Search Results (231)

Growing evidence suggests that persistent oral infectious diseases (OIDs) contribute to systemic disease, highlighting the importance of understanding their pathogenic mechanisms. Conventional dental treatments, primarily mechanical debridement, surgical intervention, or antimicrobial therapy, often struggle to fully control inflammation or prevent progressive tissue destruction. The nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome is a key regulator of innate immunity, mediating the maturation of proinflammatory cytokines (IL-1β and IL-18) and the pyroptosis-inducing protein gasdermin D. Dysregulated or excessive activation of NLRP3 contributes to the initiation and progression of major oral diseases, including periodontitis, peri-implantitis, pulpitis, and oral mucosal inflammation. Despite growing interest in NLRP3, comprehensive and up-to-date reviews integrating its pathogenic mechanisms and therapeutic potential remain limited. This review summarizes current and past evidence on the role of the NLRP3 inflammasome in oral disease development, highlights emerging pharmacological strategies, and outlines future research directions. Existing studies demonstrate that microbial components and danger signals from injured tissues activate NLRP3, thereby amplifying inflammation, tissue degradation, and bone resorption. Preclinical studies indicate that inflammasome inhibitors and several natural compounds reduce tissue damage; however, their clinical translation remains limited. These findings emphasize the need for deeper understanding of NLRP3-mediated pathways, with translational and clinical research offering promising therapeutic opportunities for oral diseases. Full article

Nucleotide-binding site-leucine-rich repeat (NLR) proteins are key intracellular immune receptors in plants. Integrated domains (IDs) can occasionally be fused with NLRs, contributing to their functional diversity. However, the diversity and evolutionary patterns of NLR-IDs across angiosperms remain poorly understood. In this study, we analyzed 305 angiosperm genomes and found that the proportion of NLR genes containing IDs (NLR-ID genes) ranges from 0% to 38.3%, with an average of 10.6%. A total of 1226 unique IDs were identified, some of which are widely distributed, while others are specific to particular taxa. Notably, 415 of these IDs are homologous to plant proteins targeted by pathogen effectors, suggesting their role as candidate decoys. Comparative analysis of NLR-IDs in two subfamilies—TIR-NLR (TNL) and CC-NLR (CNL)—revealed that TNL genes have a significantly higher frequency of IDs, with the C-JID and DUF3542 domains being most prevalent. N-terminal fusion of the DUF3542 domain in CNL genes correlates with the loss of the MADA motif. Our findings expand the understanding of NLR-ID diversity and provide insights into the dynamic evolution of NLR protein architecture in angiosperms. Full article

Bats, as the world’s second-largest mammalian order, have garnered significant attention for their ability to harbor numerous viruses without exhibiting disease symptoms. Nucleotide-binding domain and leucine-rich repeat-containing receptors (NLRs) are crucial components of the immune system. This study conducted an evolutionary analysis of the NLR gene family across 26 bat species to investigate the molecular mechanisms underlying their role in viral resistance under high viral load pressure. We identified gene duplication events in multiple genes. The NLR gene family exhibited high conservation throughout evolution, which may contribute to the occurrence of gene duplication. This conserved genomic structure also ensures functional stability, safeguarding bats’ antiviral resistance. Most NLR genes primarily function within the type I interferon (IFN) signaling pathway and the NF-κB signaling pathway. The NLR gene family enhances the innate immune capacity of bats through the adaptive evolution of some genes, combining enhanced gene functionality with the maintenance of gene conservation at a low evolutionary rate. Moreover, bats employ diverse innate immune strategies, where multiple immune pathways collectively establish the innate immune barrier. The molecular evolution of this gene family provides new insights into the molecular mechanisms and functional pathways involved in the innate immune response of bats. Full article

