Search Results (450)

Fat embolism is a critical medical emergency often resulting from long bone fractures or amputations, leading to acute respiratory distress syndrome (ARDS). The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of innate immunity, is activated by reactive oxygen species and tissue damage, contributing to inflammatory responses. This study examines the role of NLRP3 in fat embolism-induced ARDS and evaluates the therapeutic potential of MCC950, a selective NLRP3 antagonist. Fat embolism was induced by fatty micelle injection into the tail vein of Sprague Dawley rats. Pulmonary injury was assessed through lung weight gain as an edema indicator, NLRP3 expression via Western blot, and IL-1β levels using ELISA. Histological damage and macrophage infiltration were evaluated with hematoxylin and eosin staining. Fat embolism significantly increased pulmonary NLRP3 expression, lipid peroxidation, IL-1β release, and macrophage infiltration within four hours, accompanied by severe pulmonary edema. NLRP3 was localized in type I alveolar cells, co-localizing with aquaporin 5. Administration of MCC950 significantly reduced inflammatory responses, lipid peroxidation, pulmonary edema, and histological damage, while attenuating MAPK cascade phosphorylation of ERK and Raf. These findings suggest that NLRP3 plays a critical role in fat embolism-induced acute respiratory distress syndrome, and its inhibition by MCC950 may offer a promising therapeutic approach. Full article

Tuberous sclerosis complex (TSC) is a systemic disease caused by mutations in either the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) gene, with mutations in the TSC2 gene potentially leading to more severe clinical symptoms. Neurological symptoms are a common clinical manifestation of TSC, and neuroinflammation is thought to play an important role. Glial cells are a major source of neuroinflammation, but whether microglia are involved in the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and the expression of interleukin-1β (IL-1β) in TSC patients remains unclear. We used a transcriptome sequencing dataset for bioinformatics analysis to explore the differences in the expression of microglial inflammasome-associated hub genes. TSC2 knockdown (TSC2 KD) microglia (HMC3 cell line) were generated by lentivirus, and the expression of inflammasome-associated hub genes, microglial activation, and NLRP3 inflammasome activation were verified. In addition, experiments were performed to explore the regulatory effects of rapamycin. Bioinformatics analysis identified a total of eight inflammasome-associated hub genes. By detecting GFP fluorescence, TSC2 mRNA, TSC2 protein expression, and the phosphorylation of the mammalian target of rapamycin (p-mTOR)/mTOR, we confirmed that the TSC2 KD microglia model was successfully established. Compared with the control group, the TSC2 KD group presented higher mRNA levels and fluorescence intensities of microglia AIF1 and CD68, as well as greater reactive oxygen species (ROS) production. Eight inflammasome-associated hub gene mRNA assays revealed that the expression of the NLRP3 and IL1B genes was increased. Compared with the control group, the TSC2 KD group presented increased levels of NLRP3 and Pro-IL-1β proteins in cells and Cleaved-Caspase 1 and Cleaved-IL-1β proteins in the supernatant, suggesting NLRP3 inflammasome activation. Rapamycin intervention alleviated these changes, demonstrating that the TSC2 gene regulation of microglial activation and NLRP3 inflammasome activation are correlated with mTOR phosphorylation. In conclusion, microglia are activated in TSC patients and participate in the NLRP3 inflammasome-associated neuroinflammatory response, and rapamycin treatment can alleviate these changes. Full article

