Search Results (1,058)

Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the HEXB gene, which encodes the β-subunit of the enzyme β-hexosaminidase. Lysosomal storage of GM2 triggers inflammation in the CNS and periphery. The NLRP3 inflammasome is an important coordinator of pro-inflammatory responses, and we have investigated its regulation in murine SD. The NLRP3 inflammasome requires two signals, lipopolysaccharide (LPS) and ATP, to prime and activate the complex, respectively, leading to IL-1β secretion. Peritoneal, but not bone-marrow-derived, macrophages from symptomatic SD mice, but not those from pre-symptomatic animals, secrete the cytokine following priming with LPS with no requirement for activation with ATP, suggesting that such NLRP3 deregulation is related to the extent of glycosphingolipid storage. Dysregulated production of IL-1β was dependent upon caspase activity but not cathepsin B. We investigated the role of IL-1β in SD pathology using two approaches: the creation of hexb^−/−Il1r1^−/− double knockout mice or by treating hexb^−/− animals with anakinra, a recombinant form of the IL-1 receptor antagonist, IL-1Ra. Both resulted in modest but significant extensions in lifespan and improvement of neurological function. These data demonstrate that IL-1β actively participates in the disease process and provides proof-of-principle that blockade of the pro-inflammatory cytokine IL-1β may provide benefits in patients. Full article

Background: A neuroinflammatory disease such as Alzheimer’s disease, presents a significant challenge in neurotherapeutics, particularly due to the complex etiology and allostatic factors, referred to as CNS stressors, that accelerate the development and progression of the disease. These CNS stressors include cerebral hypo-glucose metabolism, hyperinsulinemia, mitochondrial dysfunction, oxidative stress, impairment of neuronal autophagy, hypoxic insults and neuroinflammation. This study aims to explore the efficacy and safety of DAG-MAG-ΒHB, a novel ketone diester, in mitigating these risk factors by sustaining therapeutic ketosis, independent of conventional metabolic pathways. Methods: We evaluated the intestinal absorption of DAG-MAG-ΒHB and the metabolic impact in human microglial cells. Utilizing the HMC3 human microglia cell line, we examined the compound’s effect on cellular viability, Acetyl-CoA and ATP levels, and key metabolic enzymes under hypoglycemia. Additionally, we assessed the impact of DAG-AG-ΒHB on inflammasome activation, mitochondrial activity, ROS levels, inflammation and phagocytic rates. Results: DAG-MAG-ΒHB showed a high rate of intestinal absorption and no cytotoxic effect. In vitro, DAG-MAG-ΒHB enhanced cell viability, preserved morphological integrity, and maintained elevated Acetyl-CoA and ATP levels under hypoglycemic conditions. DAG-MAG-ΒHB increased the activity of BDH1 and SCOT, indicating ATP production via a ketolytic pathway. DAG-MAG-ΒHB showed remarkable resilience against low glucose condition by inhibiting NLRP3 inflammasome activation. Conclusions: In summary, DAG-MAG-ΒHB emerges as a promising treatment for neuroinflammatory conditions. It enhances cellular health under varying metabolic states and exhibits neuroprotective properties against low glucose conditions. These attributes indicate its potential as an effective component in managing neuroinflammatory diseases, addressing their complex progression. Full article

