Resveratrol (RSV) ameliorates endothelial dysfunction (ED) primarily through sirtuin 1 (SIRT1). Increasing evidence shows pyroptosis as a novel mechanism in palmitic acid (PA)-induced ED. p66Shc is an adaptor protein involved in oxidative stress. However, whether RSV attenuates the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via p66Shc remains elusive. This study aims to evaluate whether the antipyroptotic effect of RSV and the SIRT1 inhibitor EX527 are related to p66Shc. High-fat diet (HFD) induced obesity in mice, and RSV was administered intragastrically with 400mg/kg/d for 22 successive weeks. The serum levels of interleukin-1β (IL-1β) and IL-18 were analyzed, and the expression of related proteins were assayed with immunohistochemistry in the thoracic aorta. human umbilical vein endothelial cells (HUVECs) were induced by PA, then treated with RSV and EX527 respectively, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP) and expression of p66Shc, NLRP3, GSDMD and pyroptosis-related genes were assayed. RSV administration ameliorated endothelial cell pyroptosis by decreasing serum IL-1β and IL-18, the expression of NLRP3, p66Shc, and gasdermin D (GSDMD), and increasing the expression of SIRT1 in the HFD-treated thoracic aorta. PA promoted GSDMD-mediated endothelial cell pyroptosis by ROS production, LDH release, decreased MMP and SIRT1 expression, increased expression of p66Shc and activation of the NLRP3 inflammasome in a dose-dependent manner. RSV attenuated PA-induced pyroptosis, whereas EX527 reversed the antipyroptotic effect of RSV in PA-treated HUVECs. Our results suggested a new mechanism that RSV improves PA-induced pyroptosis in endothelial cells via the SIRT1-p66Shc-NLRP3 pathway.

Host-directed therapies (HDTs) have been investigated as a potential solution to combat intracellular and drug-resistant bacteria. HDTs stem from extensive research on the intricate interactions between the host and intracellular bacteria, leading to a treatment approach that relies on immunoregulation. To improve the bioavailability and safety of HDTs, researchers have utilized diverse drug delivery systems (DDS) to encapsulate and transport therapeutic agents to target cells. In this review, we first introduce the three mechanisms of bactericidal action and intracellular bacterial evasion: autophagy, reactive oxygen species (ROS), and inflammatory cytokines, with a particular focus on autophagy. Special attention is given to the detailed mechanism of xenophagy in clearing intracellular bacteria, a crucial selective autophagy process that specifically targets and degrades intracellular pathogens. Following this, we present the application of DDS to modulate these regulatory methods for intracellular bacteria elimination. By integrating insights from immunology and nanomedicine, this review highlights the emerging role of DDS in advancing HDTs for intracellular bacterial infections and paving the way for innovative therapeutic interventions.

Nicotine has been reported to initiate NLRP3 inflammasome formation and activation in different pathological conditions. The current study assessed whether thioredoxin-interacting protein (TXNIP) mediates nicotine-induced NLRP3 inflammasome activation and consequent podocyte injury. Co-immunoprecipitation analysis demonstrated that nicotine-induced TXNIP/NLRP3 interaction in podocytes relative to control groups. However, pre-treatment with TXNIP inhibitors, verapamil (Vera) or SRI-37330 (SRI) attenuates nicotine-induced TXNIP/NLRP3 interaction. Confocal microscopic analysis showed that nicotine treatment significantly increased the colocalization of Nlrp3 with Asc, Nlrp3 with caspase-1 and Nlrp3 with TXNIP in podocytes compared to control cells. Pretreatment with TXNIP inhibitor Vera or SRI abolished nicotine-induced Nlrp3/Asc, Nlrp3/caspase-1 or Nlrp3/TXNIP colocalization. Correspondingly, nicotine treatment significantly increased the caspase-1 activity and IL-1β production compared to control cells. However, prior treatment with TXNIP inhibiting Vera or SRI significantly attenuated the nicotine-induced caspase-1 activity and IL-1β production. Further immunofluorescence analysis showed that nicotine treatment significantly decreased podocin and nephrin expression compared to control cells. However, pretreatment with TXNIP inhibiting Vera or SRI attenuated the nicotine-induced podocin and nephrin reduction. In addition, confocal, flow cytometry and biochemical analysis showed that nicotine treatment significantly increased desmin expression, apoptosis and cell permeability compared to control cells. However, prior treatment with TXNIP inhibiting Vera or SRI significantly attenuated the nicotine-induced desmin expression, apoptosis and cell permeability. Taken together, our results demonstrate that TXNIP/NLRP3 interaction constitutes a potentially key signalling mechanism driving nicotine-induced NLRP3 inflammasome formation, activation and subsequent podocyte damage.

Gonadotropin injections used to stimulate oocyte production during assisted reproductive technology (ART) procedures are associated with the risk of an abnormal response in predisposed patients suffering polycystic ovary syndrome (PCOS). Liver X receptors (LXR) pathway has been identified as key regulators during this process. This study explores the integration of the hormonal signals, cellular networks and molecular mechanisms linking sterol signaling with inflammation and immune infiltration. Pharmacological activation of LXR in a wild-type context protects against gonadotropin hyperstimulation mirroring the effect observed in LXR-deficient mice. Ovarian stimulation leads to immune cell infiltration orchestrated by granulosa cells in absence of LXR, resulting in an altered granulosa cell response to gonadotropin and enhanced inflammation. LXR controls inflammasome activity by regulating Thioredoxin Interacting Protein (TXNIP) gene expression in mural granulosa cells, thereby modulating IL1β production. This immune cell infiltration persists throughout ovulation in PCOS patients and is observed in cumulus oocytes complexes, highlighting the pivotal role of LXR path in regulating inflammatory processes during hormonal stimulation in ART procedures.

