Search Results (1,100)

While the beneficial effects of colchicine on inflammation and infarcted myocardium have been documented, its impact on cardiac fibroblast activation in the context of myocardial infarction (MI) remains unknown. This study aimed to investigate the effect of colchicine on the regulation of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and Interleukin-1β (IL-1β) expression in fibroblasts. 3T3 fibroblasts were exposed to 600 μM CoCl₂ for 24 h to simulate hypoxia, with normoxic cells as controls. Colchicine (1 μM) was administered for 24 h. ASC-NLRP3 colocalization and IL-1β expression were evaluated using immunofluorescence and flow cytometry, respectively. Data were analyzed using t-tests and one-way ANOVA with post hoc tests. Hypoxia treatment significantly induced apoptosis-associated speck-like protein containing a CARD (ASC)-NLRP3 colocalization (p < 0.05). Colchicine treatment of hypoxic 3T3 cells reduced ASC-NLRP3 colocalization, although this reduction was not statistically significant. Additionally, IL-1β expression was significantly inhibited in colchicine-treated hypoxic 3T3 cells compared to those treated with placebo (p < 0.05). The findings of this study indicate that colchicine treatment inhibits the activation of the NLRP3 inflammasome by disrupting the colocalization of ASC and NLRP3, thereby reducing IL-1β expression in CoCl₂-treated 3T3 cells. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects approximately one-quarter of the world’s adult population, and no effective therapeutic drugs are available. Poria cocos is a fungus used as a herb and food nutrient for centuries as well as for MAFLD treatment. Exosome-like nanovesicles have many pharmacological activities; however, studies on the effects of Poria cocos-derived exosome-like nanovesicles (PCELNs) on MAFLD are lacking. Therefore, our study aimed at identifying the effects and mechanism of action of PCELNs on MAFLD. PCELNs were isolated by ultracentrifugation and their morphology was characterized, such as particle size, zeta potential, protein distributions, as well as lipid and miRNA compositions. Then, the absorption and distribution of PCELNs were observed in vivo and in vitro. Finally, L02 cell steatosis model induced by fat emulsion and MAFLD mouse model induced by high-fat diet (HFD) were used to evaluate the effect and mechanism of PCELNs on MAFLD. PCELNs were membrane structured vesicles, with a particle size of 161.4 ± 1.7 nm, a zeta potential of −3.20 ± 0.37 mV, and contained a range of proteins, lipids, and miRNAs. PCELNs were absorbed by L02 cells and targeted the liver and spleen after intraperitoneal injection. PCELNs inhibited body weight gain and improved the index of heart, liver, spleen, and various fats, as well as decreased lipid accumulation and lipid level. They also protected mitochondrial ultrastructure and regulated oxidative stress and energy metabolism disorder. Furthermore, PCELNs increased PTEN induced kinase 1 (PINK1), E3 ubiquitin ligase (Parkin) and microtubule associated protein light chain-3 (LC3) protein expression in the liver, reduced oxidized mitochondrial DNA (Ox-mtDNA) content in mitochondria and cytoplasm of the liver, reduced nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3), pro-cysteinyl aspartate specific proteinase-1 (caspase-1), cleared-caspase-1, and mature-interleukin-1β (IL-1β) protein expression in the liver, and reduced the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and interleukin-18 (IL-18) in serum and liver. In conclusion, we demonstrated that PCELNs may alleviate HFD-induced MAFLD by promoting mitochondrial autophagy and inhibiting NLRP3 inflammasome activation. Full article

I3MT-3 (HMPSNE) has been identified as a selective inhibitor of the supersulfide-producing enzyme 3-MST. In this study, we found that I3MT-3 inhibits inflammatory responses, including the secretion of the pro-inflammatory cytokine interleukin-1β (IL-1β) and inflammatory cell death pyroptosis, induced by the activation of the inflammasomes composed of NLRP1, NLRP3, or AIM2. However, interestingly, the knockdown of 3-MST did not affect the activation of the inflammasomes, suggesting that the inhibitory effect of I3MT-3 on inflammasome activation is mediated by alternative ways rather than the inhibition of 3-MST. Interestingly, an in vitro caspase assay revealed that I3MT-3 directly inhibits caspase-1 activation, and molecular docking simulations raised the possibility that the pyrimidone ring in I3MT-3 stabilizes direct interaction of I3MT-3 with caspase-1. Taken together, our data suggest that I3MT-3 inhibits inflammasome activation by targeting caspase-1, and show I3MT-3 as a potent inhibitor of caspase-1. Full article

