Search Results (349)

Background/Objectives: Tea, the world’s second most consumed beverage after water, contains diverse phytochemicals that have garnered growing interest for their potential ability to modulate inflammasome activation. This study examined the antioxidant and anti-inflammatory properties of oolong tea (OLT) extracts, with a specific focus on their regulatory effects on NLRP3 inflammasome assembly—a critical mediator in chronic inflammatory diseases. Methods: OLT extracts were prepared from the Jin-Xuan cultivar with quantification for bioactive components (total phenolics, flavonoids, condensed tannins, and proanthocyanidins). J774A.1 murine macrophages were primed with LPS and stimulated with ATP to induce inflammasome activation. Therapeutic potentials of OLT extracts were assessed by measuring cytokine secretion, expression of NLRP3 inflammasome-related proteins (NLRP3, ASC, Caspase-1, and IL-1β), inflammasome complex formation, and ROS generation via biochemical assays, immunoblotting, and fluorescence microscopy. Results: OLT extracts, particularly at 100 µg/mL, markedly suppressed both the priming and activation phases of NLRP3 inflammasome formation. OLT treatment reduced IL-1β secretion by more than 50%, attenuated ASC oligomerization and speck formation, inhibited caspase-1 cleavage, and lowered intracellular ROS levels by approximately 50%. Conclusions: These findings suggest that OLT extracts exert potent anti-NLRP3 inflammasome activity and offer immunomodulation potential in preventing inflammation-related diseases such as infections, cancer, and neurodegenerative disorders. Further in vivo investigations, followed by clinical applications and epidemiological studies, are warranted to validate these preventive effects in human populations. Full article

Acute myocardial infarction (AMI) remains the leading cause of death worldwide, with myocardial ischemia/reperfusion injury (MIRI) emerging as a significant factor influencing patient outcomes despite timely reperfusion therapy. MIRI refers to paradoxical myocardial damage that occurs upon restoration of coronary blood flow and is driven by complex inflammatory, oxidative, and metabolic mechanisms, which can exacerbate infarct size (IS), contributing to adverse outcomes. This review explores the molecular and cellular pathophysiology of MIRI, emphasizing both its clinical and forensic relevance. The principal mechanisms discussed include oxidative stress and mitochondrial dysfunction, calcium overload and ion homeostasis imbalance, inflammatory responses, with particular focus on the NLRP3 inflammasome and cytokine pathways, and multiple forms of cell death (apoptosis, necroptosis, pyroptosis, and autophagy). Additionally, the authors present original immunohistochemical findings from autopsy cases of patients who suffered ST-segment elevation myocardial infarction (STEMI) and underwent percutaneous coronary intervention (PCI), but subsequently died. These findings underscore that successful reperfusion does not completely prevent delayed complications, like arrhythmias, ventricular fibrillation (VF), and sudden cardiac death (SCD), often caused by secondary MIRI-related mechanisms. Moreover, the case series highlight the diagnostic value of inflammatory markers for pathologists in identifying MIRI as a contributing factor in such fatalities. Finally, immunotherapeutic strategies—including IL-1 and IL-6 inhibitors such as Canakinumab and Tocilizumab—are reviewed for their potential to reduce cardiovascular events and mitigate the effects of MIRI. The review advocates for continued multidisciplinary research aimed at improving our understanding of MIRI, developing effective treatments, and informing forensic investigations of reperfusion-related deaths. Full article

