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Sinensetin Attenuated Macrophagic NLRP3 Inflammasomes Formation via SIRT1-NRF2 Signaling.

ABSTRACT: Macrophage-mediated inflammation plays essential roles in multiple-organ injury. Sinensetin (SNS) at least exhibits anti-inflammation, antioxidant, and antitumor properties. However, the underlying mechanism of SNS-targeted macrophage-mediated inflammation remains elusive. In the present study, our results showed that SNS suppressed lipopolysaccharide (LPS)-induced inflammation to ameliorate lung and liver injuries. Mechanistically, SNS significantly inhibited M1-type macrophage polarization and its NLRP3 inflammasome formation to significantly decrease tumor necrosis factor α (TNFα) and IL-6 expression, while increasing IL-10 expression. Moreover, SNS interacted and activated SIRT1 to promote NRF2 and its target gene SOD2 transcription, which subsequently decreased LPS-induced inflammation. SIRT1 knockdown impaired the effects of SNS on the inhibition of macrophage polarization, NLRP3 inflammasome formation, and NRF2/SOD2 signaling. Taken together, our results showed that SNS is a potential and promising natural active ingredient to ameliorate inflammatory injury via activating SIRT1/NRF2/SOD2 signaling.

SUBMITTER: Lin L

PROVIDER: S-EPMC10515189 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Sinensetin Attenuated Macrophagic NLRP3 Inflammasomes Formation <i>via</i> SIRT1-NRF2 Signaling.

Lin Lin L Deng Kuimiao K Gong Zongrong Z Fan Huifeng H Zhang Dongwei D Lu Gen G

ACS omega 20230907 37

Macrophage-mediated inflammation plays essential roles in multiple-organ injury. Sinensetin (SNS) at least exhibits anti-inflammation, antioxidant, and antitumor properties. However, the underlying mechanism of SNS-targeted macrophage-mediated inflammation remains elusive. In the present study, our results showed that SNS suppressed lipopolysaccharide (LPS)-induced inflammation to ameliorate lung and liver injuries. Mechanistically, SNS significantly inhibited M1-type macrophage polarization and ...[more]

PMID: 37744845

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Project description:BackgroundOsteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease.MethodsIn this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice.ResultsThe expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl- efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model.ConclusionsTherefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.

Project description:BackgroundCoronary microembolization(CME)is a common complication in acute coronary syndrome and percutaneous coronary intervention, which is closely related to poor prognosis. Pyroptosis, as an inflammatory programmed cell death, has been found to be associated with CME-induced myocardial injury. Colchicine (COL) has potential benefits in coronary artery disease due to its anti-inflammatory effect. However, the role of colchicine in pyroptosis-related CME-induced cardiomyocyte injury is unclear. This study was carried out to explore the effects and mechanisms of colchicine on myocardial pyroptosis induced by CME.MethodsThe CME animal model was constructed by injecting microspheres into the left ventricle with Sprague-Dawley rats, and colchicine (0.3 mg/kg) pretreatment seven days before and on the day of modeling or compound C(CC)co-treatment was given half an hour before modeling. The study was divided into 4 groups: Sham group, CME group, CME + COL group, and CME + COL + CC group (10 rats for each group). Cardiac function, serum myocardial injury markers, myocardial histopathology, and pyroptosis-related indicators were used to evaluate the effects of colchicine.ResultsColchicine pretreatment improved cardiac dysfunction and reduced myocardial injury induced by CME. The main manifestations were the improvement of left ventricular systolic function, the decrease of microinfarction area, and the decrease of mRNA and protein indexes related to pyroptosis. Mechanistically, colchicine increased the phosphorylation level of adenosine monophosphate-activated protein kinase (AMPK), promoted the expression of silent information regulation T1 (SIRT1), and inhibited the expression of NOD-like receptor pyrin containing 3 (NLRP3) to reduce myocardial pyroptosis. However, after CC co-treatment with COL, the effect of colchicine was partially reversed.ConclusionColchicine improves CME-induced cardiac dysfunction and myocardial injury by inhibiting cardiomyocyte pyroptosis through the AMPK/SIRT1/NLRP3 signaling pathway.

Dataset Information

Sinensetin Attenuated Macrophagic NLRP3 Inflammasomes Formation via SIRT1-NRF2 Signaling.

Publications

Sinensetin Attenuated Macrophagic NLRP3 Inflammasomes Formation <i>via</i> SIRT1-NRF2 Signaling.

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