Search Results (374)

Gut microbiota-derived trimethylamine N-oxide (TMAO) has been implicated in both intestinal and renal diseases; however, its specific role in modulating gut–kidney interactions remains unclear. This study aimed to investigate the effects of TMAO on gut–kidney crosstalk using a mouse model of diarrhea. Mice were divided into four groups: normal, model, TMAO, and TMAO + model. The normal group received sterile water, while the other groups were administered adenine + Folium sennae, TMAO, or a combination of TMAO and adenine + Folium sennae. Samples were collected to assess morphological changes in the colon and kidney, evaluate the colonic mucosal barrier and renal function, and measure NLRP3 inflammasome activity and inflammatory cytokine levels in colonic and renal tissues. TMAO levels and the gut microbiota composition were analyzed using 16S rRNA sequencing. The model group exhibited altered stool morphology, which was further aggravated by TMAO intervention. Both the model and TMAO + model groups exhibited significant damage to intestinal and renal tissues, along with compromised intestinal mucosal barriers and impaired renal function compared to controls. Inflammatory markers were elevated in these groups, with the TMAO + model group showing the most pronounced increases. Correlation analysis indicated significant relationships among TMAO levels, inflammasome activation, and inflammatory cytokines. The genera Mucispirillum and Anaerotruncus negatively correlated with TMAO, whereas Parabacteroides and Parasutterella genera positively correlated with TMAO. In conclusion, TMAO plays a critical role in modulating gut–kidney crosstalk by promoting inflammation, disrupting mucosal and renal integrity, and altering the gut microbial ecosystem. Full article

Cardiorenal syndrome (CRS) is a multifactorial clinical condition characterized by the bidirectional deterioration of cardiac and renal function, driven by mechanisms such as renin–angiotensin–aldosterone system (RAAS) overactivation, systemic inflammation, oxidative stress, endothelial dysfunction, and fibrosis. The aim of this narrative review is to explore the key molecular pathways involved in CRS and to highlight emerging therapeutic approaches, with a special emphasis on nutritional interventions. We examined recent evidence on the contribution of mitochondrial dysfunction, uremic toxins, and immune activation to CRS progression and assessed the role of dietary and micronutrient factors. Results indicate that a high dietary intake of sodium, phosphorus additives, and processed foods is associated with volume overload, vascular damage, and inflammation, whereas deficiencies in potassium, magnesium, and vitamin D correlate with worse clinical outcomes. Anti-inflammatory and antioxidant bioactives, such as omega-3 PUFAs, curcumin, and anthocyanins from maqui, demonstrate potential to modulate key CRS mechanisms, including the nuclear factor kappa B (NF-κB) pathway and the NLRP3 inflammasome. Gene therapy approaches targeting endothelial nitric oxide synthase (eNOS) and transforming growth factor-beta (TGF-β) signaling are also discussed. An integrative approach combining pharmacological RAAS modulation with personalized medical nutrition therapy and anti-inflammatory nutrients may offer a promising strategy to prevent or delay CRS progression and improve patient outcomes. Full article

Cirrhosis remains a significant global health burden, responsible for nearly 4% of annual deaths worldwide. Despite progress in antiviral therapies and public health measures, its prevalence has plateaued, particularly in regions affected by viral hepatitis, alcohol misuse, and metabolic syndrome. This review presents a comprehensive synthesis of the multifactorial drivers of cirrhosis, including hepatocyte injury, liver stellate cell activation, and immune-mediated inflammation. The emphasis is on the central role of metabolic dysfunction, characterized by mitochondrial impairment, altered lipid and glucose metabolism, hormonal imbalance, and systemic inflammation, in exacerbating disease progression. While current therapies may slow the progression of early-stage disease, they are very often ineffective in reversing established fibrosis. Emerging molecular strategies offer promising alternatives by targeting key pathogenic pathways. These include AMPK activators (e.g., metformin, AICAR), FGF21 analogs, and mitochondria-targeted agents (e.g., MitoQ, urolithin A, NAD+ precursors) to restore bioenergetic balance and reduce oxidative stress. Other approaches, such as mesenchymal stem cell therapy, inflammasome inhibition, and hormonal modulation, aim to suppress fibrogenesis and restore liver homeostasis. The integration of systems biology and multi-omics profiling supports patient stratification and precision medicine. This review highlights a shift toward mechanism-based interventions that have the potential to alter cirrhosis outcomes and improve patient survival. Full article

