Pyroptosis is a novel kind of programmed cell death and Caspase-1 plays key roles in driving pyroptosis. The current study aims to elucidate the molecular mechanism affecting cardiomyocyte pyroptosis in myocardial ischemia/reperfusion (I/R) injury, both in vivo and in vitro.

A murine model of myocardial I/R injury was established and then treated with lentivirus-mediated shRNA targeting Caspase-1 to evaluate the effect of Caspase-1 on myocardial I/R injury. Further, Caspase-1 was silenced in the cardiomyocytes following hypoxia-reoxygenation (H/R) to detect the function of Caspase-1 in mitochondrial homeostasis and cardiomyocyte pyroptosis.

Knockdown of Caspase-1 inhibited the secretion of interleukin-1 beta (IL-1β), improved cardiac dysfunction and decreased pyroptosis in vivo. The cardio-protective effect was verified in the H/R-induced cardiomyocyte model. Recombinant IL-1β protein reversed the inhibitory effect of Caspase-1 knockdown on pyroptosis.

Overall, activating the Caspase-1/IL-1β axis by myocardial I/R injury causes mitochondrial homeostasis imbalance, pyroptosis, and the consequent cardiomyocyte injury.

This study investigated the pathogenic mechanisms of Aeromonas veronii in macrophages. THP-1 derived macrophages were used as a human macrophage model and were treated with A. veronii strain AS1 isolated from intestinal biopsies of an IBD patient, or Escherichia coli strain K-12. RNA was extracted and subjected to RNA sequencing and comparative transcriptomic analyses. Protein levels of IL-8, IL-1β, IL-18, and TNFα were measured using ELISA, and apoptosis was assessed using caspase 3/7 assays. Both A. veronii AS1 and E. coli K-12 significantly upregulated the expression of many genes involving inflammation. At the protein level, A. veronii AS1 induced significantly higher levels of IL-8, TNFα, mature IL-18 and IL-1β than E. coli K-12, and led to greater elevation of caspase 3/7 activities. Both A. veronii AS1 and E. coli K-12 upregulated the expression of CASP5, but not other caspase genes. A. veronii AS1 significantly downregulated the expression of 20 genes encoding histone proteins that E. coli K-12 did not. The more profound pathogenic effects of A. veronii in inducing inflammation and apoptosis in macrophages than E. coli K-12 are consistent with its role as a human enteric pathogen. The upregulated expression of CASP5 and increased release of IL-1β and IL-18 support the role of CASP5 in activation of non-canonical inflammasome. The downregulation of histone genes by A. veronii suggests a unique impact on host cell gene expression, which may represent a novel virulence strategy. These findings advance the understanding of pathogenic mechanisms of the emerging human enteric pathogen A. veronii.

Fungal-host interaction outcomes are influenced by how the host recognizes fungal cell wall components. Mannan is a major cell wall carbohydrate and can be a glycoshield that blocks the inner cell wall β-1,3-glucan from activating pro-inflammatory immune responses. Disturbing this glycoshield in Candida albicans results in enhanced antifungal host responses and reduced fungal virulence. However, deletions affecting mannan synthesis can lead to systemic hypervirulence for Nakaseomyces glabratus (formerly Candida glabrata) suggesting that proper mannan architecture dampens virulence for this organism. N. glabratus is the second leading cause of invasive and superficial candidiasis, but little is known about how the cell wall affects N. glabratus pathogenesis. In order to better understand the importance of these species-specific cell wall adaptations in infection, we set out to investigate how the mannan polymerase II complex gene, MNN10, contributes to N. glabratus cell wall architecture, immune recognition, and virulence in reference strains BG2 and CBS138. mnn10Δ cells had thinner inner and outer cell wall layers and elevated mannan, chitin, and β-1,3-glucan exposure compared to wild-type cells. Consistent with these observations, mnn10Δ cells activated the β-1,3-glucan receptor in oral epithelial cells (OECs), EphA2, and caused less OEC damage than wild-type. mnn10Δ replication was also restricted in macrophages compared to wild-type controls. Yet, during systemic infection in Galleria mellonella larvae, mnn10Δ cells induced rapid larval melanization and BG2 mnn10Δ cells killed larvae significantly faster than wild-type. Thus, our data suggest that mannan plays context-dependent roles in N. glabratus pathogenesis, acting as a glycoshield in superficial disease models and modulating virulence during systemic infection.

Xanthine oxidoreductase (XOR) inhibitors are used to treat gout, inhibiting uric acid production, which causes clinical symptoms. Commonly used XOR inhibitors are the small molecule febuxostat (Fbx) and the purine analogue allopurinol (Allo). Recent studies show that XOR inhibitors can reduce mature interleukin (IL)-1β production by activated macrophages. This effect is not due to reduced uric acid crystal formation, which can induce NLRP3 inflammasome activation, but an independent effect. Fbx and Allo have been used interchangeably in in vitro studies to highlight the role of XOR in pro-inflammatory macrophage function. Here, we analysed the effects of Fbx and Allo on pro-inflammatory macrophage signatures. Both XOR inhibitors maintain pro-inflammatory macrophage metabolic and phenotypic hallmarks. However, only Fbx reduces the activity of caspase-1 and the release of IL-1β by preventing inflammasome assembly in macrophages isolated from both mice and humans. Our study identified an Fbx-specific reduction in IL-1β production, which could be used clinically to reduce the deleterious effects of macrophage-derived IL-1β.

Electroacupuncture (EA), a traditional Chinese medicine therapy, exhibits cardioprotective and therapeutic effects against cardiac injury. However, the precise mechanisms underlying these benefits remain unclear.

The aim of this study is to examine the impact of EA on Doxorubicin-Induced heart failure and elucidate the mechanisms involved.

C57BL/6 mice were randomly assigned to six experimental groups, including a control group, a DCM group, a DCM group receiving non-acupoint EA (NEA), and a DCM group receiving acupoint EA (EA). The cardiac function, levels of inflammatory factors, and markers of apoptosis were assessed both in vivo and in vitro. The presence of AMPK/mTOR/ULK1(Ser317) and PI3K/AKT/mTOR/ULK1(Ser757) was confirmed.

