Search Results (666)

Sideritis species (Lamiaceae), the aromatic mountain teas of the Mediterranean and Balkans, accumulate a phytochemically rich array of bioactive compounds—phenylethanoid glycosides (notably verbascoside), flavonoid aglycones and glycosides, phenolic acids, and terpenoids—whose pharmacological relevance is increasingly defined at the molecular level. This review synthesizes current evidence on the molecular mechanisms through which these constituents act in human health and disease, integrating in vitro, in vivo, in silico, and clinical data. Anti-inflammatory activity is attributed to modulation of the NF-κB and NLRP3 inflammasome pathways; direct verbascoside binding to both targets has been demonstrated in vitro by microscale thermophoresis (nanomolar-to-micromolar Kd), with suppression of TNF-α and IL-1β observed in cell-based and animal models. Neuroprotective effects are proposed to operate through amyloid-β clearance via ADAM10 upregulation and enhanced microglial phagocytosis in transgenic mouse models, together with in vitro triple monoamine (serotonin, noradrenaline, dopamine) reuptake inhibition, and are supported at the functional level by small randomized clinical trials reporting cognitive and anxiolytic benefits. Antioxidant and cytoprotective actions reflect radical scavenging, metal chelation, and restoration of SOD/CAT/GSH with attenuation of lipid peroxidation, underpinning documented hepatoprotective and gastroprotective outcomes. Preliminary cardiometabolic findings from small clinical trials include cholesterol modulation and sex-dependent effects on insulin sensitivity that remain to be confirmed in larger, adequately powered cohorts. We further evaluate structure–activity relationships, species- and tissue-level chemical variability, and green extraction strategies relevant to standardized bioactivity-preserving preparations. Critical gaps—in vivo validation of antiproliferative effects documented only in cell-based and in silico studies so far, systematic toxicological assessment, and bioavailability characterization—are identified to guide translation. Collectively, Sideritis-derived phytochemicals, exemplified by S. scardica, represent a mechanistically coherent group of plant bioactives with defined molecular targets in inflammatory, neurodegenerative, and metabolic disorders. Full article

Medical ozone has emerged as a potential redox-modulating intervention in inflammatory and degenerative conditions, particularly in dermatological contexts characterized by chronic oxidative imbalance and impaired tissue remodeling. Unlike conventional pharmacological agents, ozone exerts its biological activity through rapid chemical reactions generating transient reactive and electrophilic species that activate endogenous adaptive signaling pathways. Controlled oxidative perturbations activate antioxidant transcriptional programs, primarily mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, while modulating inflammatory signaling networks, including nuclear factor kappa B (NF-κB) and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. This dual behavior reflects hormetic responses in which low-dose exposure promotes adaptive cellular signaling, whereas excessive oxidative burden leads to structural and functional damage. This review summarizes current knowledge on the molecular mechanisms underlying ozone-induced redox modulation, with emphasis on chemical reactivity, spatiotemporal signaling dynamics, thiol-based sensing, and metabolic reinforcement of antioxidant defenses. Particular attention is given to skin and subcutaneous adipose tissue, where oxidative stress, immune activation, and extracellular matrix remodeling converge. Dose dependency, safety constraints, and methodological variability are critically discussed, highlighting the narrow threshold between adaptive signaling and oxidative injury and the need for rigorous mechanistic and clinical validation. Full article

Depression is increasingly recognized as a multifactorial disorder involving immune, metabolic, and neurobiological disturbances that extend beyond classical monoaminergic hypotheses. Among xenobiotic-based experimental approaches, lipopolysaccharide (LPS) has become a valuable tool for investigating how peripheral inflammatory stimuli are translated into central neurobiological dysfunction. This narrative review aimed to integrate current evidence regarding the mechanisms by which LPS-induced neuroimmune activation contributes to depression-related phenotypes and to discuss the translational relevance of these findings. Literature searches were performed in PubMed, ScienceDirect, and Google Scholar, focusing on studies addressing inflammatory signaling, oxidative imbalance, inflammasome activation, neurotransmitter dysfunction, and experimental modeling strategies. Current evidence suggests that LPS-induced neuroinflammation involves a dynamic interaction between peripheral immune signaling, mitochondrial dysfunction, redox imbalance, and glial activation, establishing self-amplifying mechanisms capable of sustaining chronic inflammatory states. Such alterations profoundly affect kynurenine metabolism, glutamatergic homeostasis, and reward-related neurotransmission, thereby contributing to synaptic dysfunction and behavioral impairment. Experimental findings obtained from animal, cellular, and computational platforms further support the emergence of integrated therapeutic strategies targeting multiple neuroimmune pathways. Collectively, these observations reinforce the concept that neuroinflammation represents a central biological interface linking xenobiotic exposure to depressive-like behavior. Full article

Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular–kidney–metabolic (CKM) framework, as defined by the 2026 AHA/ACC/ADA/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit. Full article

ICU-acquired weakness (ICUAW) is a clinical condition characterized by muscle weakness in critically ill patients that is not directly attributable to the underlying illness. It affects approximately 40% of intensive care unit patients, primarily impairing the limbs and respiratory muscles, and can compromise motor and respiratory function even after recovery from acute illness. ICUAW exhibits heterogeneous phenotypes. In addition, diverse risk factors influence its occurrence. Although this condition is recognized, the underlying mechanisms contributing to critical illness-associated muscle dysfunction remain poorly understood and are likely interrelated. This review summarizes the current experimental evidence from translational studies involving diverse muscle biopsies under various conditions, providing insights into normal skeletal muscle physiology and its alterations in critical illness-associated muscle dysfunction. Here, we focus on muscle ultrastructure, mitochondrial function, atrophy, protein breakdown, inflammation, and key molecular pathways, with consideration of the proposed role of NLRP3 inflammasome signalling, for which direct experimental evidence in human skeletal muscle during critical illness remains limited and constitutes a priority area for future mechanistic research. Full article

NLRP6 is a member of the NOD-like receptor family that was initially characterized as an inflammasome-forming sensor in the intestine. However, accumulating evidence over the past decade has revealed that the functions of NLRP6 extend far beyond this canonical role. NLRP6 operates in a wide range of tissues, including the intestine, liver, lung, and immune system, where it exerts context-dependent effects that can be either protective or detrimental. In the intestine, NLRP6 is most consistently associated with host protection, contributing to antiviral defense, epithelial barrier integrity, and the maintenance of microbial and metabolic homeostasis through both inflammasome-dependent and -independent mechanisms. In contrast, in systemic infection models and in certain inflammatory settings, NLRP6 can also promote pathology by suppressing NF-κB signaling; inducing IL-18–mediated lymphocyte death, or enhancing inflammatory cell death pathways. Moreover, studies using both conventional and tissue-specific knockout models have highlighted the importance of the gut–organ axis; particularly the gut–liver axis, in shaping NLRP6-dependent disease outcomes. Here, we summarize recent advances in understanding the upstream regulation, downstream signaling, and tissue-specific functions of NLRP6. Full article

Beyond their established role in lipid digestion, bile acids function as key metabolic and immune signaling molecules. This review synthesizes recent advances in bile acid metabolism within the context of gout and hyperuricemia, proposing a gut–liver–joint crosstalk framework. Dysregulated bile acid metabolism—characterized by a reduced total bile acid pool, decreased hydrophobic secondary bile acids, elevated 12α-hydroxy bile acids, and impaired enterohepatic circulation—has been mechanistically linked to both hepatic urate overproduction via the PPAR-α/xanthine oxidase pathway and monosodium urate crystal-induced NLRP3 inflammasome activation, although human causal evidence remains to be established. The nuclear receptor FXR suppresses NLRP3 at the transcriptional level, while the membrane receptor TGR5 acts post-translationally through Cyclic adenosine monophosphate/Protein Kinase A (cAMP/PKA) and Glucagon-like peptide-1 (GLP-1) signaling. Gut microbiota dysbiosis amplifies these abnormalities through a vicious cycle of reduced bile acid signaling, increased intestinal permeability, and systemic endotoxemia. Based on these insights, we summarize five therapeutic strategies: FXR modulators, TGR5 agonists, microbiota-based interventions, natural products, and ursodeoxycholic acid replacement therapy. Future research should prioritize gout-specific preclinical models, clinical trials of TGR5 agonists, standardized microbiota-based therapies, dual-target molecules, and personalized patient stratification based on bile acid profiles. Full article

