Search Results (167)

Background: Mushrooms have gained attention for their potential to improve brain health. We evaluated extracts of king oyster mushroom, as well as two of its bioactive compounds—ergothioneine (ERG) and N-acetyltryptamine (NAT)—for their ability to prevent microglia activation by reducing neuroinflammation and oxidative stress. Methods: HAPI microglial cells were pretreated with king oyster extracts (crude powder, acetone, ethanol, and methanol extracts at 100 μg/mL) and pure bioactive molecules of ergothioneine (ERG, 500 μM) and N-acetyl-tryptamine (NAT,50 μM) before stimulation with LPS. The effects on nitrite; TNF-α; and expressions of the inflammatory proteins iNOS, NOX2, and NLRP3 were compared with those of a blueberry extract (BB, 500 μg/mL) as a positive control. Results: All extracts and bioactive molecules significantly reduced nitrite production, similar to the BB. Overall, the best results for reducing inflammation and inflammatory protein expression were obtained with the extracts rich in NAT (acetone and ethanol), as well as pure NAT. Furthermore, through their inhibitory target effect on NLRP3, these two extracts and the bioactive compounds (NAT and ERG), like BB, are attractive therapeutic molecules to reduce mood disorders related to brain aging, due to evidence of enhanced Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome activity in common neurodegenerative diseases. Further interventional studies are needed to confirm mushrooms’ brain health properties. Full article

Atherosclerotic cardiovascular disease (ASCVD) is increasingly recognized not merely as a lipid-storage disorder but as a chronic, lipid-driven inflammatory condition of the arterial wall. Despite the widespread use of statins and other lipid-lowering therapies, a substantial “residual inflammatory risk” persists, propelling the search for targeted immunopharmacological interventions. At the forefront of this inflammatory cascade is the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which serves as a central orchestrator of vascular inflammation by linking metabolic dysregulation to the innate immune response. Atherogenic danger signals—such as oxidized low-density lipoprotein (ox-LDL) and cholesterol crystals—trigger NLRP3 activation through reactive oxygen species (ROS) generation, lysosomal rupture, and potassium efflux. This, in turn, drives the maturation of pro-inflammatory cytokines (IL-1β and IL-18) and initiates macrophage pyroptosis. In this review, we systematically evaluate the immunomodulatory potential of natural products—both complex extracts and single bioactive compounds—in inhibiting the NLRP3 inflammasome axis. We detail the pharmacological mechanisms by which these natural agents intercept inflammatory signaling at multiple stages: suppressing TLR4/NF-κB-mediated priming, scavenging mitochondrial ROS, and restoring autophagic flux via AMPK/mTOR pathways to prevent inflammasome assembly. By critically analyzing these pathways, we highlight natural product-derived inhibitors as a promising class of immunomodulators capable of attenuating atherosclerotic progression and addressing the persistent challenge of residual inflammatory risk. Full article

Background: Idiopathic inflammatory myopathies (IIMs), characterized by muscle weakness and chronic inflammation, currently lack highly effective therapies. This study investigated the therapeutic potential and underlying mechanism of (5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative with reduced toxicity, using an experimental autoimmune myositis (EAM) mouse model and in vitro assays. Methods: Forty female BALB/c mice were randomly assigned to five groups: normal, vehicle, methylprednisolone (MP), LLDT-8 (0.0625 mg/kg), and LLDT-8 (0.125 mg/kg). EAM mice were treated with LLDT-8 (0.0625 or 0.125 mg/kg) or methylprednisolone as a positive control. Cellular experiments and molecular docking were performed to investigate potential mechanisms of LLDT-8. Results: LLDT-8 significantly attenuated clinicopathological features, including muscle weakness and pain sensitivity, while reducing serum levels of aspartate aminotransferase and lactate dehydrogenase. Histological analysis revealed that LLDT-8 reduced inflammatory cell infiltration and the presence of CD4⁺ and CD8⁺ T cells in muscle tissues. Mechanistically, LLDT-8 inhibited the expression of nucleotide-binding oligomerization domain receptor caspase recruitment domain 5 (NLRC5), a key transcriptional regulator of major histocompatibility complex-I (MHC-I). This suppression extended to downstream antigen presentation-related molecules, including the transporter associated with antigen processing and proteasome 20S subunit beta. Molecular docking further confirmed the high binding affinity of LLDT-8 to both NLRC5 and MHC-I. Conclusions: LLDT-8 alleviates inflammatory muscle injury by targeting the NLRC5/MHC-I signaling axis, suggesting it may be a promising therapeutic candidate for IIMs. Full article

