Search Results (395)

Atherosclerotic cardiovascular disease (ASCVD) is increasingly recognized not merely as a lipid-storage disorder but as a chronic, lipid-driven inflammatory condition of the arterial wall. Despite the widespread use of statins and other lipid-lowering therapies, a substantial “residual inflammatory risk” persists, propelling the search for targeted immunopharmacological interventions. At the forefront of this inflammatory cascade is the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which serves as a central orchestrator of vascular inflammation by linking metabolic dysregulation to the innate immune response. Atherogenic danger signals—such as oxidized low-density lipoprotein (ox-LDL) and cholesterol crystals—trigger NLRP3 activation through reactive oxygen species (ROS) generation, lysosomal rupture, and potassium efflux. This, in turn, drives the maturation of pro-inflammatory cytokines (IL-1β and IL-18) and initiates macrophage pyroptosis. In this review, we systematically evaluate the immunomodulatory potential of natural products—both complex extracts and single bioactive compounds—in inhibiting the NLRP3 inflammasome axis. We detail the pharmacological mechanisms by which these natural agents intercept inflammatory signaling at multiple stages: suppressing TLR4/NF-κB-mediated priming, scavenging mitochondrial ROS, and restoring autophagic flux via AMPK/mTOR pathways to prevent inflammasome assembly. By critically analyzing these pathways, we highlight natural product-derived inhibitors as a promising class of immunomodulators capable of attenuating atherosclerotic progression and addressing the persistent challenge of residual inflammatory risk. Full article

Particulate matter (PM) is a complex mixture of airborne solid particles and liquid droplets originating from various environmental sources, and it has been implicated in the initiation, development, and progression of pulmonary inflammation and respiratory diseases. However, the underlying associated molecular mechanisms remain unclear. Adenophora divaricate Franch. & Sav. (AD) is a medicinal herb classified within the Campanulaceae family and genus Adenophora, with a broad geographic distribution across East Asia, including Korea, Asia, and Russia. In this study, we investigated the mechanisms underlying the effects of AD on PM-induced lung inflammation in both PM-stimulated RAW264.7 cells and PM-exposed mice. Considering that the reactive oxygen species (ROS)-mediated thioredoxin-interacting protein (TXNIP) and NOD-like receptor pyrin domain containing (NLRP3) inflammasome pathway plays a role in PM-induced inflammatory responses, we focused on determining whether AD exerts its anti-inflammatory effects through modulation of this signaling pathway. The anti-inflammatory properties of the methanolic extract of AD were evaluated using PM-stimulated RAW264.7 cells and PM-exposed mice. PM was administered intranasally to mice for 7 days, whereas AD or dexamethasone was orally administered for the same duration. AD treatment significantly attenuated pulmonary inflammation, as evidenced by reduced inflammatory cell counts and decreased cytokine levels in bronchoalveolar lavage fluid. In addition, AD decreased oxidative stress marker (ROS and thiobarbituric acid reactive substances) while increasing glutathione content, leading to suppression of TXNIP/NLRP3 inflammasome expression. Histopathological analysis revealed a marked alleviation of inflammatory responses in lung tissue, characterized by diminished inflammatory cell infiltration and reduced alveolar wall thickening. Collectively, these findings suggest ROS-mediated TXNIP serves as a key regulatory factor, and AD may serve as a potential therapeutic agent for pulmonary inflammation. Full article