EA stimulation significantly improved cardiac function, as evidenced by increased left ventricular ejection fraction (LVEF), E/A ratio, and fractional shortening (FS%) compared to the DCM group (p < 0.05). After EA stimulation, the phosphorylation levels of PI3K/AKT increase, leading to elevated expression of mTOR/ULK1(Ser757), which ultimately inhibited the expression of apoptosis-related proteins and inflammatory factors. Simultaneously, EA stimulation could inhibit the phosphorylation levels of AMPK, reducing the expression of mTOR/ULK1(Ser317), and thereby also inhibiting the expression of apoptosis-related proteins and inflammatory factors.

This study showed that EA stimulation can counteract myocardial damage caused by apoptosis and inflammation, thereby significantly improving cardiac function and prognosis in HF mice. The mechanism may be that EA stimulation activates the PI3K/AKT/mTOR/ULK1(ser757) pathway and inhibits the AMPK/ULK1(ser317) pathway. EA stimulation exerts the same effect by regulating these two pathways in different directions, ultimately reducing myocardial cell apoptosis and cardiac inflammation.

The COVID-19 pandemic underscored the urgency of developing effective vaccines to combat infectious diseases, especially in vulnerable populations such as the elderly and immunocompromised. While recombinant protein vaccines offer safety, their poor immunogenicity highlights the need for advanced vaccination platforms. New genetic/nucleic acid vaccine formulations like plasmid DNA and mRNA showed efficiency and safety in preclinical and clinical studies; however, they demand innovative adjuvants because their mechanism of action differs from traditional protein vaccines. Genetic adjuvants-encoded by nucleic acids within DNA, RNA, or viral vectors-emerge as a promising solution by targeting and modulating specific immune pathways, including antigen presentation, T cell activation, and memory formation. These innovative adjuvants enhance vaccine efficacy by fine-tuning innate and adaptive immune responses, overcoming immune senescence, and addressing the challenges of CD8+ T cell activation in immunocompromised populations. This review explores the potential of genetically encoded adjuvants, including cytokines, chemokines, and other immune modulators. By comparing these adjuvants to traditional formulations, we highlight their capacity to address the limitations of modern vaccines while discussing their integration with emerging technologies like RNA-based vaccines. As genetic adjuvants advance toward clinical application, understanding their mechanisms and optimizing their delivery is pivotal to unlocking next-generation immunization strategies.

Pyroptosis represents one type of programmed cell death. It is a form of inflammatory cell death that is canonically defined by caspase-1 cleavage and Gasdermin-mediated membrane pore formation. Caspase-1 initiates the inflammatory response (through IL-1β processing), and the N-terminal cleaved fragment of Gasdermin D polymerizes at the cell periphery forming pores to secrete proinflammatory markers. Cell morphology also changes in pyroptosis, with nuclear condensation and membrane rupture. However, recent research challenges canon, revealing a more complex secretome and morphological response in pyroptosis, including overlapping molecular characterization with other forms of cell death, such as apoptosis. Here, we take a multimodal, systems biology approach to characterize pyroptosis. We treated human peripheral blood mononuclear cells (PBMCs) with 36 different combinations of stimuli to induce pyroptosis or apoptosis. We applied both secretome profiling (nELISA) and high-content fluorescence microscopy (Cell Painting). To differentiate apoptotic, pyroptotic, and control cells, we used canonical secretome markers and modified our Cell Painting assay to mark the N-terminus of Gasdermin D. We trained hundreds of machine learning (ML) models to reveal intricate morphology signatures of pyroptosis that implicate changes across many different organelles and predict levels of many proinflammatory markers. Overall, our analysis provides a detailed map of pyroptosis which includes overlapping and distinct connections with apoptosis revealed through a mechanistic link between cell morphology and cell secretome.

Ulcerative colitis (UC) is an inflammatory bowel disease with an unknown cause. Previous studies have shown that Group 3 innate lymphoid cells (ILC3s) are crucial for maintaining intestinal mucosal immune homeostasis by producing key cytokines such as IL-22 and IL-17 A. While the RNA-binding protein Musashi-2 (MSI2) is recognized as essential for promoting intestinal epithelial regeneration post-injury, its impact on immune regulation remains unclear. Therefore, we aim to investigate the protective mechanisms associated with ILC3s-specific MSI2 deletion in a mouse model of ulcerative colitis.

Dextran sulfate sodium (DSS) was used to induce a mouse colitis model. Colitis severity was evaluated through weight loss, diarrhea, fecal traits, colon length, and pathological scoring. Transcriptome sequencing was utilized to identify differentially expressed genes in colon tissues. Flow cytometry was employed to measure the quantity and functionality of ILC3s. Western blot was conducted to analyze protein expression, while real-time polymerase chain reaction and enzyme-linked immunosorbent assay were employed to quantify inflammatory factors. Additionally, immunofluorescence, AB-PAS staining, and immunohistochemistry were employed to evaluate the integrity of the intestinal barrier.

Following DSS treatment, colon damage was milder in Msi2∆Rorc mice than in Msi2fl/fl mice. Transcriptomic analysis revealed the down-regulation of cytokines and pro-inflammatory factors in the colon tissue of Msi2∆Rorc mice. Flow cytometry showed that specific deletion of MSI2 reduced the infiltration of ILC3s in the intestinal lamina propria of Msi2∆Rorc mice and decreased IL-17 A production. The reduction of IL-17 A-mediated immune responses lessened inflammatory damage to the intestinal barrier, thereby reducing colitis severity.

Specific deletion of MSI2 alleviates DSS-induced colitis in mice by reducing ILC3s infiltration and IL-17 A secretion in the lamina propria of the colon. This decrease in inflammatory mediators and cell infiltration dampens the inflammatory response in the intestinal mucosa, helping to maintain the integrity of the intestinal barrier in mice with colitis. These findings enhance our understanding of UC pathogenesis and offer novel avenues for clinical diagnosis and treatment.

Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industrial and consumer products, leading to environmental contamination and human exposure. This review focuses on perfluoroalkyl acids, a subset of PFAS, which are primarily encountered through diet, including drinking water, and other pathways such as dust ingestion, and dermal contact. Impaired vaccine antibody response has been identified as the most critical effect for risk assessment by the European Food Safety Authority. Furthermore, human epidemiological studies have linked exposure to certain PFAS to various immune-related outcomes, such as asthma, allergies, and inflammatory bowel disease. This review examines potential immunomodulatory effects of perfluoroalkyl acids at the primary sites of exposure: lungs, intestines, and skin, using human epidemiological data as the basis for investigating these impacts. While animal studies are referenced for context, this paper highlights the need for further human-based research to address key questions about PFAS and their immunological impacts. The state of in vitro toxicity testing related to these effects is thoroughly reviewed and critical issues pertaining to this topic are discussed.

