Search Results (577)

Curcumin, a polyphenolic compound derived from Curcuma longa, has drawn significant attention for its pleiotropic pharmacological activities, including anti-inflammatory and anticancer effects. Pyroptosis, an inflammatory form of programmed cell death mediated by inflammasome activation and gasdermin cleavage, has emerged as a critical target in both chronic inflammatory diseases and cancer therapy. This review comprehensively explores the dual roles of curcumin in the regulation of NLRP3 inflammasome-mediated pyroptosis. Curcumin exerts inhibitory effects by suppressing NF-κB signaling, attenuating mitochondrial reactive oxygen species (ROS) and ER stress, preventing potassium efflux, and disrupting inflammasome complex assembly. Conversely, in certain cancer contexts, curcumin promotes pyroptosis by stabilizing NLRP3 through the inhibition of Smurf2-mediated ubiquitination. Molecular docking studies support curcumin’s direct binding to several pyroptosis-associated proteins, including NLRP3, AMPK, caspase-1, and Smurf2. These context-dependent regulatory effects underscore the therapeutic potential of curcumin as both an inflammasome suppressor in inflammatory diseases and a pyroptosis inducer in cancer. Full article

Status epilepticus occurs when a seizure lasts more than five minutes or when multiple seizures occur with incomplete return to baseline. SE induces a myriad of pathological changes involving synaptic and extra-synaptic factors. The transition from a self-limiting seizure to a self-sustaining one is established by maladaptive receptor trafficking, whereby GABA_A receptors are progressively endocytosed while glutamatergic receptors (NMDA and AMPA) are transported to the synaptic membrane, causing excitotoxicity and alteration in glutamate-dependent downstream signaling. The subsequent influx of Ca²⁺ exposes neurons to increased levels of [Ca²⁺]i, which overwhelms mitochondrial buffering, resulting in irreversible mitochondrial membrane depolarization and mitochondrial injury. Oxidative stress resulting from mitochondrial leakage and increased production of reactive oxygen species activates the inflammasome and induces a damage-associated molecular pattern. Neuroinflammation perpetuates oxidative stress and exacerbates mitochondrial injury, thereby jeopardizing mitochondrial energy supply in a state of accelerated ATP consumption. Additionally, Ca²⁺ overload can directly damage neurons by activating enzymes involved in the breakdown of proteins, phospholipids, and nucleic acids. The cumulative effect of these effector pathways is neuronal injury and neuronal death. Surviving neurons undergo long-term alterations that serve as a substrate for epileptogenesis. This review highlights the multifaceted mechanisms underlying SE self-sustainability, pharmacoresistance, and subsequent epileptogenesis. Full article

Cardiorenal syndrome (CRS) is a multifactorial clinical condition characterized by the bidirectional deterioration of cardiac and renal function, driven by mechanisms such as renin–angiotensin–aldosterone system (RAAS) overactivation, systemic inflammation, oxidative stress, endothelial dysfunction, and fibrosis. The aim of this narrative review is to explore the key molecular pathways involved in CRS and to highlight emerging therapeutic approaches, with a special emphasis on nutritional interventions. We examined recent evidence on the contribution of mitochondrial dysfunction, uremic toxins, and immune activation to CRS progression and assessed the role of dietary and micronutrient factors. Results indicate that a high dietary intake of sodium, phosphorus additives, and processed foods is associated with volume overload, vascular damage, and inflammation, whereas deficiencies in potassium, magnesium, and vitamin D correlate with worse clinical outcomes. Anti-inflammatory and antioxidant bioactives, such as omega-3 PUFAs, curcumin, and anthocyanins from maqui, demonstrate potential to modulate key CRS mechanisms, including the nuclear factor kappa B (NF-κB) pathway and the NLRP3 inflammasome. Gene therapy approaches targeting endothelial nitric oxide synthase (eNOS) and transforming growth factor-beta (TGF-β) signaling are also discussed. An integrative approach combining pharmacological RAAS modulation with personalized medical nutrition therapy and anti-inflammatory nutrients may offer a promising strategy to prevent or delay CRS progression and improve patient outcomes. Full article