Ischemic stroke induces complex neuroinflammatory cascades, where microglial autophagy and mitophagy serve dual roles in both injury amplification and tissue repair. This scoping review synthesized current evidence on their regulatory mechanisms and therapeutic implications. Literature was identified via PubMed and Embase, yielding 79 records, from which 39 original research articles and 13 review papers were included after eligibility screening. Search terms included “microglia,” “autophagy,” and “ischemic stroke.” Protective autophagy was frequently associated with AMPK activation, mTOR inhibition, and mitophagy pathways such as PINK1/Parkin and BNIP3/NIX, facilitating mitochondrial clearance, M2 polarization, and anti-inflammatory signaling. Therapeutic agents such as rapamycin, Tat-Beclin 1, and Urolithin A consistently demonstrated neuroprotection in preclinical stroke models. In contrast, excessive or prolonged autophagic activation was linked to inflammasome amplification, oxidative stress, and phagoptosis. Limited human studies reported associations between elevated serum ATG5 levels or ATG7 polymorphisms and worse clinical outcomes, suggesting preliminary translational relevance. These findings support the potential of phase-specific modulation of microglial autophagy as a therapeutic avenue for stroke, although further validation in human models and development of autophagy biomarkers are needed for clinical application. Full article

Inflammation is an innate immune system protecting the body from infection and injury. This process proceeds through two distinct stages: a priming phase, characterized by transcriptional activation, and a triggering phase, in which inflammasomes, cytosolic multiprotein complexes, are activated to initiate inflammatory signaling cascades. Canonical inflammasomes, the first to be identified, have been extensively implicated in the pathogenesis of diverse inflammatory disorders. In contrast, noncanonical inflammasomes have only recently been characterized, and their precise contributions to immune regulation and disease development remain incompletely defined. Diabetes mellitus (DM), simply diabetes, represents a heterogeneous group of metabolic disorders marked by chronic hyperglycemia and is associated with a broad spectrum of complications. The involvement of canonical inflammasomes in DM and its complications has been well demonstrated. More recently, however, accumulating evidence has uncovered crucial roles for noncanonical inflammasomes in the pathogenesis of DM and related complications This review comprehensively discusses current advances in understanding the regulatory functions of murine caspase-11 and human caspase-4/5 noncanonical inflammasomes in the pathogenesis of DM and diabetes-associated complications, highlighting their potential as novel therapeutic targets. Full article

Background/Objectives: The impact of COVID-19 on male reproductive health remains unclear, with existing studies reporting conflicting results. This study aimed to evaluate longitudinal changes in sperm parameters, functional tests, and key markers related to the inflammasome complex in men diagnosed with COVID-19. Methods: In this experimental study, semen and blood samples were collected from 34 men at one- and three-months following COVID-19 diagnosis. Assessments included sperm parameters, chromatin damage, protamine deficiency, residual histones, and key inflammasome pathway markers (NLRP3, ASC, and caspase-1) in sperm samples. Additionally, blood levels of LH, testosterone, interleukin-6, and TNF-ɑ were measured. Results: While semen volume, sperm count, concentration, total motility, and DNA damage showed no significant changes, notable improvements were observed in sperm vitality, rapid motility, chromatin integrity, protamine content, and residual histones at three months compared to one-month post-diagnosis. Serum levels of LH, testosterone, and interleukin-6 remained stable, whereas TNF-ɑ levels significantly decreased after three months. Western blot analysis revealed a significant increase in NLRP3 protein expression after three months, while ASC and caspase-1 levels showed no significant changes. Conclusions: These results suggest a gradual recovery in sperm function over time after COVID-19 infection, highlighting possible implications for male reproductive health. Further studies with larger populations are necessary to better understand the underlying mechanisms and long-term effects of COVID-19 on male fertility. Full article