Diesel exhaust particulate (DEP) is widely recognized to weaken lung function and skin diseases. When the skin, which defends against external factors, is exposed to PM2.5, various chronic inflammatory diseases occur. When keratinocytes recognize harmful signals, they synthesize the NOD-like receptor protein 1 (NLRP1) inflammasome. DEP enhances NF-κB signaling and NLRP1 inflammasome expression through the interaction of TXNIP with NLRP1 in keratinocytes. Although many studies have reported the anti-inflammatory and antioxidant characteristics of Impressic acid (IPA), the umbrella consequences of IPA for PM2.5-influenced inflammasomes and the associated mechanisms remain unknown. Therefore, this study aimed to examine the protective function of IPA against inflammation in human keratinocytes. IPA attenuated the NLRP1 expression, caspase-1, IL-1β actuation, and NF-κB and IκB phosphorylation induction by DEP. IPA upregulated the Nrf2, HO-1, and NQO1 expression through CaMKKβ, AMPK, and GSK3β phosphorylation. Also, IPA led to the elevation of p62 and the degradation of the Keap1 protein. ML385 reversed the suppressive effect of IPA on the NLRP1 inflammasome, which was enhanced by DEP, and NAC counteracted the effect of ML385. These findings indicate that IPA can suppress inflammation induced by PM2.5 by expressing antioxidant enzymes through the Keap1/p62/Nrf2-signaling pathway in human keratinocytes.

Inflammatory bowel disease (IBD) is a serious chronic condition marked by persistent and recurrent intestinal ulcers. Although the exact cause of IBD remains unclear, it is generally accepted that a complex interaction among dietary factors, gut microbiota, and immune responses in genetically predisposed individuals contributes to its development. Pyroptosis, an inflammatory form of programmed cell death activated by inflammasomes, is marked by the rupture of cell membranes and the subsequent release of inflammatory mediators. Emerging evidence indicates that pyroptosis plays a crucial role in the pathogenesis of IBD. Moderate pyroptosis activation can enhance intestinal immune defenses, while excessive inflammasome activation can trigger an inflammatory cascade, resulting in increased damage to intestinal tissues. This article reviews the molecular mechanisms underlying pyroptosis and highlights its role in the onset and progression of IBD. Furthermore, We explore recent advancements in IBD treatment, focusing on small molecule compounds that specifically target and inhibit pyroptosis.

Synovitis, among the most common signs of early-stage osteoarthritis (OA), is mainly mediated by fibroblast-like synoviocytes (FLSs). Cartilage destruction creates chondrocyte lysates (CLs) that activate synovial inflammation. A comprehensive understanding of chondrocyte-FLS communication might offer novel, specific therapeutic targets for treating synovitis and OA. Hence, we sought to uncover the specific role of CLs in OA-FLSs and synovitis.

Isolated CLs were cocultured with FLSs to test whether they could stimulate synovial inflammation. A model of medial meniscus destabilization was prepared in C57BL/6 mice and NLRP3 knockout mice, and adeno-associated virus overexpressing Caveolin-1 (CAV1) was intra-articularly injected for 8 weeks once a week after dissection of the medial meniscus (DMM). Proteins expressed in FLSs with and without CL coculture were screened using liquid chromatography-tandem mass spectrometry to identify CL-specific regulators of NLRP3 inflammasome-mediated pyroptosis.

CLs were engulfed by FLSs, which aggravated inflammatory cytokine release and NLRP3 inflammasome-mediated FLS pyroptosis. NLRP3 expression was significantly upregulated in human OA-FLSs and FLSs cocultured with CLs, while CAV1 was downregulated. CAV1 overexpression reversed the inflammatory phenotype in FLSs and simultaneously rescued pyroptosis in CL-pre-treated FLSs. Both synovial hyperplasia and inflammatory infiltration in C57BL/6 mice with DMM surgery were alleviated after intra-articular AAV-CAV1 injection. Moreover, the CL-specific protein LIM-containing lipoma preferred partner (LPP) markedly exacerbated FLS pyroptosis and inflammation.

CLs were endocytosed by FLSs through CAV1, and the CL-specific protein LPP stimulated NLRP3 inflammasome-mediated pyroptosis and synovitis by inhibiting CAV1 expression. Our findings offer a novel therapeutic target for treating synovitis.

The NLRP3 inflammasome plays a pivotal role in the pathogenesis of acute lung injury (ALI) by regulating pyroptosis, a highly inflammatory form of programmed cell death. NLRP3-mediated pyroptosis leads to alveolar epithelial cell injury, increased pulmonary microvascular endothelial permeability, excessive alveolar macrophage activation, and neutrophil dysfunction, collectively driving ALI progression. In addition to the classical NLRP3-dependent pathway, the non-canonical pyroptosis pathway (caspase-4/5/11) also contributes to ALI by inducing pyroptotic cell death in AECs and ECs, further amplifying NLRP3 activation through damage-associated molecular patterns (DAMP) release. Moreover, neutrophils (NE) pyroptosis exhibits dual roles in ALI, as it enhances pathogen clearance but also exacerbates excessive inflammation and tissue damage, highlighting the complexity of its regulation. Targeting the NLRP3 inflammasome and pyroptotic pathways has emerged as a promising therapeutic strategy for ALI. Various NLRP3 inhibitors (e.g., MCC950, CY-09, OLT1177) and pyroptosis inhibitors have demonstrated significant anti-inflammatory and tissue-protective effects in preclinical models. However, the clinical translation of NLRP3-targeted therapies remains challenging due to off-target effects, potential immunosuppression, lack of patient stratification strategies, and compensatory activation of alternative inflammasomes (e.g., AIM2, NLRC4). Future studies should focus on optimizing the selectivity of NLRP3 inhibitors, developing personalized therapeutic approaches, and exploring combination strategies to enhance their clinical applicability in ALI.

