Search Results (501)

Obesity contributes to the development of metabolic disorders such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) through sustained low-grade inflammation and mitochondrial dysfunction. In obesity, hypertrophied adipose tissue release high levels of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and elevates circulating free fatty acids. These changes promote systemic insulin resistance and ectopic lipid deposition. Mitochondrial dysfunction, including reduced oxidative phosphorylation, excess reactive oxygen species (ROS) production, and mitochondrial DNA damage, further stimulate inflammatory pathways such as the NLRP3 inflammasome, creating a feedback loop that worsens metabolic stress. Ultimately, this interaction disrupts energy balance, weakens insulin signaling, and accelerates β-cell dysfunction and hepatic steatosis. In both T2DM and MASLD, oxidative stress, defective mitochondrial quality control, and dysregulated immunometabolic responses are consistently observed pathophysiological features. Interventions aimed at reducing inflammation and restoring mitochondrial function—including lifestyle modification, mitochondria-targeted therapies, inflammasome regulation, and enhancement of mitochondrial biogenesis or mitophagy—may retard disease progression. Full article

Background/Objectives: Polygonatum sibiricum (PS), possessing both medicinal and edible dual functions, boasts a long history of application in Chinese traditional practices. As a component of its effectiveness, Polygonatum sibiricum polysaccharides (PSPs) have been reported to exert neuroprotective effects. However, the protective effects of PS on the cognitive deficits induced by simulated weightlessness remain unclear. This study evaluated the therapeutic potential of PSPs to counteract the cognitive deficits induced by simulated weightlessness using the Hindlimb Unloading (HU) method. Methods: Mice were subjected to HU to establish cognitive impairment, and PSP was administered for four weeks. The Morris water maze test (MWMT) and passive avoidance test (PAT) were used to evaluate the cognitive abilities of mice, followed by an analysis of molecular mechanisms. Results: PSP treatment increased learning and memory in mice. PSP treatment partially restored gut microbial diversity and composition towards beneficial taxa, including Lactobacillus and Firmicutes, while inhibiting proinflammatory genera, including Alistipes and Proteus. At the same time, PSP upregulated Claudin-5 and Zonula Occludens-1 (ZO-1) levels in the colon, suggesting improved intestinal barrier integrity, and decreased neuroinflammatory response by inhibiting NLRP3 inflammasome activation and NF-κB phosphorylation in the hippocampus. It also modulated neurotransmitter homeostasis along the microbiota–gut–brain (MGB) axis by increasing the levels of gamma-aminobutyric acid (GABA) and serotonin (5-HT) while reducing the levels of excitotoxic metabolites, including Glutamate (Glu) and 3-hydroxykynurenine (3-HK). Conclusions: These results indicate that PSP may have beneficial effects on HU-induced cognitive impairment by regulating gut microbiota, enhancing barrier function, suppressing neuroimmune signaling, and restoring neurotransmitter balance. 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

Galectins represent a family of widely expressed lectins that have the ability to bind β-galactoside in modulating “cell-to-cell” and “cell-to-matrix” interactions in all organisms. These proteins are expressed in many inflammatory cells, such as macrophages, and depending on the inflammatory environment, they promote pro-inflammatory or anti-inflammatory responses. Galectin-3 (Gal-3) is predominantly located in the cytoplasm, but, as noted, it has also been detected in the nucleus, on the cell surface and in the extracellular environment, which indicates the multifunctionality of this molecule. It has been shown in many studies that Gal-3 is involved in immune regulation, fibrosis, and tissue remodeling, making it an important player in disorders such as inflammatory bowel disease (IBD), non-alcoholic steatohepatitis (NASH), and liver fibrosis. In IBD, this protein is associated with activation of the NLRP3 inflammasome, contributing to chronic intestinal inflammation. Also, in primary biliary cholangitis and autoimmune hepatitis, Gal-3 potentiate development of fibrosis through fibroblast-to-myofibroblast transition and extracellular matrix deposition, while in liver fibrosis, it is upregulated in hepatic stellate cells and macrophages, promoting fibrosis and inflammation. Studies show that Gal-3 inhibition reduces fibrosis and inflammation, making it a promising therapeutic target. 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