The NLRP3 inflammasome, plays a critical role in the pathogenesis of rheumatoid arthritis (RA) by activating inflammatory cytokines such as IL1β and IL18. Targeting NLRP3 has emerged as a promising therapeutic strategy for RA. In this study, a multidisciplinary approach combining machine learning, quantitative structure–activity relationship (QSAR) modeling, structure–activity landscape index (SALI), docking, molecular dynamics (MD), and molecular mechanics Poisson–Boltzmann surface area MM/PBSA assays was employed to identify novel NLRP3 inhibitors. The ChEMBL database was used to retrieve compounds with known IC₅₀ values to train machine learning (ML) models using the Lazy Predict package. After data pre-processing, 401 non-redundant structures were selected for exploratory data analysis (EDA). PubChem and MACCS fingerprints were used to predict the inhibitory activities of the compounds. SALI was used to identify structurally similar compounds with significantly different biological activities. The compounds were docked using MOE to assess their binding affinities and interactions with key residues in NLRP3. The models were evaluated, and a comparative analysis revealed that the ensemble Random Forest (RF) model (PubChem fingerprints) with RMSE (0.731), R² (0.622), and MAPE (8.988) and bootstrap aggregating model (MACCS fingerprints) with RMSE (0.687), R² (0.666), and MAPE (9.216) on the testing set performed well, in accordance with the Organization for Economic Cooperation and Development (OECD) guidelines. Out of all docked compounds, the two most promising compounds (ChEMBL5289544 and ChEMBL5219789) with binding scores of −7.5 and −8.2 kcal/mol were further investigated by MD to evaluate their stability and dynamic behavior within the binding site. MD simulations (200 ns) revealed strong structural stability, flexibility, and interactions in the selected complexes. MM/PBSA binding free energy calculations revealed that van der Waals and electrostatic forces were the key drivers of the binding of the protein with ligands. The outcomes obtained can be used to design more potent and selective NLRP3 inhibitors as therapeutic agents for the treatment of inflammatory diseases such as RA. However, concerns related to the lack of large datasets, experimental validation, and high computational costs remain. Full article

Background: Monosodium urate crystal accumulation in the joints is the cause of gout, an inflammatory arthritis that is initiated by elevated serum uric acid levels. It is the most prevalent form of inflammatory arthritis, affecting millions worldwide, and requires effective treatments. The necessity for alternatives with fewer side effects is underscored by the frequent adverse effects of conventional therapies, such as urate-lowering drugs. IL-1β is a potential therapeutic target due to its significant role in the inflammatory response induced by MSU. Zanthoxylum piperitum (ZP), a shrub that possesses antibacterial, antioxidant, and anti-inflammatory properties, has demonstrated potential in the treatment of inflammatory conditions. Methods: For anti-inflammatory properties of ZP, Raw264.7 cell stimulated LPS were treated ZP and using RNA-seq with Bone marrow derived macrophage, we observed to change inflammatory gene. Pharmacological networks were conducted to select target gene associated with ZP. For in vivo, mice were injected MSU in footpad for induce gouty arthritis model. The components of ZP were analyzed using GC-MS, and distilled extracts of ZP (deZP) were prepared. Results: In vitro, deZP decreased inflammatory cytokines. However, in vivo, it also decreased paw thickness and IL-1β levels. The anti-inflammatory effects of deZP are believed to be mediated through the NLRP3 inflammasome pathway, as indicated by RNA sequencing and network pharmacology analyses. Conclusions: ZP has an anti-inflammatory effect and regulation of the NLRP3 inflammasome in vitro and in vivo. Further research, including clinical trials, is required to confirm the safety of deZP, determine the optimal dosing, and evaluate its long-term effects. Full article

Neuroinflammation is a complex and dynamic response of the central nervous system (CNS) to injury, infection, and disease. While acute neuroinflammation plays a protective role by facilitating pathogen clearance and tissue repair, chronic and dysregulated inflammation contributes significantly to the progression of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis. This review explores the cellular and molecular mechanisms underlying neuroinflammation, focusing on the roles of microglia, astrocytes, and peripheral immune cells. Key signaling pathways, including NF-κB, JAK-STAT, and the NLRP3 inflammasome, are discussed alongside emerging regulators such as non-coding RNAs, epigenetic modifications, and the gut–brain axis. The therapeutic landscape is evolving, with traditional anti-inflammatory drugs like NSAIDs and corticosteroids offering limited efficacy in chronic conditions. Immunomodulators, gene and RNA-based therapeutics, and stem cell methods have all shown promise for more specific and effective interventions. Additionally, the modulation of metabolic states and gut microbiota has emerged as a novel strategy to regulate neuroinflammation. Despite significant progress, challenges remain in translating these findings into clinically viable therapies. Future studies should concentrate on integrated, interdisciplinary methods to reduce chronic neuroinflammation and slowing the progression of neurodegenerative disorders, providing opportunities for revolutionary advances in CNS therapies. Full article