Caulerpin, a bis-indole alkaloid isolated from Caulerpa racemosa, has several documented pharmacological activities, including antineoplastic and antiviral properties. This study aimed to evaluate the anti-inflammatory and anti-tubercular potentials of caulerpin and its analogues in RAW 264.7 macrophages infected with Mycobacterium spp. Additionally, we evaluated cytokine production and NLRP3 expression in this infection model. Toxicity tests were performed using Vero E6 and HepG2 cell lines and Artemia salina. Pre-incubation of RAW 264.7 cells with caulerpin and its analogues decreased internalized M. smegmatis and M. tuberculosis H37Ra. Furthermore, treatment of M. smegmatis-infected macrophages with caulerpin and its analogues reduced bacterial loads. Caulerpin reduced the CFU count of internalized bacilli in the M. tuberculosis H37Ra infection model. In addition, caulerpin and its diethyl derivative were notably found to modulate IL-1β and TNF-α production in the M. smegmatis infection model after quantifying pro-inflammatory cytokines and NLRP3. Caulerpin and its derivates did not affect the viability of Vero E6 and HepG2 cell lines or nauplii survival in toxicity studies. These findings demonstrate that caulerpin and its analogues exhibit anti-inflammatory activity against Mycobacterium spp. infection in RAW 264.7 macrophages and show promising potential for further efficacy and safety evaluation. Full article

(1) Background: Hepatic lipid accumulation is the initial factor in metabolic-associated fatty liver disease (MAFLD) in type 2 diabetics, leading to accelerated liver damage. The NOD-like receptor protein 3 (NLRP3) inflammasome plays a critical role in this process. Dapansutrile (DAPA) is a novel NLRP3 inflammasome inhibitor; however, its effect on ectopic lipid accumulation in the liver remains unclear. This study aimed to investigate the therapeutic effect of DAPA on hepatic lipid accumulation in a diabetic mouse model and its potential mechanisms. (2) Methods: The effects of DAPA on hepatic ectopic lipid deposition and liver function under metabolic stress were evaluated in vivo using db/db and high-fat diet (HFD) + streptozotocin (STZ) mouse models. Additionally, the role and mechanism of DAPA in cellular lipid deposition, mitochondrial oxidative stress, and inflammation were assessed in HepG2 cells treated with free fatty acids (FFA) and DAPA. (3) Results: Our findings indicated that DAPA treatment improved glucose and lipid metabolism in diabetic mice, particularly addressing liver heterotopic lipid deposition and insulin resistance. DAPA treatment also ameliorated lipid accumulation and mitochondrial-related functions and inflammation in HepG2 cells through the NLRP3-Caspase-1 signaling axis. (4) Conclusions: Targeting NLRP3 with DAPA may represent a novel therapeutic approach for diabetes-related fatty liver diseases. Full article

Endothelial dysfunction (ED) is characterized by an imbalance between vasodilatory and vasoconstrictive factors, leading to impaired vascular tone, thrombosis, and inflammation. These processes are critical in the development of cardiovascular diseases (CVDs) such as atherosclerosis, hypertension and ischemia/reperfusion injury (IRI). Reduced nitric oxide (NO) production and increased oxidative stress are key contributors to ED. Aging further exacerbates ED through mitochondrial dysfunction and increased oxidative/nitrosative stress, heightening CVD risk. Antioxidant systems like superoxide-dismutase (SOD), glutathione-peroxidase (GPx), and thioredoxin/thioredoxin-reductase (Trx/TXNRD) pathways protect against oxidative stress. However, their reduced activity promotes ED, atherosclerosis, and vulnerability to IRI. Metabolic syndrome, comprising insulin resistance, obesity, and hypertension, is often accompanied by ED. Specifically, hyperglycemia worsens endothelial damage by promoting oxidative stress and inflammation. Obesity leads to chronic inflammation and changes in perivascular adipose tissue, while hypertension is associated with an increase in oxidative stress. The NLRP3 inflammasome plays a significant role in ED, being triggered by factors such as reactive oxygen and nitrogen species, ischemia, and high glucose, which contribute to inflammation, endothelial injury, and exacerbation of IRI. Treatments, such as N-acetyl-L-cysteine, SGLT2 or NLRP3 inhibitors, show promise in improving endothelial function. Yet the complexity of ED suggests that multi-targeted therapies addressing oxidative stress, inflammation, and metabolic disturbances are essential for managing CVDs associated with metabolic syndrome. Full article