Both plants and animals have developed a sophisticated two-tiered innate immune system. This involves an initial recognition of microbial patterns conserved on the cell surface (PAMP-triggered immunity) and a subsequent more specific intracellular recognition of pathogenic effectors or their activities (effector-triggered immunity). A common fundamental feature is the use of NLR-like intracellular receptors to detect insider threats. Both plant NLRs (receptors containing nucleotide-binding domains and leucine-rich repeats) and animal NLRs (NOD-like receptors) share a modular tripartite architecture, typically featuring a central nucleotide-binding domain (NBD/NOD) and C-terminal leucine-rich repeats (LRRs). The NBD/NOD is crucial for facilitating the exchange of ADP/ATP, acting as a molecular switch to promote oligomerization and activation of NLRs in both kingdoms. In this review, we summarize the similarities and differences between plant and animal molecular perception and immunity mechanisms. Additionally, we highlight the fact that some human pathogens can infect plants, and crucially, some plant pathogens are capable of causing disease in humans. This suggests conserved molecular strategies to invade and manipulate host cells belonging to different biological kingdoms, uncovering that plant and human pathology may benefit from future investigations in their respective fields. Full article

Background: Dysregulation of the innate immune system is a key feature of autoinflammatory disorders, characterized by recurrent or chronic inflammation in the absence of high-titer autoantibodies and antigen-specific T cells. Among regulators of innate immunity, NLRP12 has emerged as an important modulator of inflammatory signaling pathways. As a member of the nucleotide-binding oligomerization domain-like receptor (NLR) family, NLRP12 negatively regulates nuclear factor (NF)-κB activity and contributes to immune homeostasis. However, the clinical significance of NLRP12 variants and their association with disease phenotypes remain incompletely understood. This study aims to summarize current knowledge on the molecular role of NLRP12 and its involvement in autoinflammatory manifestations. Methods: A narrative review of the literature on NLRP12’s molecular functions and role in autoinflammatory diseases was performed. In addition, a cohort of 20 patients with recurrent fevers carrying NLRP12 variants was analyzed from a clinical perspective, evaluating genetic findings and clinical features. Results: Available evidence indicates that NLRP12 regulates inflammatory signaling, particularly through modulation of NF-κB activity. Variants in the NLRP12 gene have been associated with a spectrum of autoinflammatory phenotypes, ranging from periodic fever syndromes to broader systemic inflammatory manifestations. Clinical evaluation of the cohort confirmed the heterogeneity of disease presentations among individuals carrying NLRP12 variants. Conclusions: NLRP12 plays an important role in the regulation of innate immune responses and may contribute to autoinflammatory phenotypes. Integrating molecular data with clinical observations may improve the understanding of NLRP12 variants and support more accurate diagnostic and therapeutic strategies. Full article

Liver disease encompasses a wide range of conditions, each requiring tailored therapeutic approaches. This review describes and critically discusses treatments with robust evidence for improving liver health. Ursodeoxycholic acid (UDCA) is a drug approved by the Food and Drug Administration of the USA to treat primary biliary cholangitis (PBC). In addition, UDCA has been demonstrated to protect against metabolic dysfunction-associated steatohepatitis, fibrosis, and drug-induced liver injury (DILI). The mechanism of action of UDCA has been attributed not only to decreasing the effects of toxic bile acids but also to protecting mitochondrial integrity and function, as well as to antioxidant, anti-inflammatory, and anti-apoptotic activities. UDCA can scavenge reactive oxygen species (ROS) and activate the nuclear factor-E2-related factor-2 (Nrf2) pathway, thereby exerting antioxidant activity. The anti-inflammatory activity of UDCA is associated with its ability to inhibit the nuclear factor-κB pathway. Pirfenidone is a well-recognized antifibrotic drug for the treatment of idiopathic pulmonary fibrosis; its effects on liver fibrosis have also been demonstrated. Pirfenidone exerts anti-inflammatory effects by attenuating the nucleotide-binding oligomerization domain-like receptor 3 inflammasome signaling pathway. The antioxidant actions of pirfenidone are associated with its ability to upregulate the Nrf2 pathway. Both the anti-inflammatory and antioxidant properties of pirfenidone act together to attenuate lung and liver fibrosis, decreasing transforming growth factor-β levels, inhibiting profibrogenic hepatic stellate cell activation, and increasing extracellular matrix degradation. Methyltransferases utilize S-adenosyl-L-methionine (SAM) as a methyl donor for most transmethylation reactions in the body. SAM increases reduced glutathione (GSH) levels, exerting important antioxidant effects. Evidence indicates that SAM prevents fibrosis and attenuates hepatocellular carcinoma development, improving patient survival. N-acetylcysteine (NAC) is a precursor to L-cysteine and GSH and is used in clinical settings to treat cancer, nephropathy, heart disease, pulmonary fibrosis, polycystic ovary syndrome, and influenza. Regarding the liver, NAC is the most accepted treatment for DILI, especially after paracetamol overdose. Owing to its antioxidant and anti-inflammatory actions, NAC has been successfully used to treat chronic liver injuries, including hepatosteatosis and fibrosis. Therefore, ursodeoxycholic acid, pirfenidone, S-adenosyl-L-methionine, and N-acetylcysteine could represent therapeutic strategies for the treatment of liver pathologies. Full article