Intracranial atherosclerosis (ICAS) is a distinct, inflammation-dominant vasculopathy and a leading cause of global stroke morbidity. Unlike extracranial atherosclerosis (ECAS), which often utilizes compensatory positive remodeling to maintain patency, ICAS is characterized by a unique architecture and a localized antioxidant gap that favor maladaptive negative remodeling. We critically analyze the molecular cascade initiated by the breakdown of the Piezo-type mechanosensitive ion channel component 1 (PIEZO1) and the Krüppel-like factor 2/4 (KLF2/4) mechanotransduction axis, which triggers endothelial nitric oxide synthase (eNOS) uncoupling and establishes a state of chronic inflammation. This environment facilitates the subendothelial lipid retention of oxidized low-density lipoprotein (oxLDL), a process exacerbated by the intracranial deficiency of Apolipoprotein A-I (ApoA-I) and impaired glymphatic clearance. Crucially, we evaluate how these metabolic and mechanical insults drive vascular smooth muscle cell (VSMC) phenotypic switching; the transdifferentiation of contractile VSMCs into macrophage-like foam cells accounts for up to 60% of the plaque’s lipid-laden pool and destabilizes the fibrous cap. This vascular failure directly compromises the neurovascular unit (NVU), leading to pericyte dropout and blood–brain barrier breakdown. Beyond environmental stressors, we highlight the ring finger protein 213 (RNF213) variant as a critical genetic determinant of this susceptibility. Shifting the clinical paradigm from simple luminal narrowing toward the identification of the vulnerable plaque, we discuss how High-Resolution Vessel Wall Imaging (HR-VWI) and microRNA biomarkers can identify unstable lesions. By integrating these molecular and imaging signatures, we propose a precision medicine framework centered on the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the NVU to effectively mitigate the high residual recurrence risk that persists under conventional therapy. Full article

Myocardial ischemia–reperfusion injury (MIRI) significantly compromises the clinical benefits of revascularization and constitutes a central pathological mechanism worsening prognosis in myocardial infarction patients. Accordingly, dissecting the molecular mechanisms underlying MIRI and formulating effective therapeutic interventions are of great clinical significance. Lycium barbarum polysaccharide (LBP), the primary active constituent of Lycium barbarum, has garnered considerable attention in the prevention and treatment of cardiovascular diseases due to its anti-inflammatory, antioxidant, vasomotor function-improving, and antithrombotic properties. This study aims to investigate the ability of LBP to alleviate MIRI, with a specific focus on its role in modulating the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Myocardial ischemia/reperfusion (I/R) models in rats and hypoxia/reoxygenation (H/R) models in H9c2 cells were established. Myocardial injury and the therapeutic effect of LBP were evaluated by 2,3,5-Triphenyl tetrazolium chloride (TTC) staining, Hematoxylin-eosin (H&E) staining, Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) staining, and Enzyme-linked immunosorbent assay (ELISA). To elucidate the specific mechanism underlying LBP against MIRI, an Nrf2-overexpressing cell line was generated in H9c2 cells, and pharmacological inhibition of Nrf2 with ML385 was applied for complementary validation. The effects of LBP on H/R-induced oxidative stress, inflammatory response (IL-18, IL-1β), and pyroptosis-related protein expression (NLRP3, apoptosis associated speck-like protein containing a CARD (ASC), cysteine-dependent aspartate-specific proteases (caspase)-1, Gasdermin D (GSDMD)) were systematically evaluated. LBP administration conferred robust cardioprotection in I/R rats, as evidenced by a significant reduction in myocardial infarct size, improved preservation of myocardial fiber architecture, and attenuated leakage of cardiac injury biomarkers (lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB)). Mirroring these in vivo findings, LBP pretreatment effectively shielded H9c2 cardiomyocytes from H/R insult, markedly enhancing cell viability while curtailing reactive oxygen species (ROS) accumulation and apoptotic activation. A pivotal finding was the pronounced downregulation of Nrf2 in the H/R group, a deficit that was conclusively reversed by LBP treatment. To decisively establish a causal role for Nrf2, we employed a loss-of-function approach; Nrf2 inhibition completely abrogated the protective benefits of LBP, culminating in exacerbated tissue damage, a surge in ROS, and the upregulation of key pyroptosis effectors (NLRP3, ASC, caspase-1, GSDMD). Conversely, a complementary gain-of-function experiment demonstrated that Nrf2 overexpression alone was sufficient to mimic LBP’s effects, significantly blunting H/R-induced ROS production and pyroptosis. LBP alleviates MIRI by inhibiting pyroptosis through activating the Nrf2/NLRP3 axis, thus representing a promising therapeutic candidate for ischemic heart disease with the potential to improve patient outcomes. Full article

