Inflammasome Signaling Pathway Research Articles

Molecular Crossfires between Inflammasome Signalling and Dietary Small Molecule Inhibitors in Neurodegenerative Diseases: Implications for Medical Nutrition Therapy

Neurodegenerative disorders are a range of debilitating conditions that manifest due to the progressive loss of neuronal cells in specific brain regions. Current therapeutic options are less than adequate in many respects. Protein misfolding and aggregation are hallmarks of the most common neurodegenerative disorders. Consequently, they elicit cellular homeostasis disruption, synaptic connection loss, and subsequent cellular apoptosis. In recent years, research has increasingly linked dysregulated inflammatory responses mediated by the inflammasome complex to several neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, Epilepsy, Huntington’s disease, Autism, stroke etc. The inflammasome is a cytosolic multiprotein complex that is essential for innate immunity. Microglia are the primary cells expressing inflammasomes in the central nervous system, although astrocytes, neurons, and infiltrating myeloid cells can also express and activate inflammasomes. Regrettably, dysregulated inflammasome signaling upregulates the release of pro-inflammatory cytokines, as well as activating caspase-1. This process contributes to the continuation of neuroinflammation and subsequent damage to neurons. In this review of existing literatures, we collated empirical evidences about various inflammasome signaling pathways in selected neurological disorders. Majorly, we emphasised their influence on the advancement of diseases and neuronal cell death. Available empirical data showed that dietary small molecule inhibitors offer multi-targeted interactions to inhibit inflammasome signalling and upstream neuroinflammation. Notably, the baseline mechanisms involve suppression of free radicals, downregulating NF-κB and NLRP3 oligomerization, activating anti-inflammatory pathways, reducing ER stress, and modulating the Nrf2-ARE pathway. This shows promise for developing innovative medical nutrition therapies for various neurological conditions.

Celastrol Regulates the Hsp90-NLRP3 Interaction to Alleviate Rheumatoid Arthritis.

Previous studies have verified that celastrol (Cel) protects against rheumatoid arthritis (RA) by inhibiting the NLRP3 inflammasome signaling pathway, but the molecular mechanism by which Cel regulates NLRP3 has not been clarified. This study explored the specific mechanisms of Cel in vitro and in vivo. A type II collagen-induced arthritis (CIA) mouse model was used to study the antiarthritic activity of Cel; analysis of paw swelling, determination of the arthritis score, and pathological examinations were performed. The antiproliferative and antimigratory effects of Cel on TNF-α induced fibroblast-like synoviocytes (FLSs) were tested. Proinflammatory factors were evaluated using enzyme-linked immunosorbent assay (ELISA). The expression of NF-κB/NLRP3 pathway components was determined by western blotting and immunofluorescence staining in vitro and in vivo. The putative binding sites between Cel and Hsp90 were predicted through molecular docking, and the binding interactions were determined using the Octet RED96 system and coimmunoprecipitation. Cel decreased arthritis severity and reduced TNF-α-induced FLSs migration and proliferation. Additionally, Cel inhibited NF-κB/NLRP3 signaling pathway activation, reactive oxygen species (ROS) production, and proinflammatory cytokine secretion. Furthermore, Cel interacted directly with Hsp90 and blocked the interaction between Hsp90 and NLRP3 in FLSs. Our findings revealed that Cel regulates NLRP3 inflammasome signaling pathways both in vivo and in vitro. These effects are induced through FLSs inhibition of the proliferation and migration by blocking the interaction between Hsp90 and NLRP3.

Atractylenolide I Alleviates Indomethacin-Induced Gastric Ulcers in Rats by Inhibiting NLRP3 Inflammasome Activation.

Atractylodes macrocephala Koidz, a traditional Chinese medicine, contains atractylenolide I (ATR-I), which has potential anticancer, anti-inflammatory, and immune-modulating properties. This study evaluated the therapeutic potential of ATR-I for indomethacin (IND)-induced gastric mucosal lesions and its underlying mechanisms. Noticeable improvements were observed in the histological morphology and ultrastructures of the rat gastric mucosa after ATR-I treatment. There was improved blood flow, a significant decrease in the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and IL-18, and a marked increase in prostaglandin E2 (PGE2) expression in ATR-I-treated rats. Furthermore, there was a significant decrease in the mRNA and protein expression levels of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), and nuclear factor-κB (NF-κB) in rats treated with ATR-I. The results show that ATR-I inhibits the NLRP3 inflammasome signaling pathway and effectively alleviates local inflammation, thereby improving the therapeutic outcomes against IND-induced gastric ulcers in rats.

Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation

BackgroundMesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated.MethodsIn the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs.ResultsBoth direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs.ConclusionIn conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.

Daidzein and Equol: Ex Vivo and In Silico Approaches Targeting COX-2, iNOS, and the Canonical Inflammasome Signaling Pathway.

The inflammasome is a cytosolic multiprotein complex associated with multiple autoimmune diseases. Phytochemical compounds in soy (Glycine max) foods, such as isoflavones, have been reported for their anti-inflammatory properties. the anti-inflammatory activity of DZ (daidzein) and EQ (equol) were investigated in an ex vivo model of LPS-stimulated murine peritoneal macrophages and by molecular docking correlation. Cells were pre-treated with DZ (25, 50, and 100 µM) or EQ (5, 10, and 25 µM), followed by LPS stimulation. The levels of PGE2, NO, TNF-α, IL-6, and IL-1β were analyzed by ELISA, whereas the expressions of COX-2, iNOS, NLRP3, ASC, caspase 1, and IL-18 were measured by Western blotting. Also, the potential for transcriptional modulation by targeting NF-κB, COX-2, iNOS, NLRP3, ASC, and caspase 1 was investigated by molecular docking. The anti-inflammatory responses observed may be due to the modulation of NF-κB due to the binding of DZ or EQ, which is translated into decreased TNF-α, COX-2, iNOS, NLRP3, and ASC levels. This study establishes that DZ and EQ inhibit LPS-induced inflammatory responses in peritoneal murine macrophages via down-regulation of NO and PGE2 generation, as well as the inhibition of the canonical inflammasome pathway, regulating NLRP3, and consequently decreasing IL-1β and IL-18 activation.

MiR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signaling.

Diabetes leads to dysregulated macrophage immunometabolism, contributing to accelerated atherosclerosis progression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs (miRs) orchestrate multiple signaling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear. MiRNA profiling revealed significantly lower miR-369-3p expression in aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose containing (HFSC) diet for 12 weeks. miR-369-3p was also reduced in peripheral blood mononuclear cells (PBMCs) from diabetic patients with coronary artery disease (CAD). Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. In vitro, oxLDL treatment reduced miR-369-3p expression in mouse bone marrow-derived macrophages (BMDMs). Metabolic profiling in BMDMs revealed that miR-369-3p overexpression blocked the oxLDL-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation (lL-1β, TNF-a, IL-6). Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signaling pathways. Therapeutic administration of miR-369-3p mimics in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and diabetes-accelerated atherosclerosis, evident by a decrease in plaque size and pro-inflammatory Ly6Chi monocytes. RNA-seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p treated mice, consistent with an increase in macrophage efferocytosis in lesions. Finally, a GPR91 antagonist attenuated oxLDL-induced inflammation in primary monocytes from human subjects with diabetes. These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.

Competitive adsorption of microRNA-532-3p by circular RNA SOD2 activates Thioredoxin Interacting Protein/NLR family pyrin domain containing 3 pathway and promotes pyroptosis of non-alcoholic fatty hepatocytes