Helicobacter pylori is a prevalent gastric pathogen that establishes chronic infection and contributes to gastritis, peptic ulcer disease, and gastric cancer. Its persistence depends on immune evasion strategies that promote sustained low-grade inflammation in the gastric mucosa. Nucleotide-binding oligomerization domain-like receptors (NLRs) are cytosolic pattern recognition receptors that play key roles in innate immune responses against H. pylori. Nod1 and Nod2 detect bacterial peptidoglycan delivered via the type IV secretion system or outer membrane vesicles, activating NF-κB, MAPK, and interferon signaling pathways that regulate inflammatory cytokine production, epithelial barrier function, autophagy, and antimicrobial defense. The NLRP3 inflammasome mediates the maturation of IL-1β and IL-18 primarily in myeloid cells, thereby shaping inflammatory and immunoregulatory responses during infection. In contrast, NLRC4 functions in a context-dependent manner in epithelial cells and is largely dispensable for myeloid IL-1β production. Emerging evidence also implicates noncanonical NLRs, including NLRP6, NLRP9, NLRP12, NLRX1, and NLRC5, in regulating inflammation, epithelial homeostasis, and gastric tumorigenesis. In addition, genetic polymorphisms in NLR genes influence host susceptibility to H. pylori-associated diseases. This review highlights the interplay between NLR signaling, bacterial virulence, and host immunity and identifies potential therapeutic targets. Full article

This study investigated the therapeutic potential of a novel probiotic combination consisting of Lactococcus cremoris subsp. cremoris MP01 and Lacticaseibacillus paracasei subsp. paracasei MP02, collectively referred to as LCP, in the treatment of canine atopic dermatitis (CAD). In a 60-day open-label, single-arm trial involving eight dogs, notable clinical improvements were observed following daily LCP treatment, as evidenced by decreasing trends in Canine Atopic Dermatitis Extent and Severity Index and Pruritus Visual Analogue Scale scores, as well as a significant reduction in serum immunoglobulin E levels (p < 0.05). Microbiome and short-chain fatty acid (SCFA) analyses were subsequently conducted in a representative subset of six dogs to explore the effects of LCP on the fecal and skin microbial ecosystems. Concomitant alterations in gut and skin microbiome were observed, including a significant reduction in abundance of Erysipelotrichaceae (p < 0.05) and non-significant decreasing trends in Romboutsia, Escherichia/Shigella spp., and Shigella flexneri, along with a trend toward increased SCFA production. Functional prediction using PICRUSt suggested potential involvement of immune- and infection-related signaling pathways, including those associated with nucleotide-binding oligomerization domain-like receptors, retinoic acid-inducible gene I-like receptors and Shigellosis, supporting the hypothesis that LCP may exert its effects through modulation of the gut–skin axis. These findings support LCP as a safe and promising adjunct therapy for CAD, offering a novel microbiome-targeted approach targeting both clinical symptoms and underlying dysbiosis. Further investigation is warranted to optimize probiotic formulations and better understand the mechanisms underlying microbiome-mediated immune modulation in canine allergy. Full article