Ischemia and reperfusion (IR) injuries may produce deleterious effects on hepatic tissue after liver surgery and transplantation. The consequences of IR are more evident in pathological steatotic livers. Spirulina (Arthrospira platensis) is known for its potential to modulate inflammatory responses and enhance antioxidant defenses. The current investigation assessed whether spirulina pretreatment mitigates hepatic IR injury exacerbated by steatosis in rats. Thirty male Wistar rats were divided into five groups: sham, IR, HFD, HFD + IR, and SP1000 (HFD + IR + spirulina 1000 mg/kg/day; oral gavage). Liver injury, oxidative stress, inflammatory signaling, and inflammasome/pyroptosis-related markers were assessed using serum transaminases, hematoxylin–eosin staining, immunofluorescence, and qRT-PCR. High-fat diet-fed rats developed steatosis, which significantly worsened IR-induced liver damage, as shown by the respective steatosis histological score, the elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and higher expression of inflammatory markers, including Toll-like receptor (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) and inflammasome/pyroptosis-related transcripts, namely NOD-like receptor family pyrin domain-containing 3 (NLRP3), interleukin-18 (IL18), and gasdermin D (GSDMD). Oxidative stress was exacerbated, as reflected by higher levels of malondialdehyde (MDA) and reduced antioxidant defenses (superoxide dismutase (SOD) activity, reduced glutathione (GSH) content, glutathione peroxidase (GPx) expression, and heme oxygenase-1 (HO-1) expression). Furthermore, HFD + IR upregulated sterol regulatory element-binding protein-1c (SREBP-1c) expression and downregulated AMP-activated protein kinase (AMPK) expression. Spirulina supplementation significantly attenuated liver injury and transaminase release, reduced MDA, restored antioxidant parameters, downregulated inflammatory and inflammasome-related gene expression, and shifted both SREBP-1c and AMPK expressions toward control levels. Full article

Pyroptosis is a pro-inflammatory form of programmed cell death mediated by inflammasomes and caspases and has been implicated in various inflammatory diseases. However, its function and regulatory role in dairy cows with clinical mastitis (CM) remain poorly understood. This study was conducted to investigate the differentially expressed proteins (DEPs) involved in biological processes (BPs) and the Kyoto Encyclopedia of Genes and Genomes pathways related to inflammasome-mediated pyroptosis based on proteomic data and to further explore their potential involvement in mastitis using in vivo and in vitro models. Histopathological analysis revealed morphological features consistent with pyroptosis in the mammary glands of CM-affected cows, including mammary epithelial cell (MEC) membrane disruption, increased reactive oxygen species production, elevated TUNEL–gasdermin D (GSDMD)-positive staining, and inflammatory cell infiltration. Proteomic profiling identified 276 DEPs and 17 BPs, among which NOD-like receptor family pyrin domain-containing 3 (NLRP3) was identified as a key candidate associated with cytokine production, immune defense, and inflammatory responses. Pathway enrichment analysis indicated that NLRP3, caspase-1 (CASP1), and GSDMD were enriched in the NOD-like receptor signaling pathway and were closely associated with mastitis. Immunohistochemical and molecular analyses demonstrated cytoplasmic localization and significant upregulation of NLRP3, CASP1, and GSDMD at both the mRNA and protein levels in CM-affected tissues. In both in vitro and in vivo models, a dose-dependent increase in the expression of pyroptosis-related targets and pro-inflammatory cytokines was observed with the progression of inflammation. Moreover, the pharmacological inhibition of CASP1 attenuated pyroptosis-associated changes and inflammatory responses in BMECs. Collectively, these findings suggest that the NLRP3–CASP1 axis is associated with inflammation-related pyroptosis in bovine mastitis and may represent a potential therapeutic target for clinical mastitis. Full article