The gut microbiota influences systemic immunity and the function of distal tissues, including the brain, liver, skin, lung, and muscle. However, the role of the gut microbiota in the foreign body response and fibrosis is largely unexplored. To investigate this connection, we perturbed the homeostasis of the murine gut microbiota via infection with the pathogenic bacterial species enterotoxigenic Bacteroides fragilis (ETBF) and implanted particulate material (mean particle size <600 μm) of the synthetic polymer polycaprolactone (PCL) into a distal muscle injury. ETBF infection in mice led to increased neutrophil and γδ T cell infiltration into the PCL implant site. ETBF infection alone promoted systemic inflammation, increased levels of neutrophils in lymphoid tissues, and altered skeletal muscle gene expression. At the PCL implant site, we found significant changes in the transcriptome of sorted stromal cells between infected and control mice, including differences related to ECM components such as proteoglycans and glycosaminoglycans. However, we did not observe ETBF-induced differences in fibrosis levels. These results demonstrate the ability of the gut microbiota to mediate long-distance effects such as immune and stromal responses to a distal biomaterial implant.

Synucleinopathies and amyloidogenic disorders are the two most prevalent neurodegenerative conditions, characterized by progressive loss of neurons and aggregation of proteins in the central nervous system. Emerging evidence suggests that despite their distinct pathological hallmarks: α-synuclein in Parkinson's disease (PD) and amyloid-β in Alzheimer's disease (AD), both disorders share common molecular pathways, including oxidative stress, neuroinflammation, misfolding/aggregation of proteins and mitochondrial dysfunction. This review explores the molecular intersections between synucleinopathies and amyloidogenesis. Furthermore, this review highlights how these pathways drive neuronal loss and suggest that targeting them could provide broad therapeutic benefits. By elucidating the shared mechanisms between PD and AD, the multi-targeted therapies could address the underlying molecular disruptions common to both disorders, offering new avenues for effective disease-modifying treatments in neurodegenerative diseases.

Cypermethrin (CYP, IUPAC name: [cyano-(3-phenoxyphenyl)methyl] 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate), a type II pyrethroid insecticide, is suggested to have potential adverse effects on human endocrine, immune, and neurotoxic systems.

In this study, we aimed to investigate whether CYP causes oxidative stress and pyroptosis in thyroid follicle epithelial cells through the activation of the ROS-NFκB-NLRP3 pathway, thereby causing inflammatory responses.

Nthy-ori 3-1 cells were used as an in vitro model and exposed to CYP at different doses (0, 100, 200, 400, 800, and 1600 μmol/L) for 24 h.

CYP treatment enhanced oxidative damage in Nthy-ori 3-1 cells, characterized by cellular crumpling, indistinct borders, increased cellular gaps, appearance of intercellular grease droplets, and increased pyroptosis. Subsequent treatment with the caspase-1 inhibitor VX-765 enhanced cell viability in the VX-765 +CYP group, improving cell morphology, reducing pyroptotic vesicles, suppressing oxidative stress, and downregulating Interleukin-18(IL-18) (an inflammatory factor) level.

The results demonstrate that CYP induces pyroptosis in Nthy-ori 3-1 cells through activation of the reactive oxygen species (ROS)-NF-κB-NLRP3 pathway.

Introduction: Coronavirus (CoV) is an extremely contagious, enveloped positive-single-stranded RNA virus, which has become a global pandemic that causes several illnesses in humans and animals. Hence, it is necessary to investigate viral-induced reactions across diverse hosts. Herein, we propose utilizing naturally secreted extracellular vesicles (EVs), mainly focusing on exosomes to examine virus-host responses following CoV infection. Exosomes are small membrane-bound vesicles originating from the endosomal pathway, which play a pivotal role in intracellular communication and physiological and pathological processes. We suggested that CoV could impact EV formation, content, and diverse immune responses in vitro. Methods: In this study, we infected A-72, which is a canine fibroblast cell line, with a feline coronavirus (FCoV) and canine coronavirus (CCoV) independently in an exosome-free media at 0.001 multiplicity of infection (MOI), with incubation periods of 48 and 72 h. The cell viability was significantly downregulated with increased incubation time following FCoV and CCoV infection, which was identified by performing the 3-(4,5-dimethylthiazo-1-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. After the infection, EVs were isolated through ultracentrifugation, and the subsequent analysis involved quantifying and characterizing the purified EVs using various techniques. Results: NanoSight particle tracking analysis (NTA) verified that EV dimensions fell between 100 and 200 nm at both incubation periods. At both periods, total protein and RNA levels were significantly upregulated in A-72-derived EVs following FCoV and CCoV infections. However, total DNA levels were gradually upregulated with increased incubation time. Dot blot analysis indicated that the expression levels of ACE2, IL-1β, Flotillin-1, CD63, caspase-8, and Hsp90 were modified in A-72-derived EVs following both CoV infections. Conclusions: Our results indicated that FCoV and CCoV infections could modulate the EV production and content, which could play a role in the development of viral diseases. Investigating diverse animal CoV will provide in-depth insight into host exosome biology during CoV infection. Hence, our findings contribute to the comprehension and characterization of EVs in virus-host interactions during CoV infection.

Stroke remains the leading cause for lasting disability and death globally. Two frequent proinflammatory cytokine variants in the IL-10 and IL-1β genes, rs16944 T/C and rs1800896 G/A, may be major candidate gene loci impacting ischemic stroke vulnerability. The present case-control research aims to establish a link between both of these polymorphisms and ischemic stroke risk in the Egyptian population. The study demonstrates that the TC genotype, over dominant (TT + CC vs. TC) and dominant models (TC + CC vs. TT), exhibited greater prevalence among stroke groups as compared to the healthy group. Regarding IL-10, GA genotype, A allele, over dominant (GG + AA vs. GA), and dominant (GG vs. GA + AA) genotyping models in patients, they show highly significant differences from controls that increased the risk of stroke. Stroke patients with higher cholesterol, LDL, SBP, DBP, and lower HDL levels were more likely to develop stroke. The study found no significant link between genetic polymorphisms and smoking, gender, diabetes, or hypertension in stroke patients, except for the IL-1β heterozygous TC and dominant model, which was associated with troubles in chewing and swallowing and consciousness issues in the patients. Only troubles in chewing and swallowing manifestations were associated with the IL-10 variant. The rs16944 and rs1800896 polymorphisms differ substantially between groups, providing a more definite outcome for the Egyptian population and IS. The results validate the utilization of the rs16944 T/C and rs1800896 G/A variations in stroke prediction for Egyptians.

