Gastric cancer (GC) is recognized as one of the most prevalent and serious malignancies, distinguished by its high incidence and fatality rates. Given the considerable mortality rate associated with GC, it is imperative to clarify the related pathways of GC development and further identify feasible targets for rational targeted therapy. Accumulating evidence reveals that programmed cell death (PCD) is a crucial element in both the progression and treatment of cancer. Pyroptosis, apoptosis, and necroptosis are three well-studied types of PCD, and a link between them and GC has been established in recent studies. PANoptosis, a comparatively novel type of PCD, shares key traits with pyroptosis, apoptosis, and necroptosis, yet cannot be entirely illustrated by any single model. PANoptosis has been discovered to exert an impact on multiple diseases, including cancer, infections, and inflammatory conditions, consequently offering novel perceptions into the progression and treatment of GC. This review seeks to encapsulate the emerging roles and therapeutic potential of pyroptosis, apoptosis, necroptosis, and PANoptosis in GC, laying the groundwork for the advancement of innovative treatment methods that target important signaling pathways connected with these four forms of PCD.

JOURNAL/nrgr/04.03/01300535-202507000-00028/figure1/v/2024-09-09T124005Z/r/image-tiff Alzheimer's disease is characterized by deposition of amyloid-β, which forms extracellular neuritic plaques, and accumulation of hyperphosphorylated tau, which aggregates to form intraneuronal neurofibrillary tangles, in the brain. The NLRP3 inflammasome may play a role in the transition from amyloid-β deposition to tau phosphorylation and aggregation. Because NLRP3 is primarily found in brain microglia, and tau is predominantly located in neurons, it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines. Here, we found that neurons also express NLRP3 in vitro and in vivo, and that neuronal NLRP3 regulates tau phosphorylation. Using biochemical methods, we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons. In primary neurons and the neuroblastoma cell line Neuro2A, FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-β is present. In the brains of aged wild-type mice and a mouse model of Alzheimer's disease, FUBP3 expression was markedly increased in cortical neurons. Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses. We also found that FUBP3 trimmed the 5' end of DNA fragments that it bound, implying that FUBP3 functions in stress-induced responses. These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to-phospho-tau transition than microglial NLRP3, and that amyloid-β fundamentally alters the regulatory mechanism of NLRP3 expression in neurons. Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice, FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.

Juglone, a naphthoquinone compound that occurs naturally, is present predominantly in the fruits, leaves, and roots of walnut plants. Although its antioxidant and anti-inflammatory effects have been demonstrated in various diseases, its therapeutic potential remains unexplored in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

Our objective was to investigate the therapeutic effectiveness of juglone in treating CP/CPPS and elucidate the potential mechanism involved.

To establish experimental autoimmune prostatitis (EAP) mouse models and macrophage pyroptosis models, the therapeutic impact of juglone on CP/CPPS was evaluated. Molecular docking analysis, a cellular thermal shift assay (CETSA), and consultation with the Human Protein Atlas database were conducted to further explore the target molecules involved in juglone treatment for CP/CPPS. In addition, we utilized immunohistochemistry, immunofluorescence, Western blotting, and flow cytometry to assess macrophage pyroptosis and related pathway protein expressions. The evaluation of oxidative stress (OxS) was conducted through malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) assays. BzATP, an agonist of the NLRP3 pyroptosis pathway, was utilized for recovery experiments both in vitro and in vivo.

Administration of juglone to EAP model mice ameliorated prostatic inflammation, reduced pain symptoms, and decreased proinflammatory cytokine levels. Molecular docking analysis and CETSA, in conjunction with data from the Human Protein Atlas database, indicated that NLRP3, caspase-1, and GSDMD, along with their effects on macrophage pyroptosis, may serve as key targets for the effects of juglone. Furthermore, juglone inhibited the expression of these proteins. Assays of OxS demonstrated that the administration of juglone mitigated OxS in both animal and cellular experiments. These results were reversed with BzATP treatment.

In conclusion, juglone can alleviate EAP by suppressing the pyroptosis of macrophages mediated by NLRP3/GSDMD and alleviating OxS; therefore, juglone has the potential as a therapeutic for CP/CPPS. Furthermore, our studies confirmed that juglone can bind stably to NLRP3, caspase-1, and GSDMD. These findings validate the mechanism of action of juglone and offer valuable insights for the treatment of other diseases mediated by these proteins, such as inflammatory bowel disease, nonalcoholic steatohepatitis, and multiple sclerosis.

The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome consists of pro-caspase-1, NLRP3 and apoptosis-related speckle-like protein (ASC). It can detect multiple microorganisms, endogenous danger signals and environmental stimulus including adenosine triphosphate (ATP), urate, cholesterol crystals, and so on, thereby forming activated NLRP3 inflammasome. During the course of the activation of NLRP3 inflammasome, pro-caspase-1 is transformed into activated caspase-1 that results in the maturation and secretion of interleukin-1beta (IL-1β) and IL-18. The dysfunction of NLRP3 inflammasome participates in multiple diseases such as liver diseases, renal diseases, nervous system diseases and diabetes. Baicalin is the primary bioactive component of Scutellaria baicalensis, which has been used since ancient times. Baicalin has many types of biological functions, such as anti-bacterial, anti-tumor and antioxidant. More and more evidence suggests that baicalin regulation of NLRP3 inflammasome is involved in different diseases. However, the mechanism is still elusive. Here, we reviewed the progress of baicalin regulation of NLRP3 inflammasome in many kinds of diseases to lay a foundation for future researches.