ObjectiveThere is a growing body of evidence indicating that pyroptosis, a programmed cell death mechanism, plays a crucial role in the exacerbation of inflammation and fibrosis in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Circular RNAs (circRNAs), functioning as vital regulators within NAFLD, have been shown to mediate the process of cell pyroptosis. This study aims to elucidate the roles and mechanisms of circRNAs in NAFLD.MethodsUtilizing a high-fat diet (HFD)-induced rat model for in vivo experimentation and hepatocytes treated with palmitic acid (PA) for in vitro models, we identified circular RNA SOD2 (circSOD2) as our circRNA of interest through analysis with the circMine database. The expression levels of associated genes and pyroptosis-related proteins were determined using quantitative real-time polymerase chain reaction and Western blotting, alongside immunohistochemistry. Serum liver function markers, cellular inflammatory cytokines, malondialdehyde, lactate dehydrogenase levels, and mitochondrial membrane potential, were assessed using enzyme-linked immunosorbent assay, standard assay kits, or JC-1 staining. Flow cytometry was employed to detect pyroptotic cells, and lipid deposition in liver tissues was observed via Oil Red O staining. The interactions between miR-532-3p/circSOD2 and miR-532-3p/Thioredoxin Interacting Protein (TXNIP) were validated through dual-luciferase reporter assays and RNA immunoprecipitation experiments.ResultsOur findings demonstrate that, in both in vivo and in vitro NAFLD models, there was an upregulation of circSOD2 and TXNIP, alongside a downregulation of miR-532-3p. Mechanistically, miR-532-3p directly bound to the 3'-UTR of TXNIP, thereby mediating inflammation and cell pyroptosis through targeting the TXNIP/NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling pathway. circSOD2 directly interacted with miR-532-3p, relieving the suppression on the TXNIP/NLRP3 signaling pathway. Functionally, the knockdown of circSOD2 or TXNIP improved hepatocyte pyroptosis; the deletion of miR-532-3p reversed the effects of circSOD2 knockdown, and the deletion of TXNIP reversed the effects of circSOD2 overexpression. Furthermore, the knockdown of circSOD2 significantly mitigated the progression of NAFLD in vivo.ConclusioncircSOD2 competitively sponges miR-532-3p to activate the TXNIP/NLRP3 inflammasome signaling pathway, promoting pyroptosis in NAFLD.

Downregulation of otulin induces inflammasome activation in neutrophilic asthma

Neutrophilic asthma (NA) is a severe asthma phenotype associated with steroid resistance and IL-1β overproduction; however, the exact mechanism remains unclear. Moreover, the dysfunction of TNF-α signaling pathway, a regulator of IL-1β production, was associated with the deficiency of ovarian tumor protease deubiquitinase with linear linkage specificity (otulin) in autoimmune patients. We hypothesized that otulin downregulation in macrophages (Mφ) could trigger Mφ activation via the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway. We assessed the expressions of otulin in blood monocyte subsets from NA patients and in alveolar Mφ from NA mice. Additionally, we evaluated the functional consequences of otulin deficiency in bone marrow-derived Mφ. The effects of inhibiting receptor-interacting protein kinase (RIPK)-1 and RIPK-3 on neutrophils and group 3 innate lymphoid cells (ILC3s) were assessed invitro and invivo. When comparing nonclassical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients compared to healthy controls (P= .005). Moreover, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. After otulin knockdown in bone marrow-derived Mφ, we observed spontaneous IL-1β production depending on NLRP3 inflammasome. Moreover, the infiltrated neutrophils and ILC3s were significantly decreased by combined treatment of RIPK-1 and RIPK-3 inhibitors through blocking IL-1β release in NA. IL-1β overproduction caused by a deficiency of otulin, an upstream triggering factor, could be a promising diagnostic and therapeutic target for NA.

The Lactobacillus plantarum P-8 Probiotic Microcapsule Prevents DSS-Induced Colitis through Improving Intestinal Integrity and Reducing Colonic Inflammation in Mice.

Probiotics, recognized as beneficial and active microorganisms, often face challenges in maintaining their functionality under harsh conditions such as exposure to stomach acid and bile salts. In this investigation, we developed probiotic microcapsules and assessed their protective effects and underlying mechanisms in a murine model of dextran sulfate sodium (DSS)-induced colitis using male C57BL/6J mice. The administration of the probiotic microcapsules significantly mitigated body weight loss, prevented colon length shortening, decreased the disease activity index scores, and reduced histopathological scores in mice with DSS-induced colitis. Concurrently, the microencapsulated probiotics preserved intestinal barrier integrity by upregulating the expressions of tight junction proteins ZO-1 and occludin, as well as the mucus layer component MUC-2. Moreover, the treatment with probiotic microcapsules suppressed the activation of the NLRP3 inflammasome signaling pathway in the context of DSS-induced colitis. In conclusion, these findings support the utilization of probiotic microcapsules as a potential functional food ingredient to maintain the permeability of the intestinal barrier and alleviate colonic inflammation in UC.