Mitochondria, known as the powerhouse of cells, play a crucial role in host innate immunity during flavivirus infections such as Dengue, Zika, West Nile, and Japanese Encephalitis Virus. Mitochondrial antiviral signaling protein (MAVS) resides on the outer mitochondrial membrane which is triggered by viral RNA recognition by RIG-I-like receptors (RLRs). This activation induces IRF3 and NF-κB signaling, resulting in type I interferon (IFN) production and antiviral responses. Upon flavivirus infection, mitochondrial stress and dysfunction may lead to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which serves as a damage-associated molecular pattern (DAMP). Cytosolic mtDNA is sensed by cGAS (cyclic GMP-AMP synthase), leading to the activation of the STING (Stimulator of Interferon Genes) pathway to increase IFN production and expand inflammation. Flaviviral proteins control mitochondrial morphology by controlling mitochondrial fission (MF) and fusion (MFu), disrupting mitochondrial dynamics (MD) to inhibit MAVS signaling and immune evasion. Flaviviral proteins also cause oxidative stress, resulting in the overproduction of reactive oxygen species (ROS), which triggers NLRP3 inflammasome activation and amplifies inflammation. Additionally, flaviviruses drive metabolic reprogramming by shifting host cell metabolism from oxidative phosphorylation (OxPhos) to glycolysis and fatty acid synthesis, creating a pro-replicative environment that supports viral replication and persistence. Thus, the present review explores the complex interaction between MAVS, mtDNA, and the cGAS-STING pathway, which is key to the innate immune response against flavivirus infections. Understanding these mechanisms opens new avenues in therapeutic interventions in targeting mitochondrial pathways to enhance antiviral immunity and mitigate viral infection.

Systemic autoinflammatory diseases (SAIDs) represent a set of conditions with exaggerated innate immune responses. IL-1β and IL-18 are key cytokines involved in the pathogenesis of some SAID. We aimed to assess the diagnostic value of serum levels of IL-1β, IL-18, their respective inhibitors IL-1Ra and IL-18 binding protein (IL-18BP), and IFN-γ in SAID.

A cohort of patients with active SAID, including monogenic (mSAID) and genetically undiagnosed SAID (guSAID) from different European countries, with active disease at inclusion, was established. Serum levels of cytokines were measured by immunoassays.

Sera from 53 mSAID, 220 guSAID and 49 controls without inflammatory disease were analysed. Serum levels of total and free IL-18 were significantly increased in Still's disease in comparison to most SAID and non-inflammatory controls. Levels of total IL-18 were also elevated in patients with familial Mediterranean fever to a comparable extent as in Still's disease. In contrast, free IL-18 levels were selectively higher in Still's disease. Receiver operating characteristic curve analysis showed that total IL-18 was the most sensitive and specific marker for the diagnosis of Still's disease (area under the curve=0.91). There was a positive correlation between IL-18 and ferritin. In 10 patients with Still's disease who had a second blood collection, we found a significant decrease in serum levels of free IL-18 after treatment.

Our results show that IL-18 can discriminate Still's disease from other SAID, and free IL-18 levels may be relevant to assess response to therapy in these patients.

Asthma and cardiovascular diseases (CVDs) are the 2 common and complex health problems with a substantial global impact. Epidemiological studies indicate that asthma and CVDs are common, with evidence supporting their cooccurrence. Inflammation, oxidative stress, obesity, metabolic syndrome, smoking, secondhand smoke exposure, physical inactivity, and environmental exposures are all risk factors for asthma and CVDs. In addition, inflammatory and immunological pathways, autonomic dysfunction, endothelial dysfunction, thrombosis, coagulation, and common genetic risk factors contribute to the asthma-CVD relationship. Asthmatic individuals have higher morbidity and mortality rates related to CVDs and high-risk factors. Techniques such as screening for CVDs in asthma patients, pharmaceutical therapy, and lifestyle changes are critical for effectively managing these comorbid illnesses. Understanding the link between asthma and CVD is necessary for integrated and clinical management approaches to enhance patient outcomes and lessen the burden of these related diseases.

Inflammasomes form in response to infection, cellular stress, or damage. Gain-of-function (GOF) mutations in inflammasome receptors have been identified as the underlying cause of severe inflammatory diseases, termed 'inflammasomopathies'. Recently, molecular interrogation of these diseases revealed several distinctions at the level of the tissue affected, the inflammatory mediators that drive disease progression, and the contribution of programmed cell death. In this review we discuss key emerging differences across inflammasomopathies and the distinct inflammatory patterns seen in patients. We discuss how programmed cell death influences the progression of inflammasomopathies and the role of plasma membrane rupture. Understanding the molecular disease signatures across inflammasomopathies provides crucial insights into identifying and treating the underlying disease and opens new avenues for therapeutic interventions.