Brazilian red propolis (BRP) has emerged as a promising source of multifunctional phytochemicals with potent anti-inflammatory activity. This review provides a comprehensive analysis of the anti-inflammatory effects of BRP’s bioactive compounds, their molecular targets, and their mechanisms of action. Isolated compounds from BRP (such as formononetin, biochanin A, daidzein, calycosin, medicarpin, vestitol, and neovestitol) have demonstrated the ability to modulate critical pro-inflammatory signaling pathways, including NF-κB, TLR4, JAK/STAT, and PI3K/AKT, while concurrently activating antioxidant and cytoprotective responses via the Nrf2/HO-1 axis. These effects are further supported by the suppression of pro-inflammatory cytokines, regulation of immune cell infiltration and activation, inhibition of inflammasome components such as NLRP3, induction of autophagy, and polarization of macrophages and microglia from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype. Collectively, these findings reinforce the potential of BRP as a rich source of multifunctional phytochemicals with broad therapeutic relevance for chronic inflammation and related pathologies. Future research should address the identified knowledge gaps by employing rigorous in vitro and in vivo toxicity assessments, exploring structure–activity relationships, and leveraging advanced delivery systems to optimize bioavailability. Such methodological approaches will be essential for translating the promising biological activities of BRP compounds into clinically viable therapeutic agents. Full article

Background/Objectives: The dysregulation of NLRP3 inflammasome activation has been established as a key driver of inflammatory disease pathology, which marks NLRP3 as an attractive therapeutic target. However, the clinical development of NLRP3 inhibitors such as MCC950 has been hampered by their associated toxicity profiles, highlighting an unmet clinical need. Methods: Herein, we present LMT2368, a novel urea-based NLRP3 inhibitor identified through screening of urea-based derivatives from our in-house compound library. Results: Biolayer interferometry confirmed direct binding of LMT2368 to the NLRP3 NACHT domain with a (K_D = 27.4 ± 1.2 μM which was superior to MCC950. Molecular docking studies predicted enhanced binding interactions for LMT2368, consistent with its improved biological activity. In LPS-primed macrophages, LMT2368 dose-dependently suppressed IL-1β secretion (IC50 = 0.8 μM in J774A.1 cells) and caspase-1 activation without affecting NF-κB signaling. Importantly, LMT2368 inhibited ASC oligomerization and pyroptosis while maintaining excellent safety margins (CC50 > 50 μM). In a murine model of LPS-induced acute lung injury, LMT2368 (10 mg/kg) reduced bronchoalveolar lavage fluid immune cell infiltration by 68% (p < 0.001), suppressed pro-inflammatory cytokine release (IL-1β/IL-6/TNF-α), and preserved lung histoarchitecture. Notably, LMT2368 showed selectivity for NLRP3 inhibition without affecting TNF-α/IL-6 production during TLR4 priming in monocytic cell lines. Conclusions: Together, these findings establish LMT2368 as a promising lead compound for developing safer NLRP3 inhibitors with therapeutic potential for inflammasome-driven diseases. Full article

N-acetylchitooligosaccharides (NACOS) are functional oligosaccharides derived from shrimp and crab shells that exhibit a variety of biological activities. This study investigates the protective effects of NACOS against acute lung injury (ALI) induced by lipopolysaccharides (LPS) in mice and explores its underlying metabolic regulatory mechanisms. Histopathological analysis showed that NACOS reduced pulmonary inflammation, edema, and disruption of tight junctions in ALI mice. Molecular analysis indicated that NACOS downregulated key inflammatory mediators, including NLRP3, IL-1β, TNF-α, MPO, and GCSF. Using untargeted metabolomics, glycerophospholipid metabolism was identified as the most significantly altered pathway following NACOS pre-treatment. Key regulated metabolites included triacylglycerols, phosphatidylethanolamines, lysophosphatidylcholines, and other glycerophospholipid derivatives. These findings suggest that NACOS exerts preventive effects through two primary mechanisms: the suppression of pro-inflammatory mediators and the modulation of glycerophospholipid metabolism. The identified metabolic alterations may serve as potential biomarkers for the progression of ALI and for monitoring prophylactic interventions. Full article

