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Enhanced Anti-Inflammatory Effects of Silibinin and Capsaicin Combination in Lipopolysaccharide-Induced RAW264.7 Cells by Inhibiting NF-κB and MAPK Activation.

ABSTRACT: Silibinin and capsaicin both are natural product molecules with diverse biological activities. In this article, we investigated the anti-inflammatory effects of silibinin combined with capsaicin in lipopolysaccharide (LPS)-induced RAW264.7 cells. The results showed that silibinin combined with capsaicin strongly inhibited LPS-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and COX-2. Moreover, silibinin combined with capsaicin potently inhibited nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. The results of the present study indicate that silibinin combined with capsaicin effectively inhibits inflammation.

SUBMITTER: Zheng Y

PROVIDER: S-EPMC9279934 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Enhanced Anti-Inflammatory Effects of Silibinin and Capsaicin Combination in Lipopolysaccharide-Induced RAW264.7 Cells by Inhibiting NF-κB and MAPK Activation.

Zheng Yingying Y Chen Jie J Wu Xiaozheng X Zhang Xin X Hu Chunmei C Kang Yu Y Lin Jing J Li Jiamin J Huang Yuechang Y Zhang Xingmin X Li Chen C

Frontiers in chemistry 20220630

Silibinin and capsaicin both are natural product molecules with diverse biological activities. In this article, we investigated the anti-inflammatory effects of silibinin combined with capsaicin in lipopolysaccharide (LPS)-induced RAW264.7 cells. The results showed that silibinin combined with capsaicin strongly inhibited LPS-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and COX-2. Moreover, silibinin combined with capsaicin potently inhibited nuclear factor-κ ...[more]

PMID: 35844639

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Project description:Carboxyamidotriazole (CAI), originally developed as a non-cytotoxic anti-cancer drug, was shown to have anti-inflammatory activity according to recent studies in a number of animal models of inflammation. However, its mechanism of action has not been characterized. Therefore, the present study was performed to identify the anti-inflammatory action of CAI in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and to identify the signal transduction pathways involved. The in vitro results revealed that CAI had no direct effect on the activity of cyclooxygenase (COX), suggesting a different anti-inflammatory mechanism compared with that of COX-inhibiting non-steroidal anti-inflammatory drugs. Further investigation in RAW264.7 macrophages revealed that CAI decreased the production of nitric oxide via decreasing the LPS-stimulated expression of inducible nitric oxide synthase, and downregulated both mRNA and protein expression levels of the cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. CAI also significantly reduced the increased DNA-binding activity of nuclear factor (NF)-κB induced by LPS stimulation. With respect to the mechanisms involved on NF-κB activity, CAI exhibited suppression of the phosphorylation and degradation of the inhibitor of nuclear factor-κBα (IκB), and decreased the phosphorylation levels of the p65 subunit and its subsequent nuclear translocation. In addition, CAI significantly decreased the phosphorylated forms of p38, JNK and ERK, which were increased following LPS stimulation, while the total expression levels of p38, JNK and ERK remained unaltered. The results in the present study indicate that CAI alleviates the inflammatory responses of RAW 264.7 macrophages in response to LPS stimulation via attenuating the activation of NF-κB and MAPK signaling pathways and decreasing the levels of pro-inflammatory mediators. This offers a novel perspective for understanding the anti-inflammatory mechanism of CAI and suggests its potential use as a therapeutic treatment in inflammatory diseases with excessive macrophage activation.