Background/Objectives: Sepsis-induced cardiomyopathy (SIC) is a serious clinical disorder with a high death rate. Qifu decoction (QFD) is a renowned traditional Chinese medicine with documented pharmacological actions, such as anti-inflammatory, anti-oxidant and anti-apoptosis activities, and it has good therapeutic effects on cardiovascular diseases. This study aimed to reveal the cardioprotective effects and underlying mechanisms of QFD against SIC. Methods: Electrocardiography, histopathological examination, and biochemical indicator determination were carried out to investigate the cardioprotective effects of QFD in the treatment of LPS-induced SIC mice. Metabolomics and network pharmacology strategies were employed to preliminarily analyze and predict the mechanisms of QFD against SIC. Molecular docking and Western blot were further applied to validate the core targets and potential pathways for the treatment of SIC in in vitro and in vivo models. Results: It was found that QFD considerably enhanced cardiac function; attenuated myocardial injury; and reduced the serum levels of LDH, CK-MB, IL-1β, and TNF-α by 28.7%, 32.3%, 38.6%, and 36.7%, respectively. Metabolomic analysis showed that QFD could regulate seven metabolic pathways, namely, glutathione metabolism; alanine, aspartate, and glutamate metabolism; arachidonic acid metabolism; glycerophospholipid metabolism; purine metabolism; sphingolipid metabolism; and fatty acid metabolism. Network pharmacology suggested that the anti-SIC effect of QFD may be mediated through the TNF, toll-like receptor, NOD-like receptor, NF-κB, and PPAR signaling pathways. Additionally, 26 core targets were obtained. Molecular docking revealed that active ingredients such as formononetin, kaempferol, quercetin, and (R)-norcoclaurine in QFD had a high affinity for binding to PPARα and TLR4. Further Western blot validation indicated that QFD could regulate the protein levels of NLRP3, TLR4, NF-κB, IL-6, TNF-α, COX2, sPLA2, PPARα, CPT1B, and CPT2. Conclusions: This study demonstrates that QFD can alleviate SIC by suppressing the TLR4/NF-κB/NLRP3 inflammatory pathway and modulating impaired FAO through the activation of the PPARα/CPT pathway, highlighting QFD as a promising candidate drug for SIC treatment. Full article

Chronic inflammation plays a central role in the progression and complications of chronic kidney disease (CKD). The nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome pathway has emerged as a crucial mediator of the inflammatory response in CKD. This cross-sectional study evaluated the expression of NLRP3 in patients with CKD undergoing different treatments. Blood samples were collected from 32 non-dialysis (ND) patients [63 (11.2) years, estimated glomerular filtration rate, 43.5 (22.0) mL/min, BMI, 29.5 (10.0) kg/m²)], 50 hemodialysis (HD) patients [48.5 (16.5) years, 60.5 (50) months on HD, BMI, 24.2 (4.9) kg/m²)], and 8 peritoneal dialysis (PD) patients [56.5 (8.5) years, 40.5 (41.2) months on PD, BMI, 28.8 (2.6) kg/m²)]. The mRNA expression level of NLRP3 was measured using real-time PCR. The cytokines and the malondialdehyde (MDA) levels were also assessed. The results indicated that the mRNA level of NLRP3 was significantly elevated in patients undergoing HD (1.23, IQR = 0.95) compared with that in non-dialysis patients (0.79, IQR = 0.35) and in patients undergoing PD (0.77, IQR = 0.38) after adjusting for confounding variables, including age, sex, BMI, and dialysis duration. Furthermore, the MDA levels were significantly higher in HD patients. NLRP3 is upregulated in HD patients, and the results suggested that the inflammasome may be associated with oxidative stress in patients with CKD. Full article

Cutibacterium acnes (C. acnes) is a commensal bacterium of the skin microbiota that can transform itself into a pathogen depending on the peculiar susceptibility of the host: it is the sole microorganism so far to be found in the specific organ lesions of sarcoidosis, and C. acnes-induced activation of T-helper-type-1 cell responses is generally higher in patients with sarcoidosis than in healthy subjects. This bacterium acts as an opportunistic agent in several inflammatory conditions other than sarcoidosis, such as prostate cancer and prosthetic joint infections. Both innate and adaptive immunity systems are involved in the pathogenesis of C. acnes-mediated sarcoid lesions, and a seminal role is played by host toll-like receptor (TLR)-2, TLR-4, TLR-6, NOD-like receptors, and mononuclear cell cytoplasmic receptors. This review summarizes current knowledge on the potential cause–effect relationship existing between C. acnes and sarcoidosis, addressing issues of future research directions and novel therapeutic strategies in the management of a complex disease such as sarcoidosis. Full article