Lipopolysaccharide (LPS, endotoxin) -mediated signaling of caspase-4 (human) and -11 (rodent) can induce the maturation of inflammatory cytokine IL-1β and cell pyroptosis, which is associated with the pathophysiology of many diseases such as obesity. However, the process by which LPS induces inflammation through caspase 4/11 is not fully understood. We found here that lncRNA29RIK plays a key role in LPS-mediated maturation of inflammatory cytokine IL-1β and pyroptosis of macrophages. Mechanistic ally, the binding of caspase 4/11 to LPS requires lncRNARIK to cause activation of the caspase 4/11 complex, which ultimately caused inflammation to promote sensitivity to high fat diet (HFD) -mediated obesity. Notably, lncRNA29RIK expression can be up-regulated by LPS. This lncRNA29 is highly conserved between humans and mice. Taken together, these results suggest that lncRNA29RIK determines the occurrence and progression of LPS-related diseases such as obesity.

Exposure to stress during sensitive developmental periods comes with long term consequences for neurobehavioral outcomes and increases vulnerability to psychopathology later in life. While we have advanced our understanding of the mechanisms underlying the programming effects of early-life stress (ES), these are not yet fully understood and often hard to target, making the development of effective interventions challenging. In recent years, we and others have suggested that nutrition might be instrumental in modulating and possibly combatting the ES-induced increased risk to psychopathologies and neurobehavioral impairments. Nutritional strategies are very promising as they might be relatively safe, cheap and easy to implement. Here, we set out to comprehensively review the existing literature on nutritional interventions aimed at counteracting the effects of ES on neurobehavioral outcomes in preclinical and clinical settings. We identified eighty six rodent and ten human studies investigating a nutritional intervention to ameliorate ES-induced impairments. The human evidence to date, is too few and heterogeneous in terms of interventions, thus not allowing hard conclusions, however the preclinical studies, despite their heterogeneity in terms of designs, interventions used, and outcomes measured, showed nutritional interventions to be promising in combatting ES-induced impairments. Furthermore, we discuss the possible mechanisms involved in the beneficial effects of nutrition on the brain after ES, including neuroinflammation, oxidative stress, hypothalamus-pituitary-adrenal axis regulation and the microbiome-gut-brain axis. Lastly, we highlight the critical gaps in our current knowledge and make recommendations for future research to move the field forward.

The regeneration of the enthesis remains a formidable challenge in regenerative medicine. However, key regulators underlying unsatisfactory regeneration remain poorly understood. This study reveals that the purinergic receptor P2X7 (P2X7R)/Nod-like receptor family protein 3 (NLRP3) inflammasome axis suppresses enthesis regeneration by amplifying IL-1β-mediated inflammatory cross-talk and suppressing docosatrienoic acid (DTA) metabolic cross-talk. NLRP3 inflammasomes were activated in macrophages following enthesis injury, thereby impairing the histological and functional recovery of the injured enthesis. Single-cell RNA sequencing (scRNA-seq) indicated that Nlrp3 knockout attenuated pathological inflammation and ameliorated the detrimental effects of IL-1β signaling cross-talk. Furthermore, NLRP3 inflammasomes suppressed the secretion of anti-inflammatory cytokines (IL-10 and IL-13) and DTA. The NLRP3 inflammasome-mediated secretome reduced differentiation and migration of stem cells. Neutralizing IL-1β or replenishing docosatrienoic acid accelerated enthesis regeneration. Moreover, conditional knockout of P2rx7 in myeloid cells attenuated NLRP3 inflammasome activation and facilitated enthesis regeneration. This study demonstrates that the P2X7R/NLRP3 inflammasome axis represents a promising therapeutic target for enthesis repair.

Dengue virus (DENV) infection imposes a significant global health burden, driven by its ability to manipulate host cellular processes to facilitate replication and evade immune defenses. This review explores the complex interplay between DENV, host immunometabolism, and signaling pathways. DENV induces metabolic reprogramming, including glycolytic upregulation, lipid droplet utilization through lipophagy, and alterations in amino acid metabolism, to fulfill its energy and biosynthetic needs. The virus also disrupts mitochondrial dynamics, leading to increased reactive oxygen species (ROS) production, which modulates immune responses but may also contribute to oxidative stress and severe pathology. Concurrently, DENV hijacks host signaling pathways, including PI3K/Akt, NF-κB, and JAK/STAT, to suppress apoptosis, evade type I interferon responses, and drive pro-inflammatory cytokine production. The interplay between these signaling and metabolic pathways highlights a dual role of host processes: enabling viral replication while activating antiviral immune responses. The review also examines potential therapeutic strategies targeting metabolic and signaling pathways to combat DENV infection, including glycolysis inhibitors, lipid metabolism modulators, and host-directed therapies. While significant progress has been made in understanding DENV-induced immunometabolism, further research is needed to elucidate the precise molecular mechanisms and translate these findings into clinical applications. This study underscores the importance of integrating metabolic and signaling insights to identify novel therapeutic targets against DENV and related flaviviruses, addressing the critical need for effective antiviral interventions.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the head and neck. More and more evidence emphasizes the importance of inflammation in the progression of OSCC. The main signaling pathway of acute and chronic inflammation consists of the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome.

This review focuses on the role of NLRP3 immune kinase body and giving a contribution to the development of new treatment strategies against OSCC.

The NLRP3 inflammasome plays a vital role in the pathogenesis and development of OSCC and may serve as a promising therapeutic target for autoimmune diseases.