This study aimed to evaluate whether probiotic administration could protect against cognitive impairments in a scopolamine-induced cognitive impairment mice model. Male C57BL/6 mice (8 weeks of age) were injected with scopolamine hydrobromide to induce memory impairments. The experimental groups were additionally supplemented with 10⁹ colony-forming units (CFU)/day probiotics containing Lactobacillus helveticus CNU395 or L. paracasei CNU396. Behavioral test results and histopathological evaluations showed that the spatial memory ability and pathological tissue abnormalities of the mice in the CNU395 and CNU396 groups significantly improved compared with those in the disease group. CNU395 and CNU396 mitigated scopolamine-induced neuroinflammation by reducing the expression of pro-inflammatory cytokines (IL-6, IL-8, IL-10, and TNF-α) and the NLRP3 inflammasome, through the inhibition of MAPK and NF-κB inflammatory pathways. Additionally, the CNU395 and CNU396 groups showed decreased levels of Iba-1 and Bax, alongside increased levels of BDNF and Bcl-2, relative to the disease group. Therefore, CNU395 or CNU396 supplementation might help prevent the onset of cognitive deficits and neuroinflammation. Full article

Tonsils are secondary lymphoid organs that play a crucial role in the immunological response, with B cells being a major component involved in both innate and adaptive immunity. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and obstructive sleep apnea syndrome (OSAS) are both common pediatric conditions involving tonsillar pathology. In both syndromes, the molecular pathways dysregulated in tonsillar B cells are still to be understood. The study aimed to unravel and compare the proteomic profiles of tonsillar CD19+ B cells isolated from pediatric patients with PFAPA (n = 6) and OSAS (n = 6) to identify disease-specific molecular signatures. B cells were isolated from the tonsillar tissue using magnetic microbeads (with a purity of 93.50%). Proteomic analysis was performed by nanoLC-MS/MS with both data-dependent (DDA) and data-independent acquisition (DIA) methods, followed by comprehensive bioinformatic analysis. By merging DDA and DIA datasets, a total of 18.078 unique proteins were identified. Differential expression analysis revealed 83 proteins increased and 49 proteins decreased in OSAS B cells compared to PFAPA B cells (fold change ≥ 1.5 or ≤0.6, p < 0.05). Distinct pathway enrichments were highlighted, including alterations in the regulation of PTEN gene transcription, circadian gene expression, inflammasome pathways (IPAF and AIM2), and the metabolism of angiotensinogen to angiotensin. Specific proteins such as p53, Hdac3, RPTOR, MED1, Caspase-1, Cathepsin D, Chymase, and TLR2 (validated by WB) were shown to be differentially expressed. These findings reveal distinct proteomic signatures in tonsillar B cells from patients with PFAPA and OSAS, offering novel insights into the pathophysiology and potential avenues for biomarker discovery. Full article

Background/Objectives: Rheumatoid arthritis (RA) is a chronic, systemic, and progressive autoimmune–inflammatory disease primarily affecting small joints. Inonotus obliquus polysaccharide (IOP) is the main component of the parasitic fungus obliquus, which has anti-tumor, anti-inflammatory, and antioxidant effects. However, whether IOP has a therapeutic effect on RA is still unclear. Thus, this study aimed to reveal the effect of IOP on MH7A cells and collagen-induced arthritis (CIA) rats and to investigate the molecular mechanism of IOP in RA. Methods: In this study, network pharmacology was used to identify the key signaling pathways in IOP treatment of RA. The effect of IOP was verified in rats with CIA. We performed CCK-8, EdU, colony formation assay, cell apoptosis, cell migration and invasion, Western blot analysis, and immunofluorescence to elucidate the effect of IOP on the proliferation, apoptosis, migration and invasion of MH7A cells and revealed its modulation of the NF-κB and NLRP3 inflammasome signaling pathways. Results: IOP treatment of CIA rats significantly alleviated joint swelling, synovial tissue proliferation and erosion, and reduced the expression of inflammatory factors TNF-α, IL-6, IL-1β and IL-18. In vitro, IOP significantly inhibited the proliferation, migration, and invasion abilities of TNF-α-stimulated MH7A cells and promoted their apoptosis. Mechanistically, IOP inhibited the NF-κB and NLRP3 inflammasome activation. Conclusions: This study revealed that IOP exerts anti-RA effects by downregulating the NF-κB and NLRP3 inflammasome signaling pathways, promoting cell apoptosis, and inhibiting the expression of inflammatory cytokines, representing a promising therapeutic option for RA. Full article