MTORC1 accelerates osteosarcoma progression via m6A-dependent stabilization of USP7 mRNA

Osteosarcoma (OS) is considered a sex steroid hormone-dependent bone tumor. The development and progression of OS are regulated by 17β-estradiol (E2). However, the detailed mechanisms of E2-modulated OS progression remained to be elucidated. Here, we found that E2-activated mammalian target of rapamycin (mTOR) signaling promoted N6-methyladenosine (m6A) modification through regulating WTAP. Inhibition of mTOR complex 1 (mTORC1) reversed E2-activated WTAP expression. Meanwhile, inhibition of mTORC1 suppressed OS cell proliferation and migration. Deficiency of TSC2 activated mTORC1 signaling and enhanced OS cell proliferation and migration, while abrogated by Rapamycin. Interestingly, mTOMC1 promoted mRNA stability of ubiquitin-specific protease 7 (USP7) through m6A modification. Loss of USP7 suppressed the proliferation, migration, and ASC specks, while promoted apoptosis of OS cells. USP7 interacted with NLRP3 and deubiquitinated NLRP3 through K48-ubiquitination. USP7 was upregulated and positive correlation with NLRP3 in OS patients with high level of E2. Loss of USP7 suppressed the progression of OS via inhibiting NLRP3 inflammasome signaling pathway. Our results demonstrated that E2-activtated mTORC1 promoted USP7 stability, which promoted OS cell proliferation and migration via upregulating NLRP3 expression and enhancing NLRP3 inflammasome signaling pathway. These results discover a novel mechanism of E2 regulating OS progression and provide a promising therapeutic target for OS progression.

Fucoxanthin Alleviates Dextran Sulfate Sodium-Induced Colitis and Gut Microbiota Dysbiosis in Mice.

The purpose of this study was to evaluate the preventive role and underlying mechanisms of fucoxanthin (Fx) on dextran sulfate sodium (DSS)-induced colitis in mice. The present data demonstrated that oral administration of Fx (50 and 200 mg/kg body weight/day) for 36 days significantly alleviated the severity of colitis in DSS-treated mice, as evidenced by attenuating body weight loss, bloody stool, diarrhea, shortened colon length, colonic epithelium distortion, a thin mucus layer, goblet cell depletion, damaged crypts, and extensive infiltration of inflammatory cells in the colonic mucosa. Additionally, Fx notably relieved DSS-induced intestinal epithelial barrier dysfunction via maintaining the tight junction function and preventing excessive apoptosis of colonic epithelial cells. Moreover, Fx effectively diminished colonic inflammation and oxidative stress in DSS-treated mice, and its mechanisms might be due to blunting the activation of NF-κB and NLRP3 inflammasome signaling pathways. Furthermore, Fx also modulates DSS-induced gut microbiota dysbiosis via recovering the richness and diversity of gut microbiota and reshaping the structure of gut microbiota, such as increasing the Firmicutes and Bacteroidota (F/B) ratio and elevating the relative abundance of some potential beneficial bacteria, including Lactobacillaceae and Lachnospiraceae. Overall, Fx might be developed as a promising functional ingredient to prevent colitis and maintain intestinal homeostasis.

Effects of NLRP3 Inflammasome Mediated Pyroptosis on Cardiovascular Diseases and Intervention Mechanism of Chinese Medicine.

Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway is an important mechanism underlying myocardial pyroptosis and plays an important role in inflammatory damage to myocardial tissue in patients with cardiovascular diseases (CVDs), such as diabetic cardiomyopathy, ischemia/reperfusion injury, myocardial infarction, heart failure and hypertension. Noncoding RNAs (ncRNAs) are important regulatory factors. Many Chinese medicine (CM) compounds, including their effective components, can regulate pyroptosis and exert myocardium-protecting effects. The mechanisms underlying this protection include inhibition of inflammasome protein expression, Toll-like receptor 4-NF-κB signal pathway activation, oxidative stress, endoplasmic reticulum stress (ERS), and mixed lineage kinase 3 expression and the regulation of silent information regulator 1. The NLRP3 protein is an important regulatory target for CVD prevention and treatment with CM. Exploring the effects of the interventions mediated by CM and the related mechanisms provides new ideas and perspectives for CVD prevention and treatment.