Inflammasomes are multiprotein complexes of the innate immune system that sense different pathogens or danger signals, and have been implicated in the pathogenesis of multiple human inflammatory diseases. The translocation of adaptor protein ASC from the nucleus to the cytosol is important for inflammasome assembly and activation, but the mechanism remains unclear. Here we show that pharmacological inhibition or genetic deletion of chromosome region maintenance 1 (CRM1) in macrophages significantly inhibits the activation of NLRP3, AIM2, NLRC4 and pyrin inflammasomes. Mechanistically, CRM1 directly binds to the PYD domain of ASC to promote its nuclear-cytosolic transport. More importantly, treatment with CRM1 inhibitor KPT-330 or deletion of CRM1 in myeloid cells attenuates the pathological symptoms of experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our findings reveal that CRM1 is an essential mediator for ASC nuclear export to promote inflammasome assembly and activation, which provides a potential target for inflammasome-related diseases.

Leucine-rich repeat containing 25 (LRRC25), a type I membrane protein, is specifically expressed in myeloid cells including neutrophils and macrophages. The anti-inflammatory role of LRRC25 was suggested in a few pathogenic models. However, its role in cancer immunity has not been interrogated. Here, we demonstrate that LRRC25 is robustly expressed in tumor-associated macrophages (TAMs). Lrrc25 deficiency in the tumor microenvironment (TME) suppresses growth of multiple murine tumor models by reprogramming TAMs toward an anti-tumor phenotype and thereby enhancing infiltration and activation of CD8+ T cells. The Nox2-ROS-Nlrp3-Il1β pathway is elevated in Lrrc25-deficient TAMs. Furthermore, a human myeloid cell line or mice with loss of Lrrc25 appear normal, indicating that LRRC25 is a safe immune target. Our results suggest that as an unappreciated immune checkpoint for tumor immunotherapy, the myeloid-specific membrane protein LRRC25 orchestrates the activity of TAMs via the canonical Nlrp3-IL1β inflammatory pathway and influences CD8+ T cell chemotaxis to the TME.

Spinal cord injury (SCI) represents a significant challenge in the field of neurology due to its complex pathology and the limited efficacy of current treatments. The search for effective therapeutic strategies has led to investigations into molecules that can promote neural repair and functional recovery. Netrin-3, previously known for its roles in axonal guidance and development, emerges as a potential candidate for enhancing recovery post-SCI. Hereby, we used gene therapy to increase Netrin-3 expression in SCI mouse models and evaluated neurological recovery through behavioral tests, histological assessments, and biochemical analyses. Additionally, we examined the activation of the NOD-like receptor family pyrin domain containing 1 (NLRP1) inflammasome and production of interleukin-1β (IL-1β) and IL-18, and confirmed the dependency of Netrin-3's neuroprotective effects on the Adenosine Monophosphate-activated Protein Kinase (AMPK) pathway using an AMPK inhibitor. Our results explores the impact of Netrin-3 on neurological recovery following SCI. It was observed that Netrin-3 expression markedly decreased at both mRNA and protein levels after injury. Enhancing Netrin-3 levels through gene therapy improved neurological outcomes, including locomotor function, reduced lesion size, and normalized spinal cord water content compared to untreated injured mice. Furthermore, Netrin-3 administration mitigated oxidative stress by modulating malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity, and inhibited NLRP1 inflammasome activation, resulting in suppressed IL-1β and IL-18 production. The AMPK pathway was activated by Netrin-3 post-injury, suggesting a mechanism underlying its neuroprotective effects. However, these beneficial impacts were abolished by an AMPK inhibitor, indicating the dependency of Netrin-3's protective actions on the AMPK pathway. Collectively, these findings highlight Netrin-3 as a promising target for developing novel therapies aimed at improving restoration from SCI.

Sensorineural hearing loss (SNHL), the most commonly-occurring form of hearing loss, is caused mainly by injury to or the loss of hair cells and spiral ganglion neurons in the cochlea. Numerous environmental and physiological factors have been shown to cause acquired SNHL, such as ototoxic drugs, noise exposure, aging, infections, and diseases. Several programmed cell death (PCD) pathways have been reported to be involved in SNHL, especially some novel PCD pathways that have only recently been reported, such as ferroptosis, necroptosis, and pyroptosis. Here we summarize these PCD pathways and their roles and mechanisms in SNHL, aiming to provide new insights and potential therapeutic strategies for SNHL by targeting these PCD pathways.

Pyroptosis, a highly inflammatory form of programmed cell death, plays a key role in diseases such as sepsis, rheumatoid arthritis, Alzheimer's disease, and COPD. It is driven by inflammasome activation, leading to the release of pro-inflammatory cytokines. Pyridoxine (Vitamin B6), an essential micronutrient with known anti-inflammatory effects, has been suggested as a potential regulator of inflammasome activation and pyroptosis. This review examines current evidence on pyridoxine's role in modulating pyroptosis.

A literature search was conducted in PubMed, Scopus, and Web of Science for studies published between 2014 and 2024. The search focused on pyridoxine's relationship with inflammation, inflammasomes, and pyroptosis pathways using keywords such as "pyridoxine," "Vitamin B6," "pyroptosis," "inflammasome," "caspase-1," and "gasdermin D." Both preclinical and human studies were reviewed, with emphasis on molecular mechanisms underlying pyridoxine's anti-inflammatory effects.

Studies consistently showed that pyridoxine reduced inflammasome activation, decreased pro-inflammatory cytokine production, and inhibited caspase-1 (CASP-1) activity, thereby suppressing pyroptosis. Human studies, though indirect, linked higher pyridoxine levels to reduced systemic inflammation, suggesting a possible anti-pyroptotic effect.

Pyridoxine shows potential as an anti-pyroptotic agent due to its anti-inflammatory and immunomodulatory properties. However, further well-designed clinical trials are needed to confirm its role in controlling pyroptosis, especially in diseases associated with excessive inflammasome activation.