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.

Background: Besides diabetes mellitus, metformin has been identified as a potential therapeutic agent for treating various other conditions that include various cancers, cardiovascular diseases, neurodegenerative diseases, and aging. In cancer, metformin increased apoptotic cell death, while inhibiting it in neurodegenerative diseases. Thus, different modes of metformin action at the molecular level have been proposed. Methods: In this study, we present the mitochondria and the VDAC1 (voltage-dependent anion channel) as a potential target of metformin. Results: Metformin induces VDAC1 overexpression, its oligomerization, and subsequent apoptosis. Metformin analogs phenformin and buformin at much lower concentrations also induce VDAC1 overexpression, oligomerization, and cell death. We demonstrate the interaction of metformin with purified VDAC1, which inhibited its channel conduction in a voltage-dependent manner. Metformin bound to the synthetic VDAC1-N-terminal peptide and binding to this domain was also found by its molecular docking with VDAC1. Moreover, we demonstrated metformin binding to purified hexokinases (HK-I) with a 400-fold lower metformin concentration than that required for cell death induction. In cells, metformin induced HK-I detachment from the mitochondrial VDAC1. Lastly, metformin increased the expression of NLRP3 and ASC and induced their co-localization, suggesting inflammasome activation. Conclusions: The results suggest that VDAC1 is a target for metformin and its analogs, and this is associated with metformin's adverse effects on many diseases.

Liver fibrosis resulting from severe liver damage is a major clinical problem for which effective pharmacological drugs and treatment strategies are lacking. TGF-β, a hallmark of liver fibrosis, has been shown to promote ALK5 phosphorylation in an activated state. Hence, the suppression of ALK5 signal transduction has emerged as a promising therapeutic strategy for the treatment of liver fibrosis. In this study, the imidazole derivative J-1149, which exhibited inhibitory activity against ALK5, was synthesized to exert antifibrotic effects, and the inhibition mechanisms were uncovered. Our findings suggested that J-1149 significantly attenuated HSC activation and liver fibrogenesis by acting on the TGF-β/Smad signaling pathway. Concurrently, the potential of J-1149 to impede the P2X7R/NLRP3 axis, curtail the infiltration of macrophages and neutrophils, and reduce liver fibrogenesis was also highlighted. These results demonstrated that J-1149 is a promising candidate for the treatment of liver fibrosis.

Diabetic encephalopathy (DE) is a neurological complication characterized by neuroinflammation, cognitive impairment, and memory decline, with its pathogenesis closely linked to the activation of the NLRP3 inflammasome. As a central regulator of the innate immune system, the NLRP3 inflammasome plays a pivotal role in DE progression by mediating neuroinflammation, pyroptosis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and microglial polarization. This review systematically explores the molecular mechanisms by which the NLRP3 inflammasome contributes to DE, focusing on its role in neuroinflammatory cascades and neuronal damage, as well as the diabetes-associated physiological changes that exacerbate DE pathogenesis. Furthermore, we summarize emerging therapeutic strategies targeting the NLRP3 inflammasome, including small-molecule inhibitors and bioactive compounds derived from traditional herbal medicine, highlighting their potential for DE treatment. These findings not only advance our understanding of DE but also provide a foundation for developing NLRP3-targeted pharmacological interventions.

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. This comprehensive review aims to elucidate the intricate mechanisms by which inflammation contributes to the development and progression of HF. The review synthesizes current research on the involvement of both innate and adaptive immune responses in HF, highlighting the roles of cytokines, chemokines, and other inflammatory mediators. Recent studies have demonstrated that chronic inflammation, driven by factors such as oxidative stress, neurohormonal activation, and metabolic disturbances, leads to adverse cardiac remodeling and impaired myocardial function. The review explores how systemic inflammation, characterized by elevated levels of inflammatory biomarkers like C-reactive protein (CRP) and interleukin-6 (IL-6), correlates with HF severity and outcomes. Additionally, it discusses the impact of comorbid conditions such as diabetes, obesity, and hypertension on inflammatory pathways and HF risk. The review also delves into the therapeutic implications of targeting inflammation in HF. Despite mixed results from early clinical trials, emerging evidence suggests that anti-inflammatory therapies offer benefits in specific HF phenotypes. The potential of novel therapeutic strategies, including the use of biologics and small molecule inhibitors, is examined in the context of their ability to modulate inflammatory responses and improve clinical outcomes.

Chronic inflammation is a hallmark for Metabolic Syndrome (MetS). It is also one of the most important risk factors for insulin resistance and metabolic disorders. Inflammasomes, which are intracellular multiprotein complexes within the innate immune system, regulate the production and maturation of pro-inflammatory cytokines including interleukin-1β (IL-1β) and IL-18 upon sensing pathogens or danger signals in the cytosol. A growing body of evidence indicates that inflammasomes play a pivotal role in the pathophysiology and progression of metabolic diseases, as deficiency in the key component of inflammasomes protects mice from high fat diet induced obesity and insulin resistance. Thus, in this review, we will summarize the role of inflammasomes in MetS and how to treat MetS by targeting inflammasomes. This may provide novel insights and therapeutic targets for treating metabolic disorders.

