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Resveratrol Confers Vascular Protection by Suppressing TLR4/Syk/NLRP3 Signaling in Oxidized Low-Density Lipoprotein-Activated Platelets

ABSTRACT: This study investigated the effect of resveratrol on Toll-like receptor 4- (TLR4-) mediated matrix metalloproteinase 3 (MMP3) and MMP9 expression in oxidized low-density lipoprotein- (ox-LDL-) activated platelets and the potential molecule mechanism. Human platelets were used in the present study. The results showed that resveratrol suppressed TLR4, MMP3, and MMP9 expression in ox-LDL-activated platelets. The TLR4 inhibitor CLI-095 also inhibited MMP3 and MMP9 expression and secretion in ox-LDL- and lipopolysaccharide- (LPS-) activated platelets. The combination of resveratrol and CLI-095 synergistically suppressed MMP3 and MMP9 expression in ox-LDL- and LPS-activated platelets. These findings suggest that the resveratrol-induced inhibition of MMP3 and MMP9 expression is linked to the suppression of TLR4 activation. Resveratrol also suppressed spleen tyrosine kinase (Syk) phosphorylation and nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) expression and IL-1? secretion in ox-LDL- and LPS-treated platelets. The coimmunoprecipitation results showed that resveratrol inhibited the binding of Syk and NLRP3. Finally, resveratrol reduced vascular senescence cells and the expression of TLR4, MMP3, and MMP9 and prevented alterations of vascular structure in 52-week-old mice. Our findings demonstrated that resveratrol decreased inflammatory protein expression and improved vascular structure in aged mice. Resveratrol inhibited the expression of TLR4 and secretion of MMP3, MMP9, and IL-1?. The mechanism of action of resveratrol appears to be associated with the inhibition of TLR4/Syk/NLRP3 activation in ox-LDL-activated platelets.

SUBMITTER: Xue Y

PROVIDER: S-EPMC7935581 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe NLRP3-mediated pyroptosis, which could be regulated by miRNA-27a, is a key player in the development of depression. Isoliquiritin is a phenolic flavonoid compound that has been demonstrated to suppress NLRP3-mediated pyroptosis. However, it is still unknown whether isoliquiritin could confer antidepressant activity via decreasing NLRP3-mediated pyroptosis by stimulating miRNA-27a. Thus, in the current study, we explored the antidepressant activity of isoliquiritin and its underlying mechanism.MethodsExpression of miRNA-27a in depressed patients or mice was measured using qRT-PCR. Luciferase reporter assay was performed to illustrate the link between miRNA-27a and SYK. Lipopolysaccharide (LPS) and chronic social defeat stress (CSDS) depression models were established to investigate the antidepressant actions of isoliquiritin. Changes in miRNA-27a/SYK/NF-?B axis and NLRP3-mediated pyroptosis were also examined. The role of miRNA-27a in isoliquiritin-related antidepressant effect was further investigated by using miRNA-27a inhibitors and mimics of miRNA-27a.ResultsOur results showed the miRNA-27a expression was downregulated in the serum of depressed patients, and decreased serum and hippocampus expression of miRNA-27a were observed in rodent models of depression. SYK gene expression was significantly reduced by miRNA-27a mimic incubation. Isoliquiritin profoundly attenuated LPS or CSDS-induced depressive symptoms, as well as CSDS-induced anxiety behavior. In the hippocampus, LPS and CSDS decreased miRNA-27a mRNA expression; increased the protein levels of SYK, p-NF-?B, and NLRP3: cleaved Caspase-1, IL-1?, and GSDMD-N: and elevated the concentration of IL-1?, IL-6, and TNF-?, which were all restored by isoliquiritin administration. Meanwhile, isoliquiritin upregulated the hippocampal NeuN protein level, improved the survival and morphology of neurons, and decreased pyroptosis-related neuronal cell death. Moreover, isoliquiritin protected primary microglia against LPS and adenosine triphosphate (ATP) elicited NLRP3 inflammasome activation in vitro, evidenced by declined protein levels of p-NF-?B, NLRP3; cleaved Caspase-1, IL-1?, and GSDMD-N; upregulated miRNA-27a mRNA expression; and decreased the mRNA and protein levels of SYK. Nevertheless, miRNA-27a inhibitors significantly reversed isoliquiritin-generated therapeutic efficacy in CSDS mice and in vitro. Furthermore, the cytoprotective effect of isoliquiritin was similar to that of miRNA-27a mimics in LPS and ATP-treated primary microglia. Taken together, these findings suggest that isoliquiritin possesses potent antidepressant property, which requires miRNA-27a/SYK/NF-?B axis controlled decrease of pyroptosis via NLRP3 cascade.

Project description:BackgroundPlatelets play an important role in the progression of atherosclerosis and cardiovascular events. The inhibition of platelet function is a main strategy to reduce risk of cardiovascular events. Some studies have shown that tomato extracts inhibit platelet function, but the molecular mechanisms remain unclear. Fruitflow is a water-solute tomato extract and the main ingredients including flavonoids, adenosine, chlorogenic acid, phytosterols, naringenin, and carotenoids. The present study investigated the effects of fruitflow on adenosine diphosphate (ADP)- and collagen- stimulated platelet aggregation, platelet adhesion, and levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (PGF1α), and platelet factor 4 (PF4) and explored the underlying molecular mechanisms.MethodsPlatelet-rich plasma (PRP) was used for measurement of platelet aggregation, TXB2, 6-keto- PGF1α, and PF4 levels. Platelet aggregation was analyzed using a Chrono-Log aggregometer. TXB2, 6-keto- PGF1α, and PF4 levels were determined using enzyme-linked immunosorbent assay kits. Immunoblotting was used to detect protein expression and phosphorylation on washed platelets. Platelet adhesion and spreading were determined by immunofluorescence.ResultsFruitflow (1, 3, 10 and 100 μg/ml) dose-dependently inhibited platelet aggregation that was induced by ADP and collagen. Fruitflow (100 μg/ml) treatment completely suppressed ADP- and collagen-stimulated platelet aggregation. Fruitflow (100 μg/ml) significantly decreased TXB2 and 6-keto-PGF1α generation and PF4 release in ADP- and collagen-stimulated platelets. Treatment with fruitflow effectively blocked collagen-induced platelet spreading. To determine the potential molecule mechanism of action of fruitflow, we investigated the protein expression and phosphorylation of several signaling molecules in collagen-activated platelets. Fruitflow dose-dependently suppressed Akt, Glycogen synthase kinase-3β (GSK-3β), spleen tyrosine kinase (Syk) and phospholipase Cγ2 (PLCγ2) and p38 MAPK phosphorylation that was induced by collagen.ConclusionFruitflow inhibited platelet aggregation and reduced TXB2, 6-keto-PGF1α, and PF4 levels in ADP- and collagen-stimulated platelets. The mechanism of action of fruitflow may be associated with the suppression of Akt/GSK3β, Syk/PLCγ2, and p38 MAPK phosphorylation in collagen-activated platelets. Fruitflow is a natural product derived from tomato and can be used as a health food for decreasing platelet activity.

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Resveratrol Confers Vascular Protection by Suppressing TLR4/Syk/NLRP3 Signaling in Oxidized Low-Density Lipoprotein-Activated Platelets

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