Circadian rhythms govern cellular metabolism, redox balance, and endocrine signaling in numerous tissues. However, chronic disturbance of these biological rhythms, mediated by modern lifestyle factors including shift work, sleep irregularity, and prolonged light exposure, has been increasingly associated with oxidative stress, metabolic dysregulation, and the pathogenesis of chronic diseases. This review discusses recent mechanistic advances that link circadian misalignment with tissue-specific metabolic reprogramming and impaired proteostasis, focusing on metabolic inflammation and associated pathologies. Emerging work reveals a close interdependence between the circadian clock and proteasome-mediated protein turnover and highlights this interplay’s importance in maintaining redox homeostasis. Furthermore, circadian modulation of the activity of the inflammasome complex is suggested to represent an important, but largely unexplored, risk factor in the pathobiology of both malignancy and metabolic syndrome. Recently, researchers have proposed them as novel endocrine regulators of systemic energy balance and inflammation, with a focus on their circadian regulation. In addition, the emerging domains of chrono-epigenetics and tissue-specific programming of the clock pathways may serve to usher in novel therapies through precision medicine. Moving ahead, circadian-based therapeutic approaches, including time-restricted feeding, chronopharmacology, and metabolic rewiring, have high potential for re-establishing physiological domain homeostasis linked to metabolic inflammation pathologies. Elucidating this reciprocal relationship between circadian biology and cellular stress pathways may one day facilitate the generation of precise interventions aiming to alleviate the health burden associated with circadian disruption. Full article

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited therapeutic options. Current therapies (pirfenidone, nintedanib) exhibit modest efficacy and significant side effects, underscoring the need for novel strategies targeting early pathogenic drivers. Saroglitazar (SGZ), a dual PPARα/γ agonist with anti-inflammatory properties approved for diabetic dyslipidemia, has not been explored for IPF. We aimed to investigate SGZ’s therapeutic potential in pulmonary fibrosis and elucidate its mechanisms of action. Materials and Methods: Using a bleomycin (BLM)-induced murine pulmonary fibrosis model, we administered SGZ therapeutically. A histopathological assessment (H&E, Masson’s trichrome, collagen I immunofluorescence), Western blotting, and qRT-PCR analyzed the fibrosis progression and inflammatory markers. Flow cytometry evaluated the macrophage polarization. In vitro studies used RAW264.7 macrophages stimulated with BLM/LPS and MRC-5 fibroblast co-cultures. The NF-κB/NLRP3 pathway activation was assessed through protein and gene expression. Results: SGZ significantly attenuated BLM-induced histopathological hallmarks, including alveolar wall thickening, collagen deposition, and inflammatory infiltration. Fibrotic markers (OPN, α-SMA) and pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) were downregulated in the SGZ-treated mice. Mechanistically, SGZ suppressed the M1 macrophage polarization (reduced CD86⁺ populations) and inhibited the NF-κB/NLRP3 pathway activation in the alveolar macrophages. In the RAW264.7 cells, SGZ decreased the NLRP3 inflammasome components (ASC, cleaved IL-1β) and cytokine secretion. Co-cultures demonstrated that the SGZ-treated macrophage supernatants suppressed the fibroblast activation (α-SMA, collagen I) in MRC-5 cells. Conclusions: SGZ attenuates pulmonary fibrosis by suppressing macrophage-driven inflammation via NF-κB/NLRP3 inhibition and disrupting the macrophage–fibroblast crosstalk. These findings nominate SGZ as a promising candidate for preclinical optimization and future clinical evaluation in IPF. Full article