Excretory/secretory products from parasites (ESPs) can act as pathogen-associated molecular patterns (PAMPs) to activate innate immunity. Parasites may achieve immune evasion by modulating the interaction between PAMPs and the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing three (NLRP3) inflammasome. Previous studies have suggested that some components of ESPs from Clonorchis sinensis (CsESPs) can induce the host’s immune responses, but the components that balance immunopathology and maintain chronic infection in chronic Clonorchis sinensis (C. sinensis) remain unclear. We previously found that the iNOS-interacting protein from C. sinensis (CsNOSIP), a component of CsESP, stimulates macrophages to produce reactive oxygen species (ROS) and nitric oxide (NO), both of which inhibit NLRP3 inflammasome activation. Therefore, this study investigated the effects of CsESP and CsNOSIP on inflammasome activation using RT-PCR, Western blot, and ELISA. This study showed that CsESPs promoted NLRP3 inflammasome activation in RAW264.7 cells, while CsNOSIP inhibited LPS-induced IL-1β secretion through an NLRP3-caspase-1-dependent pathway and reversed the CsESPs-induced activation through the iNOS/NO–NF-κB pathway. These results reveal the antagonistic effects of CsESPs and CsNOSIP in inflammasome regulation, suggesting that this balance contributes to the regulation of the host’s immunity and the promotion of chronic infection of C. sinensis, providing potential targets for prevention and treatment. Full article

Background/Objectives: Diabetic nephropathy (DN) is a major complication of diabetes and a leading cause of end-stage renal disease, a condition associated with high mortality risks. Recently, supplementation with probiotics and postbiotics has been attracting attention. Especially, metabolites of natural products bioconverted by beneficial bacteria have emerged as a novel therapeutic intervention for metabolic diseases, including diabetes, due to the enhanced bioavailability of their metabolites. This study investigated the alleviating effects of metabolites derived from guava leaf extract bioconverted by Limosilactobacillus fermentum (GBL) on renal inflammation in type 2 diabetic mice. Methods: For this purpose, diabetes was induced in male C57BL/6J mice by a high-fat diet and streptozotocin injection (80 mg/kg BW) twice. Subsequently, mice with fasting blood glucose levels higher than 300 mg/dL were administered metabolites of L. fermentum (LF) (50 mg/kg BW/day) or guava leaf extract bioconverted by L. fermentum (GBL) (50 mg/kg BW/day) by oral gavage for 15 weeks. Results: GBL demonstrated potential in alleviating hyperglycemia-induced DN in diabetic mice. It markedly improved hyperglycemia, glucose tolerance, and morphological alterations, which might stem from activation of key regulators of energy metabolism. GBL uniquely reduced advanced glycation end products (AGEs) and suppressed nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-driven inflammatory pathways, which significantly alleviated oxidative stress and apoptosis. Conclusions: This highlights the distinct therapeutic efficacy of GBL in addressing DN, primarily through its effects on renal inflammation. Taken together, GBL can be used as a promising nutraceutical to mitigate hyperglycemia and its associated renal inflammation, thereby alleviating the progression of DN. Full article

Due to their evolutionary divergence from mammals, zebrafish (Zf, Danio rerio), which are frequently employed in biomedical research, provide a distinctive viewpoint on innate immune systems. The Toll-like receptor 4/myeloid differentiation factor 2/cluster of differentiation 14 (TLR4/MD-2/CD14) complex in mammals detects lipopolysaccharide (LPS), a crucial component of Gram-negative bacteria, and it causes potent inflammatory reactions through a Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF)-dependent and myeloid differentiation primary response 88 (MyD88)-dependent pathways. However, key components of this system, such as a responsive TLR4 axis and a functional CD14 ortholog, are absent in Zf. The Zf species nevertheless reacts to LPS, which leads to research into other recognition systems. This review looks at a number of TLR4-independent processes in Zf, such as scavenger receptors (SRs) including scavenger receptor class B type 1 (SR-BI) and cluster of differentiation 36 (CD36), nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-dependent cytosolic sensing, peptidoglycan recognition proteins (PGRPs), Complement Component 3 (C3), and caspase-1-like protein 2 (Caspy2)-mediated inflammasome activation. An alternative and flexible immune system that makes up for the lack of canonical TLR4 signaling is revealed by these mechanisms. Additionally, the discovery of lymphocyte antigen 96 (ly96), an ortholog of MD-2 found in Zf, suggests evolutionary similarity; however, as it is only functional in artificial systems, it demonstrates minimal overlap with mammalian MD-2 activity. Knowing these pathways provides important information for studying inflammation, infection, and immunological modulation in vertebrates using Zf as a model. It also clarifies the evolutionary flexibility of innate immune recognition. Full article