Objectives: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by MEFV mutations, leading to recurrent fever and inflammation. Dysregulation of innate and adaptive immunity, including altered expression of microRNAs and immune regulatory molecules, may contribute to disease heterogeneity. The role of CTLA-4, DTX1, and selected miRNAs in FMF pathogenesis remains unclear. Methods: We conducted a case–control study including 48 pediatric FMF patients and 36 age- and sex-matched healthy controls. Serum miR-204-3p and miR-223-3p levels were assessed via qRT-PCR. Plasma concentrations of pyrin, CTLA-4, and DTX1 were measured using ELISA. Clinical data and MEFV mutation types were analyzed in relation to biomarker levels. Results: There was no statistical significance between the groups in plasma CTLA-4 levels. Serum miR-204-3p, miR-223-3p, and plasma DTX1 levels were found to be significantly lower in FMF patients, while plasma pyrin levels (p < 0.05, in all) were significantly higher. CTLA-4 levels were positively correlated with pyrin and DTX1 levels (r = 0.602; p < 0.001; r = 0.740; p < 0.001, respectively). Conclusions: miR-204-3p and miR-223-3p may be associated with FMF pathogenesis. Increased levels of the pyrin protein, encoded by the MEFV gene, may have an important role in apoptotic and inflammatory signaling pathways. A decrease in DTX1 levels and a positive correlation between DTX1 and CTLA-4 suggest that subclinical inflammation may continue in attack-free periods in FMF patients. Full article

Systemic infection with Acanthamoeba spp. can induce inflammatory responses within the visual axis, yet the underlying molecular mechanisms in the optic nerve remain poorly understood. The aim of the study was to determine the gene expression of Nlrp3 (encoding NOD-, LRP- and pyrin domain-containing protein 3, NLRP3), Ptgs2 (encoding cyclooxygenase-2, COX-2), Rela (encoding nuclear factor kappa B, NF-κB), and several cytokines in the optic nerve of mice during disseminated infection with Acanthamoeba sp. (T16 genotype) under various immunological conditions. In immunocompetent mice, Ptgs2 and Ifng expressions were upregulated at the beginning of infection. In the late stages, we found increased levels of Il10 and Nlrp3. In immunosuppressed mice, higher expressions of Nlrp3, Ptgs2, Rela, Il1b, Il10, Il17a, Il21, and Ifng were found in the infected mice compared to the control group. These results indicate that immunosuppression promotes prolonged inflammation by altering innate and adaptive immune responses, contributing to sustained neuroinflammatory processes affecting the optic nerve. This study provides mechanistic insight into host–pathogen interactions in the optic nerve during systemic Acanthamoeba infection. Due to the analysis being based on mRNA expression levels, direct inference regarding protein levels and the actual activity of the investigated immunological pathways is limited. Full article

Bovine mastitis threatens the dairy industry with limited effective therapies. The selenoprotein family offers potential anti-inflammatory interventions, yet the role of Selenoprotein F (SELENOF) remains unclear. This study investigated SELENOF in mitochondrial damage and pyroptosis using clinical mammary biopsies and a Staphylococcus aureus-induced Mammary alveolar cell-type T (MAC-T) cell model. Histology, TEM, immunofluorescence, Western blot, qPCR, RNA-seq, and mitochondrial staining (MitoTracker Red and JC-1) were employed. Mastitic mammary tissue exhibited severe architectural disruption, including focal necrosis with coalescing vacuoles of variable size, extensive epithelial denudation, and interstitial thickening with dense inflammatory infiltrates. At the ultrastructural level, mitochondrial swelling, cristae loss, and plasma membrane rupture were evident. Additionally, these tissue specimens exhibited marked upregulation of inflammatory mediator transcripts, notably IL-1β, IL-6, and TNF-α, alongside heightened abundance of pyroptosis-associated proteins including NOD-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, and GSDMD-N (Gasdermin D N-terminal domain). RNA-seq identified SELENOF as significantly downregulated. The MAC-T model recapitulated the mitochondrial dysfunction, inflammatory response, and pyroptosis observed in mastitic tissue. SELENOF overexpression restored mitochondrial membrane potential, dampened the output of inflammatory signaling molecules, and suppressed NLRP3-mediated pyroptosis via attenuation of caspase-1/GSDMD-N pathway activation. These findings establish SELENOF as a novel target that mitigates bovine mastitis by preserving mitochondrial homeostasis and suppressing NLRP3-mediated pyroptosis. Full article