Pepper (Capsicum annuum), a widely cultivated vegetable of significant economic importance globally, is frequently subjected to attacks from pathogens such as Ralstonia solanacearum, as well as high-temperature stress. However, the mechanisms by which pepper combats these stresses remain poorly understood. Herein, we reported that the expression of the leucine-rich repeat protein CaLRR13, which lacks a nucleotide-binding site (NBS), kinase domains, and a transmembrane region, was transcriptionally activated by both R. solanacearum inoculation and high-temperature stress. Through transient overexpression in the epidermal cells of Nicotiana benthamiana leaves, we found that CaLRR13 localized in both the cytoplasm and the nuclei. Reducing the expression of CaLRR13 via virus-induced gene silencing (VIGS) increased the sensitivity of pepper to R. solanacearum infection and high-temperature exposure, accompanied by reduced expression of immunity- and thermotolerance-related genes, including CaWRKY40, CaPR1, CaNPR1, CaDEF1, and CaHSP24. In contrast, transient overexpression of CaLRR13 in pepper leaves induced a like-hypersensitive response (HR) and enhanced the expression of the aforementioned immunity- and thermotolerance-related genes. Thus, we conclude that CaLRR13 plays a positive role in pepper immunity against R. solanacearum and thermotolerance, providing a new perspective on the crosstalk and management of plant responses to these two stresses. Full article

The absent in melanoma 2 (AIM2) inflammasome is a cytosolic DNA sensor that links genomic instability, mitochondrial dysfunction, and chronic inflammation. Unlike the nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome, AIM2 is activated directly by double-stranded Deoxyribonucleic Acid (dsDNA), including mitochondrial DNA (mtDNA) released under stress conditions. This positions AIM2 at the intersection of oxidative stress, impaired mitophagy, and innate immune dysregulation. Current therapies for ankylosis spondylitis (AS), such as anti-tumor necrosis factor (TNF), anti-interleukin 17 (IL-17), and Janus kinase (JAK) inhibitors, improve clinical outcomes; however, they do not address upstream mitochondrial dysfunction or DNA-driven inflammasome activation. By contrast, other inflammasomes, such as AIM2, remain comparatively less studied. Since autoimmune diseases, including AS, are frequently accompanied by uncontrolled innate immune responses to self-DNA, these findings provide a framework for comprehending the mechanisms of AIM2 activation and its interaction with inflammation, mitophagy, and oxidative stress. Here, we review the current evidence on AIM2 inflammasome involvement in AS pathogenesis and its potential as a therapeutic target. This approach offers new insight into disease control through re-establishing the balance between mitochondrial dysfunction and autoimmunity. Full article

Pyrenophora tritici-repentis (Ptr), the causal agent of tan spot, is a necrotrophic fungus that represents a significant threat to wheat production worldwide. The development of resistant cultivars is limited by an incomplete understanding of wheat defence responses against Ptr. Here, weighted gene co-expression network analysis (WGCNA) was applied to RNA-seq data from resistant (Robigus) and susceptible (Hereward) wheat lines before and after Ptr infection to identify coordinated host responses. Eight co-expression modules were identified, three of which were linked to either resistance, susceptibility, or Ptr infection. The resistance-associated module was enriched with chloroplast ribosomal machinery genes (e.g., 50S ribosome-binding GTPase, L28, L6), and transcriptional regulators. This suggested that maintaining chloroplast function, coupled with large-scale transcriptional reprogramming, was important for resistance. The susceptibility-associated module indicated the high expression of post-transcriptional modifiers, including SGS3, RBX1, and SENPs. The Ptr-responsive module showed common responses in both genotypes and included several defence-related genes (nucleotide-binding domain leucine-rich repeat R-genes [NLRs], chitinases, beta-1,3-glucanases) and metabolic pathways, such as phenylpropanoid biosynthesis and nitrogen metabolism (phenylpropanoid ammonia lyase [PAL], cytochrome P450s, glutamine synthase, and ammonium transporters). These results define distinct and shared molecular networks that are linked to resistance and susceptibility, providing valuable candidate genes for functional validation that could ultimately be exploited to enhance wheat resilience against necrotrophic fungal pathogens. Full article