Drug-induced toxicity is an important issue in clinical medicine, which typically results in organ dysfunction and adverse health consequences. The family of NOD-like receptors (NLRs) includes intracellular proteins involved in recognizing pathogens and triggering innate immune responses, including the activation of the NLRP3 inflammasome. The NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3) inflammasome is a critical component for both innate and adaptive immune responses and has been implicated in various drug-induced toxicities, including hepatic, renal, and cardiovascular diseases. The unusual activation of the NLRP3 inflammasome causes the release of pro-inflammatory cytokines, such as IL-1β and IL-18, which can lead to more damage to tissues. Targeting NLRP3 inflammasome is a potential therapeutic endeavour for suppressing drug-induced toxicity. This review provides insights into the mechanism, drug-induced organ toxicity, therapeutic strategies, and prospective therapeutic approaches of the NLRP3 inflammasome and summarizes the developing therapies that target the inflammasome unit. This review has taken up one of the foremost endeavours in understanding and inhibiting the NLRP3 inflammasome as a means of generating safer pharmacological therapies.

SARS-CoV-2 hijacks multiple organelles for virion assembly, of which the mechanisms have not been fully understood. Here, we identified a SARS-CoV-2-driven membrane structure named the 3a dense body (3DB). 3DBs are unusual electron-dense and dynamic structures driven by the accessory protein ORF3a via remodeling a specific subset of the trans-Golgi network (TGN) and early endosomal membrane. 3DB formation is conserved in related bat and pangolin coronaviruses but was lost during the evolution to SARS-CoV. During SARS-CoV-2 infection, 3DB recruits the viral structural proteins spike (S) and membrane (M) and undergoes dynamic fusion/fission to maintain the optimal unprocessed-to-processed ratio of S on assembled virions. Disruption of 3DB formation resulted in virions assembled with an abnormal S processing rate, leading to a dramatic reduction in viral entry efficiency. Our study uncovers the crucial role of 3DB in maintaining maximal SARS-CoV-2 infectivity and highlights its potential as a target for COVID-19 prophylactics and therapeutics.

As people age, degenerative bone and joint diseases (DBJDs) become more prevalent. When middle-aged and elderly people are diagnosed with one or more disorders such as osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD), it often signals the onset of prolonged pain and reduced functionality. Chronic inflammation has been identified as the underlying cause of various degenerative diseases, including DBJDs. Recently, excessive activation of pyroptosis, a form of programed cell death (PCD) mediated by inflammasomes, has emerged as a primary driver of harmful chronic inflammation. Consequently, pyroptosis has become a potential target for preventing and treating DBJDs.

This review explored the physiological and pathological roles of the pyroptosis pathway in bone and joint development and its relation to DBJDs. Meanwhile, it elaborated the molecular mechanisms of pyroptosis within individual cell types in the bone marrow and joints, as well as the interplay among different cell types in the context of DBJDs. Furthermore, this review presented the latest compelling evidence supporting the idea of regulating the pyroptosis pathway for DBJDs treatment, and discussed the potential, limitations, and challenges of various therapeutic strategies involving pyroptosis regulation.

In summary, an interesting identity for the unregulated pyroptosis pathway in the context of DBJDs was proposed in this review, which was undertaken as a spoiler of peaceful coexistence between cells in a degenerative environment. Over the extended course of DBJDs, pyroptosis pathway perpetuated its activity through crosstalk among pyroptosis cascades in different cell types, thus exacerbating the inflammatory environment throughout the entire bone marrow and joint degeneration environment. Correspondingly, pyroptosis regulation therapy emerged as a promising option for clinical treatment of DBJDs.

Baicalin is a flavonoid extracted from dried roots of the plant Scutellariabaicalensis. Baicalin n-butyl ester (BNE) is a flavonoid obtained by esterification of baicalin and has anti-inflammatory and antioxidant effects.

The therapeutic efficacy and potential mechanism of BNE in inflammatory bowel disease remain unclear. This study investigated the effects and underlying mechanisms of BNE in ulcerative colitis.

Dextran sulfate sodium (DSS) was used to construct a mouse model of ulcerative colitis, and mice were given intragastric administration of BNE. During the experiment, the changes of body weight and hematochezia of mice were observed. At the end of administration, the levels of inflammatory factors, colonic microbial changes and pyroptosis of colonic cells were measured. Mouse intestinal epithelial cells were stimulated by lipopolysaccharide/adenosine-5'-triphosphate to establish an in vitro model. ELISA, qRT-PCR and immunoblotting were used to explore the effect and mechanism of BNE on pyroptosis.

In vivo, BNE drastically attenuated ulcerative colitis symptoms by relieving body weight loss, a decline in colon length, and destruction of colon tissue structure. BNE also reduced the secretion of pro-inflammatory cytokines, including IL-1β, IL-18, and TNF-α, and reactive oxygen species (ROS). Furthermore, 16S rRNA sequencing analyses of gut microbiota revealed that BNE reversed gut microbiota dysbiosis by reducing the abundance of unclassified-Clostridia-UCG-014 and increasing that of Lachnospiraceae. BNE also inhibited cell pyroptosis in mice with DSS-induced colitis. In vitro analyses showed that BNE decreased the secretion of IL-1β, IL-18, TNF-α, and ROS in lipopolysaccharide/adenosine-5'-triphosphate-stimulated mouse intestinal epithelial cells, and it inhibited pyroptosis mediated by oligomeric domain-like receptor protein 3 (NLRP3). Addition of ROS scavenger and ERK inhibitor further confirmed that BNE down-regulated ROS and inhibited the phosphorylation of ERK, thus inhibiting NLRP3-mediated cell pyroptosis. The magnetic beads pull-down assay showed that BNE had the capacity to bind directly to the ERK proteinin MODE-K cells.

