Elaidic acid-induced intestinal barrier damage led to gut-liver axis derangement and triggered NLRP3 inflammasome in the liver of SD rats

Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investigated the effects of elaidic acid(EA),a typical TFA,on the gut microbiota to understand the underlying mechanisms of TFA-related chronic diseases.16S rDNA gene sequencing on faecal samples from Sprague-Dawley rats were performed to explore the composition change of the gut microbiota by EA gavage for 4 weeks.The results showed that the intake of EA increased the abundance of well-documented harmful bacteria,such as Proteobacteria,Anaerotruncus,Oscillibacter and Desulfovibrionaceae.Plus,EA induced translocation of lipopolysaccharides(LPS) and the above pathogenic bacteria,disrupted the intestinal barrier,led to gut-liver axis derangement and TLR4 pathway activation in the liver.Overall,EA induced intestinal barrier damage and regulated TLR4-MyD88-NF-κB/MAPK pathways in the liver of SD rats,leading to the activation of NLRP3 inflammasome and inflammatory liver damage.

Mechanism of Sanshi decoction in the treatment of gouty arthritis by NLRP3 inflammasome

Objective:To observe the effect of Sanshi decoction on P2X7R/PKR pathway-mediated activation of macrophage NLRP3 inflammasome to elucidate the molecular mechanism of Sanshi decoction in the treatment of gouty arthritis.Methods:THP-1 macrophages were divided into control group,model group,low dose group,medium dose group,high dose group of Sanshi decoction and inhibitor group.The remaining groups were induced with monosodium urate crystals to establish a gouty arthritis cell model except the control group.Flow cytometry was used to detect macrophage ROS levels in each group,ELISA to detect MDA levels and SOD and GSH-PX activities in each group,and Western blot to detect P2X7R/PKR pathway and NLRP3 inflammasome-associated protein expression.We also used CCK-8 and flow cytometry to measure MH7A activity and apoptotic levels.Results:Compared with the control group,the ROS level,the content of MDA,the activities of SOD and GSH-PX were significantly increased,and the expression levels of NLRP3,full-length IL-1β,pro-IL-1β,full-length IL-18,pro-IL-18,full-length caspase-1,GSDMD-NT,P2X7R and p-PKR protein expression levels were significantly upregulated,and GSDMD-FL protein expression was significantly downregulated in the model group,and that the differences between them were statistically significant(P<0.05 and P<0.01).Compared with the model group,Sanshi decoction could reduce macrophage ROS levels,MDA content,SOD and GSHPX activities,and downregulate macrophage NLRP3,mature IL-1β,pro IL-1β,mature IL-18,pro IL-18,mature caspase-1,GSDMD-NT,P2X7R and p-PKR protein expression,and upregulate GSDMD-FL protein expression,with statistically significant differences(P<0.05 and P<0.01).In addition,MH7A activity was downregulated,and apoptosis level was upregulated in the model group in comparison with the control group,and differences were all significantly different(P<0.05).As compared to the model group,Sanshi decoction could significantly increase the activity of MH7A and inhibit the level of apoptosis,and that the differences between them were statistically significant(P<0.05 and P<0.01).Conclusion:Sanshi decoction can achieve the therapeutic effect of gouty arthritis by inhibiting P2X7R/PKR pathway activation,thus reducing the activation level of NLRP3.

Acacetin protects against cerebral ischemia-reperfusion injury via the NLRP3 signaling pathway

Acacetin(5,7-dihydroxy-4′-methoxyflavone), a potential neuroprotective agent, has an inhibitory effect on lipopolysaccharide-induced neuroinflammatory reactions. However, whether acacetin has an effect on inflammatory corpuscle 3(NLRP3) after cerebral ischemia-reperfusion injury has not been fully determined. This study used an improved suture method to establish a cerebral ischemia-reperfusion injury model in C57BL/6 mice. After ischemia with middle cerebral artery occlusion for 1 hour, reperfusion with intraperitoneal injection of 25 mg/kg of acacetin(acacetin group) or an equal volume of saline(0.1 mL/10 g, middle cerebral artery occlusion group) was used to investigate the effect of acacetin on cerebral ischemia-reperfusion injury. Infarct volume and neurological function scores were determined by 2,3,5-triphenyltetrazolium chloride staining and the Zea-Longa scoring method. Compared with the middle cerebral artery occlusion group, neurological function scores and cerebral infarction volumes were significantly reduced in the acacetin group. To understand the effect of acacetin on microglia-mediated inflammatory response after cerebral ischemia-reperfusion injury, immunohistochemistry for the microglia marker calcium adapter protein ionized calcium-binding adaptor molecule 1(Iba1) was examined in the hippocampus of ischemic brain tissue. In addition, tumor necrosis factor-α, interleukin-1β, and interleukin-6 expression in ischemic brain tissue of mice was quantified by enzyme-linked immunosorbent assay. Expression of Iba1, tumor necrosis factor-α, interleukin-1β and interleukin-6 was significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Western blot assay results showed that expression of Toll-like receptor 4, nuclear factor kappa B, NLRP3, procaspase-1, caspase-1, pro-interleukin-1β, and interleukin-1β were significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Our findings indicate that acacetin has a protective effect on cerebral ischemia-reperfusion injury, and its mechanism of action is associated with inhibition of microglia-mediated inflammation and the NLRP3 signaling pathway.