Background/Objectives: Osteoporosis is caused by excessive osteoclast activation via the receptor activator nuclear factor kappa B ligand (RANKL), which is released from osteoblasts or osteocytes. RANKL regulates osteoclast activity by binding to the receptor activator of nuclear factor kappa B (RANK) in the canonical pathway or leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) in the non-canonical pathway. In this study, we attempted to develop an intact small-fragment protein based on RANKL by removing the RANK-binding site and transforming the amino acid residues at crucial sites to inhibit osteoclast activity and treat osteoporosis. Methods: We expressed a small-fragment variant of RANKL as a soluble glutathione S-transferase (GST) or 6x histidine (His)-tagged fusion protein using a GST- or His-binding domain tag expression vector system. To generate an intact form of small-fragment RANKL, ribosome-inactivating protein–His-fusion RANKL was purified using HisTrap affinity chromatography and treated with tobacco etch virus nuclear inclusion endopeptidase to remove the His-tag fusion protein. Tartrate-resistant acid phosphatase (TRAP) and bone resorption pit formation assays were performed to analyze the inhibitory effects on osteoclast differentiation and activation. Results: The intact forms of 225RANKL295P and 225RANKL295A showed the strongest inhibitory effects on TRAP activity and bone resorption pit formation. Conclusions: Using an optimal construct design, a large and diverse range of small RANKL fragments could be generated. This suggests that the generation of small-fragment RANKL provides a promising avenue for the advancement of novel therapeutic approaches to osteoporosis. Full article

Capsicum annuum (pepper) is a globally significant Solanaceous crop vulnerable to devastating pathogens such as Phytophthora capsici. Nucleotide-binding leucine-rich repeat (NLRs) proteins are crucial intracellular immune receptors mediating effector-triggered immunity (ETI). This study presents the comprehensive genome-wide identification and analysis of the NLR gene family in pepper using the high-quality ‘Zhangshugang’ reference genome. We identified 288 high-confidence canonical NLR genes. Chromosomal distribution analysis showed significant clustering, particularly near telomeric regions, with Chr09 harboring the highest density (63 NLRs). Evolutionary analysis demonstrated that tandem duplication is the primary driver of NLR family expansion, accounting for 18.4% of NLR genes (53/288), predominantly on Chr08 and Chr09. Analysis of promoter cis-regulatory elements (CREs) revealed enrichment in defense-related motifs, with 82.6% of promoters (238 genes) containing binding sites for salicylic acid (SA) and/or jasmonic acid (JA) signaling. Transcriptome profiling of Phytophthora capsici-infected resistant (C. annuum cv. CM334) and susceptible (C. annuum cv. NMCA10399) cultivars identified 44 significantly differentially expressed NLR genes, and protein–protein interaction (PPI) network analysis predicted key interactions among them, with Caz01g22900 and Caz09g03820 as potential hubs. This study elucidates the tandem-duplication-driven expansion, domain-specific functional implications, and expression dynamics of the pepper NLR family. It identifies conserved and lineage-specific candidate NLR genes, including Caz03g40070, Caz09g03770, Caz10g20900, and Caz10g21150. These findings provide valuable candidate gene targets for the development of molecular markers for pepper resistance to Phytophthora capsici. Full article

Background/Objectives: This review article highlights the role of the nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing 3 protein (NLRP3) inflammasomes in various gastrointestinal and hepatic disorders in the pediatric age group. NLRP3 inflammasomes are one of the principal intracellular innate immune sensors. During inflammation, molecules such as caspase-1 and the release of IL-1β and IL-18 are produced. The NLRP3 inflammasome participates in the preservation of intestinal homeostasis and mucosal immune response. The objective is to evaluate the published articles related to the role of NLRP3 inflammasomes in common pediatric gastrointestinal and hepatic disorders in order to identify the future perspective regarding their possible therapeutic values. Methods: We searched Medline for NLRP3 inflammasomes and disorders of the digestive system during childhood. Results: Although the majority of articles were related to various disorders of adults, such as Alzheimer’s disease, Parkinson’s disease, atherosclerosis, as well as neurodevelopmental disorders, such as schizophrenia, a few published datasets were related to the roles of NLRP3 in the pediatric age group: they addressed autism, rheumatoid arthritis, and other autoimmune diseases, as well as inflammatory bowel diseases (IBD) and hepatic infection. Some research demonstrated that the NLRP3 inflammasome has a protective role; however, it also has a pathogenic function. Conclusions: This review focused on the comprehensive role of inflammasome NLRP3 in the most common pediatric and neonatal gastrointestinal and hepatic diseases, including clinical and experimental studies, as well as the pharmacological inhibitors for NLRP3 inflammasomes, which may provide future therapy for GIT problems, such as IBD. Full article