Yiqi Congming Decoction (YQCM) is a traditional Chinese medicine formula widely used as a complementary and alternative therapy for dry eye and other ophthalmic disorders.

This study aims to investigate the potential effects of YQCM on dry eye and to identify the active components responsible for its therapeutic efficacy using a rat model.

Using Ultra-High Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry (HPLC-QTOF/MS), the chemical constituents of YQCM were identified. In vivo experiments demonstrated the protective effects of YQCM on the corneal barrier in a rat model of dry eye and determined the optimal therapeutic dose. YQCM and agomiR-146a were administered either individually or in combination to rat over 14 days, followed by evaluations of Schirmer I test (SⅠT) results, tear film breakup time (BUT), fluorescein staining (FL) levels, corneal epithelial cell inflammation, and apoptosis. Furthermore, the expression of proteins in the miR-146a/IRAK1/JNK1 pathway, as well as inflammation and apoptosis-related proteins, was examined to explore the mechanisms through which YQCM modulates inflammation and improves tear film stability. In vitro experiments employed serum containing YQCM, agomiR-146a, and the IRAK1 inhibitor (AZ1495) to further investigate the regulatory effects of YQCM on the miR-146a/IRAK1/JNK1 pathway and its impact on inflammation and apoptosis in human corneal epithelial cells (HCECs) under hypertonic conditions.

In vivo experimental results demonstrated that YQCM significantly restored tear film stability. Treatment with varying doses of YQCM improved corneal epithelial damage in rats, with the medium dose exhibiting the most pronounced effect. YQCM increased the SⅠT and BUT levels, effectively reduced FL levels, and inhibited apoptosis and inflammatory damage in corneal epithelial cells. Additionally, scanning electron microscopy, hematoxylin-eosin (HE) staining, TUNEL assays, and Western blot (WB) and qPCR analyses revealed that YQCM significantly ameliorated corneal damage in dry eye rats and reduced the expression levels of MMP-9, TNF-α, IL-1β, Caspase-3, IL-6, and IFN-γ. Moreover, YQCM modulated the expression of proteins in the miR-146a/IRAK1/JNK1 pathway. In vitro experiments demonstrated that YQCM regulated the levels of miR-146a/IRAK1/JNK1 in HCECs under hypertonic conditions and enhanced cell viability by reducing the expression of MMP-9, TNF-α, IL-1β, Caspase-3, IL-6, and IFN-γ. Using Annexin V-FITC/PI double staining and other techniques, it was further confirmed that YQCM alleviated apoptosis in HCECs under hypertonic conditions.

YQCM protects tear film stability in a rat model of dry eye by suppressing corneal epithelial inflammatory responses and reducing apoptosis through modulation of the miR-146a/IRAK1/JNK1 pathway.

Sulfated polysaccharides from edible marine algae have gained significant attention for their remarkable nutritional and therapeutic potential. Caulerpa racemosa (sea grape), a widely consumed edible algae, is a source of bioactive compounds with significant medicinal potential. This study focuses on CRP-2, a sulfated (1 → 4) galactan derived from C. racemosa, and its anti-inflammatory effects in lipopolysaccharide (LPS)-induced CALU-1 cells. CRP-2, at a concentration of 125 μg/mL, reduced the expression of pro-inflammatory cytokines interleukin-1β and tumor necrosis factor-α by 41-49 % in CALU-1 cells. Additionally, it significantly downregulated transforming growth factor-β levels, as indicated by a decrease in mean fluorescence intensity from 20 to 4 units, compared to cells treated with LPS alone. Concurrently, downregulated expressions level of interleukin-33, interferon-α and interleukin-10 in LPS-induced CALU-1 cells were substantially elevated after the treatment with CRP-2 (mean fluorescence intensities 25-35-fold), in a dose-dependent manner. Gene expression analysis by qRT-PCR revealed downregulation of interferon-γ levels by 2 folds (at 125 μg/mL) from an overly expressed levels of 9-fold in LPS-induced cells. Structure-activity and molecular docking analyses emphasized the role of sulfate moieties in its bioactivity. These findings highlight the potential of CRP-2 as a natural anti-inflammatory agent and suggest its promise as a functional food ingredient with notable health benefits.

Inflammatory bowel disease (IBD) is a complex immune-mediated condition, and biologics are the most commonly used drugs for its treatment. However, there are still cases of ineffective treatment. B-cell lymphoma 6 (Bcl6), a transcriptional suppressor, is known to have regulatory effects on multiple immune-associated cell subsets. FX1, a novel specific BCL6 Bric-à-brac (BTB) inhibitor, has shown positive effects in many disease models, but its effects and mechanisms in IBD control remain unclear.

We observed colon length and DAI score of colitis mice after treatment. HE staining section was used to evaluate colonic injury, while the expression of colonic pro-inflammatory cytokines by RT-qPCR. And differences in immune cell subsets between the two groups was analyzed by flow cytometry. Additionally, IHC and RT-qPCR were employed to evaluate the expression of colonic tight junction proteins. Furthermore, RAW264.7 cells and co-cultured Caco2 cells were detected by ELISA and RT-qPCR.

In the treat group, colitis symptoms in mice were significantly improved, and there was a decrease in proportion of macrophages and protection of intestinal mucosal integrity-indicating anti-inflammatory effects of FX1. In cell experiments, we found that FX1 decreased secretion of pro-inflammatory factors by macrophages and increased expression of tight junction proteins in Caco2 cells after co-culture.

The experimental findings demonstrate the inhibitory effect of FX1 on inflammation in murine colitis model as well as its potential mechanism. BCL6 is a potential target for treating IBD.