Pyroptosis is a programmed cell death pathway that initiates and sustains inflammation to protect the host against invading pathogens or stress. Activation of caspase-1-mediated canonical pyroptosis takes place via formation of multi-protein cytoplasmic immune signaling complexes known as inflammasomes. Because we have shown previously that the canonical pyroptosis pathway plays a significant role in the pathogenesis of experimental murine cytomegalovirus (MCMV) retinal necrosis in mice with retrovirus-induced immunosuppression (MAIDS), we performed additional studies to determine whether this pathogenic involvement extends to inflammasomes as initiators of the canonical pyroptosis pathway. Initial studies demonstrated significant transcription of three different pyroptosis-associated inflammasomes, NLRP3, NLRP1b, and AIM2, within the ocular compartments of MCMV-infected eyes of MAIDS mice. Subsequent histopathologic findings revealed MCMV-infected eyes of groups of NLRP3^−/− MAIDS mice, NLRP1b^−/− MAIDS mice, or AIM2^−/− MAIDS mice each exhibited a similar atypical retinal pathology characterized by loss of photoreceptors and proliferation and/or loss of retinal pigmented epithelium but with relative sparing of the neurosensory retina, an outcome different from typical full-thickness retinal necrosis of MCMV-infected eyes of wildtype MAIDS mice. We conclude that multiple inflammasomes are individually stimulated within MCMV-infected eyes of MAIDS mice and each independently contributes to MAIDS-related MCMV full-thickness retinal necrosis pathogenesis. Full article

Cerebral ischemia–reperfusion injury (CIRI) is a complex pathological process that arises when blood flow is restored to the brain after ischemia, often resulting in significant neuronal damage and triggering secondary inflammatory responses. This review explores the immune mechanisms underlying CIRI, focusing on the activation and polarization of resident central nervous system (CNS) cells—particularly microglia and astrocytes—and the infiltration of peripheral immune cells such as neutrophils, monocytes/macrophages, and T lymphocytes. We discuss the central role of microglia in the neuroinflammatory cascade, their polarization between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, and how this process influences neuronal damage and tissue repair. This review highlights the roles of the complement system, inflammasome activation, and blood–brain barrier disruption as key drivers of inflammation and neuronal injury. Additionally, we elaborate on the dynamic interactions between resident and infiltrating immune cells, which amplify inflammation and impede post-ischemic recovery. Finally, we discuss emerging therapeutic strategies targeting immune modulation, including cytokine regulation, microglial reprogramming, and targeted drug delivery systems, which offer promising avenues for improving outcomes in ischemic stroke. Full article

Due to their evolutionary divergence from mammals, zebrafish (Zf, Danio rerio), which are frequently employed in biomedical research, provide a distinctive viewpoint on innate immune systems. The Toll-like receptor 4/myeloid differentiation factor 2/cluster of differentiation 14 (TLR4/MD-2/CD14) complex in mammals detects lipopolysaccharide (LPS), a crucial component of Gram-negative bacteria, and it causes potent inflammatory reactions through a Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF)-dependent and myeloid differentiation primary response 88 (MyD88)-dependent pathways. However, key components of this system, such as a responsive TLR4 axis and a functional CD14 ortholog, are absent in Zf. The Zf species nevertheless reacts to LPS, which leads to research into other recognition systems. This review looks at a number of TLR4-independent processes in Zf, such as scavenger receptors (SRs) including scavenger receptor class B type 1 (SR-BI) and cluster of differentiation 36 (CD36), nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-dependent cytosolic sensing, peptidoglycan recognition proteins (PGRPs), Complement Component 3 (C3), and caspase-1-like protein 2 (Caspy2)-mediated inflammasome activation. An alternative and flexible immune system that makes up for the lack of canonical TLR4 signaling is revealed by these mechanisms. Additionally, the discovery of lymphocyte antigen 96 (ly96), an ortholog of MD-2 found in Zf, suggests evolutionary similarity; however, as it is only functional in artificial systems, it demonstrates minimal overlap with mammalian MD-2 activity. Knowing these pathways provides important information for studying inflammation, infection, and immunological modulation in vertebrates using Zf as a model. It also clarifies the evolutionary flexibility of innate immune recognition. Full article

Inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) are chronic immune-mediated inflammatory diseases (IMIDs) that affect the gastrointestinal and hepatobiliary systems. They are characterized by persistent inflammation, potentially progressive fibrosis, and an elevated risk of developing cholangiocarcinoma and colorectal cancer. IBD and PSC share phenotypical, genetic, and immunological features, largely due to the central role of immune cell dysregulation. Despite their increasing global prevalence, the underlying drivers remain poorly understood, and effective treatment options are still lacking. Efforts towards an improved comprehension of their pathogenic mechanisms are therefore pivotal. Emerging evidence highlights the role of canonical ASC-dependent inflammasomes—multiprotein bioactive Interleukin (IL)-1-producing complexes of the innate immune system—and serum amyloid A (SAA) as key structures of gastrointestinal and hepatobiliary inflammation, tissue remodeling, stromal crosstalk, and fibrosis. In this review, we explore immunological connections and analogies between IBD and PSC, highlighting the converging roles of canonical ASC-dependent inflammasomes, the IL-1 superfamily, SAA, and sustained gut microbiota-driven chronic inflammation in disease pathology and their surging potential as therapeutic targets across the gut–liver axis. Full article

This review provides an overview of the most significant developments in gout pathophysiology research published in 2024. Thirteen studies were selected based on originality, scientific rigor, and potential clinical impact and grouped into four major categories: inflammation and pain mechanisms (LRRC8 anion channels, CXCL5-CXCR2 axis, CD38 and NAD⁺ metabolism, PLK1 and NLRP3 inflammasome localization, and IFN1 suppression), biomarkers and proteomics (scRNA-seq reveals monocyte and T-cell flare signatures, and Olink serum profiling reveals a proinflammatory signature in hyperuricemia and also identifies TNFSF14 as a novel flare biomarker, while a multi-omics integrative study implicates TRIM46 as a key causal gene), gut virome, and novel therapies (vagus nerve stimulation, biomimetic nanosystem, and restoration of Urate Oxidase (Uox) function). The studies selected focused primarily on work on subjects other than on hyperuricemia. The findings collectively expand our understanding of gout’s complex pathophysiology and highlight potential strategies for diagnosis, management, and innovative treatments. Full article

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

Preeclampsia (PE) is a multifactorial hypertensive disorder unique to pregnancy and a leading cause of maternal and fetal morbidity and mortality worldwide. Its pathogenesis involves placental dysfunction and an exaggerated maternal inflammatory response. Uric acid (UA), traditionally regarded as a marker of renal impairment, is increasingly recognized as an active contributor to the development of PE. Elevated UA levels are associated with oxidative stress, endothelial dysfunction, immune activation, and reduced renal clearance. Clinically, UA is measured in the second and third trimesters to assess disease severity and guide obstetric management, with higher levels correlating with early-onset PE and adverse perinatal outcomes. Its predictive accuracy improves when combined with other clinical and biochemical markers, particularly in low-resource settings. Mechanistically, UA and its monosodium urate crystals can activate the NLRP3 inflammasome, a cytosolic multiprotein complex of the innate immune system. This activation promotes the release of IL-1β and IL-18, exacerbating placental, vascular, and renal inflammation. NLRP3 inflammasome activation has been documented in placental tissues, immune cells, and kidneys of women with PE and is associated with hypertension, proteinuria, and endothelial injury. Experimental studies indicate that targeting UA metabolism or inhibiting NLRP3 activation, using agents such as allopurinol, metformin, or MCC950, can mitigate the clinical and histopathological features of PE. These findings support the dual role of UA as both a biomarker and a potential therapeutic target in the management of the disease. Full article