Gout is a form of sterile inflammatory arthritis in which monosodium urate (MSU) crystals deposit and provoke a neutrophil-predominant response, primarily driven by activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Here, we show that auranofin, a Food and Drug Administration (FDA)-approved anti-rheumatic agent, exerts anti-inflammatory effects in both in vitro and in vivo models of gout. Auranofin inhibited NLRP3 inflammasome activation in human THP-1 cells and murine macrophages, leading to reduced cleavage of caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18). In MSU crystal-induced mouse models, auranofin treatment reduced paw swelling, serum cytokine levels, and tissue inflammation. Notably, auranofin suppressed neutrophil migration and decreased expression of C-X-C motif chemokine ligand 1 (CXCL1) in inflamed foot tissue and air-pouch exudates. Mechanistically, auranofin disrupted the interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis, a key signaling pathway promoting neutrophil recruitment. Overexpression of IL-33 abolished the anti-inflammatory effects of auranofin, highlighting the central role of IL-33 in gout pathogenesis. Together, our findings suggest that auranofin alleviates MSU-induced inflammation by concurrently inhibiting NLRP3 inflammasome activation and IL-33-mediated neutrophil recruitment, supporting its potential as a dual-action therapeutic candidate for gout. Full article

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, characterized by pruritic and eczematous lesions. Skin barrier dysfunction and aberrant inflammatory responses are hallmark features of AD. Recent genome-wide association studies have implicated NLRP10, a unique member of the NOD-like receptors (NLRs) lacking a leucine-rich repeat (LRR) domain, in AD susceptibility. Unlike other NLRs, the physiological role of NLRP10 in skin remains incompletely understood. Emerging evidence shows that NLRP10 regulates keratinocyte survival and differentiation, acts as a molecular sensor for mitochondrial damage, enhances anti-microbial response and contributes to skin barrier function. This review summarizes current insights into NLRP10′s functions in skin homeostasis, its interplay with cell death pathways, and its role in maintaining skin barrier function. Furthermore, therapeutic opportunities to target NLRP10 as a novel strategy for modulating epidermal cell death and restoring barrier function in AD are highlighted. Full article

Iron is essential for cellular respiration, oxidative defense, and host immunity, but its dysregulation is increasingly associated with metabolic disorders, such as obesity and type 2 diabetes. In these diseases, regional iron accumulation occurs in adipose tissue, independent of systemic overload. This process disrupts the mitochondrial redox balance, induces ferroptotic stress, and activates the innate immune pathways. Recent studies have highlighted the NLRP3 (nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing protein 3) inflammasome and its effector cytokine interleukin-1β (IL-1β) as important mediators of the interface between iron and inflammation. In both adipocytes and macrophages, labile iron increased reactive oxygen species (ROS) production and promoted inflammasome formation. Simultaneously, metabolic stress factors upregulate hepcidin expression, suppress ferroportin activity and exacerbate intracellular iron retention. These molecular events converge to maintain low-grade inflammation and impair insulin signaling. Despite these compelling associations, direct mechanistic evidence remains limited, particularly with respect to depot-specific responses and cell type resolution. In this review, I examine the current evidence linking iron handling and inflammasome biology in adipose tissue, focusing on ferroptosis, thioredoxin-interacting protein (TXNIP) signaling, and spatial mapping of iron–cytokine networks. I also discuss novel therapeutic strategies targeting iron overload and inflammasome activation, including chelation, hepcidin modulation, and inflammasome inhibition in the context of metabolic diseases. Full article