Astrocytes play a pivotal role in the inflammatory response triggered by traumatic brain injury (TBI). They are not only involved in the initial inflammatory response following injury but also significantly contribute to Astrocyte activation and inflammasome release are key processes in the pathophysiology of TBI, significantly affecting the progression of secondary injury and long-term outcomes. This comprehensive review explores the complex triggering mechanisms of astrocyte activation following TBI, the intricate pathways controlling the release of inflammasomes from activated astrocytes, and the subsequent neuroinflammatory cascade and its multifaceted roles after injury. The exploration of these processes not only deepens our understanding of the neuroinflammatory cascade but also highlights the potential of astrocytes as critical therapeutic targets for TBI interventions. We then evaluate cutting-edge research aimed at targeted therapeutic approaches to modulate pro-inflammatory astrocytes and discuss emerging pharmacological interventions and their efficacy in preclinical models. Given that there has yet to be a relevant review elucidating the specific intracellular mechanisms targeting astrocyte release of inflammatory substances, this review aims to provide a nuanced understanding of astrocyte-mediated neuroinflammation in TBI and elucidate promising avenues for therapeutic interventions that could fundamentally change TBI management and improve patient outcomes. The development of secondary brain injury and long-term neurological sequelae. By releasing a variety of cytokines and chemokines, astrocytes regulate neuroinflammation, thereby influencing the survival and function of surrounding cells. In recent years, researchers have concentrated their efforts on elucidating the signaling crosstalk between astrocytes and other cells under various conditions, while exploring potential therapeutic interventions targeting these cells. This paper highlights the specific mechanisms by which astrocytes produce inflammatory mediators during the acute phase post-TBI, including their roles in inflammatory signaling, blood-brain barrier integrity, and neuronal protection. Additionally, we discuss current preclinical and clinical intervention strategies targeting astrocytes and their potential to mitigate neurological damage and enhance recovery following TBI. Finally, we explore the feasibility of pharmacologically assessing astrocyte activity post-TBI as a biomarker for predicting acute-phase neuroinflammatory changes.

Intracellular bacterial components represent an emerging tumor element that has recently been documented in multiple cancer types, yet their biological functions remain poorly understood. Oral squamous cell carcinoma (OSCC) is a particularly aggressive malignancy lacking highly effective targeted treatments. Here, we explored the functional significance of intracellular bacterial lipopolysaccharide (LPS) in OSCC. Normal human oral keratinocytes (HOKs), HPV-transformed oral keratinocytes (IHGK), and three OSCC cell lines were transfected with ultrapure bacterial LPS. Cytotoxicity was assessed via lactate dehydrogenase (LDH) release assays. Production of interleukin (IL)-1β and IL-18 was measured using ELISA. Impact on tumor progression was evaluated using cell proliferation, migration, invasion, and tubulogenesis assays. Intracellular LPS-induced significant LDH release and increased secretion of IL-18 and IL-1β in IHGK and cancer cells, but not in normal HOKs, indicating selective cytotoxicity and pyroptosis. Notably, metastatic cancer cells exhibited enhanced invasive and vessel-like structures upon LPS exposure, while IHGK cells exhibited increased proliferation without changes in migration. Our findings suggest that intracellular LPS may not merely reside passively within the tumor milieu, but could contribute to OSCC progression by triggering noncanonical inflammasome activation and pyroptosis. This process may enhance pro-inflammatory signaling and more aggressive cellular phenotypes, especially in metastatic settings. Targeting intracellular LPS or its downstream inflammasome pathways may thus represent a promising therapeutic strategy for OSCC, warranting further in vivo and clinical investigations.

Glyphosate and tetrabromobisphenol A (TBBPA) are pollutants that pose a serious threat to the ecological safety of aquatic environments. However, there has been no report on the effects of combined exposure on the toxicity of carp fish gills in water. Therefore, we constructed a model of carp gill tissue and the carp epithelioma cells (EPC) cells exposed to glyphosate and/or TBBPA in vitro and in vivo, established a control group, a glyphosate group, a TBBPA group, and a glyphosate + TBBPA group, and added PI3K/AKT pathway activator musk ketone in vitro to verify the relationship between toxins and pathways. qRT-PCR and western blotting methods were used to detect the expression of oxidative stress-related indicators (CAT, GSH-Px, T-AOC, H2O2) and related genes. In vitro and in vivo results showed that glyphosate and/or TBBPA exposure resulted in overproduction of ROS, decreased activity of CAT, GSH-Px, T-AOC, and increased H2O2 content. Glyphosate and/or TBBPA exposure inhibited the PI3K/AKT/mTOR signaling pathway, further resulting in increased autophagy related genes LC3, ATG-5, Beclin-1, and decreased p62 expression. Inflammation related genes TNF-α, IL-1β, IL-6, IL-18 increased. And it was more significant when exposed in combination than when exposed alone. The addition of PI3K/AKT signaling pathway activator musk ketone in vitro can significantly alleviate the changes of autophagy and inflammation-related indicators. In summary, glyphosate and/or TBBPA induce oxidative stress by promoting gill autophagy and inflammation via the PI3K/AKT/mTOR pathway.

Fucoidans, a complex water-soluble sulfated polysaccharide is regarded as a valuable source of new drug development. The aim of this study was to characterize the chemical properties of fucoidans isolated from two brown algae Dyctyopteris membranaceae and Padina pavonica and to evaluate their anti-inflammatory, gastroprotective, antioxidant and immunomodulatory activities. The characterization of fucoidans was investigated with colorimetric techniques and Fourier transform infrared spectroscopy. The different macromolecular characteristics of fucoidans were determined by size exclusion chromatography. The immunomodulatory activity was evaluated using cytometric bead array technology to follow up the secretion of TNF-α in lipopolysaccharide activated THP-1 cells. The antioxidant effect was determined using the stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The anti-inflammatory activity was evaluated using the carrageenan-induced rat paw edema model. The gastroprotective activity was determined using HCl/EtOH induced gastric ulcers in rats. Pharmacokinetic and molecular docking analysis was conducted. As a result, only fucoidan from D. membranaceae showed an effect on the synthesis of TNF-α in THP-1 cells induced by LPS with IC50 of 77 μg/mL. Fucoidans from both algae showed antioxidant properties with EC50 of 0.2 mg/mL for fucoidan from D. membranaceae, and 0.21 mg/mL for fucoidan from P. pavonica. Furthermore, isolated fucoidans from D. membranaceae and P. pavonica showed important anti-inflammatory activity with percentages of inhibition of oedema of 75 % and 57 %, respectively, at dose of 50 mg/kg, associated with significant gastroprotective activity with percentages of ulcer inhibition of 97 % and 88 %, respectively, at the same dose. Docking study showed the reactivity of this fucoidans. The study highlights the potential pharmacological importance of D. membranaceae and P. pavonica as sources of natural compounds with biological activities.