Neuroinflammation, driven by activated microglia, contributes to the progression of neurodegenerative diseases. Extracellular vesicles mediate intercellular communication and influence immune responses. Chrysin, a natural flavone found in fruits and propolis, has demonstrated anti-inflammatory effects. This study explored the immunomodulatory potential of chrysin-loaded EVs (EVs-Chry) derived from BV2 microglial cells. BV2 cells were treated with chrysin for 24 h to assess cytotoxicity and proliferation. EVs were isolated from treated and untreated cells, characterized by nanoparticle tracking analysis, and applied to naïve BV2 cells prior to LPS stimulation. Effects on cell morphology, migration, cytokine expression (IL-1β, IL-6), inflammasome activity (caspase-1), and apoptosis-related protein Bcl-xL were investigated. Our results show that EVs-Chry significantly reduced LPS-induced cell proliferation, restored resting microglial morphology, and reduced migratory capacity. Furthermore, co-treatment with EVs-Chry and LPS reduced pro-inflammatory cytokines such as IL-1β, IL-6, and caspase-1 expression while enhancing anti-apoptotic Bcl-xL levels, indicating a shift toward an anti-inflammatory, neuroprotective micro-glial phenotype. Together, our results demonstrated that EVs-Chry have neuroprotective effects on LPS-induced microglial activation and modulate microglial responses to inflammatory stimuli, attenuating pro-inflammatory signaling and promoting cellular homeostasis. These findings support the therapeutic potential of EVs-Chry in the context of neuroinflammatory and neurodegenerative disorders. Full article

Over the past four decades, cardioprotective research has revealed an extraordinary complexity of cellular and molecular mechanisms capable of mitigating ischemia/reperfusion injury (IRI). Among these, ischemic conditioning has emerged as one of the most influential discoveries: brief episodes of ischemia followed by reperfusion activate protective programs that reduce myocardial damage. These effects can be elicited locally (pre- or postconditioning) or remotely (remote conditioning), acting mainly through paracrine signaling and mitochondria-linked kinase pathways, with both early and delayed windows of protection. We have contributed to clarifying the roles of mitochondria, oxidative stress, prosurvival kinases, connexins, extracellular vesicles, and sterile inflammation, particularly via activation of the NLRP3 inflammasome. Despite robust preclinical evidence, clinical translation of these approaches has remained disappointing. The challenges largely stem from experimental models that poorly reflect real-world clinical settings—such as advanced age, comorbidities, and multidrug therapy—as well as the reliance on surrogate endpoints that do not reliably predict clinical outcomes. Nevertheless, interest in multi-target protective strategies remains strong. New lines of investigation are focusing on emerging mediators—such as gasotransmitters, extracellular vesicles, and endogenous peptides—as well as targeted modulation of inflammatory responses. Future perspectives point toward personalized cardioprotection tailored to patient metabolic and immune profiles, with special attention to high-risk populations in whom IRI continues to represent a major clinical challenge. Full article

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, with increasing evidence suggesting that their origins may lie in prenatal life. Endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), have been implicated in the alteration of fetal programming mechanisms that cause a predisposition to long-term cardiovascular vulnerability. However, the impact of prenatal endocrine disruption on fetal heart development and its sex-specific nature remains incompletely understood. This study investigates the molecular and structural effects of low-dose prenatal BPA exposure on fetal rat hearts. Our results reveal that BPA disrupts estrogen receptor (ER) signaling in a sex-dependent manner, with distinct alterations in ERα, ERβ, and GPER expression. BPA exposure also triggers significant inflammation, oxidative stress, and ferroptosis; this is evidenced by elevated NF-κB, IL-1β, TNF-α, and NLRP3 inflammasome activation, as well as impaired antioxidant defenses (SOD1, SOD2, CAT, and SELENOT), increased lipid peroxidation (MDA) and protein oxidation, decreased GPX4, and increased ACSL4 levels. These alterations are accompanied by increased markers of cardiac distension (ANP, BNP), extracellular matrix remodeling mediators, and pro-fibrotic regulators (Col1A1, Col3A1, TGF-β, and CTGF), with a more pronounced response in males. Histological analyses corroborated these molecular findings, revealing structural alterations as well as glycogen depletion in male fetal hearts, consistent with altered cardiac morphogenesis and metabolic stress. These effects were milder in females, reinforcing the notion of sex-specific vulnerability. Moreover, prenatal BPA exposure affected myocardial fiber architecture and vascular remodeling in a sex-dependent manner, as evidenced by reduced expression of desmin alongside increased levels of CD34 and Ki67. Overall, our findings provide novel insights into the crucial role of prenatal endocrine disruption during fetal heart development and its contribution to the early origins of CVD, underscoring the urgent need for targeted preventive strategies and further research into the functional impact of BPA-induced alterations on postnatal cardiac function and long-term disease susceptibility. Full article