Sepsis remains a critical global health challenge characterized by life-threatening organ dysfunction arising from a dysregulated host response to infection. Immunothrombosis refers to the intersection of immune activation and coagulation pathways, particularly relevant in the context of sepsis. A growing body of evidence identifies immunothrombosis, a tightly interwoven process between innate immunity and coagulation. While immunothrombosis serves as a host defense mechanism under physiological conditions, its aberrant activation in sepsis precipitates microvascular thrombosis, organ ischemia, and progression toward disseminated intravascular coagulation (DIC). This review provides a comprehensive overview of the cellular contributors to immunothrombosis, including neutrophils, monocytes, platelets, and endothelial cells, and elucidates the signaling cascades, such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and inflammasome activation, that govern their interplay. We further highlight emerging molecular mediators, including extracellular traps, tissue factor expression, and cytokine amplification loops, that collectively promote pathological thromboinflammation. A deeper understanding of these interconnected pathways offers critical insights into the pathogenesis of sepsis and unveils potential targets for timely intervention. Ultimately, this review aims to bridge immunological and hematological perspectives to inform the development of novel therapeutic strategies against sepsis-induced coagulopathy. Full article

Sepsis is a life-threatening syndrome characterized by a dysregulated immune response to infection, frequently leading to multiorgan failure and high mortality. Inflammasomes—cytosolic multiprotein complexes of the innate immune system—serve as critical platforms for sensing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Key sensors such as NLRP3, AIM2, and IFI16 initiate caspase-1 activation, IL-1β and IL-18 maturation, and gasdermin D–mediated pyroptosis. In sepsis, excessive inflammasome activation drives oxidative stress, endothelial dysfunction, immunothrombosis, and immune exhaustion. This maladaptive cascade is further aggravated by the release of DAMPs and procoagulant factors, compromising vascular integrity and immune homeostasis. Prolonged activation contributes to immunoparalysis, lymphopenia, and increased susceptibility to secondary infections. Inflammasome signaling also intersects with necroptosis and ferroptosis, amplifying systemic inflammation and tissue injury. Additionally, various pathogens exploit immune evasion strategies to modulate inflammasome responses and enhance virulence. Therapeutic interventions under investigation include selective NLRP3 inhibitors, IL-1 blockers, gasdermin D antagonists, and extracorporeal cytokine hemoadsorption. Emerging approaches emphasize biomarker-guided immunomodulation to achieve personalized therapy. While preclinical studies have shown promising results, clinical translation remains limited. Targeting inflammasomes may offer a path toward precision immunotherapy in sepsis, with potential to reduce organ dysfunction and improve survival. Full article

Chronic exposure to arsenic via drinking water can induce bladder cancer in humans. Nevertheless, there is little knowledge about the precise mechanisms of this. Abnormal elevations in cell proliferation and migration have repeatedly been identified as the first cellular traits of carcinogenesis. The aims of this study are to uncover the molecular mechanisms underlying arsenic-induced aberrant proliferation and migration of uroepithelium cells by exploring the role of cellular redox modulation. Our results show significant elevations in the levels of ROS and GSH, Trx1, components of the Nrf2 system, and NLRP3 inflammasome activity in the cells chronically treated with arsenite, which also experienced markedly enhanced proliferation and migration capacities. Additionally, ROS inhibitors, NLRP3, and the above antioxidant system could suppress this enhancement of the proliferation and migration capacities and reverse overexpression in these cells. However, only the AKT and ERK inhibitors were capable of reversing EGF, TGFα, and HSP90 overexpression. In conclusion, our findings indicate that the cellular redox status in the uroepithelium following chronic treatment with low-level arsenite was rebalanced due to ROS overproduction and compensatory upregulation of the redox control systems, which may allow ROS and Trx1 to be maintained at higher levels to facilitate cell proliferation and migration via overstimulation of the related signaling pathways. Full article

Aim: Despite a persistent presence in periodontitis, calculus remains a paradox. This narrative review reevaluates the role of calculus in periodontitis based on in situ, ex vivo, and in vitro studies published over the last two decades. Review: Results from multiple studies argue for the reconsideration of calculus as an independent risk factor in periodontitis. The results of a human study suggest that calculus contributes more to inflammation than simply serving as a substrate for biofilm accumulation. Ultrastructure studies have revealed residual calculus embedded in cementum following scaling and root planing (SRP). In vitro studies show that calculus particles can stimulate IL-1β secretion via the NLRP3 inflammasome in human and mouse phagocytes, and the crystalline structure is partially responsible for the activation. Other studies indicate that calculus particles may promote bone resorption via IL-1β induction in patients with periodontitis. Further, heat-treated calculus particles and hydroxyapatite crystals induce cell death in epithelial cell lines, suggesting that calculus plays a role in the breakdown of pocket epithelial integrity. Conclusions: Studies have shown that particles of microscopic calculus persist following traditional SRP. In vitro studies report that sterile and calcined calculus particles free of proteinaceous material are cytotoxic to cultured oral epithelial cells. Collectively, these studies suggest that residual microscopic calculus may be a potential risk factor for the failure of periodontal therapy. Full article