Inflammatory factors and cigarette smoking have been associated with sleep disorders but molecular mechanisms that regulate sleep, specifically the role of interleukin-1β (IL-1β), remain controversial. Individuals' cerebrospinal fluid (CSF) IL-1β, smoking behavior, and sleep data were collected to investigate how smoking may influence the relationship between CSF IL-1β and sleep via moderation analysis.

A total of 191 Chinese male patients, including 104 non-smokers and 87 active smokers, scheduled for anterior cruciate ligament reconstructive surgery, were recruited. Pittsburgh Sleep Quality Index (PSQI) scores were collected prior to surgery, and CSF samples were obtained during preoperative lumbar puncture.

Active smokers compared to non-smokers exhibited higher scores across various subdimensions of PSQI, specifically poorer sleep quality, increased sleep latency, reduced sleep efficiency, and heightened sleep disturbance (all p < 0.05). Positive correlations were observed between CSF IL-1β levels and PSQI total scores, as well as several subdimensions of sleep (all p < 0.05) in non-smokers. In contrast, a negative correlation was observed between CSF IL-1β levels and sleep efficiency scores (p < 0.05) among active smokers. Moderation analysis revealed that smoking negatively moderated the relationship between CSF IL-1β and sleep, particularly in PSQI total scores (β = -0.95, p < 0.001), sleep latency scores (β = -1.05, p < 0.001), and sleep disturbance scores (β = -0.45, p < 0.05).

The current study found that smoking disrupts multiple subdimensions of sleep and moderates the effect of the neuroinflammatory factor CSF IL-1β on PSQI sleep latency and sleep disturbance scores.

H9N2 Influenza A virus (IAV) can contribute to Pseudomonas aeruginosa (P. aeruginosa) superinfection, causing severe pneumonia. But the underlying mechanisms remain unclear. In this study, to investigate molecular ecology of the lung tissues co-infected with H9N2 IAV and P. aeruginosa, the mouse models were developed to analyze proteome of the lung tissues. As a result, the differential proteins of the lungs sampled from the mice with single H9N2 IAV infection, single P. aeruginosa infection and co-infection with H9N2 IAV and P. aeruginosa were related to immune responses, cell proliferation and apoptosis, which were involved in NF-κB pathway, Toll-like signaling pathway, RIG-I signaling pathway and JAK-STAT signaling pathway. It implied that the different infection combinations of H9N2 IAV and P. aeruginosa influenced the protein expression levels. Based on the proteomics assays, the three proteins, NLRX1, ISG15 and IRF9, were screened to be further characterized using the in vitro MH-S cell models with H9N2 IAV and P. aeruginosa co-infection. The findings demonstrated that NLRX1, IRF9 and ISG15 might play the important roles in immune response against H9N2 IAV and P. aeruginosa co-infection and are potential targets for the development of drugs to prevent and treat the diseases.

The immune system is vital for maintaining homeostasis, defending against external threats, and regulating inflammation, forming the cornerstone of human health. Sanghuangporus, a natural medicinal mushroom, contains flavonoids that may increase immune cell activity, potentially improving human health. This study investigated the immunomodulatory effects of Sanghuangporus flavonoids (PBF) via network pharmacology and in vitro and in vivo experiments. Network pharmacology identified PBF compounds targeting 46 immunosuppression-related targets, with rutin emerging as a key component. Molecular docking confirmed the strong binding affinity of rutin for the core targets IL6, TNF, and IL1B. In vitro, PBF activated mouse macrophages, promoting their proliferation, phagocytic activity, NO production, and cytokine regulation. In vivo, PBF enhanced immune function in normal mice by promoting thymus and spleen growth, increasing cellular and humoral immunity, and restoring immune function in immunosuppressed mice. These findings highlight the potential of PBFs in increasing immunity and treating immunosuppressive diseases.

Background: Reactive oxygen species (ROS) generated by mitochondrial dysfunction damage cellular organelles and contribute to skin aging. Therefore, strategies to reduce mitochondrial ROS production are considered important for alleviating skin aging, but no effective methods have been identified. Methods: In this study, we evaluated substances utilized as cosmetic ingredients and discovered Camellia sinensis (C. sinensis) as a substance that reduces mitochondrial ROS levels. Results:C. sinensis extracts were found to act as senolytics that selectively kill senescent fibroblasts containing dysfunctional mitochondria. In addition, C. sinensis extracts facilitated efficient electron transport in the mitochondrial electron transport chain (ETC) by increasing the efficiency of oxidative phosphorylation (OXPHOS), thereby reducing mitochondrial ROS production, a byproduct of the inefficient ETC. This novel mechanism of C. sinensis extracts led to the restoration of skin aging and the skin barrier. Furthermore, epigallocatechin gallate (EGCG) was identified as an active ingredient that plays a key role in C. sinensis extract-mediated skin aging recovery. Indeed, similar to C. sinensis extracts, EGCG reduced ROS and improved skin aging in an artificial skin model. Conclusions: Our data uncovered a novel mechanism by which C. sinensis extract reverses skin aging by reducing mitochondrial ROS production via selective senescent cell death/increased OXPHOS efficiency. Our results suggest that C. sinensis extract or EGCG may be used as a therapeutic agent to reverse skin aging in clinical and cosmetic applications.

Patients with peritoneal metastasized colorectal cancer (PM-CRC) have a dismal prognosis. We hypothesized that an immunosuppressive environment in the peritoneal cavity underlies poor prognosis. We define the composition of the human peritoneal immune system (PerIS) using single-cell technologies in 18 patients with- and without PM-CRC, as well as in matched peritoneal metastases (n = 8). Here we show that the PerIS contains abundant immunosuppressive C1Q+VSIG4+ and SPP1+VSIG4+ peritoneal-resident macrophages (PRMs), as well as monocyte-like cavity macrophages (mono-CMs), which share features with tumor-associated macrophages, even in homeostasis. In PM-CRC, expression of immunosuppressive cytokines IL10 and VEGF increases, while simultaneously expression of antigen-presenting molecules decreases in PRMs. These intratumoral suppressive PRMs originate from the PerIS, and intraperitoneal depletion of PRMs in vivo using anti-CSF1R combined with anti-PD1 significantly reduces tumor burden and improves survival. Thus, PRMs define a metastatic site-specific immunosuppressive niche, and targeting PRMs is a promising treatment strategy for PM-CRC.

