic comorbidity. This structured narrative review uses a gout-specific redox-switch framework, defined as a context-dependent shift in uric acid biology according to concentration, compartment, crystallization state, xanthine oxidoreductase (XOR) activity, inflammatory priming, and disease stage rather than as a binary molecular event. We integrate evidence on XOR-derived reactive oxygen species (ROS), mitochondrial stress, NLRP3 inflammasome signaling, neutrophil oxidative responses, neutrophil extracellular traps (NETs), lipid peroxidation, and potential ferroptosis-related mechanisms. Evidence is classified into five categories: established, mechanistically supported, human-associative, conceptual, and emerging/unvalidated. The available human data support lipid-peroxidation and ferroptosis-associated molecular signatures, but do not yet establish ferroptotic cell death as a driver of gout. Therapeutic implications are therefore framed conservatively: urate-lowering therapy remains foundational, whereas redox-directed approaches require pathway specificity, disease-stage definition, and biomarker validation. The redox-switch concept is proposed as an organizing framework for mechanistic and translational research, not as a validated clinical algorithm. Full article