Background/Objectives: Rheumatoid arthritis (RA) is a chronic, systemic, and progressive autoimmune–inflammatory disease primarily affecting small joints. Inonotus obliquus polysaccharide (IOP) is the main component of the parasitic fungus obliquus, which has anti-tumor, anti-inflammatory, and antioxidant effects. However, whether IOP has a therapeutic effect on RA is still unclear. Thus, this study aimed to reveal the effect of IOP on MH7A cells and collagen-induced arthritis (CIA) rats and to investigate the molecular mechanism of IOP in RA. Methods: In this study, network pharmacology was used to identify the key signaling pathways in IOP treatment of RA. The effect of IOP was verified in rats with CIA. We performed CCK-8, EdU, colony formation assay, cell apoptosis, cell migration and invasion, Western blot analysis, and immunofluorescence to elucidate the effect of IOP on the proliferation, apoptosis, migration and invasion of MH7A cells and revealed its modulation of the NF-κB and NLRP3 inflammasome signaling pathways. Results: IOP treatment of CIA rats significantly alleviated joint swelling, synovial tissue proliferation and erosion, and reduced the expression of inflammatory factors TNF-α, IL-6, IL-1β and IL-18. In vitro, IOP significantly inhibited the proliferation, migration, and invasion abilities of TNF-α-stimulated MH7A cells and promoted their apoptosis. Mechanistically, IOP inhibited the NF-κB and NLRP3 inflammasome activation. Conclusions: This study revealed that IOP exerts anti-RA effects by downregulating the NF-κB and NLRP3 inflammasome signaling pathways, promoting cell apoptosis, and inhibiting the expression of inflammatory cytokines, representing a promising therapeutic option for RA. Full article

Background: An acute angle-closure attack (AAC) is an ocular emergency that results from a rapid increase in intraocular pressure (IOP). Sustained IOP elevation induces severe degeneration of retinal ganglion cells (RGCs) without treatment. Overactivated microglia, key participants in innate immune responses, have critical roles in the pathogenesis of IOP-induced RGC death, although precise mechanisms remain unclear. In the present study, we used a rat ex vivo acute glaucoma model to investigate the role of microglial signaling in RGC death and examined whether pharmacological depletion of microglia using a CSF-1R inhibitor, PLX5622, exerts neuroprotection against pressure-induced retinal injury. Methods: Ex vivo rat retinas were exposed to hydrostatic pressure (10 mmHg or 75 mmHg) for 24 h. Pressure-dependent changes in retinal microglia and RGCs were detected by immunofluorescence. Morphological changes in the retina and RGC apoptosis were examined using light microscopy and TUNEL staining, respectively. The expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β were examined using Western blotting. Effects of PLX5622, an agent that depletes microglia, were examined in morphology, apoptosis, and protein expression assays, while TAK-242, a TLR4 inhibitor, was examined against protein expression. Results: Pressure loading at 75 mmHg markedly increased activated microglia and apoptotic RGCs in the isolated retinas. Western blotting revealed increases in expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg compared to 10 mmHg. Inhibition of pressure-induced increases in NLRP3 by TAK-242 indicates that pressure elevation induces RGC death via activation of the TLR4–NLRP3 inflammasome cascade. PLX5622 depleted microglia at 75 mmHg and significantly decreased expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg, resulting in preservation of RGCs. Conclusions: These results indicate that pressure elevation induces proliferation of inflammatory microglia and promotes IL-1β production via activation of the TLR4–NLRP3 inflammasome cascade, resulting in RGC death. Pharmacological depletion of microglia with PLX5622 could be a potential neuroprotective approach to preserve RGCs from inflammatory cytokines in AAC eyes. Full article