Autoinflammation and autoimmunity are almost "opposite" phenomena characterized by chronic activation of the immune system, 'innate' in the first and 'adaptive' in the second, leading to inflammation of several tissues with specific protean effectors of tissue damage. The mechanism of involvement of multiprotein complexes called 'inflammasomes' within autoimmune pictures, differently from autoinflammatory conditions, is yet undeciphered. In this review we provide a comprehensive overview on NLRP3 inflammasome contribution into the pathogenesis of some autoimmune diseases. In response to autoantibodies against nucleic acids or tissue-specific antigens the NLRP3 inflammasome is activated within dendritic cells and macrophages of patients with systemic lupus erythematosus. Crucial is NLRP3 inflammasome to amplify tissue inflammation with interleukin-1 overexpression and matrix metalloproteinase production at the joint level in rheumatoid arthritis. A deregulated NLRP3 inflammasome activation occurs in the serous acini of salivary and lacrimal glands prone to Sjogren's syndrome, but also in the inflammatory process involving endothelial cells, leucocyte recruitment, and platelet plugging of vasculitides. Furthermore, organ-specific autoimmune diseases such as thyroiditis and hepatitis may display hyperactive NLRP3 inflammasomes at the level of resident immune cells within thyroid or liver, respectively. Therefore, it is not unexpected that preclinical studies have shown how specific inflammasome inhibitors may significantly overthrow the severity of different autoimmune diseases and slow down their trend towards an ominous progression. Specific markers of inflammasome activation could also reveal subclinical inflammatory components escaping conventional diagnostic approaches or improve monitoring of autoimmune diseases and personalizing their treatment.

To investigate the effects of cold environment exposure on female reproductive capacity and explore its potential regulatory mechanisms.

Female mice were subjected to cold water immersion to simulate cold environment exposure. Weight changes during cold exposure were recorded. Serum levels of anti-Müllerian hormone (AMH), estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured using enzyme-linked immunosorbent assay (ELISA). Ovarian and uterine tissues were collected via surgical procedures, and transcriptomic sequencing was performed to explore potential regulatory mechanisms. ELISA was used to assess the levels of inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18), and tumor necrosis factor-alpha (TNF-α) in peritoneal fluid. Furthermore, immunohistochemistry was used to detect the expression levels of IL-1, IL-6, and IL-18 in ovarian tissues, as well as IL-6 and IL-18 in uterine tissues.

Compared with the control group, female mice exposed to cold environments exhibited a significant increase in body weight and elevated serum levels of AMH, E2, FSH, and LH. Transcriptomic sequencing of ovarian and uterine tissues indicated that differentially expressed genes were primarily enriched in inflammation-related pathways, including the cAMP signaling pathway, cytokine-cytokine receptor interaction, and PI3K-Akt signaling pathway. Additionally, levels of inflammatory cytokines in the peritoneal fluid, including IL-1β, IL-6, IL-18, and TNF-α, were significantly elevated. Immunohistochemical analysis showed that the expression levels of IL-1, IL-6, and IL-18 were markedly increased in ovarian tissue, while IL-6 and IL-18 expression levels were significantly elevated in uterine tissue. These differences were statistically significant (P < 0.05).

Cold environment exposure may induce inflammatory responses in the uterus and ovaries, contributing to the formation of an inflammatory microenvironment in the reproductive system. This process may lead to disruptions in sex hormone levels and ultimately impair female reproductive capacity.

Cardio-rheumatology is an evolving and interdisciplinary field lying at the intersection of rheumatology and cardiovascular medicine that recognizes that individuals with autoimmune and inflammatory rheumatic complications have a much higher likelihood of developing cardiovascular diseases (CVDs). Inflammasomes are multiprotein complexes stimulated by the immune system after the detection of pathogens or cellular injury. Inflammasomes undergo a two-stage activation process initiated by nuclear factor (NF)-κB, subsequently playing a crucial role in innate immunity through activation of caspase 1 and the consequent release of proinflammatory cytokines such as IL-18 and IL-1β. However, a loss of control of inflammasome activation can cause inflammatory diseases in humans. Recent studies have focused on the role of inflammasomes in inflammatory cascades implicated in the pathogenesis of several diseases. Here, we review inflammasome activation, its mechanism of action, and its role in CVD. In particular, we describe the role of inflammasomes in rheumatic heart disease, Kawasaki disease, familial Mediterranean fever, ankylosing spondylitis, and rheumatoid arthritis as exemplars to illustrate pathobiological mechanisms and the potential for targeting inflammasomes for therapeutic benefit.

Alzheimer's disease (AD) is a neurodegenerative disorder influenced by both genetic and environmental factors. Identifying therapeutic targets and interventions remains challenging. This study utilized Mendelian Randomization (MR) to investigate causal relationships between plasma proteins, lifestyle factors, and AD, along with virtual screening to identify potential drug compounds. A two-sample MR analysis assessed associations between plasma proteins, identified through genome-wide association studies (GWAS), and AD risk. Co-localization analysis (CA) confirmed the overlap between protein expression and AD susceptibility loci, and reverse MR ruled out reverse causality. A protein-protein interaction (PPI) network was constructed to explore therapeutic targets, followed by virtual screening to identify small-molecule inhibitors for selected proteins. The analysis found significant associations between eight plasma proteins and AD, with five proteins (GSTP1, BIN1, Siglec-3, SERPINF2, and GRN) showing strong evidence of involvement in AD pathogenesis. Virtual screening identified six compounds as potential inhibitors of GSTP1 and four compounds as potential inhibitors of BIN1. Furthermore, MR analysis of lifestyle factors, such as dietary behaviors and smoking cessation, indicated they may influence AD risk through their effects on specific proteins. These findings offer novel insights into the genetic mechanisms underlying AD and highlight the potential of combining MR with virtual screening to identify therapeutic targets. The study also suggests that lifestyle modifications could offer alternative prevention and treatment strategies for AD. Future research should focus on the experimental validation of the identified compounds and further explore the mechanisms linking lifestyle factors to AD.