Background: Glioblastoma multiforme (GBM) represents one of the most aggressive and lethal primary brain malignancies, characterized by rapid proliferation, extensive invasiveness, and a dismal prognosis. Emerging evidence implicates nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor, as a potential driver of GBM progression. This study investigates NOD2’s role in promoting glioblastoma through its effects on the epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) markers. Methods: NOD2 expression levels and survival outcomes were assessed using TCGA data from GBM tumor samples (n = 153) and normal brain tissues (n = 5). NOD2 protein expression was validated in glioma cell lines using Western blot and immunofluorescence analyses. Functional studies employed siRNA-mediated NOD2 knockdown to evaluate effects on cellular proliferation, migration, invasion, and colony formation, while correlations between NOD2 and EMT/CSC markers were assessed. Results: The analysis of TCGA data revealed a significantly elevated NOD2 expression in GBM tumors compared to normal brain tissue, with a high NOD2 expression correlating with a reduced disease-free survival in GBM patients. All tested glioma cell lines demonstrated robust NOD2 expression. Functional analyses demonstrated that NOD2 depletion substantially impaired cellular proliferation, migration, invasion, and the colony-forming capacity. Mechanistically, siRNA-mediated NOD2 knockdown significantly decreased the expression of EMT (Snail, SLUG, Vimentin) and CSC markers (CD44, CD133) at both protein and mRNA levels. Conclusions: Our results indicate that NOD2 contributes to GBM progression by influencing EMT and CSC pathways. These findings suggest NOD2’s potential as a therapeutic target in glioblastoma, highlighting the need for further mechanistic studies and therapeutic exploration. 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

Inorganic polyphosphate (iPolyP) is a ubiquitous molecule composed of a variable number of orthophosphate units. Recent studies have highlighted its involvement in colorectal cancer (CRC) cell proliferation. However, further investigations are needed to elucidate its role in CRC cell progression and migration, as well as its influence on the tumor microenvironment. This study focuses on the inorganic polyphosphate (iPolyP)/transient receptor potential cation channel subfamily M member 8 (TRPM8) axis and its impact on CRC progression. To investigate these issues, western blotting, fixed and live cells immunofluorescence, 2D and 3D cell culture on CRC-patient derived tissues, ELISA, and wound healing assays were performed. Our results show that inorganic polyphosphate induces the expression of epithelial-to-mesenchymal transition (EMT) markers in CRC cells. Furthermore, the iPolyP/TRPM8 axis indirectly promotes tumor growth through activation of the Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain-containing protein 3 (NLRP3) inflammasome in immune cells, leading to increased levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the tumor microenvironment (TME), thereby advancing CRC. These findings suggest that targeting the iPolyP/TRPM8 pathway may be a promising strategy to inhibit CRC progression and metastasis. Full article

The Bacillus Calmette-Guérin (BCG) vaccine confers broad, non-specific immunity that may bolster defenses against respiratory viruses. While NOD2 (nucleotide-binding oligomerization domain-containing protein 2)-driven pathways are central to innate immune responses, the contribution of surface receptor modulation on monocytes to shaping these responses remains underexplored. We analyzed whole-blood cultures from BCG-vaccinated Polish children, stratified by serostatus to SARS-CoV-2 and RSV, and stimulated for 48 h with live BCG, purified viral antigens, or both. RT-qPCR quantified mRNA levels of NOD2 and key cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF), while flow cytometry assessed CD14, HLA-DR, CD11b, and CD206 expression. Co-stimulation with BCG + RSV elicited the strongest transcriptional response, notably a 2–4-fold upregulation of NOD2, IL-1β, and IL-6 versus RSV alone. In SARS-CoV-2(+) donors, RSV alone induced higher NOD2 expression than BCG or BCG + RSV, while IL-2 peaked following BCG + SARS-CoV-2. Across conditions, NOD2 positively correlated with IL-4 and IL-6 but negatively correlated with IL-1β in SARS-CoV-2 cultures. Viral antigens increased CD14 and HLA-DR on monocytes, suggesting activation; CD206 rose only in dual-seropositive children. Our findings indicate that BCG stimulation affects pediatric antiviral immunity through NOD2-related cytokine production and induction of a CD14⁺HLA-DR⁺ phenotype, supporting its potential role in boosting innate defenses against respiratory pathogens. Full article