BNE protects against colitis by increasing the abundance of Lachnospiraceae in vivo and suppressing pyroptosis via binding ERK protein and inhibiting ROS/ERK/P-ERK/NLRP3 in vivo and in vitro.

The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) through pattern recognition receptors (PRRs). Inflammasomes, cytoplasmic protein complexes, are activated in response to PAMPs and DAMPs, leading to the release of inflammatory cytokines such as IL-1β and IL-18. NLRP3 inflammasome is one of the best characterized inflammasomes and recently its activation has been associated with granuloma formation, structures that aggregate immune cells in response to infections, such as those caused by bacteria, fungi and parasites, and autoinflammatory diseases, such as sarcoidosis. Activation of NLRP3 inflammasomes in macrophages induces the release of cytokines that recruit immune cells, such as monocytes and lymphocytes, to the site of infection. Neutrophils, monocytes, T and B lymphocytes are important in the formation and maintenance of granulomas. Although NLRP3 plays a key role in the immune response, cell recruitment and granuloma formation, many aspects of its function in different cell types remain to be elucidated. In this review, we aim to outline the NLRP3 inflammasome not only as a protein complex that aids innate immune cells in combating intracellular pathogens but also as a platform with broader implications in orchestrating immune responses. This underexplored aspect of the NLRP3 inflammasome presents a novel perspective on its involvement in immunity. Thus, we review the current understanding of the role of the NLRP3 inflammasome in immune cell infiltration and its significance in the organization and formation of granulomas in inflammatory diseases.

Subarachnoid hemorrhage is one type of strokes with high mortality and disability and there exists several mechanisms in SAH pathology. G-protein-coupled receptor 40 (GPR40) is proven to exert anti-inflammatory effects in several central nervous system (CNS) diseases. However, the precise role of GPR40 in SAH pathogenesis remains largely unknown. In this study, both in vivo and in vitro SAH models were used to investigate the mechanism of GPR40 attenuating neuroinflammation after SAH onset. We found that GPR40 expression in microglia decreased, which promoted IL-1β secretion and aggravated neuronal death after SAH onset. The GPR40 agonist GW9508 attenuated neuronal damage and ameliorated neurological deficits in SAH-model mice. Mechanistically, GPR40 in microglia inhibited pyroptosis, and cytokine production via inhibiting NLRP3/caspase-1/IL-1β pathway. Then the level of IL-1β secreted by microglia and transported to neurons via exosome were decreased, which down-regulated glutaminase, counteracted glutamate accumulation, and facilitated neuronal survival. These results revealed that GPR40 is a novel regulator that inhibits microglia-mediated neuroinflammation and is a potential therapeutic target in SAH therapy.

The NLRP3 inflammasome plays a crucial role as a critical regulator of the immune response and has been implicated in the pathogenesis of numerous diseases. Peptides, known for their remarkable potency, selectivity, and low toxicity, have been extensively employed in disease treatment. Recent research has unveiled the potential of peptides in modulating the activity of the NLRP3 inflammasome. This review begins by examining the structure of the NLRP3 inflammasome, encompassing NLRP3, ASC, and Caspase-1, along with the three activation pathways: canonical, non-canonical, and alternative. Subsequently, we provide a comprehensive summary of peptide modulators targeting the NLRP3 inflammasome and elucidate their underlying mechanisms. The efficacy of these modulators has been validated through in vitro and in vivo experiments on NLRP3 inflammasome regulation. Furthermore, we conduct sequence alignment of the identified peptides and investigate their binding sites on the NLRP3 protein. This work is a foundational exploration for advancing peptides as potential therapeutic agents for NLRP3-related diseases.

Background: Diabetes mellitus (DM) is a common chronic endocrine and metabolic disease, and its complications can involve multiple organs and seriously threaten human health. Double-stranded DNA (dsDNA) plays an important role in the autoimmune system; however, the correlation between dsDNA and DM has not been fully studied. Methods: This study recruited 388 diabetic patients and 2970 healthy controls to investigate the relationship between serum dsDNA and DM. The diagnosis of DM was based on the medical diagnostic and treatment standards for DM published by the American Diabetes Association (ADA). The study adhered to ethical principles and obtained informed consent from all participants. We measured serum dsDNA levels in both diabetic patients and healthy controls. The study examined differences in serum dsDNA levels among diabetic patients under various conditions, including different temperatures, ultraviolet (UV) light exposure, seasons, and clinical indicators. Additionally, quantitative PCR was used to assess the expression of dsDNA receptors, single-stranded RNA (ssRNA) receptors, absent in melanoma factor 2 (AIM2)-related inflammatory factors, and Type I interferon (INF) in the peripheral blood of patients and control groups. Results: Peripheral blood serum dsDNA levels were elevated in diabetic patients compared to controls (mean values 1.09 and 0.97 ng/ml, respectively, p < 0.001). We also found that the gene expression levels of dsDNA receptor, ssRNA receptor, AIM2-related inflammatory factors, and Type I IFN in diabetic patients were upregulated. And serum dsDNA levels correlated with clinical indicators. Conclusions: We have confirmed that DM is closely associated with serum dsDNA levels. Therefore, dsDNA detection shows promise as a novel approach for evaluating DM progression, offering new insights for the future diagnosis and treatment of DM.