Gasdermins: a dual role in pyroptosis and tumor immunity.

The gasdermin (GSDM) protein family plays a pivotal role in pyroptosis, a process critical to the body's immune response, particularly in combatting bacterial infections, impeding tumor invasion, and contributing to the pathogenesis of various inflammatory diseases. These proteins are adept at activating inflammasome signaling pathways, recruiting immune effector cells, creating an inflammatory immune microenvironment, and initiating pyroptosis. This article serves as an introduction to the GSDM protein-mediated pyroptosis signaling pathways, providing an overview of GSDMs' involvement in tumor immunity. Additionally, we explore the potential applications of GSDMs in both innovative and established antitumor strategies.

A novel flavonol-polysaccharide from Tamarix chinensis alleviates influenza A virus-induced acute lung injury. Evidences for its mechanism of action

BackgroundTamarix chinensis Lour. is a Chinese medicine used for treating inflammation-related diseases and its crude polysaccharides (MBAP90) exhibited significant anticomplement activities in vitro. PurposeTo obtain anticomplement homogenous polysaccharides from MBAP90 and explore its therapeutic effects and potential mechanism on influenza A virus (IAV)-induced acute lung injury (ALI). MethodsAnticomplement activity-guided fractionation of the water-soluble crude polysaccharides from the leaves and twigs of T. chinensis were performed by diethylaminoethyl-52 (DEAE-52) cellulose and gel permeation columns to yield a homogeneous polysaccharide MBAP-5, which was further characterized using ultra-high-performance liquid chromatography-ion trap tandem mass spectrometry (UPLC-IT-MS) and nuclear magnetic resonance (NMR) analysis. In vitro, the anticomplement activity of MBAP-5 through classical pathway was measured using a hemolytic test. The therapeutic effects of MBAP-5 on ALI were evaluated in H1N1-infected mice. H&E staining, enzyme linked immunosorbent assay (ELISA), immunohistochemistry, and western blot were used to systematically access lung histomorphology, inflammatory cytokines, degree of complement component 3c, 5aR, and 5b-9 (C3c, C5aR, and C5b-9) deposition, and inflammasome signaling pathway protein expressions in lung tissues. ResultsMBAP-5 was a novel flavonol-polysaccharide with the molecular weight (Mw) of 153.6 kDa. Its structure was characterized to process a backbone of →4)-α-D-GlcpA-(1→, →6)-α-D-Glcp-(1→, →3,4)-α-D-Glcp-(1→, →3,4,6)-α-D-Glcp-(1→, and →4,6)-β-D-Glcp-(1→, as well as branches of α-L-Araf-(1→ and β-D-Galp-(1→. Particularly, O-3 of →3,4,6)-α-D-Glcp-(1→ was substituted by quercetin. In vitro assay showed that MBAP-5 had a potent anticomplement activity with a CH50 value of 102 ± 4 µg/ml. Oral administration of MBAP-5 (50 and 100 mg/kg) effectively attenuated the H1N1-induced pulmonary injury in vivo by reducing pulmonary edema, virus replication, and inflammatory responses. Mechanistically, MBAP-5 inhibited the striking deposition and contents of complement activation products (C3c, C5aR, and C5b-9) in the lung. Toll-like receptor 4 (TLR4) /transcription factor nuclear factor κB (NF-κB) signaling pathway was constrained by MBAP-5 treatment. In addition, MBAP-5 could suppress activation of the inflammasome pathways, including Nod‐like receptor pyrin domain 3 (NLRP3), cysteinyl aspartate specific proteinase-1/12 (caspase-1/12), apoptosis‑associated speck‑like protein (ASC), gasdermin D (GSDMD), interleukin (IL)-1β, and IL-18 expressions. ConclusionsA novel flavonol-polysaccharide MBAP-5 isolated from T. chinensis demonstrated a therapeutic effect against ALI induced by IAV attack. The mechanism might be associated with inhibition of complement system and inflammasome pathways activation.