Peptic ulcers have long been a focus of medical research due to their significant impact on public health worldwide. Traditionally attributed to factors such as Helicobacter pylori infection and excessive gastric acid secretion, recent scientific endeavors have increasingly unveiled the pivotal role of immunohematological responses in the pathogenesis and clinical course of peptic ulcers. This review aims to synthesize and analyze the intricate relationship between peptic ulcers and immunohematological responses, shedding light on the complex interplay between the immune system and ulcer development, progression, and healing. Immunological factors, encompassing inflammatory mediators, immune cells, and the host response to H pylori, play a substantial role in the multifaceted landscape of peptic ulcers. Inflammation orchestrated by cytokines and chemokines derived from immune cells intricately contributes to mucosal damage and repair processes. Moreover, the chronic nature of H pylori infection triggers a cascade of immune responses, involving both innate and adaptive immunity, which significantly influences the course of ulceration. This paper consolidates current knowledge while highlighting the need for further research elucidating the intricate immunological pathways involved in peptic ulcer pathogenesis. The integration of immunology into the broader context of peptic ulcer disease presents opportunities for innovative therapeutic interventions aimed at modulating immune responses for improved clinical outcomes and enhanced patient care. Ultimately, unraveling the intricate relationship between peptic ulcers and immunohematological responses holds significant promise in advancing the understanding and management of this prevalent gastrointestinal disorder.

Immune checkpoint blockade (ICB) therapies have emerged as promising treatment of cancer, but the efficacy is limited. NLRP3 inflammasome activation in tumor microenvironment can promote the infiltration of cytotoxic lymphocytes and antitumor immunity, but it is unclear whether ICB resistance can be overcome by directly targeting NLRP3. Here we show that a small molecule compound directly targeting NLRP3 can induce inflammasome activation and anti-tumor immunity. 2-guanidinobezimidazole (2GBI) directly bound to NLRP3 and induced inflammasome activation, which was independent of potassium efflux, chloride efflux and mitochondrial dysfunction. 2GBI treatment alone promoted anti-tumor immunity and inhibited tumor growth via NLRP3-dependent manner. Moreover, 2GBI treatment could overcome ICB resistance and exerted synergistic anti-tumor effects. These results suggest that targeting NLRP3 is a potential strategy to induce anti-tumor immunity and improve the efficacy of ICB.

Neuropsychiatric disorders significantly impact global health and socioeconomic well-being, highlighting the urgent need for effective treatments. Chronic inflammation, often driven by the innate immune system, is a key feature of many neuropsychiatric conditions. NOD-like receptors (NLRs), which are intracellular sensors, detect danger signals and trigger inflammation. Among these, NLR protein (NLRP) inflammasomes play a crucial role by releasing pro-inflammatory cytokines and inducing a particular cell death process known as pyroptosis. Pyroptosis is defined as a proinflammatory form of programmed cell death executed by cysteine-aspartic proteases, also known as caspases. Currently, the role of pyroptotic flux has emerged as a critical factor in innate immunity and the pathogenesis of multiple diseases. Emerging evidence suggests that the induction of pyroptosis, primarily due to NLRP inflammasome activation, is involved in the pathophysiology of various neuropsychiatric disorders, including depression, stress-related issues, schizophrenia, autism spectrum disorders, and neurodegenerative diseases. Within this framework, the current review explores the complex relationship between pyroptosis and neuropsychiatric diseases, aiming to identify potential therapeutic targets for these challenging conditions.

NLRP3 (NOD, LRR and pyrin domain-containing protein 3) inflammasome is important for host defense against infections and maintaining homeostasis. Aberrant activation of NLRP3 inflammasome is closely related to various inflammatory diseases. Post-translational modifications are critical for NLRP3 inflammasome regulation. However, the mechanism of NLRP3 inflammasome activation remains incompletely understood. Here, it is demonstrated that the Ufm1 E3 ligase Ufl1 mediated UFMylation is essential for NLRP3 inflammasome activation. Mechanistically, Ufl1 binds and UFMylates NLRP3 in the priming stage of NLRP3 activation, thereby sustaining the stability of NLRP3 by preventing NLRP3 K63-linked ubiquitination and the subsequent autophagic degradation. It is further demonstrated that myeloid cell-specific Ufl1 or Ufm1 deficiency in mice significantly alleviated inflammatory responses and tissue damage following lipopolysaccharide (LPS)-induced endotoxemia and alum-induced peritonitis. Thus, the findings offer new insights into potential therapeutic targets for NLRP3 inflammasome-related diseases by targeting the UFMylation system.

Gasdermins (GSDMs), functioning as membrane perforating proteins, can be activated by canonical inflammasomes, noncanonical inflammasomes, as well as non-inflammasomes, leading to cell pyroptosis and the subsequent release of inflammatory mediators. Increasing evidence has implicated that GSDMs are associated with chronic kidney disease (CKD), including diabetes nephropathy, lupus nephritis, obstructive nephropathy, and crystalline nephropathy. This review centers on the role of GSDMs-mediated pyroptosis in the pathogenesis of CKD, providing novel ideas for enhancing the prognosis and therapeutic strategies of CKD.

Neutrophils are increasingly recognized as key contributors to the pathogenesis of Type 1 Diabetes (T1D), yet their precise mechanistic role in disease onset and progression remains incompletely understood. While these innate immune cells reside in pancreatic tissue and support tissue homeostasis under physiological conditions, they can also drive tissue damage by triggering innate immune responses and modulating inflammation. Within the inflammatory milieu, neutrophils establish complex, bidirectional interactions with various immune cells, including macrophages, dendritic cells, natural killer cells, and lymphocytes. Once activated, they may enhance the innate immune response through direct or indirect crosstalk with immune cells, antigen presentation, and β-cell destruction or dysfunction. These mechanisms underscore the multifaceted and dynamic role of neutrophils in T1D, shaped by their intricate immunological interactions. Further research into the diverse functional capabilities of neutrophils is crucial for uncovering novel aspects of their involvement in T1D, potentially revealing new therapeutic targets to modulate disease progression.