Interstitial cystitis/bladder pain syndrome (IC/BPS) causes significant discomfort in patients and impairs the quality of urination. Pterostilbene (PTE), a natural polyphenol antioxidant, has demonstrated beneficial effects in mitigating inflammation, enhancing antioxidant capacity, and ameliorating organ dysfunction in various chronic nonspecific inflammatory conditions. The aim of this study was to evaluate the efficacy of PTE in IC/BPS and elucidate its underlying mechanisms using a rat model of cyclophosphamide (CYP)-induced interstitial cystitis. In comparison, chronic pain progression, histopathological features, and cytokine levels demonstrated that PTE mitigated the severity of symptoms in CYP-induced rats by inhibiting the NLRP3 inflammasome in a dose-dependent manner. Further mechanistic investigations indicated that PTE intervention alleviated oxidative stress in CYP-induced IC in rats via activation of the Nrf2/HO-1 signaling pathway. Moreover, inhibitors of the Nrf2/HO-1 pathway effectively blocked PTE-mediated attenuation of oxidative stress. The suppression of NLRP3 inflammasome activation by PTE could also be reversed by inhibition of the Nrf2/HO-1 pathway. In vitro studies revealed that PTE enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and suppressed NLRP3 inflammasome activation in SV-HUC-1 cells exposed to lipopolysaccharide (LPS) and Adenosine Triphosphate (ATP). These findings collectively suggest that PTE treatment inhibits oxidative stress and suppresses NLRP3 inflammasome activation through modulation of the Nrf2/HO-1 pathway. Full article

Inflammation is a vital physiological response that plays a crucial role in regulating host defense against pathogens while maintaining tissue homeostasis. Inflammasomes, a family of protein complexes, are responsible for controlling the expression of pro-inflammatory cytokines IL-1β and IL-18, and they play significant roles in inflammatory responses. However, dysregulated inflammation can become a risk factor for the pathogenesis of various diseases. The discovery of anti-inflammatory substances derived from natural products represents an important strategy for new drug development. In this study, we found that the essential oil derived from the heartwood of Cinnamomum kanehirai Hayata (EOC) exhibits anti-inflammatory activities by inhibiting the NLRP3, NLRP1, NLRC4, AIM2, and non-canonical inflammasomes in macrophages. EOC also suppresses the expression of NLRP3, TNF-α, IL-6, and NO in LPS-activated macrophages. The mechanisms underlying the anti-inflammatory activity of EOC were shown to involve a reduction in reactive oxygen species production and NF-κB activation. Furthermore, terpinen-4-ol may be the key anti-inflammatory compound present in EOC. These results suggest that EOC has potential as an anti-inflammatory agent for future development. Full article

Diesel exhaust particulate (DEP) is widely recognized to weaken lung function and skin diseases. When the skin, which defends against external factors, is exposed to PM2.5, various chronic inflammatory diseases occur. When keratinocytes recognize harmful signals, they synthesize the NOD-like receptor protein 1 (NLRP1) inflammasome. DEP enhances NF-κB signaling and NLRP1 inflammasome expression through the interaction of TXNIP with NLRP1 in keratinocytes. Although many studies have reported the anti-inflammatory and antioxidant characteristics of Impressic acid (IPA), the umbrella consequences of IPA for PM2.5-influenced inflammasomes and the associated mechanisms remain unknown. Therefore, this study aimed to examine the protective function of IPA against inflammation in human keratinocytes. IPA attenuated the NLRP1 expression, caspase-1, IL-1β actuation, and NF-κB and IκB phosphorylation induction by DEP. IPA upregulated the Nrf2, HO-1, and NQO1 expression through CaMKKβ, AMPK, and GSK3β phosphorylation. Also, IPA led to the elevation of p62 and the degradation of the Keap1 protein. ML385 reversed the suppressive effect of IPA on the NLRP1 inflammasome, which was enhanced by DEP, and NAC counteracted the effect of ML385. These findings indicate that IPA can suppress inflammation induced by PM2.5 by expressing antioxidant enzymes through the Keap1/p62/Nrf2-signaling pathway in human keratinocytes. Full article