Aging is associated with complex immune dysfunction that contributes to the onset and progression of the “geriatric giants”, including frailty, sarcopenia, cognitive decline, falls, and incontinence. Central to these conditions is immunosenescence, marked by thymic involution, the loss of naïve T cells, T-cell exhaustion, impaired B-cell class switch recombination, and increased autoreactivity. Concurrently, innate immunity deteriorates due to macrophage, neutrophil, and NK cell dysfunction, while chronic low-grade inflammation—or “inflammaging”—amplifies systemic decline. Key molecular pathways such as NF-κB, mTOR, and the NLRP3 inflammasome mediate immune aging, interacting with oxidative stress, mitochondrial dysfunction, and epigenetic modifications. These processes not only impair infection control and vaccine responsiveness but also promote tissue degeneration and multimorbidity. This review explores emerging interventions—ranging from senolytics and immunonutrition to microbiome-targeted therapies and exercise—that may restore immune homeostasis and extend healthspan. Despite advances, challenges remain in translating immunological insights into clinical strategies tailored to older adults. Standardization in microbiome trials and safety optimization in senolytic therapies are critical next steps. Integrating geroscience into clinical care could help to mitigate the burden of aging-related diseases by targeting fundamental drivers of immune dysfunction. Full article

Tuberous sclerosis complex (TSC) is a systemic disease caused by mutations in either the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) gene, with mutations in the TSC2 gene potentially leading to more severe clinical symptoms. Neurological symptoms are a common clinical manifestation of TSC, and neuroinflammation is thought to play an important role. Glial cells are a major source of neuroinflammation, but whether microglia are involved in the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and the expression of interleukin-1β (IL-1β) in TSC patients remains unclear. We used a transcriptome sequencing dataset for bioinformatics analysis to explore the differences in the expression of microglial inflammasome-associated hub genes. TSC2 knockdown (TSC2 KD) microglia (HMC3 cell line) were generated by lentivirus, and the expression of inflammasome-associated hub genes, microglial activation, and NLRP3 inflammasome activation were verified. In addition, experiments were performed to explore the regulatory effects of rapamycin. Bioinformatics analysis identified a total of eight inflammasome-associated hub genes. By detecting GFP fluorescence, TSC2 mRNA, TSC2 protein expression, and the phosphorylation of the mammalian target of rapamycin (p-mTOR)/mTOR, we confirmed that the TSC2 KD microglia model was successfully established. Compared with the control group, the TSC2 KD group presented higher mRNA levels and fluorescence intensities of microglia AIF1 and CD68, as well as greater reactive oxygen species (ROS) production. Eight inflammasome-associated hub gene mRNA assays revealed that the expression of the NLRP3 and IL1B genes was increased. Compared with the control group, the TSC2 KD group presented increased levels of NLRP3 and Pro-IL-1β proteins in cells and Cleaved-Caspase 1 and Cleaved-IL-1β proteins in the supernatant, suggesting NLRP3 inflammasome activation. Rapamycin intervention alleviated these changes, demonstrating that the TSC2 gene regulation of microglial activation and NLRP3 inflammasome activation are correlated with mTOR phosphorylation. In conclusion, microglia are activated in TSC patients and participate in the NLRP3 inflammasome-associated neuroinflammatory response, and rapamycin treatment can alleviate these changes. Full article

Atherosclerosis (AS) is a complex pathological process characterized by the pivotal involvement of foam cells in its pathogenesis. As the primary cellular components of arterial plaques, foam cells critically determine plaque stability. Foam cells derive mainly from macrophages, and their formation is driven by dysregulated lipid metabolism within these immune cells. Macrophage cholesterol metabolism is a highly regulated process comprising four key phases: uptake, esterification, hydrolysis, and efflux. Under physiological conditions, these four phases maintain a delicate balance. However, disruption of cholesterol homeostasis results in the excessive accumulation of intracellular lipid, promoting the formation of foam cell and inflammasome activation, thereby accelerating the atherosclerotic progression. Therefore, targeting macrophage cholesterol metabolism has emerged as a promising therapeutic approach for AS. This review summarizes the mechanisms underlying macrophage cholesterol metabolism and highlights recent progress in identifying bioactive components of traditional Chinese medicines (TCMs) that mitigate AS through the modulation of macrophage cholesterol homeostasis. These findings may offer novel insights into the development of clinically effective therapies for the prevention of AS. Full article