There has been abundant research on the variety of programmed cell death pathways. Apoptosis, pyroptosis, and necroptosis under the action of the caspase family are essential for the innate immune response. Caspases are classified into inflammatory caspase-1/4/5/11, apoptotic caspase-3/6/7, and caspase-2/8/9/10. Although necroptosis is not caspase-dependent to transmit cell death signals, it can cross-link with pyroptosis and apoptosis signals under the regulation of caspase-8. An increasing number of studies have reiterated the involvement of the caspase family in acute lung injuries caused by bacterial and viral infections, blood transfusion, and ventilation, which is influenced by noxious stimuli that activate or inhibit caspase engagement pathways, leading to subsequent lung injury. This article reviews the role of caspases implicated in diverse programmed cell death mechanisms in acute lung injury and the status of research on relevant inhibitors against essential target proteins of the described cell death mechanisms. The findings of this review may help in delineating novel therapeutic targets for acute lung injury.

Ischemic stroke, the most prevalent form of stroke, is responsible for the highest disability rates globally and ranks as the primary cause of mortality worldwide. Sirt1, extensively investigated in neurodegenerative disorders, is the most well-known and earliest member of the sirtuins family. However, its mechanism of action during ischemic stroke remains ambiguous. The literature examination revealed the intricate involvement of Sirt1 in regulating both physiological and pathological mechanisms during ischemic stroke. Sirt1 demonstrates deacetylation effects on PGC-1α, HMGB1, FOXOs, and p53. It hinders the activation of NLRP3 inflammasome and NF-κB while also engaging with AMPK. It regulates inflammatory response, oxidative stress, mitochondrial dysfunction, autophagy, pro-death, and necrotic apoptosis. Therefore, the potential of Sirt1 as a therapeutic target for the management of ischemic stroke is promising.

Epidemiological investigations consistently demonstrate an overrepresentation of the elderly in COVID-19 hospitalizations and fatalities, making the advanced age as a major predictor of disease severity. Despite this, a comprehensive understanding of the cellular and molecular mechanisms explaining how old age represents a major risk factor remain elusive. To investigate this, we compared SARS-CoV-2 infection outcomes in young adults (2 months) and geriatric (15-22 months) mice. Both groups of K18-ACE2 mice were intranasally infected with 500 TCID50 of SARS-CoV-2 Delta variant with analyses performed on days 3, 5, and 7 post-infection (DPI). Analyses included pulmonary cytokines, lung RNA-seq, viral loads, lipidomic profiles, and histological assessments, with a concurrent evaluation of the percentage of mice reaching humane endpoints. The findings unveiled notable differences, with aged mice exhibiting impaired viral clearance, reduced survival, and failure to recover weight loss due to infection. RNA-seq data suggested greater lung damage and reduced respiratory function in infected aged mice. Additionally, elderly-infected mice exhibited a deficient antiviral response characterized by reduced Th1-associated mediators (IFNγ, CCL2, CCL3, CXCL9) and diminished number of macrophages, NK cells, and T cells. Furthermore, mass-spectrometry analysis of the lung lipidome indicated altered expression of several lipids with immunomodulatory and pro-resolution effects in aged mice such as Resolvin, HOTrEs, and NeuroP, but also DiHOMEs-related ARDS. These findings indicate that aging affects antiviral immunity, leading to prolonged infection, greater lung damage, and poorer clinical outcomes. This underscores the potential efficacy of immunomodulatory treatments for elderly subjects experiencing symptoms of severe COVID-19.

Colorectal cancer (CRC) ranks third globally in cancer diagnoses. The dysregulation of the NLRP3 inflammasome is prominently linked to several types of cancers. Oridonin, a principal component of Rabdosia rubescens, exhibits inhibitory activity against NLRP3 and is well-recognized for its diverse pharmacological benefits. However, its role in an animal model of colitis-associated colorectal cancer (CACC) remains unexplored. In the present study, the effectiveness of oridonin was investigated against CACC, developed using azoxymethane (AOM), a tumour initiator, and dextran sulphate sodium (DSS), a tumour promoter, in male BALB/c mice. The two-stage murine model of inflammation-associated cancer was established by administering AOM (10 mg/kg b.w.; i.p., once) followed by DSS (2% w/v) in drinking water (3 cycles, 7 days/cycle). Over a span of 10 weeks, the dose-dependent (2.5, 5, and 10 mg/kg, b.w.; i.p.) effects of oridonin were investigated in BALB/c mice. Oridonin significantly alleviated CACC severity, as evidenced by reduced DAI scores and restored body weight. Moreover, it attenuated surrogate markers of inflammation, including myeloperoxidase, nitrite, plasma LPS, TNF-α, IL-1β, and DNA damage. Histopathological examination revealed diminished tumorigenesis and apoptotic cells, corroborated by reduced Ki-67 and TNF-α, along with increased p53 expression in the colon. Following oridonin treatment, IHC/immunofluorescence analyses demonstrated a significantly reduced expression of the components of NLRP3 inflammasome including NLRP3, ASC-1, and caspase-1. Notably, the high dose of oridonin (10 mg/kg) consistently exhibited significant protective effects against CACC by modulating various molecular targets. Present findings confirmed the potential of oridonin in the protection of colitis-associated colorectal cancer, providing valuable insights into its mechanism of action and clinical significance.