The inhibition of the TLR4 receptor has been shown to protect neural structure and improve neurological functions in peripheral nervous system (PNS) diseases. There is a scarcity of research regarding the effect of inflammasomes during the process of neuroinflammation in immune related PNS disorders, such as, Guillain-Barré syndrome (GBS), even though it is an essential part for pathophysiology from immunological diseases that impact central nervous system (CNS). In this investigation, we found that TLR4 expression and formation and activation of the NLRP3 inflammasome were increased in the sciatic nerve of experimental autoimmune neuritis (EAN). Further intraperitoneal injection of the selective TLR4 receptor inhibitor TAK-242 (Resatorvid) showed that TAK-242 not only stopped the advancement of EAN to a certain extent, but also alleviated peripheral nerve injury brought on by EAN, as evidenced by improvements in body weight loss, neurological function scores, and nerve conduction deficits. More importantly, TAK-242 effectively inhibited neuroinflammation in EAN rats, mitigated myelin loss and helped the regeneration and repair of EAN peripheral nerve injury, mainly through suppressing TLR4/NF-κB signaling pathway and decreasing NLRP3 inflammasome activation. Based on these findings, administration of TAK-242 can be used as a potential therapy approach for GBS.

Probiotic therapy holds potential for preventing and treating various gastrointestinal diseases, including diarrhea-predominant irritable bowel syndrome (IBS-D). Previous studies have suggested that it can help restore intestinal mucosal immunity and gut microbiota dysbiosis in IBS-D patients. Probiotics regulate host microbial metabolism and immune homeostasis, thereby improving host health. Effective and persistent colonization is crucial for probiotic therapy, but oral probiotics often suffer from limited efficacy due to loss of biological activity and insufficient colonization in the complex intestinal environment. Currently, formulations that specifically target gut mucosal colonization are scarce. We developed a "Janus" structured nanoclay microgel via microfluidics encapsulating Pediococcus pentosaceus Li05 (Li05) towards this end. Polydopamine enhanced the microgel's adhesion to the intestinal mucosa, prolonging its residence time in the intestine and enabling targeted delivery of active Li05. The nanoclay promoted Li05 aggregation and growth through charge adsorption, preserving its biological activity and ensuring an effective dose for gut colonization. In vivo studies demonstrated that the nanoclay microgel significantly alleviated diarrhea, mucosal inflammation, and gut microbiota dysbiosis in an IBS-D rat model. These findings suggest that this nanoclay microgel is an effective gut targeted formulation able to promote probiotic growth, offering new approaches for future probiotic therapy in IBS-D.

There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.

Doxorubicin (DOX) has received widespread attention as a broad-spectrum antitumor drug. However, it has been a recognized challenge that long-term DOX injections can lead to severe cardiotoxicity. There are numerous interventions to DOX-induced cardiotoxicity, and the most cost-effective is phytochemicals. It has been reported that phytochemicals have complex and diverse biological properties, facilitating the mitigation of DOX-induced cardiotoxicity. DOX-induced cardiotoxicity has numerous pathological mechanisms, and the nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated cardiomyocyte pyroptosis is one of them. This review initially presents an overview of the pathological mechanisms that underlie cardiotoxicity induced by DOX. Subsequently, we present a comprehensive elucidation of the structure and activation of the NLRP3 inflammasome. Finally, we provide a detailed summary of phytochemicals that can mitigate DOX-induced cardiotoxicity by influencing the expression of the NLRP3 inflammasome in cardiomyocytes.

The innate immune system plays a crucial role in defending against Salmonella infection. Inflammasomes are macromolecular complexes that assemble in response to the recognition of pathogen- or danger-associated molecular patterns. These complexes serve as signaling platforms for the activation of inflammatory Caspases, which subsequently triggers the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. This process also initiates pyroptosis, a highly inflammatory form of programmed cell death characterized by lytic cell lysis. Salmonella are intracellular pathogens that proliferate within epithelial cells and macrophages, posing a significant public health risk in both developed and developing countries. During Salmonella infection, the canonical NLRP3 and NLRC4 inflammasome, as well as non-canonical inflammasome, are activated. Unlike NLRC4 and non-canonical inflammasomes, which play crucial roles during intestinal infection phases, the role of NLRP3 inflammasome in resisting Salmonella infection demonstrates a higher degree of complexity and uncertainty. Nonetheless, the activation of NLRP3 inflammasome, along with the downstream innate and adaptive responses, form a robust host immune barrier against potential pathogens. Therefore, successful pathogens must evolve multiple mechanisms to circumvent or counteract these immune barriers. Here we review and discuss the mechanisms of NLRP3 inflammasome activation triggered by intracellular Salmonella, as well as the multiple strategies employed by Salmonella to avoid or delay NLRP3 inflammasome activation. A deeper understanding of how NLRP3 inflammasomes recognize Salmonella and how pathogens evade NLRP3 activation has the potential to facilitate the development of novel prevention and control measures for Salmonella infection.