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel target for reducing low-density lipoprotein cholesterol. PCSK9 activates the atherosclerosis process through pro-inflammation signaling. Furthermore, the serum level of PCSK9 is positively correlated with mortality in patients with heart failure (HF). Cardiac fibrosis plays a crucial role in the pathophysiology of HF. In this study, we intended to examine whether PCSK9 can increase fibroblast activities and explore what its underlying mechanisms are. Migration, proliferation analyses, and Western blotting were used on human cardiac fibroblasts with and without PCSK9. Alirocumab (a PCSK9 inhibitor, 10 mg/kg/week intra-peritoneally for 28 consecutive days) was treated in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats. PCSK9 (50, 100 ng/mL) increased proliferation, myofibroblast differentiation capability, and collagen type I production. Compared with control cells, PCSK9 (100 ng/mL)-treated cardiac fibroblasts showed higher nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), interleukin (IL)-1, myofibroblast differentiation, and collagen production capabilities, which were attenuated by MCC950 (an NLRP3 inhibitor, 100 μmol/L). PCSK9 upregulated Myd88 and NF-κB signaling, which were reduced by TAK242 (a toll-like receptor (TLR) 4 inhibitor, 10 μmol/L). Moreover, alirocumab significantly improved left ventricular systolic function and attenuated fibrosis in HF rats. In conclusion, PCSK9 upregulates NLRP3 signaling and the profibrotic activities of cardiac fibroblasts through the activation of TLR4/Myd88/NF-κB signaling. Full article

Experimental evidence suggests that alkaloids have anti-influenza and anti-inflammatory effects. However, the risk of translating existing evidence into clinical practice is relatively high. We conducted a systematic review and meta-analysis of animal studies to evaluate the therapeutic effects of alkaloids in treating influenza, providing valuable references for future studies. Seven electronic databases were searched until October 2024 for relevant studies. The Review Manager 5.2 software was utilized to perform the meta-analysis. Our study was registered within the International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42024607535. Alkaloids are significantly correlated with viral titers, pulmonary inflammation scores, survival rates, lung indices, and body weight. However, alkaloid therapy is not effective in reducing the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In addition, the therapeutic effects of alkaloids may be related to the inhibition of the Toll-like receptor 4 or 7/Nuclear factor (NF)-κB signaling pathway, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome pathway, and the Antiviral innate immune response receptor RIG-I (RIG-I) pathway. Alkaloids are potential candidates for the prevention and treatment of influenza. However, extensive preclinical studies and clinical studies are needed to confirm the anti-influenza and anti-inflammatory properties of alkaloids. Full article

Kezimuke granules (KZMK), derived from traditional Kazakh folk medicine, exhibit a variety of pharmacological properties. Long-term clinical studies have demonstrated their efficacy in clearing heat, detoxifying, promoting qi circulation, and alleviating gonorrhea. However, their specific pharmacological effects on urinary tract infections remain unclear. This study employed UHPLC-MS/MS technology to identify the blood components of KZMK and integrated network pharmacology with bioinformatics analysis for molecular docking validation. The anti-inflammatory activity of KZMK was further evaluated using a rat model of LPS-induced cystitis. A total of 17 components in KZMK were identified as capable of entering the bloodstream. Predictive analysis revealed that its primary targets include Caspase-1, NLRP3, STAT1, TLR4, and TNF, with the NLRP3 inflammasome signaling pathway emerging as the key mechanism. In vivo studies showed that KZMK effectively reduced the white blood cell (WBC) count and bladder index in urine sediments of rats with cystitis. Additionally, KZMK alleviated bladder congestion, edema, and histopathological changes in the animals. Treatment with KZMK led to decreased levels of IL-18 and IL-1β cytokines. KZMK significantly inhibited the expression of NLRP3, GSDMD, and Caspase-1 in LPS-induced cystitis, further confirming its anti-inflammatory effects. These findings indicate that KZMK provides protection against LPS-induced cystitis, primarily by inhibiting the activation of the NLRP3 inflammasome. Collectively, the results suggest that KZMK holds promise as a potential therapeutic option for urinary tract infections. Full article