Diabetes mellitus (DM) is a chronic metabolic disease that often leads to vascular endothelial injury and peripheral neuropathy. Erectile dysfunction (ED), a common condition in andrology, is frequently associated with DM. The incidence of diabetes mellitus-induced ED (DMED) is second only to the cardiovascular complications of diabetes. Compared to other types of ED, DMED presents with more severe symptoms, rapid progression, and notable resistance to phosphodiesterase type 5 inhibitors (PDE5is). Various forms of programmed cell death (PCD)-including apoptosis, autophagy, pyroptosis, and ferroptosis-play pivotal roles in the pathogenesis of DMED. An exacerbation of DMED is linked to critical irritants like advanced glycation end-products (AGEs) and reactive oxygen species (ROS) in the corpus cavernosum tissue. These irritants can spark anomalous activations of diverse PCDs, which damage primary corpus cavernosum cells like cavernous nerve cells, endothelial cells, and myocytes, leading to ED. Hence, we reviewed current knowledge on the mechanisms and therapeutic potential of targeting PCDs in DMED, aiming to advance strategies for enhancing erectile function.

Air pollution has emerged as one of the leading causes of mortality, aggravating cardiovascular diseases. Urban-particulate matter (PM) can accumulate in the cardiovascular system and through inflammation, trigger systemic damage. One of the key mechanisms of this process could be related to the activation of the inflammasome through the pre-existence of a low-grade endotoxemia and PM presence in the cells. Herein, we studied the deleterious effects of urban-PM and Lipopolysaccharide (LPS) exposure in a HL-1 mouse cardiomyocyte cell line. Urban-PM induced biological changes, including mRNA expression of pro-inflammatory genes, intracellular reactive oxygen species (ROS) generation and overexpression of inflammasome-related and structural proteins. The results revealed that urban-PM with different ultrastructure, as determined by transmission electron microscopy (TEM), is embedded inside the cardiomyocytes, leading to the recognition and activation of the inflammatory process. The increase of ROS levels and mRNA levels of pro-inflammatory genes were similarly observed in a dose-dependent manner. In addition, components and proteins of the inflammasome such as associated speck-like protein containing a CARD (ASC), caspase-1 and IL-1β were differentially overexpressed in treated HL-1 cells, as well as structural proteins like Connexin 43 (Cx43). These results provide new insights into the mechanisms that mediate innate pro-inflammatory activation in cardiomyocytes in response to air suspension pollutants.

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous obstructive diseases characterized by airflow limitations and are recognized as significant contributors to fatality all over the globe. Asthma accounts for about 4, 55,000 deaths, and COPD is the 3rd leading contributor of mortality worldwide. The pathogenesis of these two obstructive disorders is complex and involves numerous mechanistic pathways, including inflammation-mediated and non-inflammation-mediated pathways. Among all the pathological categorizations, programmed cell deaths (PCDs) play a dominating role in the progression of these obstructive diseases. The two major PCDs that are involved in structural and functional remodeling in the progression of asthma and COPD are Pyroptosis and Ferroptosis. Pyroptosis is a PCD mechanism mediated by the activation of the Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, leading to the maturation and release of Interleukin-1β and Interleukin-18, whereas ferroptosis is a lipid peroxidation-associated cell death. In this review, the major molecular pathways contributing to these multifaceted cell deaths have been discussed, and crosstalk among them regarding the pathogenesis of asthma and COPD has been highlighted. Further, the possible therapeutic approaches that can be utilized to mitigate both cell deaths at once have also been illustrated.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.

Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS) is a severe clinical syndrome characterized by high morbidity and mortality, primarily due to lung injury. However, the pathogenesis of ALI/ARDS remains a complex issue. In recent years, the role of macrophage pyroptosis in lung injury has garnered extensive attention worldwide. This paper reviews the mechanism of macrophage pyroptosis, discusses its role in ALI/ARDS, and introduces several drugs and intervening measures that can regulate macrophage pyroptosis to influence the progression of ALI/ARDS. By doing so, we aim to enhance the understanding of the mechanism of macrophage pyroptosis in ALI/ARDS and provide novel insights for its treatment.

Involvement of non-canonical inflammasome, comprising inflammatory human caspase-4, caspase-5, and Gasdermin D, in the pathogenesis of oral lichen planus (OLP) has never been demonstrated. We aimed to determine human caspase-4, caspase-5, and Gasdermin D expressions in OLP, to correlate their expressions with OLP severity, and to measure salivary interleukin (IL)-1β levels.

OLP and normal oral mucosal specimens (n = 42 each) were processed for immunohistochemistry or immunoblotting. The clinical score for OLP severity was assessed at the most severe site. The immunohistochemical (IHC) score was a summation of intensity and positive cell scores. Salivary IL-1β levels were measured by enzyme-linked immunosorbent assay (ELISA).

Median IHC scores of caspase-4 and Gasdermin D in OLP group were significantly greater than those in normal mucosal group (P < .01), consistent with significantly upregulated expressions by immunoblotting (P < .05). The IHC scores of caspase-4 and Gasdermin D were positively correlated with the clinical scores (P < .05). Salivary IL-1β levels in the OLP group were significantly greater than those in the normal mucosal group (P < .001).

Our study demonstrates enhanced human caspase-4 and Gasdermin D expressions in relation to increased OLP severity with elevated salivary IL-1β levels, proposing clinical applications of these biomolecules as potential prognostic markers and/or new therapeutic intervention for OLP.