The COVID-19-related long-standing effect or Post-Acute Sequelae of COVID-19 (PASC) is often associated with NLRP3 inflammasome activation in pulmonary inflammation elicited by SARS-CoV-2 spike proteins. Spike proteins engage toll-like receptors (TLRs) in respiratory epithelial cells, leading to excessive cytokine production. Given the need for effective therapeutic strategies to mitigate spike protein-stimulated lung inflammation, we examined the anti-inflammatory properties of luteolin and ethanolic extract from Harrisonia perforata (Blanco) Merr. root. The ethanolic extract of H. perforata root (HPEE) contained a high concentration of luteolin flavonoid (143.53 ± 1.58 mg/g extract). Both HPEE (25–100 μg/mL) and luteolin (4.5–36 μM) significantly inhibited inflammation stimulated by the Wuhan (W) and Omicron (O) spike protein S1, as evidenced by a dose-dependent significant decrease in IL-6, IL-1β, and IL-18 secretion in A549 lung epithelial cells (p < 0.05). Furthermore, pretreatment with HPEE or luteolin prior to spike protein exposure (100 ng/mL) significantly, in a dose-dependent manner, repressed the inflammatory mRNA expression (p < 0.05). Mechanistic study revealed that HPEE and luteolin suppressed NLRP3 inflammasome signaling activation by reducing their machinery protein expressions. Additionally, they inhibited the ERK/JNK/p38 MAPK signaling activation, resulting in decreased inflammatory mRNA expression and cytokine release. These findings suggest that H. perforata root extract and its major flavonoid luteolin exert potent anti-inflammatory effects and may offer therapeutic potential against spike protein-induced lung inflammation. Full article

Ultraviolet (UV) radiation stimulates melanogenesis, leading to various esthetic problems. UV increases oxidative stress and nuclear factor-kappa B (NF-κB), which increase the nucleotide-binding oligomerization domain (NOD) or leucine-rich repeat and pyrin do-main containing 3 (NLRP3) inflammasome. Given that polydeoxyribonucleotides reduce melanogenesis and polynucleotide (PN) has molecular similarity to polydeoxyribonucleotides, we hypothesized that PN can decrease melanogenesis. We compared the anti-melanogenic effect of PN with that of a PN mixture (PNM) that contained other antioxidants, such as glutathione and hyaluronic acid, in UVB-irradiated keratinocytes and animal skin. PN and PNM both decreased oxidative stress, which was evaluated according to the expression of NADPH oxidase (NOX) 1/2/4, the glutathione (GSH):oxidized glutathione (GSSG) ratio, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in UVB-irradiated keratinocytes. The expression of NLRP3 inflammasome components (NLRP3, ASC, and pro-caspase-1) and IL-18 was increased by UVB radiation and reduced by PN and PNM. When conditioned media from PN or PNM were administered to UVB-radiated keratinocytes, melanogenesis-related signals (MITF, tyrosinase, and tyrosinase-related protein1/2) were decreased. These effects were similar in the UVB-irradiated animal skin. Both PN and PNM decreased melanin accumulation and increased skin lightness in UVB-irradiated skin. The anti-melanogenic effect of PNM was greater than that of PN. In conclusion, PN and PNM decreased melanogenesis by decreasing oxidative stress, NF-κB, and NLRP3 inflammasome activation. Full article

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, with complex pathophysiological mechanisms. As an important post-translational modification, protein ubiquitination exhibits multiple non-traditional functions in sepsis beyond its conventional role in protein degradation. Regulating the network of inflammatory cytokines, the dynamic balance of immune cells and organ-specific protective pathways is deeply involved in the pathological process of sepsis. This review focuses on the unconventional roles of protein ubiquitination in sepsis, including its regulation of the inflammatory response, immune cell functions, and organ protection. It systematically summarizes the regulatory mechanisms of ubiquitination in the non-degradative activation of the nuclear factor kappa B (NF-κB) signaling pathway, the dynamic assembly of the NLRP3 inflammasome, the reprogramming of macrophage polarization, and the injuries of organs such as the heart, liver, and lungs. These processes demonstrate that ubiquitination serves as a pivotal nexus between immunological dysregulation and multi-organ impairment in sepsis. This review suggests that targeting non-degradative ubiquitination alterations may provide viable therapeutic options to mitigate excessive inflammation and organ failure in sepsis. Full article

The objective of this study was to formulate a compound suspension comprising paeoniflorin and curcumin, assess its quality characteristics, and investigate its protective efficacy against acute liver injury in mice. The prescriptions were screened using a single-factor test, and nine groups of suspensions were prepared using the dispersion method. Fifty KM mice (four weeks old) were selected and randomly divided into five groups: the CON, LD, PF, CUR, and PC groups. The doses of both paeoniflorin and curcumin were 100 mg/kg BW, and different suspensions were given to different groups by gavage for 14 days. All the groups except the CON group were injected intraperitoneally with 20 μg/kg LPS and 700 mg/kg D-GalN on the last day. According to the results, the suspension prepared using the optimal prescriptions was orange-yellow in color, with homogeneous turbidity and good re-dispersibility. The combination treatment could reduce the severity of pathological injuries of liver, improve the ultrastructure of hepatocytes, increase the activities of T-SOD, GSH-Px, and CAT, decrease the levels of IFN-γ, TNF-α, and IL-1, and down-regulate the expression of genes such as TLR4, MyD88, IκBα, and NLRP3. The underlying mechanism might be associated with the enhancement of antioxidant enzyme activities, inhibition of the TLR4/NF-κB/NLRP3 signaling pathway, and suppression of inflammasome assembly and release in hepatic tissues. Full article