NLRP3 inflammasome is critical in innate immunity and inflammatory responses. A series of novel sulfonylurea-based NLRP3 inflammasome inhibitors was designed and synthesized. Notably, compound 15 exhibited the potent NLRP3 inhibitory activity, effectively suppressing IL-1β secretion in THP-1 (IC50 = 23 nM), demonstrating better efficacy compared to MCC950. It selectively inhibits NLRP3 activation by disrupting inflammasome assembly, with no effect on NLRC4 or AIM2 inflammasomes. Molecular docking showed that the 1-methyl-4-(methylamino)piperidine moiety forms a novel hydrogen bond with Asp662 in the hydrophilic region of NLRP3. Additionally, compound 15 displayed excellent pharmacokinetic properties with 99.6% oral bioavailability in mice. It exhibited superior efficacy in acute peritonitis and diabetic kidney disease models, surpassing MCC950. Tissue distribution studies confirmed that compound 15 specifically targeted the gut and showed efficacy in an IBD model, comparable to MCC950. These findings highlight compound 15 as a promising lead for novel oral NLRP3 inflammasome inhibitors.

Enzymatic reactions can achieve efficient flow-polymerization with specificity and high stereoselectivity. However, current enzyme-mimic polymerization systems cannot achieve high stereoregularity in flow reactions under mild conditions. This inefficient chain control may be due to the absence of a specific catalyst structure for the target monomer. This study reports a model of enzyme-mimic catalytic material for the polymerization of a specific monomer. In particular, the specific enzyme-mimic photoinitiated flow-polymerization of benzyl acrylate was realized at 22 °C using zinc porphyrin metal-organic framework (Zn-PMOF) membranes with one-dimensional nanochannels, achieving the efficient synthesis of highly heterotactic polymers. Under visible light irradiation, the zinc porphyrin core on the membrane surface could initiate polymerization, while copper porphyrin MOF with similar structures could not. The specific channel structure of the Zn-PMOF membrane provided space for stereochemical control. Control experiments, density functional theory simulations, and spectroscopic characterizations show that the combination of size effect and channel-monomer interactions realized higher monomer conversion and polymer stereoregularity in the flow reaction. Furthermore, the crystallinity, shear stress, and ionic conductivity of enzyme-mimic polymers were considerably better than those of bulk polymerization products. Thus, this study provides a method for enzyme-mimic polymerization with high stereoselectivity under mild conditions.

NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome, integral to innate immunity, has become a pivotal figure in the inflammatory cascade.

This article provides an overview of the NLRP3 inflammasome, reviewing its complicated structure, as well as the diverse signals that trigger its assembly. Furthermore, we explored the intricate relationship between the NLRP3 inflammasome and acute and chronic rejection in solid organ transplantation. Solid organ transplantation stands as a crucial medical intervention, yet its efficacy is challenged by immune-mediated complications, including acute rejection, ischemia-reperfusion injury, and chronic allograft rejection. We also investigated the encouraging potential of immunosuppressive therapies targeting NLRP3 signaling to alleviate inflammatory responses linked to transplantation.

In recent years, the NLRP3 inflammasome has garnered considerable attention owing to its critical functions spanning diverse fields. This study highlights the critical function of the NLRP3 inflammasome and presents insights, offering fresh perspectives on how its modulation might help to improve the outcomes among patients who undergo solid organ transplantations.

NLRP3 inflammasome is activated by diverse stimuli including infections, intracellular and environmental irritants. How NLRP3 senses these unrelated stimuli and what activates NLRP3 remain unknown. Here we report that signal-dependent NLRP3 phase separation initiated its activation, in which the palmitoyltransferase ZDHHC7-mediated tonic NLRP3 palmitoylation and an IDR region in the FISNA domain of NLRP3 play important roles. Moreover, three conserved hydrophobic residues in the IDR critically mediate multivalent weak interactions. NLRP3-activating stimuli including K+ efflux and NLRP3-interacting molecules imiquimod, palmitate, and cardiolipin all cause NLRP3 conformational change and induce its phase separation and activation in cells and/or in vitro. Surprisingly, amphiphilic molecules like di-alcohols used to inhibit biomolecular phase separation and chemotherapeutic drugs doxorubicin and paclitaxel activate NLRP3 independently of ZDHHC7 by directly inducing NLRP3 phase separation. Mechanistically, amphiphilic molecules decrease the solubility of both palmitoylated and non-palmitoylated NLRP3 to directly induce its phase separation and activation while NLRP3 palmitoylation reduces its solubility to some extent without activation. Therefore, ZDHHC7-mediated NLRP3 palmitoylation in resting cells licenses its activation by lowering the threshold for NLRP3 phase separation in response to any of the diverse stimuli whereas NLRP3 solubility-reducing molecules like di-alcohols and chemotherapeutic drugs activate NLRP3 directly. The signal-induced NLRP3 phase separation likely provides the simplest and most direct mechanistic basis for NLRP3 activation.

Parkinson's disease is the second most common neurodegenerative disease, characterized by substantial loss of dopaminergic (DA) neurons, the formation of Lewy bodies (LBs) in the substantia nigra, and pronounced neuroinflammation. The nucleotide-binding domain like leucine-rich repeat- and pyrin domain-containing protein 3 (NLRP3) inflammasome is one of the pattern recognition receptors (PRRs) that function as intracellular sensors in response to both pathogenic microbes and sterile triggers associated with Parkinson's disease. These triggers include reactive oxygen species (ROS), misfolding protein aggregation, and potassium ion (K+) efflux. Upon activation, it recruits and activates caspase-1, then processes the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, which mediate neuroinflammation in Parkinson's disease. In this review, we provide a comprehensive overview of NLRP3 inflammasome, detailing its structure, activation pathways, and the factors that trigger its activation. We also explore the pathological mechanisms by which NLRP3 contributes to Parkinson's disease and discuss potential strategies for targeting NLRP3 as a therapeutic approach.