Aside from its immediate traumatic effects, spinal cord injury (SCI) presents multiple secondary complications that can be harmful to those who have been affected by SCI. Among these secondary effects, gut dysbiosis (GD) and the activation of the NOD (nucleotide-binding oligomerization domain) like receptor-family pyrin-domain-containing three (NLRP3) inflammasome are of special interest for their roles in impacting mental health. Studies have found that the state of the gut microbiome is thrown into disarray after SCI, providing a chance for GD to occur. Metabolites such as short-chain fatty acids (SCFAs) and a variety of neurotransmitters produced by the gut microbiome are hampered by GD. This disrupts healthy cognitive processes and opens the door for SCI patients to be impacted by mental health disorders. Additionally, some studies have found an increased presence and activation of the NLRP3 inflammasome and its respective parts in SCI patients. Preclinical and clinical studies have shown that NLRP3 inflammasome plays a key role in the maturation of pro-inflammatory cytokines that can initiate and eventually aggravate mental health disorders after SCI. In addition to the mechanisms of GD and the NLRP3 inflammasome in intensifying mental health disorders after SCI, this review article further focuses on three promising treatments: fecal microbiome transplants, phytochemicals, and melatonin. Studies have found these treatments to be effective in combating the pathogenic mechanisms of GD and NLRP3 inflammasome, as well as alleviating the symptoms these complications may have on mental health. Another area of focus of this review article is exploring how artificial intelligence (AI) can be used to support treatments. AI models have already been developed to track changes in the gut microbiome, simulate drug-gut interactions, and design novel anti-NLRP3 inflammasome peptides. While these are promising, further research into the applications of AI for the treatment of mental health disorders in SCI is needed. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction, oxidative stress, and neuroinflammation are recognized as critical pathological mechanisms driving neurodegeneration in PD. Exosome (Exo)-based therapies, particularly those derived from human neural stem cells (hNSCs), offer promising neuroprotective effects due to their ability to transfer bioactive molecules that modulate cellular processes. Resveratrol (RES), a polyphenolic compound with potent antioxidant and anti-inflammatory properties, has been shown to enhance the therapeutic potential of stem cell (SC)-derived Exos. This study investigated the neuroprotective effects of RES-treated hNSCs-derived Exos (RES-hNSCs-Exos) on SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP⁺), a neurotoxin commonly used to model Parkinsonian neurotoxicity. Treating SH-SY5Y cells with MPP⁺ led to significant reductions in cell viability, mitochondrial dysfunction, increased oxidative stress, and the activation of inflammatory pathways. Treatment with RES-hNSCs-Exos rescued SH-SY5Y cells from MPP⁺-induced toxicity by improving cell viability, enhancing ATP production, increasing mitochondrial biogenesis, and reducing reactive oxygen species (ROS) generation. The findings also demonstrated the increased expression of essential genes involved in mitochondrial biogenesis, such as PGC1α, NRF1, and Tfam, indicating improved mitochondrial function in the presence of RES-hNSCs-Exos. Further analysis revealed that these protective effects were mediated by activating the AMP-activated protein kinase (AMPK) and Nrf2 signaling pathways, which promoted mitochondrial health and reduced oxidative stress. Moreover, RES-hNSCs-Exos treatment suppressed neuroinflammation by downregulating NLRP3 inflammasome activation and reducing the secretion of pro-inflammatory cytokines IL-1β and IL-18. In conclusion, the results suggest that RES-hNSCs-Exos exhibit potent neuroprotective effects against MPP⁺-induced neurotoxicity by enhancing mitochondrial function, reducing oxidative stress, and inhibiting neuroinflammation. These findings highlight the potential of hNSCs-Exos as a novel therapeutic strategy for neurodegenerative diseases like PD, with RES as a valuable enhancer of Exos efficacy. Full article

Neurotoxic damage resulting from lead pollution exposure constitutes a significant public health concern. The regulatory impact of lead (Pb) exposure on neuronal dendritic spine plasticity, a crucial mechanism for neuronal adaptation, warrants further investigation. To elucidate the role and mechanism of the Mitofilin–mtDNA axis in hippocampal synaptic plasticity and learning and memory impairment induced by lead exposure, in this study, both in vivo and in vitro models were subjected to chronic lead exposure. The results showed that the spatial learning and memory abilities of lead-exposed mice were significantly reduced. Furthermore, Western blotting and RT-PCR analyses demonstrated a significant down-regulation in the expression of the mitochondrial inner membrane protein Mitofilin. Extended exposure to lead has the potential to compromise the plasticity of dendritic spines within the CA1 region of hippocampal neurons and disrupt the structural integrity of neuronal mitochondria. Furthermore, lead exposure was associated with elevated levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in neurons. The study additionally demonstrated that the overexpression of Mitofilin ameliorated deficits in spatial learning and memory in mice subjected to chronic lead exposure. This overexpression also facilitated the normal formation of neuronal dendritic spines, preserved the structural integrity of the mitochondrial inner membrane, and mitigated mitochondrial damage. The study further revealed that the overexpression of Mitofilin markedly suppressed the release of mitochondrial DNA (mtDNA) in neurons subjected to chronic lead exposure, while concurrently reducing the expression levels of the inflammasome Nlrp3 and the inflammatory cytokine IL-1β. Additionally, there was a significant reduction in the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in lead-exposed neurons with Mitofilin overexpression. These findings suggest that the mitochondrial inner membrane protein Mitofilin may play a role in mediating synaptic plasticity impairment following chronic lead exposure through the regulation of mitochondrial function. Full article