Purpose: To investigate the mechanisms by which plasma extracellular vesicles (EVs) from preterm infants with bronchopulmonary dysplasia (BPD) elicit inflammation and abnormal angiogenesis in neonatal mouse retinas. Methods: EVs from the plasma of 7-day-old preterm infants, born between 23^0/7 and 29^6/7 weeks of gestation, with BPD or without BPD (nBPD) at 36 weeks postmenstrual ages, were adoptively transferred into postnatal day 3 (P3) mice via intravenous retro-orbital sinus injection. Inflammation and pathological neovascularization in neonatal mouse retinas were examined by immunohistochemistry of retinal flat mounts for Allograft Inflammatory Factor 1 (AIF1), CD206, or Glial Fibrillary Acidic Protein (GFAP) and isolectin-B4 (IB4) staining on P17. Retinal inflammation-related transcripts were assessed by qRT-PCR. Proteomic profiles of BPD and nBPD EVs were examined by Liquid Chromatograph Mass Spectrometer/Mass Spectrometer (LC-MS/MS) and Gene Set Enrichment Analysis (GSEA). Results: Adoptively transferred EVs from BPD and nBPD infants crossed the blood–retinal barrier (BRB) in recipient mouse pups. BPD-EVs increased retinal activated microglia, Müller cells, and twisted proliferative neovascularization compared to nBPD-EVs. BPD-EVs also elevated retinal transcripts regulating inflammation and angiogenesis, including NOD-, LRR- and pyrin domain-containing protein 3 (Nlrp3), Apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc), Caspase 3 (Casp3), Caspase 8 (Casp8), Gasdermin D (Gsdmd), Il1β, Il6, Aif1, and Vascular endothelial growth factor (Vegf). Proteomics analysis revealed that BPD-EVs had significantly elevated levels of inflammation and angiogenesis-related proteins compared to nBPD-EVs. Conclusions: BPD-EVs promote inflammation and abnormal neovascularization by upregulating genes related to apoptosis and inflammation in neonatal mouse retinas. EV protein profiles suggest that elevated levels of proteins such as Defensin alpha 1B (DEFA1B), Insulin-like growth factor binding protein 2 (IGFBP2), CD5 antigen-like (CD5L), von Willebrand factor (vWF), and Tenascin C (TNC) in BPD-EVs may contribute to the observed inflammation and angiogenesis. Full article