Haemolysin Ahh1 secreted from Aeromonas dhakensis activates the NLRP3 inflammasome in macrophages and mediates severe soft tissue infection

Severe soft tissue infections caused by Aeromonas dhakensis, such as necrotizing fasciitis or cellulitis, are prevalent in southern Taiwan and around the world. However, the mechanism by which A. dhakensis causes tissue damage remains unclear. Here, we found that the haemolysin Ahh1, which is the major virulence factor of A. dhakensis, causes cellular damage and activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome signalling pathway. Deletion of ahh1 significantly downregulated caspase-1, the proinflammatory cytokine interleukin 1β (IL-1β) and gasdermin D (GSDMD) and further decreased the damage caused by A. dhakensis in THP-1 cells. In addition, we found that knockdown of the NLRP3 inflammasome confers resistance to A. dhakensis infection in both THP-1 NLRP3-/- cells and C57BL/6 NLRP3-/- mice. In addition, we demonstrated that severe soft-tissue infections treated with antibiotics combined with a neutralizing antibody targeting IL-1β significantly increased the survival rate and alleviated the degree of tissue damage in model mice compared control mice. These findings show that antibiotics combined with therapies targeting IL-1β are potential strategies to treat severe tissue infections caused by toxin-producing bacteria.

The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage and bone. RA is commonly accompanied by extra-articular comorbidities. The pathogenesis of RA and its comorbidities is complex and not completely elucidated. The assembly of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces the maturation of interleukin (IL)-1β and IL-18 and leads to the cleavage of gasdermin D with promoting pyroptosis. Accumulative evidence indicates the pathogenic role of NLRP3 inflammasome signaling in RA and its comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, and interstitial lung diseases. Although the available therapeutic agents are effective for RA treatment, their high cost and increased infection rate are causes for concern. Recent evidence revealed the components of the NLRP3 inflammasome as potential therapeutic targets in RA and its comorbidities. In this review, we searched the MEDLINE database using the PubMed interface and reviewed English-language literature on the NLRP3 inflammasome in RA and its comorbidities from 2000 to 2023. The current evidence reveals that the NLRP3 inflammasome contributes to the pathogenesis of RA and its comorbidities. Consequently, the components of the NLRP3 inflammasome signaling pathway represent promising therapeutic targets, and ongoing research might lead to the development of new, effective treatments for RA and its comorbidities.

Fucoxanthin alleviates lipopolysaccharide-induced intestinal barrier injury in mice.

The aim of this study was to evaluate the preventive role and underlying mechanisms of fucoxanthin (Fx) on lipopolysaccharide (LPS)-induced intestinal barrier injury in mice. Our results demonstrated that the oral administration of Fx (50 and 200 mg per kg body weight per day) for consecutive 7 days significantly alleviated the severity of LPS-induced intestinal barrier injury in mice, as evidenced by attenuating body weight loss, improving intestinal permeability, and ameliorating intestinal morphological damage such as reduction in the ratio of the villus length to the crypt depth (V/C), intestinal epithelium distortion, goblet cell depletion, and low mucin 2 (MUC2) expression. Fx also significantly mitigated LPS-induced excessive apoptosis of intestinal epithelial cells (IECs) and curbed the decrease of tight junction proteins including claudin-1, occludin, and zonula occludens-1 in the ileum and colon. Additionally, Fx effectively alleviated LPS-induced extensive infiltration of macrophages and neutrophils into the intestinal mucosa, the overproduction of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1beta (IL-1β) and IL-6, and gasdermin D (GSDMD)-mediated pyroptosis of IECs. The underlying mechanisms might be associated with inhibiting the activation of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs) and nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathways. Moreover, Fx also notably restrained intestinal reactive oxygen species (ROS), malondialdehyde and protein carbonylation levels in LPS-treated mice, and it might be mediated by activating the nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway. Overall, these findings indicated that Fx might be developed as a potential effective dietary supplement to prevent intestinal barrier injury.