Diabetes Mellitus (DM) is among the most common non-infectious causes of death globally, with Type 2 DM (T2DM) representing the majority of cases. T2DM is primarily characterized by insulin resistance, leading to hyperglycemia and compensatory hyperinsulinemia. Rapid changes in lifestyle, technological advancement, and societal evolution have fueled a global rise in T2DM, making it a major public health concern. The condition is associated with numerous complications—both macrovascular and microvascular—including coronary artery disease, heart failure, chronic kidney disease, and diabetic retinopathy, all of which contribute to increased morbidity and early mortality. Chronic tissue inflammation is now recognized as a key factor in the development of T2DM, with elevated inflammatory markers serving as predictors of the disease. In particular, the NLRP3 inflammasome complex has emerged as a central player in this inflammatory process. NLRP3 acts as an intracellular sensor for danger signals and tissue injury, triggering inflammatory responses and contributing to endothelial dysfunction and T2DM pathogenesis. Its role in linking metabolic stress to inflammation has positioned it as a promising therapeutic target. This review focuses on the mechanisms underlying NLRP3 inflammasome activation and its role in T2DM and related vascular complications. Additionally, it highlights emerging therapies that target NLRP3, offering new potential strategies for the prevention and treatment of T2DM. Full article

Circadian rhythms govern cellular metabolism, redox balance, and endocrine signaling in numerous tissues. However, chronic disturbance of these biological rhythms, mediated by modern lifestyle factors including shift work, sleep irregularity, and prolonged light exposure, has been increasingly associated with oxidative stress, metabolic dysregulation, and the pathogenesis of chronic diseases. This review discusses recent mechanistic advances that link circadian misalignment with tissue-specific metabolic reprogramming and impaired proteostasis, focusing on metabolic inflammation and associated pathologies. Emerging work reveals a close interdependence between the circadian clock and proteasome-mediated protein turnover and highlights this interplay’s importance in maintaining redox homeostasis. Furthermore, circadian modulation of the activity of the inflammasome complex is suggested to represent an important, but largely unexplored, risk factor in the pathobiology of both malignancy and metabolic syndrome. Recently, researchers have proposed them as novel endocrine regulators of systemic energy balance and inflammation, with a focus on their circadian regulation. In addition, the emerging domains of chrono-epigenetics and tissue-specific programming of the clock pathways may serve to usher in novel therapies through precision medicine. Moving ahead, circadian-based therapeutic approaches, including time-restricted feeding, chronopharmacology, and metabolic rewiring, have high potential for re-establishing physiological domain homeostasis linked to metabolic inflammation pathologies. Elucidating this reciprocal relationship between circadian biology and cellular stress pathways may one day facilitate the generation of precise interventions aiming to alleviate the health burden associated with circadian disruption. Full article

IFI16 is a well-characterized nuclear innate immune DNA sensor that detects foreign dsDNA, including herpesviral genomes, to activate the inflammasome and interferon pathways. Beyond immune signaling, IFI16 also functions as an antiviral restriction factor, promoting the silencing of invading viral genes through transcriptional and epigenetic mechanisms. We recently demonstrated another role of IFI16, in which it interacts with and recruits the class I histone deacetylases, HDAC1 and 2, to the KSHV latency protein LANA, modulating its acetylation and function. In this study, we asked whether these IFI16-HDAC1/2 interactions contribute to broader epigenetic regulation of the KSHV chromatin. Our findings reveal that IFI16 associates with and facilitates the recruitment of the NuRD and Sin3A co-repressor complexes—both multiprotein, HDAC1/2-containing chromatin regulators—on KSHV episomes. Depletion of IFI16 led to reductions in NuRD and Sin3A occupancy on viral chromatin, accompanied by increased histone acetylation at lytic gene promoters. These results suggest that IFI16 plays a critical role in recruiting or stabilizing these HDAC-containing co-repressor complexes on the KSHV genome, thereby enforcing transcriptional silencing of lytic genes and maintaining latency in KSHV. Our study expands the known functions of IFI16 and identifies a novel epigenetic mechanism by which it modulates herpesviral chromatin states. Full article