Notoginsenoside R1 Protects against Diabetic Nephropathy through TXNIP-NLRP3 Signaling Pathway

Background:Diabetic nephropathy(DN)is a microvascular complication of diabetes mellitus(DM).DN results from many factors,including changes in glomerular hemodynamics,oxidative stress and inflammation,and in-terstitial fibrosis and tubular atrophy.Panax notoginseng,a commonly used Chinese medicine,has been used in the treatment of kidney disease.Notoginsenoside R1(NGR1),the main compound isolated from P.notoginseng,has been reported to have a renoprotective role in DN.However,the therapeutic effect and mechanism of NGR1 in DN remain unclear.Objective:The present study aimed to investigate the therapeutic effect and mechanism of NGR1 in DN.Methods:In this study,mouse podocytes(MPC-5 cells)and db/db mice were used to investigate the effect of NGR1 on DN in vitro and in vivo,respectively.Blood glucose,renal function,inflammatory factors,and PI3K/AKT-Nrf2-NLRP3 signaling pathway proteins were assessed.Results:The study results indicated that NGR1 reversed cell viability induced by high glucose(HG,30 mM).The related mechanism results showed that NGR1 decreased oxidative stress by inhibiting reactive oxygen species(ROS)level and upregulating the expression of Nrf2,NQO1,and HO-1 via TXNIP targeting.In addition,NLRP3 inflammasome and PI3K/AKT were engaged in NGR1-based protection against HG-stimulated podocytes.In db/db mice,NGR1 significantly decreased blood glucose,urine protein,urine output,blood urea nitrogen,and other parameters as well as reversed kidney injury by inhibiting oxidative stress and proinflammatory response.Conclusion:Taken together,this study revealed that NGR1 exerted a significant therapeutic effect on DN both in vitro and in vivo via a mechanism related to the TXNIP-Nrf2 pathway and NLRP3 inflammasome,suggesting that NGR1 is a potential therapeutic option for DN.

Potential Mechanisms and Effects of Chinese Medicines in Treatment of Diabetic Atherosclerosis by Modulating NLRP3 Inflammasome:A Narrative Review

Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)is an intracellular sensor that detects endogenous danger signals and environmental irritants to assemble into the NLRP3 inflammasome.Activation of the NLRP3 inflammasome leads to the secretion of the proinflammatory cytokines interleutkin(IL)-1β and IL-18 and induces pyroptosis.Recent studies have shown that the NLRP3 inflammasome participates in the initiation and progression of diabetic atherosclerosis through pathological mechanisms such as β-cell dysfunction,insulin resistance,endothelial cell dysfunction,monocyte adhesion and infiltration,and smooth muscle cell proliferation and migration.In diabetic atherosclerosis,Chinese medicine has been proven effective for the inflammatory response mediated by the NLRP3 inflammasome.This review summarizes the latest progress on the NLRP3 inflammasome in the pathogenesis and potential Chinese medicine treatment of diabetic atherosclerosis.

Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes

Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.

Cytokines Activation kinetics in lung due to COVID-19 infection

COVID-19,as a concern in the world,can lead to death with a wide range of symptoms.Coronavirus,like other viral diseases,leads to the activation of inflammatory responses such as triggering the cytokine cascade.During the contact of the surface of the virus and its internal components with the human immune system,the path of expression and activation of cytokines begins.The body fights the virus through this operation and sometimes cell apoptosis.In the current review study,PubMed,Scopes,and Google Scholar were searched to provide information have shown the inflammasomes of COVID-19.In a review study,we examine the evidence that shows that COVID-19 activates inflammasomes;inflammasomes are cytosolic receptors that can identify microbial pathogens and endogenous signals resulting from stress or cell damage,including NLRP3(NLR Family Pyrin Domain Containing 3)type,NLRP4(NLR Family Pyrin Domain Containing 4),NLRP3.Through the activation of ASC and caspase 1,inflammasomes lead to the secretion of cytokines IL-1β(Interleukin-1 beta),IL-18(Interleukin-18),and IL6(Interleukin-6),TNF-α(Tumor Necrosis Factor-alpha).They can lead to the activation of inflammatory pathways.The results of this research can be useful in clarifying the relationship between the inflammatory pathways caused by the COVID-19 virus in people and the discovery of drugs in infected people.