Novel therapies for MDS and future prospects

Myelodysplastic syndromes (MDS) are clonal diseases resulting from the accumulation of genetic mutations. In general, MDS is categorized into two risk groups, with management and treatment varying significantly based on this classification. Over the past two decades, allogeneic transplantation and hypomethylating agents (HMAs) have become the standard of care and remain crucial for higher-risk MDS. Unfortunately, no new drugs have emerged to replace HMAs as the standard of care. However, the landscape of practice and research in MDS has evolved. In 2022, the focus of diagnostic classification of MDS shifted significantly from morphology to genetic alterations. As a result, treatment strategies centered on genetic mutations are now already used internationally. Revisions made to the International Working Group (IWG) criteria for assessing treatment response in 2023 are expected to further improve accuracy. Meanwhile, interest has increased in understanding the relationship between inflammation and the development and progression of lower-risk MDS. This year, luspatercept, an anti-anemic agent targeting the TGFβ pathway, became available for clinical use in Japan. Various research initiatives are currently underway to develop new medicines targeting specific molecules within innate immune and inflammasome-signaling pathways, including IL-1β, CD33, TLR, IRAK4, and p38MAPK.

Role of Pyroptosis in Endometrial Cancer and Its Therapeutic Regulation.

Pyroptosis is an inflammatory cell death induced by inflammasomes that release several pro-inflammatory mediators such as interleukin-18 (IL-18) and interleukin-1β (IL-1β). Pyroptosis, a type of programmed cell death, has recently received increased interest both as a therapeutic and immunological mechanism. Numerous studies have provided substantial evidence supporting the involvement of inflammasomes and pyroptosis in a variety of pathological conditions including cancers, nerve damage, inflammatory diseases and metabolic conditions. Researchers have demonstrated that dysregulation of pyroptosis and inflammasomes contribute to the progression of endometriosis and gynecological malignancies. Current research also indicates that inflammasome and pyroptosis-dependent signaling pathways may further induce the progression of endometrial cancer (EC). More specifically, dysregulation of NLR family pyrin domain 3 (NLRP3) and caspase-1-dependent pyroptosis play a contributory role in the pathogenesis and development of EC. Therefore, pyroptosis-regulated protein gasdermin D (GSDMD) may be an independent prognostic biomarker for the detection of EC. This review presents the molecular mechanisms of pyroptosis-dependent signaling pathways and their contributory role and function in advancing EC. Moreover, this review offers new insights into potential future applications and innovative approaches in utilizing pyroptosis to develop effective anti-cancer therapies.

Protective effect of short-chain fructo-oligosaccharides from chicory on alcohol-induced injury in GES-1 cells via Keap1/Nrf2 and NLRP3 inflammasome signaling pathways.

Numerous studies have demonstrated that polysaccharides derived from chicory possess the ability to regulate host signaling and modify mucosal damage. Yet, the effect and mechanism of short-chain fructo-oligosaccharides (scFOS) on gastric mucosa remain unclear. Hence, the protective effect of three scFOS (1-Kestose, Nystose, and 1F-Fructofuranosylnystose) against ethanol-induced injury in gastric epithelial (GES-1) cells, and the underlying molecular mechanism involved was investigated in this study. Treatment with 7% ethanol decreased the cell viability of GES-1 cells, resulting in oxidative stress and inflammation. However, pretreatment with scFOS exhibited significant improvements in cell viability, and mitigated oxidative stress and inflammation. scFOS markedly elevated the protein expression of Nrf2, HO-1, SOD1 and SOD2, while suppressing the expression of Keap1. scFOS pretreatment could also maintain mitochondrial membrane potential balance and reduce apoptosis. In addition, scFOS was observed to reduce the protein level of NLRP3, Caspase-1 and ASC. In conclusion, scFOS served a preventive function in mitigating oxidative stress and inflammation in ethanol-exposed GES-1 cells through modulation of the Keap1/Nrf2 and NLRP3 inflammasome signaling pathways. Collectively, the results indicated that scFOS could significantly mitigate ethanol-induced gastric cell damage, suggesting its potential for safeguarding gastrointestinal health.