Inflammasomes are cytoplasmic macromolecular complexes playing an important role in sensing exogenous and endogenous stimuli. Inflammasome activation leads to IL-1β and IL-18 secretion and pyroptosis. The concept of non-self recognition triggering inflammasome activation has been well-established for myeloid cells. However, increasing evidence suggests the presence of functional inflammasome or inflammasome-related components in lymphocytes. Dysregulated expression of inflammasome contributes to the development of many diseases, including cardiovascular, infectious, neurodegenerative diseases and cancer. Multiple clinical trials are being conducted to assess drugs targeting various inflammasome components. This review discusses current knowledge on inflammasome activation in T, B and NK cells and explores their potential as therapeutic targets. Further understanding inflammasome and pyroptotic pathways in lymphocytes may have implications in the development of novel immunotherapeutic strategies.

The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in the exacerbation of myocardial damage and the subsequent development of heart failure following myocardial infarction (MI). Inhibiting NLRP3 inflammasome activation offers a promising therapeutic strategy for mitigating MI-related injury, although no NLRP3 inhibitors have received Food and Drug administration (FDA) approval to date. To identify novel NLRP3 inflammasome inhibitors through the repurposing of FDA-approved drugs, Tamibarotene emerged as a potent inhibitor with a favorable safety profile. Mechanistically, Tamibarotene inhibits NLRP3 inflammasome activation independently of retinoic acid receptor activation, binding to Phe410 and Ile417 within the nucleotide-binding and oligomerization (NACHT) domain in an ATPase activity-dependent manner. This interaction further inhibits the assembly of the NLRP3 inflammasome. In a murine model of MI, Tamibarotene significantly reduced myocardial damage and improved cardiac function by inhibiting NLRP3 inflammasome activation. In summary, NLRP3 has been identified as a direct target of Tamibarotene for myocardial repair following MI, indicating that Tamibarotene could serve as a potential precursor for the development of innovative NLRP3 inhibitors.

Subarachnoid hemorrhage (SAH) is one of the most devastating hemorrhagic strokes. SAH causes neuroinflammation and leads to both early brain injury and delayed brain injury. G-protein-coupled receptor 84 (GPR84), one of the orphan class-A G protein-coupled receptors (GPCRs), exerts pro-inflammatory and pro-phagocytic effects via targeting microglia in the central nervous system (CNS). This research investigated the role of GPR84 on SAH pathology via neuroinflammation.

An enzyme-linked immunosorbent assay was used for GPR84 expression in cerebrospinal fluid (CSF) samples from patients with SAH. An experimental SAH-model mouse was established by stereotactic injection of autologous blood into the chiasmatic cisterna. The SAH model in vitro was established by exposing microglia to hemoglobin. After inhibition of GPR84 in mice by GPR84-siRNA and GPR84-antagonist 3, the neurological deficits were evaluated by modified Garcia test, beam balance test, and Morris water maze. Neuronal death in SAH-model mice was evaluated by Nissl staining. GPR84, NLRP3 inflammasome, and cAMP/PKA expressions were detected by western blot and immunofluorescence.

GPR84 was upregulated in patients after SAH onset. The GPR84 expression in microglia increased after SAH onset, activated NLRP3 inflammasome, and promoted IL-1β secretion. Both GPR84-shRNA and GPR84-antagonist 3 improved neurological deficits in SAH-model mice. Mechanistically, GPR84 activated the NLRP3 inflammasome via the cAMP/PKA signaling pathway to aggravate neuronal injury.

GPR84 promotes NLRP3-mediated pyroptosis and activated NLRP3 inflammation via cAMP/PKA pathway.

This study aimed to investigate the therapeutic potential of scopoletin in ulcerative colitis, with a primary focus on its impact on crucial inflammatory pathways and immune responses. A male mouse model of DSS-induced colitis was employed with six distinct groups: a control group, a group subjected to DSS only, three groups treated with varying scopoletin doses, and the final group treated with dexamethasone. The investigation included an assessment of the effects of scopoletin on colitis symptoms, including alterations in body weight, Disease Activity Index (DAI), and histopathological changes in colonic tissue. Furthermore, this study scrutinized the influence of scopoletin on cytokine production, PPARγ and NF-κB expression, NLRP3 inflammasome, and the composition of intestinal bacteria. Scopoletin treatment yielded noteworthy improvements in DSS-induced colitis in mice, as evidenced by reduced weight loss and colonic shortening (p < 0.05, < 0.01, respectively). It effectively diminished TNF-α, IL-1β, and IL-12 cytokine levels (p < 0.01, p < 0.05), attenuated NLRP3 inflammasome activation and the associated cytokine release (p < 0.05, p < 0.01), and modulated the immune response by elevating PPARγ expression while suppressing NF-κB pathway activation (p < 0.05, p < 0.01). Additionally, scopoletin induced alterations in the gut microbiota composition, augmenting beneficial Lactobacillus and Bifidobacteria while reducing E. coli (p < 0.05). It also enhanced tight junction proteins, signifying an improvement in the intestinal barrier integrity (p < 0.05, < 0.01). Scopoletin is a promising therapeutic agent for managing ulcerative colitis, showing benefits that extend beyond mere anti-inflammatory actions to encompass regulatory effects on gut microbiota and restoration of intestinal integrity.