Besides various infectious and inflammatory complications, recent studies also indicated the significance of NLRP3 inflammasome in cancer progression and therapy. NLRP3-mediated immune response and pyroptosis could be helpful or harmful in the progression of cancer, and also depend on the nature of the tumor microenvironment. The activation of NLRP3 inflammasome could increase immune surveillance and the efficacy of immunotherapy. It can also lead to the removal of tumor cells by the recruitment of phagocytic macrophages, T-lymphocytes, and other immune cells to the tumor site. On the other hand, NLRP3 activation can also be harmful, as chronic inflammation driven by NLRP3 supports tumor progression by creating an environment that facilitates cancer cell proliferation, migration, invasion, and metastasis. The release of pro-inflammatory cytokines such as IL-1β and IL-18 can promote tumor growth and angiogenesis, while sustained inflammation may lead to immune suppression, hindering effective anti-tumor responses. In this review article, we discuss the role of NLRP3 inflammasome-mediated inflammatory response in the pathophysiology of various cancer types; understanding this role is essential for the development of innovative therapeutic strategies for cancer growth and spread. Full article

Background: Luteolin-7-O-glucuronide (L7Gn) is a flavonoid isolated from numerous traditional Chinese herbal medicines that exerts anti-inflammatory effects. Previous research has revealed that aerosol inhalation is the most straightforward way of administration for the delivery of respiratory agents. Thus far, the impact of aerosol inhalation of L7Gn on lung inflammation and the underlying mechanisms remain unknown. Methods: The real-time particle size for L7Gn aerosol inhalation was detected by the Spraytec spray droplet size measurement system, including transmission and size diameters. The acute lung injury (ALI) rat model was induced by aerosol inhalation of LPS to evaluate the protective effect of L7Gn. The inhibitory effect of NLRP3 inflammasome activation assays was conducted in LPS-induced MH-S cells. Elisa, Western blotting, and RT-PCR were utilized to investigate the expression of NLRP3 inflammasome-relevant proteins and genes. Results: In this study, we found that inhalation of L7Gn aerosol significantly reduced pulmonary injury by inhibiting inflammatory infiltration and enhancing lung function. Meanwhile, the NLR family pyrin domain containing 3 (NLRP3) inflammasome was activated dramatically, accompanied by upregulated expression of IL-1β and IL-18, both in the ALI rat model and in LPS-induced MH-S cells. Moreover, L7Gn was found to significantly downregulate the expression of NLRP3, ASC, caspase-1, and cleaved caspase-1, which are critical components of the NLRP3 inflammasome, as well as the expression of IL-1β and IL-18. Conclusions: Based on our findings, L7Gn could exert anti-inflammatory effects by inhibiting NLRP3 inflammasome activation, which may emerge as potential therapeutic agents for the treatment of ALI. Full article

Porcine epidemic diarrhea virus (PEDV) induces enteritis and diarrhea in piglets. Mitochondrial DNA (mtDNA) contributes to virus-induced inflammatory responses; however, the involvement of inflammasomes in PEDV infection responses remains unclear. We investigated the mechanism underlying inflammasome-mediated interleukin (IL)-1β secretion during the PEDV infection of porcine intestinal epithelial (IPEC-J2) cells. IL-1β production and caspase-1 activity were assessed by quantitative PCR and enzyme-linked immunosorbent assay. NLRP3 inflammasome activation was assessed using immunoprecipitation experiments. Mitochondrial damage was evaluated by analyzing the mitochondrial membrane potential and ATP levels and by the flow cytometry examination of mitochondrial reactive oxygen species (mtROS). Mitochondria and mtDNA localization were observed using immunofluorescence. The inhibition of mtROS and mtDNA production allowed NLRP3 inflammasome and IL-1β expression detection and the evaluation of the pathway underlying NLRP3 inflammasome activation in PEDV-infected IPEC-J2 cells. IPEC-J2 cells upregulated IL-1β upon PEDV infection, where mature IL-1β secretion depended on caspase-1 activity, triggered NLRP3 inflammasome expression and assembly, and caused mitochondrial dysfunction, leading to mtDNA release and NLRP3 inflammasome activation, while mtROS contributed to NF-κB pathway activation, enhancing IL-1β secretion. This is the first demonstration of the mechanism underlying mtDNA release and NLRP3 inflammasome activation facilitating IL-1β secretion from PEDV-infected IPEC-J2 cells. These data enhance our understanding of the inflammatory mechanisms triggered by PEDV. Full article

Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus that, among humans, can cause a severe and often fatal illness. The zoonotic EEEV enzootic cycle involves a cycle of transmission between Culiseta melanura and avian hosts, frequently resulting in spillover to dead-end vertebrate hosts such as humans and horses. Interestingly, it has been described that the W132G mutation of the very low-density lipoprotein receptor (VLDLR), the receptor of EEEV, significantly enhanced the VLDLR-mediated cell attachment of EEEV. The patient’s metabolism plays a pivotal role in shaping the complex landscape of viral zoonosis. EEEV represents a significant public health concern due to its severe clinical outcomes, challenging epidemiological characteristics, and certain risk factors that heighten susceptibility among specific populations or age groups. Age is one of several predictors that can impact the outcome of EEEV infection; juvenile animals appear to be particularly vulnerable to severe disease. This has also been observed in natural infections, as children are often the most severely impacted humans. The aim of this piece is to shed light on the intricate relationship between human metabolism and the Eastern equine encephalitis virus. Full article

Misshapen/NIKs-related kinase (MINK) 1 belongs to the mammalian germinal center kinase (GCK) family. It contains the N-terminal, conserved kinase domain, a coiled-coil region, a proline-rich region, and a GCK, C-terminal domain with the Citron-NIK-Homology (CNH) domain. The kinase is an essential component of cellular signaling pathways, which include Wnt signaling, JNK signaling, pathways engaging Ras proteins, the Hippo pathway, and STRIPAK complexes. It thus contributes to regulating the cell cycle, apoptosis, cytoskeleton organization, cell migration, embryogenesis, or tissue homeostasis. MINK1 plays an important role in immunological responses, inhibiting Th17 and Th1 cell differentiation and regulating NLRP3 inflammasome function. It may be considered a link between ROS and the immunological system, and a potential antiviral target for human enteroviruses. The kinase has been implicated in the pathogenesis of sepsis, rheumatoid arthritis, asthma, SLE, and more. It is also involved in tumorigenesis and drug resistance in cancer. Silencing MINK1 reduces cancer cell migration, suggesting potential for new therapeutic approaches. Targeting MINK1 could be a promising treatment strategy for patients insensitive to current chemotherapies, and could improve their prognosis. Moreover, MINK1 plays an important role in the nervous system and the cardiovascular system development and function. The modulation of MINK1 activity could influence the course of neurodegenerative diseases, including Alzheimer’s disease. Further exploration of the activity of the kinase could also help in gaining more insight into factors involved in thrombosis or congenital heart disease. This review aims to summarize the current knowledge on MINK1, highlight its therapeutic and prognostic potential, and encourage more studies in this area. Full article

Background: Uric acid (UA), a metabolite of purine and fructose metabolism, is linked to inflammation and metabolic disorders, including gout and cardiovascular disease. Its pro-inflammatory effects are largely driven by the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, leading to increased cytokine production. Beta-hydroxybutyrate (BHB), a ketone produced during fasting or carbohydrate restriction, has been shown to reduce inflammation. This study explores the role of BHB in mitigating the inflammatory and metabolic effects of elevated uric acid levels. Methods: We utilized a murine muscle cell culture treated with UA and BHB. Results: Muscle cells treated with UA had increased production of pro-inflammatory cytokines and reduced cell viability. Co-treatment with BHB reversed these effects, improving cell survival and reducing cytokine levels. Additionally, uric acid impaired mitochondrial function and increased oxidative stress, which were mitigated by BHB. Furthermore, uric acid disrupted insulin signaling, but BHB co-treatment restored insulin sensitivity. Conclusions: These findings suggest that BHB holds therapeutic potential by counteracting the inflammatory and metabolic disruptions caused by elevated uric acid, making it a promising target for conditions such as hyperuricemia and metabolic syndrome. Full article

Familial Mediterranean fever (FMF) is a genetically determined autoinflammatory disease transmitted mostly by an autosomal recessive mechanism and caused by point mutations of the MEFV (Mediterranean FeVer) gene. The aim of this study was to evaluate the expression of inflammasome genes (p65, Casp1, MEFV, and NLRP3) in patients with FMF compared to controls to understand the changes playing a key role in disease development. We found altered expression levels of the full-length MEFV isoform as well as Casp1 and p65 in FMF patients versus controls. This, once again, highlighted the significance of inflammasome genes in terms of FMF. Full article