This study evaluated the therapeutic potential of 70% ethanol extracts from six medicinal plants (Chenopodium album, Cassia tora, Cudrania tricuspidata, Dioscorea polystachya, Lonicera japonica, Solidago virgaurea subsp. gigantea) through their antibacterial, antioxidant, cytotoxic, and immunomodulatory activities, targeting applications in aquaculture. All extracts exhibited potent antibacterial activity (MIC ≤ 10 μg/mL) against Aeromonas spp. and Photobacterium damselae subsp. damselae, but limited efficacy against Streptococcus parauberis. C. tricuspidata (CTR) and C. tora (CTO) demonstrated superior antioxidant activity (IC₅₀ = 1292 μg/mL and IC₅₀ = 227 μg/mL, respectively), correlating with high polyphenol content (1498 and 1409 mg GAE/g). CTR displayed significant concentration-dependent cytotoxicity (IC₅₀ = 904.2 μg/mL), while C. album (CA) promoted cell proliferation (132.3% viability). In LPS-stimulated CHSE-214 cells, D. polystachya (DP) induced the highest IL-8 expression (207-fold), followed by Chenopodium album (CA) (194-fold IL-8, 49-fold TNF-α) and CTR (245-fold RIPK2), activating NF-κB, MAPK, and NOD-like receptor pathways critical for teleost immunity. Lonicera japonica (LJ) suppressed TNF-α (0.4-fold) and IRF1 (0.3-fold), indicating anti-inflammatory potential, while S. virgaurea subsp. gigantea (SV) showed biphasic TNF-α modulation (79-fold at 10 μg/mL, 5-fold at 100 μg/mL). These diverse bioactivities, particularly the robust immunomodulatory effects, highlight the promise of these extracts as natural therapeutic agents for fish health management in aquaculture. Full article

Elderly individuals infected with SARS-CoV-2 are at higher risk of developing cytokine storms and severe outcomes, yet specific biomarkers remain unclear. In this study, we investigated the alteration of primary bile acid metabolism in elderly patients with severe COVID-19 using untargeted metabolomics (n = 31), followed by targeted metabolomics to compare patients with disease progression (n = 16) to those without (n = 48). Significant reductions in chenodeoxycholic acid (CDCA) and glycochenodeoxycholic acid (GCDCA) levels were identified in severe cases, with GCDCA levels at admission correlating strongly with peak inflammatory markers. In vitro, CDCA, GCDCA, and their receptors, Farnesoid X Receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), effectively inhibited the inflammatory response induced by SARS-CoV-2. NOD-like receptor pathway, activated by SARS-CoV-2, may modulate inflammatory cytokines under the treatment of CDCA, GCDCA, and TGR5. CDCA and GCDCA levels at admission predicted disease progression, suggesting their potential as biomarkers for severe COVID-19 in the elderly and highlighting their regulatory role in inflammation, pointing to new therapeutic avenues. Full article

Cognitive problems are associated with impaired learning ability and memory dysfunction. Neuroinflammation has been identified as an important factor in the progression of anxiety and depressive disorders. Zingerone is a phenolic alkanone derived from ginger (Zingiber officinale Roscoe), which is known for its antioxidant and anti-inflammatory properties. A number of studies have investigated the effect of zingerone on neuroinflammation and cognitive impairment. However, this evidence has not been systematically reviewed. This study sought to systematically review the effect of zingerone on neuroinflammation and neurobehavioural changes associated with memory and learning impairment and anxiety-like and depressive-like behaviours. A systematic review was conducted using pre-defined search criteria on Google Scholar, Scopus and Web of Science. The records obtained were screened based on inclusion criteria, and data was extracted from the included studies. Out of the 482 studies that were identified, only 9 studies met the inclusion criteria. Neuroinflammatory markers such as interleukin 1β (IL-1β), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-α) and ionized calcium binding adaptor molecule (IBA-1), as well as behavioural parameters including Morris water maze, Y-Maze, recognition test, passive avoidance test, elevated plus maze, sucrose preference test and forced swimming test were measured. Zingerone exhibited anti-neuroinflammatory effects by improving IL-1β, IL-6 and TNF-α levels. However, zingerone did not show any significant changes on activated microglia. The anti-neuroinflammatory mechanisms of zingerone were linked to the inhibition of nuclear factor kappa B (NF-kB) activation and the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, as well as the reduction in neuronal nitric oxide synthase (nNOS). The anxiolytic and anti-depressive effects of zingerone were also associated with an improvement in cortical cholinergic transmission, the mitigation of oxidative stress and the upregulation of neurotransmitters such as serotonin and dopamine. This review provides scientific evidence on the cognitive enhancing and neuroprotective mechanisms of zingerone, which may be beneficial for future experimental investigations. Full article