Aging is the dominant risk factor for most chronic diseases, yet the mechanisms driving this relationship remain poorly integrated across biological scales. Existing frameworks have catalogued key hallmarks of aging but do not explain how these processes converge to produce organism-level decline and multimorbidity. A systems-level framework is introduced in which aging is conceptualized as progressive destabilization of interacting regulatory networks. Mitochondrial quality control, nutrient-sensing pathways, and chronic inflammatory signaling form a putative high-centrality network core: mitochondria coordinate redox balance, bioenergetics, and transcriptional adaptation, while NAD⁺-dependent signaling and NLRP3 inflammasome activation propagate perturbations across regulatory layers. This architecture provides a mechanistic basis for the convergence of neurodegenerative, cardiovascular, metabolic, and oncological phenotypes as emergent consequences of shared network instability. Reframing the hallmarks as coupled network nodes shifts the explanatory focus from isolated mechanisms to system-level resilience and non-linear dynamics. This narrative and conceptual review integrates evidence across mitochondrial biology, metabolic signaling, and inflammatory pathways to develop these arguments, with explicit acknowledgment that the proposed framework is hypothesis-generating rather than formally validated. Interventions targeting high-centrality nodes, including mTOR modulation, NAD⁺ restoration, mitophagy activation, and anti-inflammatory strategies, may exert system-wide effects by reconfiguring network dynamics rather than correcting individual pathways. This perspective suggests that biomarker-stratified, network-calibrated interventions may offer a broader systems-level therapeutic rationale than single-pathway approaches. Full article

Sugarcane polyphenols (SP) are investigated for their antidepressant potential using a CUMS-induced mouse model and a corticosterone-induced neuronal injury cell model. Results demonstrate that SP alleviates depressive-like behaviors, inhibits hippocampal neuronal apoptosis, and reduces neuroinflammation. Mechanistically, SP activates the MAPK/ERK pathway, which in turn suppresses NLRP3 inflammasome-mediated pyroptosis; this effect is attenuated by the MAPK/ERK inhibitor PD98059. Furthermore, SP synergizes with the caspase-1 inhibitor VX-765 to inhibit pyroptosis. Full article

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and progressive organ dysfunction. Although early antimicrobial therapy, source control, hemodynamic resuscitation, and organ support remain the foundations of care, these approaches do not directly reverse the cellular mechanisms that connect systemic inflammation to multi-organ failure. Mitochondrial dysfunction has emerged as a central mechanism linking impaired oxygen utilization, oxidative and nitrosative stress, immune-cell metabolic reprogramming, inflammatory amplification, and organ injury. During sepsis, inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium dysregulation, and metabolic stress converge on mitochondria, impairing oxidative phosphorylation and promoting mitochondrial reactive oxygen species/reactive nitrogen species (ROS/RNS) generation. When mitochondrial quality-control programs, including fission, fusion, mitophagy, and mitochondrial biogenesis, fail to restore network integrity, damaged mitochondria accumulate and become persistent sources of oxidative stress and danger signals. Mitochondrial damage-associated molecular patterns, particularly mitochondrial DNA, oxidized mitochondrial DNA, cardiolipin, ATP, and N-formyl peptides, activate innate immune pathways such as TLR9-MyD88-NF-kappaB, the NLRP3 inflammasome, and cGAS-STING signaling. In parallel, mitochondrial metabolism shapes macrophage activation, neutrophil function, T-cell competence, pyruvate-lactate handling through the pyruvate dehydrogenase complex, and the transition between hyperinflammation and immunosuppression. Clinical translation remains challenging because sepsis is biologically heterogeneous and mitochondrial dysfunction is dynamic, tissue-specific, and influenced by disease stage. This review synthesizes current knowledge on mitochondrial dysfunction in sepsis, emphasizing oxidative and nitrosative stress, mitochondrial quality control, mitochondrial damage-associated molecular pattern (DAMP) signaling, immunometabolism, organ-specific injury, candidate biomarkers, clinical translational strategies for mitochondria-targeted therapy, and future approaches based on multi-omics and artificial intelligence-assisted patient stratification. We argue that future therapeutic development should move beyond nonspecific antioxidant supplementation toward time-sensitive, phenotype-informed, and biomarker-guided mitochondrial medicine. Full article