The concept of higher-order assembly signalling or signalling by co-operative assembly formation (SCAF) was proposed based on the structures of signalling assemblies formed by proteins featuring domains from the death-fold family and the Toll/interleukin-1 receptor domain family. Because these domains form filamentous assemblies upon stimulation and activate downstream pathways through induced proximity, they were envisioned to sharpen response thresholds through the extreme co-operativity of higher-order assembly. Recent findings demonstrate that a central feature of the SCAF mechanism is the nucleation barrier that allows a switch-like, digital or 'all-or-none' response to minute stimuli. In agreement, this signalling mechanism features in cell-death and innate immunity activation pathways where a binary decision is required. Here, we broaden the concept of SCAF to encapsulate the essential kinetic properties of open-ended assembly in signalling, compare properties of filamentous assemblies and other co-operative assemblies such as biomolecular condensates, and review how this concept operates in cells.

Accumulating evidence shows that neuroinflammation substantially contributes to the pathology of depression, a severe psychiatric disease with an increasing prevalence worldwide. Although modulating microglial phenotypes is recognized as a promising therapeutic strategy, effective treatments are still lacking. Previous studies have shown that luteolin (LUT) has anti-inflammatory effects and confers benefits on chronic stress-induced depression. In this study, we investigated the molecular mechanisms by which LUT regulates the functional phenotypes of microglia in mice with depressive-like behaviors. Mice were exposed to chronic restraint stress (CRS) for 7 weeks, and were administered LUT (10, 30, 40 mg· kg-1 ·day-1, i.g.) in the last 4 weeks. We showed that LUT administration significantly ameliorated depressive-like behaviors and decreased hippocampal inflammation. LUT administration induced pro-inflammatory microglia to undergo anti-inflammatory arginase (Arg)-1+ phenotypic polarization, which was associated with its antidepressant effects. Furthermore, we showed that LUT concentration-dependently increased the expression of PPARγ in LPS + ATP-treated microglia and the hippocampus of CRS-exposed mice, promoting the subsequent inhibition of the NLRP3 inflammasome. Molecular dynamics (MD) simulation and microscale thermophoresis (MST) analysis confirmed a direct interaction between LUT and peroxisome proliferator-activated receptor gamma (PPARγ). By using the PPARγ antagonist GW9662, we demonstrated that LUT-driven protection, both in vivo and in vitro, resulted from targeting PPARγ. First, LUT-induced Arg-1+ microglia were no longer detected when PPARγ was blocked. Next, LUT-mediated inhibition of the NLRP3 inflammasome and downregulation of pro-inflammatory cytokine production were reversed by the inhibition of PPARγ. Finally, the protective effects of LUT, which attenuated the microglial engulfment of synapses and prevented apparent synapse loss in the hippocampus of CRS-exposed mice, were eliminated by blocking PPARγ. In conclusion, this study showed that LUT ameliorates CRS-induced depressive-like behaviors by promoting the Arg-1+ microglial phenotype through a PPARγ-dependent mechanism, thereby alleviating microglial pro-inflammatory responses and reversing microglial phagocytosis-mediated synapse loss.

Cardiovascular disease (CVD) continues to be the leading cause of mortality worldwide. The nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in numerous types of CVD. As part of innate immunity, the NLRP3 inflammasome plays a vital role, requiring priming and activation signals to trigger inflammation. The NLRP3 inflammasome leads both to the release of IL-1 family cytokines and to a distinct form of programmed cell death called pyroptosis. Inflammation related to CVD has been extensively investigated in relation to the NLRP3 inflammasome. In this review, we describe the pathways triggering NLRP3 priming and activation and discuss its pathogenic effects on CVD. This study also provides an overview of potential therapeutic approaches targeting the NLRP3 inflammasome.

Quantifying systemic inflammation (SI) in acutely decompensated cirrhosis (ADC) is of major importance because SI is a driver of the most severe forms of ADC, including acute-on-chronic liver failure (ACLF). Blood biomarkers of SI already evaluated in ADC failed to appropriately assess SI in ADC. We aimed to investigate whether gene expression related to circulating immune cells could quantify SI in ADC.

Standard biomarkers (white cell count, C reactive protein, cytokines) and genome-wide RNA expression (RNA-sequencing) were obtained in blood from 700 patients with ADC at the time of their hospital admission. A composite score based on standard biomarkers of SI (Chronic Liver Failure-Standard Biomarkers Composite (CLIF-SBC) score) and a gene score (CLIF-Systemic Inflammation Gene (SIG) score) composed of the 28 top differentially expressed immune cell-related genes in the comparison between high-severity and low-severity clinical phenotypes were computed. Among the 700 patients, the CLIF-SIG score was repeated once during follow-up in 375 patients, and 3 times or more in 46 patients.

The CLIF-SIG score was more accurate in reflecting clinical severity induced by SI than the CLIF-SBC score (area under the curve 0.803 vs 0.658). A CLIF-SIG score of 0.386 (Youden Index) was the best cut-off level discriminating patients with poor outcomes from the others, in all clinical scenarios. Sequential measurement of the CLIF-SIG score showed that 78% of patients were admitted at the peak or descending part of the SI-wave. ACLF developed during hospitalisation in 80% of patients with a CLIF-SIG score >0.386 on admission.

In patients with ADC, the CLIF-SIG score is an accurate estimator of SI, clinical course severity and prognosis.