Background and Objectives: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a key innate immune complex, and its aberrant activation contributes to metabolic and neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with anti-inflammatory and metabolic regulatory functions, but its role in NLRP3 inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis remains unclear. The aim of this study was to investigate the effects of BDNF deficiency on LPS- and nigericin-induced NLRP3 inflammasome activation and GSDMD-mediated pyroptosis in vivo, and to elucidate the involvement of NF-κB signaling, autophagy, and ESCRT-III-dependent plasma membrane repair in this process. Materials and Methods: In this in vivo study, male Bdnf ^+/+ and Bdnf ^+/− mice were subjected to lipopolysaccharide (LPS) plus nigericin-induced NLRP3 inflammasome activation. Serum and hippocampus, cortex, liver, epididymal adipose, and muscle tissues were collected 24 h after stimulation for analysis of inflammasome-related, autophagy-related, and membrane repair-related proteins by Western blotting and of serum BDNF, interleukin-1β (IL-1β), and interleukin-18 (IL-18) by ELISA. Results: Bdnf ^+/− mice displayed significantly reduced circulating BDNF levels and exhibited exaggerated LPS plus nigericin-induced increases in IL-1β and IL-18 compared with Bdnf ^+/+ mice. Across all tissues, BDNF deficiency enhanced NF-κB p65, NLRP3, active caspase-1 p20, and GSDMD expression, indicating amplified inflammasome activation and pyroptosis. Conversely, LC3B and SQSTM1/p62 levels were decreased, and VPS4A expression, a key component of the ESCRT-III membrane repair machinery, was suppressed in Bdnf ^+/− mice, suggesting impaired selective autophagy, autophagosome formation, and plasma membrane repair. Conclusions: Together, these findings indicate that BDNF restrains NLRP3 inflammasome activation and GSDMD-mediated pyroptosis through inhibition of NF-κB signaling and coordinated activation of autophagy and ESCRT-III-dependent membrane repair. BDNF thus emerges as an endogenous negative regulator of inflammasome activity and a potential therapeutic target for conditions characterized by aberrant NLRP3-driven inflammation. Full article

Painful diabetic neuropathy (PDN) is a prevalent and debilitating complication of diabetes, characterized by persistent neuropathic pain that severely impairs quality of life. Current management strategies predominantly target peripheral nerve dysfunction and offer only symptomatic relief, with no disease-modifying therapies available. Emerging evidence now underscores the critical role of central nervous system (CNS) glial cells—microglia, astrocytes, and oligodendrocytes, collectively termed the “glial triad”—in driving PDN pathogenesis. This review synthesizes recent advances elucidating how these glial cells contribute to neuroinflammation, metabolic dysregulation, and central sensitization. We detail specific mechanisms including microglial NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation and metabolic reprogramming, astrocytic aquaporin-4 (AQP4) polarity disruption impairing glymphatic function, and oligodendrocyte myelination deficits via Mammalian Target of Rapamycin (mTOR) signaling. Furthermore, we discuss the translational potential of glia-derived biomarkers (e.g., Translocator Protein (TSPO), Glial Fibrillary Acidic Protein (GFAP), myelin basic protein (MBP)) for early diagnosis and patient stratification. Finally, we highlight promising therapeutic avenues that target glial pathways, such as interleukin-35 (IL-35), β-hydroxybutyrate, and metformin, which aim to shift the treatment paradigm from symptomatic control to disease modification. By integrating preclinical and clinical insights, this review proposes the glial triad as a central player in PDN and suggests that targeted glial interventions may represent a promising frontier for future disease-modifying strategies. Full article

The innate immune system’s core sensor, the NLRP3 inflammasome (Nucleotide-binding Oligomerization Domain, Leucine-rich Repeat, and Pyrin Domain-Containing Protein 3), is a pivotal multi-protein complex that detects cellular danger and microbial threats. While its activation is fundamental for host defense, chronic dysregulation of NLRP3 is a central driver of pathology in diverse diseases, ranging from neurodegeneration to cancer. This review comprehensively examines the complex and often paradoxical roles of the NLRP3 inflammasome in these two distinct domains. In neurodegenerative disorders, including Alzheimer’s and Parkinson’s, aberrant NLRP3 activation drives persistent neuroinflammation, leading to synaptic dysfunction and neuronal loss through the sustained release of mature IL-1β and IL-18. Conversely, NLRP3 exhibits a striking bimodal role in oncology; it can promote tumorigenesis by fueling chronic inflammation, metastasis, and immune evasion in certain tumor microenvironments, yet simultaneously enhances anti-tumor immunity and pyroptotic cell death in other specific contexts. This context-dependent function highlights a critical therapeutic challenge. We delineate the shared molecular pathways, contrast disease-specific outcomes, and the current landscape of therapeutic strategies aimed at modulating NLRP3. Understanding the nuanced role of the inflammasome offers novel insights into the convergence of chronic inflammation, neurodegeneration, and tumor biology, and holds promise for the development of targeted, context-dependent therapies with dual clinical applications. Full article