This study investigated the effects of potassium magnesium sulfate (PMS) on intestinal dissociation and absorption rate, immune function, and expression of the NOD-like receptor thermal domain-associated protein 3 (NLRP3) inflammasome, aquaporins (AQPs), and potassium and magnesium ion channels in weaned piglets. Experiment 1 involved the assessment of the dissociation rate of PMS in pig digestive fluid and the absorption rate of PMS in the small intestine using an Ussing chamber in vitro. In Experiment 2, 216 healthy 21-day-old weaned piglets were selected and randomly assigned to six groups (0%, 0.15%, 0.30%, 0.45%, 0.60%, and 0.75% PMS), with each group 6 replicates of six piglets per replicate. The in vitro Ussing chamber results indicated that the absorption of K⁺ and Mg²⁺ in the jejunum and ileum was significantly higher than that in the duodenum (p < 0.05). The in vivo study demonstrated that the addition of PMS resulted in a linear increase in serum K⁺, IgG, and interleukin (IL)-2 levels while simultaneously reducing serum IL-1β levels (p < 0.05). Dietary PMS significantly elevated serum IL-10 and Mg²⁺ levels in feces (p < 0.05). Furthermore, supplementation with 0.60% or 0.75% PMS significantly downregulated the mRNA expression of NLRP3 in the jejunum (p < 0.05). Dietary PMS supplementation linearly reduced the mRNA expression levels of cysteine protease 1 (Caspase-1) and IL-1β in both the jejunum and colon as well as the mRNA expression levels of two-pore domain channel subfamily K member 5 (KCNK5) in these regions (p < 0.05). Notably, supplementation with 0.15% PMS significantly decreased the mRNA expression of transient receptor potential channel 6 (TRPM6) in the jejunum and significantly increased the expression of TRPM6 in the colon (p < 0.05). Dietary addition of 0.45% and 0.60% PMS significantly increased the mRNA expression of aquaporin 3 (AQP3) in the colon (p < 0.05), whereas 0.75% PMS significantly increased the mRNA expression of aquaporin 8 (AQP8) in both the jejunum and colon. Moreover, the expression levels of AQP3 and AQP8 were significantly negatively correlated with the diarrhea rate observed between days 29 and 42. In conclusion, dietary PMS supplementation improved immune function, inhibited the activation of intestinal NLRP3, and modulated the expression of water and ion channels in weaned piglets, thereby contributing to the maintenance of intestinal water and ion homeostasis, which could potentially alleviate post-weaning diarrhea in piglets. The recommended supplemental level of PMS in the corn-soybean basal diet for weaned piglets is 0.30%. Full article

Background/Objectives: Depression ranks among the most prevalent mental health conditions globally, marked by a variety of symptoms that frequently cause significant emotional distress and impairment in individuals, alongside a high recurrence rate. The predominant approach to treating depression revolves around monoamine theory, utilizing SSRIs and SNRIs, with Esketamine emerging as a supplementary option in recent times. Nevertheless, there is a growing focus on exploring the relationship between inflammation and depression, revealing a strong correlation between the two. This insight prompts consideration of the anti-inflammatory properties of current antidepressants in their therapeutic application. Methods: A systematic literature search was conducted using the PubMed database to identify randomized controlled trials (RCTs) and clinical trials (CTs) that assessed the in vivo anti-inflammatory effects of SSRIs (fluoxetine, escitalopram, sertraline, and paroxetine), the SNRI venlafaxine, and esketamine/ketamine in human subjects undergoing treatment for depression. The included studies were evaluated based on changes in levels of pro-inflammatory and anti-inflammatory markers in response to the antidepressant treatments. Results: SSRIs, SNRIs, esketamine, and ketamine (a racemic mixture of S- and R-ketamine not formally approved for the treatment of depression) exhibit anti-inflammatory effects through diverse mechanisms, such as reducing pro-inflammatory cytokines or enhancing anti-inflammatory cytokines in serum or within specific brain regions like the hippocampus and prefrontal cortex. These actions are mediated through various inflammatory pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the brain Nod-like receptor pyrin-containing 3 (NLRP3) inflammasome, the glutamatergic system, the gut–brain axis, the hypothalamic–pituitary axis, impaired neuroplasticity, and the kynurenine pathway. Conclusions: In summary, SSRIs, SNRIs, esketamine, and ketamine exert an anti-inflammatory role alongside their antidepressant effects via these intricate mechanisms. Full article