Background: Dengue virus (DENV) is the most widespread mosquito-borne virus, which can cause dengue fever with mild symptoms, or progress to fatal dengue hemorrhagic fever and dengue shock syndrome. As the main target cells of DENV, macrophages are responsible for the innate immune response against the virus. Methods: In this study, we investigated the role of pyroptosis in the pathogenic mechanism of dengue fever by examining the level of pyroptosis in DENV-1-infected macrophages and further screened differentially expressed microRNAs by high-throughput sequencing to predict microRNAs that could affect the pyroptosis of the macrophage. Results: Macrophages infected with DENV-1 were induced with decreased cell viability, decreased release of lactate dehydrogenase and IL-1β, activation of NLRP3 inflammasome and caspase-1, cleavage of GSDMD to produce an N-terminal fragment bound to cell membrane, and finally induced macrophage pyroptosis. MicroRNA expression profiles were obtained by sequencing macrophages from all periods of DENV-1 infection and comparing with the negative control. Sixty-three microRNAs differentially expressed in both the early and later stages of infection were also identified. In particular, miR-223-3p, miR-148a-3p, miR-125a-5p, miR-146a-5p and miR-34a-5p were recognized as small molecules that may be involved in the regulation of inflammation. Conclusions: In summary, this study aimed to understand the pathogenic mechanism of DENV through relevant molecular mechanisms and provide new targets for dengue-specific therapy. Full article

Neuroinflammation is defined as an immune response involving various cell types, particularly microglia, which monitor the neuroimmune axis. Microglia activate in two distinct ways: M1, which is pro-inflammatory and capable of inducing phagocytosis and releasing pro-inflammatory factors, and M2, which has anti-inflammatory properties. Inflammasomes are large protein complexes that form in response to internal danger signals, activating caspase-1 and leading to the release of pro-inflammatory cytokines such as interleukin 1β. Irisin, a peptide primarily released by muscles during exercise, was examined for its effects on BV2 microglial cells in vitro. Even at low concentrations, irisin was observed to influence the NLRP3 inflammasome, showing potential as a neuroprotective and anti-inflammatory agent after stimulation with lipopolysaccharides (LPSs). Irisin helped maintain microglia in their typical physiological state and reduced their migratory capacity. Irisin also increased Arg-1 protein expression, a marker of M2 polarization, while downregulating NLRP3, Pycard, caspase-1, IL-1β, and CD14. The results of this study indicate that irisin may serve as a crucial mediator of neuroprotection, thus representing an innovative tool for the prevention of neurodegenerative diseases. Full article

As a critical disease usually infected by Staphylococcus aureus, with a worldwide effect on dairy animals, subclinical mastitis is characterized by persistence and treatment resistance. During mastitis, the blood–milk barrier (BMB)’s integrity is impaired, resulting in pathogen invasion and milk quality decline. In this study, it was found that ginsenoside Rg1 (Rg1), a natural anti-inflammatory and antioxidant compound derived from ginseng, inhibited the onset of tight junction (TJ) dysfunction and ameliorated lipoteichoic acid (LTA)-induced BMB disruption inside and outside the organisms. According to subsequent mechanistic studies, Rg1 inhibited excessive autophagy and inactivated the NLRP3 inflammasome by blockading ROS generation, thereby alleviating TJ dysfunction. Peroxisome proliferator-activated receptor gamma (PPARγ) was identified as a potential target of Rg1 by means of molecular docking plus network pharmacology analysis. Furthermore, it was demonstrated that Rg1 inhibited the oxidative stress levels by activating PPARγ, and regulating the upstream autophagy-related AMPK/mTOR signaling pathway, thus decreasing excessive in vivo and in vitro autophagy. The ROS/autophagy/NLRP3 inflammasome axis was identified as a promising target for treating subclinical bovine mastitis in this study. In conclusion, Rg1 is proven to alleviate BMB disruption by activating PPARγ to inhibit oxidative stress and subsequent excessive autophagy in the case of subclinical bovine mastitis. Full article