Background: Gastrointestinal (GI) cancers are common and pose a major public health issue. An inflammatory microenvironment drives their development and progression. The α7nAChR receptor, known to suppress autoimmune and inflammatory bowel diseases, is also linked to colorectal cancer. It enhances anti-inflammatory activity, influences tumor growth, metastasis, and treatment response, and is associated with tobacco use. NLRP3, a key inflammatory mediator, connects immunity and cancer. The α7nAChR receptor modulates tumorigenesis and therapy response by suppressing inflammatory pathways, while also regulating NLRP3 inflammasome activation through inhibition of mitochondrial DNA release. This study examines α7nAChR and NLRP3 expression in gastric and colorectal cancers, colitis, and normal tissues to clarify pathogenic mechanisms and identify therapeutic targets. Methods: Tissue samples of gastric tumor (S-Tm) (n = 10), colorectal tumor (C-Tm) (n = 10), colitis (UC) (n = 10), healthy stomach (S-C) (n = 10) and healthy colorectal tissue (C-C) (n = 10) taken during routine endoscopy protocols were homogenized. The α7nAChR and NLRP3 levels were examined using the ELISA method, and groups were compared. Results: We identified statistically significant differences in α7nAChR levels between the S-C and S-Tm (p < 0.05), C-C and C-Tm (p < 0.05), and S-C and C-Tm (p < 0.001) groups. The NRLP3 levels also differed significantly between the UC and C-Tm (p < 0.05), the S-C and C-Tm (p < 0.01), and the C-C and C-Tm groups (p < 0.01). Conclusions: Paradoxically, given the inflammatory regulatory role and oncogenic effects of α7nAChR, the relationship between α7nAChR and NLRP3 has become an important target for both oncological and inflammatory therapeutic approaches, particularly in inflammation-related GI cancers. Full article

Introduction: Sepsis is a dysregulated systemic immune response to infection which may result in mortality. It may also lead to organ injury, including injury to the lung. French maritime pine bark extract (MPBE) has been proposed to prevent/treat various inflammatory diseases due to its strong anti-inflammatory and antioxidant effects. This study evaluates the protective and therapeutic effects of MPBE on lung injury induced by intraperitoneal E. coli lipopolysaccharide (LPS) in rats. Materials and Methods: The study design was as follows: Control, MPBE20, MPBE50, LPS, LPS+MPBE20 and LPS+MPBE50. Blood and lung tissue samples were collected 6 h after the LPS induction following a 10-day administration of MPBE. Results: LPS-induced sepsis was confirmed by the overproduction of IL-1β and TNF-α in bloodstream compared to the Control (p < 0.001). Lung injury was determined by severe histopathological changes and neutrophil infiltration in the lung tissue following intraperitoneal LPS injection. In lung tissue, MPBE improved the levels of P2X7R, TLR4, NLRP3, IL-1β, TNF-α, JNK, H2AX, 8-OHdG, MDA, GSH, Caspase-1 and Caspase-3, and pathological changes in MPBE+LPS groups compared to the LPS group. Conclusions: MPBE appears to regulate P2X7R signaling and the inflammatory–apoptotic pathway by protecting the lung from oxidative cell damage in LPS-induced sepsis in vivo. Full article