Myricetin, a flavonoid present in numerous fruits, vegetables, and medicinal plants, is recognized for its potent antioxidant, anti-inflammatory, and anti-cancer activities. Nevertheless, its involvement in mitigating inflammation caused by the endocrine-disrupting chemical Di(2-ethylhexyl) phthalate (DEHP), commonly used in polyvinyl chloride (PVC) manufacturing to improve flexibility, has not been investigated. Here, we found that DEHP markedly increased IL-1β production through inflammatory pathways in RAW 264.7 murine macrophages. Treatment with myricetin at a concentration of 10 μM significantly reduced the elevated IL-1β levels. Myricetin achieves this by inhibiting the activation of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK), which are driven by reactive oxygen species (ROS), thereby suppressing IL-1β transcription via nuclear factor-kappa B (NF-κB). Additionally, myricetin prevents ROS-induced activation of the NLRP3 inflammasome and subsequent caspase-1 activation, further decreasing IL-1β production. These dual actions highlight myricetin's therapeutic potential in countering the oxidative stress-mediated inflammatory pathways triggered by environmental toxins like DEHP.

Terpenoids are important components that exert pharmacological effects in Rubiaceae plants. In this study, two Rubiaceae plants, Nauclea officinalis and Paederia scandens, which are widely distributed in Hainan, China, were collected. The extracts of these two plants were obtained through boiling water extraction and analyzed using UHPLC-ESI-QE-Orbitrap-MS. By comparing with the mzCloud database, terpenoids with a matching rate of 85 % were identified. The results revealed that the aqueous extracts of N. officinalis mainly contain six pentacyclic triterpenoids, one diterpenoid, and one iridoid. The aqueous extracts of P. scandens contains one monoterpenoid, one diterpenoid, two pentacyclic triterpenes, and 4 iridoids. To verify the anti-inflammatory efficacy of the two extracts, in this study, they were added to the lipopolysaccharide (LPS)-induced RAW264.7 macrophages inflammation model. The results showed that the two extracts can reduce the secretion of proinflammatory cytokines IL-1β, IL-6, and TNF-α (p < 0.05) and the mortality rate of cell inflammation (p < 0.05) by inhibiting the activation of the NF-κB/NLRP3 pathway (p < 0.05). The study identified the terpenoids in N. officinalis and P. scandens and verified their anti-inflammatory effects in the RAW264.7 macrophages inflammation model.

Development of electrospun nanofibers with suitable properties to promote wound healing is an advantage in developing non-invasive skin treatments. We showed the potential application of Polyvinyl acetate (PVA) and Polyvinylpyrrolidone (PVP) combined with Helichrysum italicum oil (HO) in wound healing. During this process, Tight junctions (TJs) play a crucial role in maintaining skin integrity. TJs are intercellular junctions composed of a variety of transmembrane proteins, including Occludin (OCLN), observed also in migrating epithelial cells. Changes in OCLN expression affect epidermal permeability, indicating an active role in the healing process. Within this context, we studied the OCLN expression during healing after scratch assay on Keratinocytes (HaCaT), by a confocal microscopic analysis. In addition, we evaluated the effect of treatment after scratch on cell elasticity by Atomic Force Microscopy (AFM) analysis. All results show a positive trend in cell proliferation and viability on HaCaT treated with functionalized nanofibers. These results were confirmed by the expression of genes involved in the early stages of the regenerative process. Understanding the cell mechanisms involved in skin changes during repair process would allow future application of nanomaterials combined with HO in vivo.

In agriculture and public health, insecticides are vital chemicals that help manage diseases and control pests. However, their extensive use has raised concerns about their negative consequences on both humans and animals. Pesticide exposure impacts numerous human organs, including the reproductive system. Infertility is caused by reproductive system disorders, which is why they have received a lot of attention in recent decades. According to what is currently known, insecticides are among the substances that may lower the quality of the semen produced by exposed workers. The mechanisms of this action are still unclear, even though numerous underlying mechanisms have been suggested. With an emphasis on the harmful effects of insecticides on male reproductive processes, this review provides a thorough analysis of the toxicity profile of these substances. To reduce insecticides' negative impacts on human and animal health and to direct future research initiatives, it is essential to comprehend their harmful consequences.

Ubiquitin ligases play pivotal roles in the regulation of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, a critical process in innate immunity and inflammatory responses. This review explores the intricate mechanisms by which various E3 ubiquitin ligases exert both positive and negative influences on NLRP3 inflammasome activity through diverse post-translational modifications. Negative regulation of NLRP3 inflammasome assembly is mediated by several E3 ligases, including F-box and leucine-rich repeat protein 2 (FBXL2), tripartite motif-containing protein 31 (TRIM31), and Casitas B-lineage lymphoma b (Cbl-b), which induce K48-linked ubiquitination of NLRP3, targeting it for proteasomal degradation. Membrane-associated RING-CH 7 (MARCH7) similarly promotes K48-linked ubiquitination leading to autophagic degradation, while RING finger protein (RNF125) induces K63-linked ubiquitination to modulate NLRP3 function. Ariadne homolog 2 (ARIH2) targets the nucleotide-binding domain (NBD) domain of NLRP3, inhibiting its activation, and tripartite motif-containing protein (TRIM65) employs dual K48 and K63-linked ubiquitination to suppress inflammasome assembly. Conversely, Pellino2 exemplifies a positive regulator, promoting NLRP3 inflammasome activation through K63-linked ubiquitination. Additionally, ubiquitin ligases influence other components critical for inflammasome function. TNF receptor-associated factor 3 (TRAF3) mediates K63 polyubiquitination of apoptosis-associated speck-like protein containing a CARD (ASC), facilitating its degradation, while E3 ligases regulate caspase-1 activation and DEAH-box helicase 33 (DHX33)-NLRP3 complex formation through specific ubiquitination events. Beyond direct inflammasome regulation, ubiquitin ligases impact broader innate immune signaling pathways, modulating pattern-recognition receptor responses and dendritic cell maturation. Furthermore, they intricately control NOD1/NOD2 signaling through K63-linked polyubiquitination of receptor-interacting protein 2 (RIP2), crucial for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) activation. Furthermore, we explore how various pathogens, including bacteria, viruses, and parasites, have evolved sophisticated strategies to hijack the host ubiquitination machinery, manipulating NLRP3 inflammasome activation to evade immune responses. This comprehensive analysis provides insights into the molecular mechanisms underlying inflammasome regulation and their implications for inflammatory diseases, offering potential avenues for therapeutic interventions targeting the NLRP3 inflammasome. In conclusion, ubiquitin ligases emerge as key regulators of NLRP3 inflammasome activation, exhibiting a complex array of functions that finely tune immune responses. Understanding these regulatory mechanisms not only sheds light on fundamental aspects of inflammation but also offers potential therapeutic avenues for inflammatory disorders and infectious diseases.