This study investigates the anti-inflammatory effects of the marine diterpene glycosides pseudopterosin A-D (PsA-D) in mitigating nickel sulfate (NiSO₄)-induced skin sensitization. In dermal dendritic cell (DDC) surrogates, PsA-D pre-treatment significantly reduced NiSO₄-induced upregulation of key activation surface markers, cluster of differentiation (CD)54 (~1.2-fold), and CD86 (~1.6-fold). Additionally, PsA-D inhibited the NiSO₄-induced activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by suppressing inhibitor of kappa B alpha (IκBα) degradation. Furthermore, PsA-D suppressed inflammatory responses by inhibiting the NiSO₄-induced secretion of pro-inflammatory cytokines, including interleukin (IL)-8 (~6.8-fold), IL-6 (~2.2-fold), and IL-1β (~5.3-fold). In a full-thickness human skin model incorporating DDC surrogates, topical application of PsA-D effectively attenuated NiSO₄-induced mRNA expression of IL-8 (~2.1-fold), IL-6 (~2.6-fold), and IL-1β (~2.2-fold), along with the key inflammatory mediators cyclooxygenase-2 (COX-2) (~3.5-fold) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) (~2.1-fold). Overall, PsA-D demonstrated comparable efficacy to dexamethasone, a benchmark corticosteroid, providing a promising therapeutic alternative to corticosteroids for the treatment of skin sensitization and allergic contact dermatitis. However, to maximize PsA-D’s therapeutic potential, future studies on optimizing the bioavailability and formulation of PsA-D are required. Full article

Chronic inflammation is an important contributor to the development of cardiovascular disorders, and inflammasomes, especially the NOD-like receptor protein 3 (NLRP3), are emerging as crucial mediators in this context. Inflammasomes are activated through receptor-mediated danger signals, such as cholesterol crystals and cellular damage products, thereby stimulating the secretion of pro-inflammatory cytokines, which sustains inflammation. This mechanism drives atherosclerosis (via plaque formation and destabilization), heart failure (via fibrotic remodeling), and pericarditis (via exacerbation of pericardial inflammation). Therapeutic approaches seek to block inflammasome activation or their pro-inflammatory pathways. Colchicine, interleukin-1 inhibitors (anakinra, canakinumab), and Sodium-Glucose Transport Protein 2 (SGLT2) inhibitors have a positive impact on cardiovascular inflammation. Various new compounds, such as MCC950, have been described as novel specific inhibitors of NLRP3. Further studies are needed to validate the effectiveness and safety of these treatments. Further elucidating the role of inflammasomes in cardiovascular disease could open the way to achieving more effective therapies, allowing for better management of high-risk cardiovascular patients. 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

Background: Growing evidence suggests that the prevalence of sarcopenic obesity (SOB) is on the rise across the globe. However, the key molecular mechanisms behind this disease have not been clarified. Methods: In this experiment, we fed zebrafish a high-fat diet (HFD) for 16 weeks to induce sarcopenic obesity. Results: After a dietary trial, HFD zebrafish exhibited an obese phenotype with skeletal muscle atrophy and decreased swimming capacity. We demonstrated that mitochondrial content and function were abnormal in SOB zebrafish skeletal muscle. These results may be associated with the impairment of mitophagy regulated by the PTEN-induced putative kinase 1 (PINK1)/Parkin (PRKN) pathway. In addition, we also found that NOD-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD) signaling was activated with the upregulation of NLRP3, GSDMD-NT, and mature-IL1β, which indicated that pyroptosis was induced in SOB zebrafish skeletal muscle. Conclusions: Our study identified that impaired mitophagy and pyroptosis were associated with the pathogenesis of SOB. These results could potentially offer novel therapeutic objectives for the treatment of sarcopenic obesity. Full article

Deregulation of microRNAs (miRNAs) has been implicated in the development of inflammatory bowel disease (IBD). Specific miRNAs are differentially expressed in patients with IBD compared to healthy individuals. Regulation of their expression can modulate the inflammatory response, the composition of the intestinal microbiota, and intestinal barrier function. miRNAs can regulate the immune and inflammatory response via multiple mechanisms, from Th1/Th17 regulation and ferroptosis to modulation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) and control of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway. The use of miRNAs as biomarkers and therapeutic targets may help monitor IBD treatment and support the development of new, more individualized therapies that minimize common side effects. Full article