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has become a worldwide health concern. Soy protein isolate (SPI) is a plant-derived protein with high nutritional value and has shown promising effects in regulating lipid metabolism and inflammation. Objectives: This study aimed to investigate the effects of an α-subunit-deficient SPI (α-lack-SPI) on MASLD and the underlying molecular mechanisms. Methods: Rats were fed with a high-fat, high-cholesterol diet (HFD) to induce MASLD. Results: The results showed that α-lack-SPI significantly reduced the levels of hepatic TG and TC, serum ALT, AST, TC, and LDL-C, and increased serum HDL-C in rats with HFD-induced MASLD. α-lack-SPI significantly attenuated hepatic steatosis and hepatocyte ballooning revealed by histopathological analysis. Meanwhile, α-lack-SPI markedly downregulated the mRNA expressions of Srebf1, Acaca, Fasn, Pcsk9, and Hmgcr, while significantly upregulating Pparα. Additionally, α-lack-SPI treatment significantly reduced the mRNA expressions of hepatic pro-inflammatory cytokines (Tnf-α, Il-1β, Il6), chemokine (Ccl2), and inflammasome component (Nlrp3), as well as the protein expression of COX-2. Conclusions: In conclusion, α-lack-SPI alleviated MASLD in HFD-fed rats probably via improving hepatic lipid metabolism and mitigating hepatic inflammation. These findings indicate that α-lack-SPI may serve as a promising nutritional intervention for MASLD management. Full article

Background/Objectives: Dülmen wild horses are kept in a fenced wooden and marsh area around Dülmen in Westphalia, Germany, since 1856. Previous analyses supported early genetic divergence from other domesticated horse populations and the Przewalski horse. Therefore, the objective of this study was to evaluate genetic diversity using high-density genomic data. Methods: We collected 337 one-year-old male Dülmen wild horses, captured at 12 annual auctions, for genotyping on the Illumina GGP Equine Plus Beadchip. All analyses were performed for 63,123 autosomal SNPs. Results: On average, each horse had 27.96 ROH with an average length of 8.237 Mb, resulting in an average genomic inbreeding coefficient F_ROH of 0.107. ROH with a length of 2–4 Mb were most frequent, and the next frequent ROH fall into the length categories of 4–8 and 8–16 Mb. The effective population size (N_e) steadily decreased in the last 100 generations by 4.57 individuals per generation from 498 to 41. We identified 10 ROH islands on equine chromosomes 1, 4, 5, 7, 9, and 10. Only one ROH island on ECA 1 was shared by 45% of the horses. Overrepresented genes of ROH islands were associated with glycerophospholipid catabolism through phospholipase A2 genes, skeletal muscle contraction (TNNI3, TNNT1), synapse activity and structure (CTTNBP2), regulation of inflammatory response (NLRP genes), and zinc finger protein genes, which are involved in many cellular processes and may also act as tumor suppressors and oncogenes. Conclusions: This study highlights the development of genomic inbreeding and shows the importance of the stallions selected for breeding on the genetic diversity of the Dülmen wild horses. The results of this study should be used to develop strategies to slow down increase in inbreeding and prevent transmitting unfavorable alleles from the stallions to the next generation. Full article