Obesity has been identified as an independent risk factor for severe COVID-19 unfavorable outcomes. Several factors, such as increased ACE2 receptor expression and chronic inflammation, can contribute to this relationship, yet the activation of the NLRP3 inflammasome pathway is also a key element. Our primary goal was to determine whether chronic NLRP3 inflammasome activation in people with obesity is different in critical COVID-19 and in critical chronic conditions. A retrospective analysis was conducted using clinical data and post-mortem lung tissue samples from 14 COVID-19 patients with obesity (group A) and 9 patients with obesity who died from non-COVID-19 causes (group B). Immunohistochemical analysis assessed twelve markers related to the NLRP3 inflammasome pathway. Group A showed a significantly higher expression of ASC (p = 0.0387) and CASP-1 (p = 0.0142). No significant differences were found for IL-8, TNF-α, NF-kB, NLRP3, IL-1β, and gasdermin-D. Group B had higher levels of IL-6 (p < 0.0001), IL-18 (p = 0.002), CASP-9 (p < 0.0001), and HIF (p = 0.0327). We concluded that COVID-19 activates the NLRP3 inflammasome pathway, possibly leading to pyroptotic cell death mediated by caspase-1. In contrast, people with obesity without COVID-19, despite exhibiting some markers of the NLRP3 inflammasome, are more likely to experience necroptosis mediated by caspase-9. Full article

Background: Recent studies have shown that Nlrp3 inflammasome activation is importantly involved in podocyte dysfunction induced by nicotine. The present study was designed to test whether acid sphingomyelinase (Asm) and ceramide signaling play a role in mediating nicotine-induced Nlrp3 inflammasome activation and subsequent podocyte damage. Methods and Results: Nicotine treatment significantly increased the Asm expression and ceramide production compared to control cells. However, prior treatment with amitriptyline, an Asm inhibitor significantly attenuated the nicotine-induced Asm expression and ceramide production. Confocal microscopic and biochemical analyses showed that nicotine treatment increased the colocalization of NLRP3 with Asc, Nlrp3 vs. caspase-1, IL-1? production, caspase-1 activity, and desmin expression in podocytes compared to control cells. Pretreatment with amitriptyline abolished the nicotine-induced colocalization of NLRP3 with Asc, Nlrp3 with caspase-1, IL-1? production, caspase-1 activity and desmin expression. Immunofluorescence analyses showed that nicotine treatment significantly decreased the podocin expression compared to control cells. However, prior treatment with amitriptyline attenuated the nicotine-induced podocin reduction. In addition, nicotine treatment significantly increased the cell permeability, O₂ production, and apoptosis compared to control cells. However, prior treatment with amitriptyline significantly attenuated the nicotine-induced cell permeability, O₂ production and apoptosis in podocytes. Conclusions: Asm is one of the important mediators of nicotine-induced inflammasome activation and podocyte injury. Asm may be a therapeutic target for the treatment or prevention of glomerulosclerosis associated with smoking. Full article

Cachexia is a multifactorial syndrome characterized by severe muscle wasting and is a debilitating condition frequently associated with cancer. Previous studies from our group revealed that withaferin A (WFA), a steroidal lactone, mitigated muscle cachexia induced by ovarian tumors in NSG mice. However, it remains unclear whether WFA’s protective effects are direct or secondary to its antitumor properties. We developed a cachectic model through continuous angiotensin II (Ang II) infusion in C57BL/6 mice to address this issue. Ang II infusion resulted in profound muscle atrophy, evidenced by significant reductions in grip strength and in the TA, GA, and GF muscle mass. Molecular analyses indicated elevated expression of inflammatory cytokines (TNFα, IL-6, MIP-2, IL-18, IL-1β), NLRP3 inflammasome, and genes associated with the UPS (MuRF1, MAFBx) and autophagy pathways (Bacl1, LC3B), along with suppression of anti-inflammatory heme oxygenase-1 (HO-1) and myogenic regulators (Pax7, Myod1). Strikingly, WFA treatment reversed these pathological changes, restoring muscle mass, strength, and molecular markers to near-normal levels. These findings demonstrate that WFA exerts direct anti-cachectic effects by targeting key inflammatory and atrophic pathways in skeletal muscle, highlighting its potential as a novel therapeutic agent for cachexia management. Full article