Background: Cholestatic liver injury (CLI) is characterized by complex pathogenesis; however, oxidative stress-mediated inflammatory response due to bile acid accumulation in the liver is considered a primary cause. Cynarin (CN), an artichoke phytochemical, has demonstrated different biological activities, including antioxidant and anti-inflammatory ones. The current study aimed to explore the potential hepatoprotective effect of CN on CLI induced by alpha-naphthyl isothiocyanate (ANIT) in mice and investigate the possible involved mechanisms. Methods: Mice received CN (25 and 50 mg/kg) for four consecutive days and were challenged with ANIT (75 mg/kg) once on the second day. Liver injury was examined through biochemical determination of liver injury biomarkers and confirmed by histopathological evaluation. Oxidative stress biomarkers and pro-inflammatory cytokines were detected in the hepatic tissue. RT-PCR, Western blotting, and ELISA were applied to address gene and protein expression of potential underlying molecular targets, including thioredoxin-interacting protein (TXNIP), NLR family pyrin domain-containing 3 (NLRP3) inflammasome, and high-mobility group box 1 (HMGB1). Moreover, nuclear factor kappa-B (NF-κB) activation was determined by immunohistochemical analysis. Results: Our findings revealed that CN remarkably ameliorated ANIT-induced hepatic necro-inflammatory changes and biliary duct injury and restored redox balance in the liver. Mechanistically, CN markedly decreased the expression of TXNIP, NLRP3, active caspase-1, gasdermin D N-terminal (GSDMD-N), interleukin (IL)-1β, and IL-18, which were elevated upon ANIT administration. Moreover, CN suppressed ANIT-induced expression of HMGB1 and NF-κB. Conclusions: Our findings suggest that CN has a protective effect against ANIT-induced CLI in mice that is associated with modulation of the TXNIP/NLRP3 and HMGB1/NF-κB signaling cascades. Full article

Deregulated Nlrp3 (NOD-like receptor pyrin 3) inflammasome activation is strongly associated with age-related blinding diseases, including cataract. Previously, we demonstrated that loss of peroxiredoxin6 (Prdx6) promotes reactive oxygen species (ROS) amplification and aberrant activation of Klf9 and Nlrp3 inflammasome activity–driven pyroptosis. In this study, using aging mouse(m)/human(h) lenses and lens epithelial cells (LECs), we reveal a critical link between Nlrp3 and thioredoxin (TRX)-interacting protein (TXNIP), which increases during aging and oxidative stress conditions. We found that aging lenses exhibiting opacity showed elevated ROS levels, increased TXNIP expression, along with upregulation of Nlrp3 inflammasome components, including caspase-1, ASC, IL-1β, IL-18, and gasderminD (GSDMD), with significantly reduced TRX1. mLECs overexpressing TXNIP were more susceptible to hydrogen peroxide (H₂O₂), Lipopolysaccharide (LPS), ultraviolet B (UVB)-induced oxidative stress, displaying increased ROS accumulation, reduced cell viability, and enhanced activation of Nlrp3 inflammasome and its downstream inflammatory mediators, hallmarks of pyroptotic cell death. Conversely, TXNIP knockdown suppressed Nlrp3 inflammasome activation, decreased ROS production, and significantly improved cell survival, indicating a protective effect against oxidative injury. Ex vivo, TAT-HA-Prdx6 delivery inhibited H₂O₂-induced Nlrp3 activation and preserved lens transparency, demonstrating its potent antioxidant and anti-inflammatory effects. Collectively, these findings identify TXNIP as a key regulator of Nlrp3 inflammasome signaling and thereby highlight the therapeutic potential of TXNIP silencing (ShTXNIP) or TAT-HA-Prdx6 delivery to halt Nlrp3-mediated pyroptosis during aging or oxidative stress conditions. Full article