Oxidative stress destabilizes microRNA homeostasis in the retinal pigment epithelium (RPE), driving apoptosis and the epithelial-to-mesenchymal transition, which contribute to age-related macular degeneration. We investigated whether Quantum Molecular Resonance (QMR^®) electrostimulation, alone or combined with Patient Blood-Derived (PBD) secretoma, can reprogram the RPE miRNome and mitigate stress-induced damage. Human ARPE-19 cells were exposed to tert-butyl-hydroperoxide and treated with QMR^®, PBD secretome, or their combination. The deep sequencing of small RNAs at 24 h and 72 h, followed by differential expression and pathway enrichment analyses, delineated treatment-driven miRNA signatures. Oxidative stress deregulated > 50 miRNAs, enriching pro-apoptotic, fibrotic, and inflammatory pathways. QMR^® restored roughly 40% of these miRNAs and upregulated additional cytoprotective species such as miR-590-3p, a known regulator of the NF-κB and NLRP3 pathways according to validated target databases. While these observations suggest the potential involvement of inflammatory and stress-related cascades, functional assays will be required to directly confirm such effects. Secretome treatment preferentially increased anti-inflammatory miR-146a-5p and regenerative miR-204-5p while suppressing pro-fibrotic let-7f-5p. Combined QMR^® + secretome triggered the broadest miRNA response, normalizing over two-thirds of stress-altered miRNAs. These changes are predicted to influence antioxidant, anti-apoptotic, and anti-fibrotic pathways, although they did not translate into additional short-term cytoprotection compared with QMR^® alone. These data indicate that QMR^® and PBD secretome modulate complementary miRNA programs that converge on stress response networks. This broader molecular reprogramming may reflect regulatory complementarity, but functional validation is needed to determine whether it provides benefits beyond those observed with QMR^® alone. These findings offer molecular insights into potential non-invasive, cell-free strategies for retinal degeneration, although in vivo validation will be required before any clinical translation to Age-Related Macular Degeneration (AMD) therapy. Full article

Influenza A virus (IAV) infection triggers excessive activation of PANoptosis—a coordinated form of programmed cell death integrating pyroptosis, apoptosis, and necroptosis—which contributes to severe immunopathology and acute lung injury. However, the molecular regulators that drive PANoptosis during IAV infection remain poorly understood. In this study, we integrated bulk and single-cell RNA sequencing (scRNA-seq) datasets to dissect the cellular heterogeneity and transcriptional dynamics of PANoptosis in the influenza-infected lung. PANoptosis-related gene activity was quantified using the AUCell, ssGSEA, and AddModuleScore algorithms. Machine learning approaches, including Support Vector Machine (SVM), Random Forest (RF), and Least Absolute Shrinkage and Selection Operator (LASSO) regression, were employed to identify key regulatory genes. scRNA-seq analysis revealed that PANoptosis activity was primarily enriched in macrophages and neutrophils. Integration of transcriptomic and computational data identified cathepsin B (CTSB) as a central regulator of PANoptosis. In vivo validation in an IAV-infected mouse model confirmed elevated expression of PANoptosis markers and upregulation of CTSB. Mechanistically, CTSB may facilitate NLRP3 inflammasome activation and promote lysosomal dysfunction-associated inflammatory cell death. These findings identify CTSB as a critical mediatoCTSBr linking lysosomal integrity to innate immune-driven lung injury and suggest that targeting CTSB could represent a promising therapeutic strategy to alleviate influenza-associated immunopathology. Full article

Environmental pollutants such as heavy metals, endocrine-disrupting chemicals, microplastics, and airborne particulates are increasingly recognized for their potential to influence immune function through epigenetic mechanisms. This review examines conserved pollutant-associated pathways at interfaces of immunity and epigenetics, with particular attention to Toll-like receptor–NF-κB signalling, NLRP3 inflammasome activity, and reactive oxygen species-driven cascades. Evidence from cellular, animal, and epidemiological studies indicates that these pathways may converge on chromatin regulators such as DNA methyltransferases, histone deacetylases, and EZH2, leading to DNA methylation shifts, histone modifications, and altered chromatin accessibility. Pollutants are also reported to modulate non-coding RNAs, including miR-21, miR-155, and several lncRNAs, which can act as intermediaries between cytokine signalling and epigenetic remodelling. Findings from transgenerational models suggest that pollutant-linked immune–epigenetic alterations might persist across generations, raising the possibility of long-term consequences for immune and neurodevelopmental health. Comparative analyses further indicate convergence across diverse pollutant classes, pointing to a shared mechanistic axis of immune–epigenetic disruption. Overall, these insights suggest that pollutant-induced immune–epigenetic signatures may contribute to inflammation, altered immune responses, and heritable disease risks, and their clarification could inform biomarker discovery and future precision approaches in immunotoxicology. Full article