Wheat powdery mildew, caused by Blumeria graminis f. sp. tritici, represents one of the most threatening biotic stresses of this crop. The cultivated wheat variety ‘Brock’ exhibits resistance not only to rust but also to powdery mildew, making it a valuable resource for exploitation in wheat disease-resistant breeding. This study identified a novel gene in ‘Brock’ distinct from Pm2. In order to identify the disease resistance gene in ‘Brock’, genetic mapping was performed using F₂ and F_2:3 populations derived from the cross ‘Jing411/Brock’. The candidate powdery mildew resistance gene was located within a 6.88 Mb physical interval on chromosome 2D, which harbors a highly expressed gene, TaRPM1-2D. The protein encoded by TaRPM1-2D possesses a typical nucleotide binding, leucine-rich repeat receptor (NLR) domain, and its sequence significantly differs among ‘Jing411’, ‘BJ-1’, and ‘Brock’. Expression of TaRPM1-2D was markedly higher in resistant wheat ‘Brock’ and ‘BJ-1’ compared to the susceptible ‘Jing411’. Both overexpression and gene silencing experiments demonstrated that TaRPM1-2D contributes to enhance resistance against powdery mildew in wheat. These findings reveal the function of TaRPM1-2D in conferring powdery mildew resistance in ‘Brock’ and provide a candidate gene for disease-resistance breeding. Full article

The progression of inflammation during sepsis represents a multifaceted biological cascade that requires effective therapeutic interventions to improve survival. In septic neonatal foals, oxidative stress (OS) arises due to a compromised antioxidant defense system. Oxidative stress may disrupt the functionality of redox-sensitive organelles, such as the endoplasmic reticulum (ER). Endoplasmic reticulum stress disorder affects multiple cellular signaling pathways, including redox balance, inflammation, and apoptosis, and contributes to the pathogenesis of sepsis. The study aimed to elucidate whether OS conditions in sepsis influenced gene expression associated with ER stress. Blood samples were collected from 7 healthy and 21 hospitalized neonatal foals and processed for RNA extraction. RNA sequencing was employed to identify ER stress-responsive genes. Novel findings reported here indicate activation of the ER stress pathway in foals with sepsis. Several genes associated with ER stress, such as clusterin (CLU), BCL2-like 1 (BCL2L1), ubiquitin specific peptidase 14 (USP14), bifunctional apoptosis regulator (BFAR), and optic atrophy 1 (OPA1), were upregulated and positively correlated with sepsis scores and negatively correlated with the combined activities of antioxidant enzymes. In contrast, X-box binding protein 1 (XBP1), homocysteine inducible ER protein with ubiquitin-like domain 1 (HERPUD1), leucine-rich repeat kinase 2 (LRRK2), and selenoprotein S (SELENOS) were negatively correlated with sepsis scores and were downregulated in sepsis and positively correlated with the combined activities of antioxidant enzymes. Furthermore, a positive correlation was observed between cAMP responsive element binding protein 3 like 2 (CREB3L2) and BCL2L1, as well as between the expressions of USP14 and YOD1 deubiquitinase (YOD1) in sepsis. Similarly, the expression levels of XBP1 and Herpud1 demonstrated a positive correlation with each other in sepsis. Additionally, the downregulation of genes with protective function against OS, such as XBP1, HERPUD1, and SELENOS, in septic foals also highlights their significance in mitigating OS in sepsis treatment. The study reported here highlights the potential of ER stress as a promising therapeutic target and prognostic marker in septic foals. Full article

Sepsis is a life-threatening condition caused by an abnormal host response to infection, leading to organ dysfunction and potentially death. Acute kidney injury (AKI) is a critical complication of sepsis. Various pathways, especially signaling through Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, contribute to inflammation and tissue damage. Cilastatin, a renal dehydropeptidase I inhibitor, has shown promise in protecting against AKI induced by nephrotoxic drugs. This study assessed cilastatin’s effectiveness in preventing AKI and inflammation caused by sepsis and its impact on survival. Sepsis was induced in male Sprague-Dawley rats using the cecal ligation puncture (CLP) model, with four groups: sham (control), CLP, sham + cilastatin, and CLP + cilastatin. Cilastatin (150 mg/kg) was administered immediately and 24 h after sepsis induction. Kidney injury was evaluated 48 h later by assessing serum creatinine, blood urea nitrogen, glomerular filtration rate, proteinuria, kidney injury molecule-1 levels, and renal morphology. Inflammatory and fibrotic biomarkers, particularly related to the TLR4 and NLRP3 pathways, were also measured. Cilastatin treatment prevented kidney dysfunction, reduced inflammatory markers, and improved survival by 33%. These results suggest that cilastatin could be a beneficial therapeutic strategy for sepsis-related AKI, improving outcomes and reducing mortality. Full article