Background/Objectives: Glucocorticoid therapy remains clinically indispensable, yet its long-term use is profoundly constrained by insulin resistance (IR), hepatic steatosis, and progressive metabolic dysfunction. Methylsulfonylmethane (MSM), a naturally occurring sulfur-containing nutraceutical with established antioxidant and anti-inflammatory activities, has emerged as a promising metabolic modulator; however, its therapeutic relevance in glucocorticoid-induced hepatic IR has not previously been explored. Methods: Male Wistar rats received MSM (200 or 400 mg/kg/day, p.o.) for 14 days, while dexamethasone (DEX) (8 mg/kg/day, i.p.) was administered during the final 7 days to induce severe metabolic dysfunction. Results: DEX provoked profound IR, dyslipidemia, oxidative stress, hepatocellular injury, and steatotic degeneration accompanied by marked ultrastructural abnormalities. Remarkably, MSM conferred dose-dependent metabolic and hepatoprotective effects, significantly restoring glucose homeostasis, insulin responsiveness, lipid metabolism, and hepatic structural integrity. Mechanistically, MSM exerted a pleiotropic regulatory effect through suppression of the glucocorticoid-responsive kinase SGK1, restoration of AMPK/mTOR signaling balance, and normalization of insulin signaling pathways and metabolic transcriptional regulators. Furthermore, MSM effectively attenuated oxidative stress and inflammatory amplification consistent with modulation of the NLRP3/NF-κB/IL-6 axis. Importantly, the current work identifies angiogenic remodeling demonstrated by DEX-induced upregulation of VEGF and CD34, both of which were substantially suppressed by MSM treatment. Conclusions: This study provides novel evidence that MSM mitigates glucocorticoid-induced hepatic IR through coordinated modulation of glucocorticoid-responsive kinases, metabolic signaling networks, redox–inflammatory cascades, and pathological angiogenesis. Consequently, MSM may represent a promising candidate for further preclinical and clinical evaluation regarding its capacity to limit glucocorticoid-associated metabolic burdens. Full article

Cold seawater immersion is a critical lethal risk in maritime accidents and military operations, frequently inducing fatal myocardial dysfunction. However, the mechanisms underlying this seawater immersion hypothermia-induced cardiac injury remain poorly defined. This study aimed to elucidate the pathological progression and underlying mechanisms of myocardial injury induced by cold seawater immersion. A male SD rat model was immersed in 15 °C seawater for 2 h. Echocardiography, transmission electron microscopy, transcriptomics, and Western blot were performed to assess cardiac function, mitochondrial ultrastructure, and molecular mechanisms. Cold stress triggered progressive bradycardia (~480 to ~100 bpm) with initial Frank–Starling compensation, followed by decompensation with reduced cardiac output and impaired diastolic function. Mitochondrial ultrastructural damage preceded histological lesions and was accompanied by elevated cardiac injury markers (cTnT, CK-MB, BNP). Cardiac tissue exhibited upregulated TNF-α, IL-1β, and IL-6, while transcriptomic analysis revealed enrichment of inflammatory pathways (TNF, NF-κB) and coordinated upregulation of pattern recognition receptors including scavenger receptor, Toll-like receptor, and NOD-like receptor families. The Western blot confirmed NF-κB activation, NLRP3 inflammasome assembly, and the N-terminal fragment of gasdermin D (GSDMD-NT) accumulation, indicating pyroptotic cell death. These findings demonstrate that cold seawater stress disrupts mitochondrial homeostasis and activates the NF-κB/NLRP3/pyroptosis cascade, contributing to inflammatory cardiomyocyte death and cardiac decompensation. This mechanistic insight may inform therapeutic strategies for seawater immersion hypothermia. Full article

Epilepsy is a chronic neurological disorder prevalent worldwide, characterized by recurrent episodes of epileptic seizures. The primary current treatment approach is pharmacological, aimed at reducing the intensity and frequency of seizures, though it does not provide a cure. Neuroinflammation plays a central role in epilepsy by activating glial cells and stimulating the release of inflammatory mediators, further disrupting the balance between excitation and inhibition, thereby promoting the onset and recurrence of seizures. Furthermore, persistent inflammatory processes induce synaptic remodeling and the formation of dysfunctional neural circuits, establishing a pathological cycle in which inflammation and epileptic activity feed into each other. In this regard, natural products represent an important avenue for the discovery of new treatments. Thus, this review aimed to relate the role of the main inflammatory targets (Inflammasome/NLRP3, NF-κB, MAPK, mTOR, COX-2/PGE2, and TLR4/HMGB1) to epilepsy and to investigate in the literature natural products acting through these pathways in the treatment of epileptic seizures. Consequently, inflammatory pathways have emerged as critical targets in epilepsy, highlighting the importance of strategies capable of modulating neuroinflammatory processes. In this context, natural products stand out as promising therapeutic alternatives, given their multitarget mechanisms of action, potential to attenuate neuroinflammation and neuronal hyperexcitability. Full article

Dysregulated activation of the NLRP3 inflammasome is a key driver in the pathogenesis of numerous inflammatory disorders. This study aimed to evaluate the protective effect of Platycodon grandiflorus polysaccharide (PGPS_t) against NLRP3-inflammasome-mediated inflammation and elucidate its underlying mechanisms. An in vitro inflammatory model was established in porcine alveolar macrophages (3D4/21) using LPS/ATP co-stimulation. The effects of PGPS_t were assessed by measuring inflammasome activation, intracellular reactive oxygen species (ROS) generation, and pro-inflammatory cytokine secretion. Molecular docking, alongside inhibitors (NAC, MCC950) and siRNA targeting NEK7, was employed to probe the involved mechanisms. PGPS_t significantly suppressed NLRP3 inflammasome assembly and activation, reduced caspase-1 cleavage, and decreased the maturation and release of IL-1β and IL-18. It exerted its inhibitory effects through dual mechanisms: scavenging intracellular ROS and directly binding to NEK7 and NLRP3 to disrupt their interaction, as supported by molecular docking. The anti-inflammatory effect was diminished upon NEK7 knockdown. In conclusion, PGPS_t is an effective natural inhibitor of the NLRP3 inflammasome, functioning through ROS clearance and direct interference with the NLRP3–NEK7 interaction. These findings propose PGPS_t as a promising therapeutic candidate and further validate NEK7 as a potential target for treating NLRP3-driven inflammatory diseases. Full article

Background: The NLRP3 inflammasome is a key driver of obesity-associated chronic low-grade inflammation, contributing to hypothalamic neuroinflammation and disruption of energy homeostasis. Quercetin, a bioactive flavonoid, has been proposed as a modulator of inflammatory and metabolic pathways, including the fat mass and obesity-associated gene (FTO). Objective: This study evaluated the effects of quercetin on hypothalamic mRNA expression of Fto and components of the TNF-α/NF-κB/NLRP3 pathway. Methodology: In a high-fat diet (HFD)-induced obesity model, male Wistar rats (n = 18) were divided into three groups: standard diet (SD), HFD, and HFD + Q (supplemented with quercetin 50 mg/kg/day for 12 weeks). Gene expression was analyzed by quantitative PCR using the 2^−ΔΔCt method. Results: HFD significantly increased the expression of Fto and pro-inflammatory genes, including Tnf, Nlrp3, Casp1, Il1b, and Il18. Quercetin supplementation attenuated this upregulation, restoring expression levels toward baseline. Conclusions: These findings indicate that quercetin reduces hypothalamic neuroinflammation and modulates Fto expression, likely through inhibition of NF-κB signaling and suppression of NLRP3 inflammasome activation. Quercetin may represent a potential molecular modulator of obesity-associated neuroinflammatory processes. Full article