Project description:BackgroundSepsis is a life-threatening organ dysfunction syndrome resulted from severe infection with high morbidity and mortality. Cluster of differentiation 38 (CD38) is a multifunctional type II transmembrane glycoprotein widely expressed on the surface of various immunocytes membranes that mediates host immune response to infection and plays an important role in many inflammatory diseases. Daphnetin (Daph), isolated from the daphne genus plant, is a natural coumarin derivative that possesses anti-inflammatory and anti-apoptotic effects. The current study aimed to investigate the role and mechanism of Daph in alleviating lipopolysaccharide (LPS)-induced septic lung injury, and to explore whether the protective effect of Daph in mice and cell models was related to CD38.MethodsFirstly, network pharmacology analysis of Daph was performed. Secondly, LPS-induced septic lung injury in mice were treated with Daph or vehicle control respectively and then assessed for survival, pulmonary inflammation and pathological changes. Lastly, Mouse lung epithelial cells (MLE-12 cells) were transfected with CD38 shRNA plasmid or CD38 overexpressed plasmid, followed by LPS and Daph treatment. Cells were assessed for viability and transfection efficiency, inflammatory and signaling.ResultsOur results indicated that Daph treatment improved survival rate and alleviated pulmonary pathological damage of the sepsis mice, as well as reduced the excessive release of pro-inflammatory cytokines IL-1β, IL-18, IL-6, iNOS and chemokines MCP-1 regulated by MAPK/NF-κB pathway in pulmonary injury. Daph treatment decreased Caspase-3 and Bax, increased Bcl-2, inhibited nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis in lung tissues of septic lung injury. Also, Daph treatment reduced the level of excessive inflammatory mediators, inhibited apoptosis and pyroptosis in MLE-12 cells. It is noteworthy that the protective effect of Daph on MLE-12 cells damage and death was assisted by the enhanced expression of CD38.ConclusionsOur results demonstrated that Daph offered a beneficial therapeutic effect for septic lung injury via the up-regulation of CD38 and inhibition of MAPK/NF-κB/NLRP3 pathway. Video Abstract.

Project description:BackgroundInflammation-mediated lung injury is a major cause of health problems in many countries and has been the leading cause of morbidity/mortality in intensive care units. In the current COVID-19 pandemic, the majority of the patients experienced serious pneumonia resulting from inflammation (Acute respiratory distress syndrome/ARDS). Pathogenic infections cause cytokine release syndrome (CRS) by hyperactivation of immune cells, which in turn release excessive cytokines causing ARDS. Currently, there are no standard therapies for viral, bacterial or pathogen-mediated CRS.PurposeThis study aimed to investigate and validate the protective effects of Dehydrozingerone (DHZ) against LPS induced lung cell injury by in-vitro and in-vivo models and to gain insights into the molecular mechanisms that mediate these therapeutic effects.MethodsThe therapeutic activity of DHZ was determined in in-vitro models by pre-treating the cells with DHZ and exposed to LPS to stimulate the inflammatory cascade of events. We analysed the effect of DHZ on LPS induced inflammatory cytokines, chemokines and cell damage markers expression/levels using various cell lines. We performed gene expression, ELISA, and western blot analysis to elucidate the effect of DHZ on inflammation and its modulation of MAPK and NF-κB pathways. Further, the prophylactic and therapeutic effect of DHZ was evaluated against the LPS induced ARDS model in rats.ResultsDHZ significantly (p < 0.01) attenuated the LPS induced ROS, inflammatory cytokine, chemokine gene expression and protein release in macrophages. Similarly, DHZ treatment protected the lung epithelial and endothelial cells by mitigating the LPS induced inflammatory events in a dose-dependent manner. In vivo analysis showed that DHZ treatment significantly (p < 0.001) mitigated the LPS induced ARDS pathophysiology of increase in the inflammatory cells in BALF, inflammatory cytokine and chemokines in lung tissues. LPS stimulated neutrophil-mediated events, apoptosis, alveolar wall thickening and alveolar inflammation were profoundly reduced by DHZ treatment in a rat model.ConclusionThis study demonstrates for the first time that DHZ has the potential to ameliorate LPS induced ARDS by inhibiting cytokine storm and oxidative through modulating the MAPK and NF-κB pathways. This data provides pre-clinical support to develop DHZ as a potential therapeutic agent against ARDS.

Dataset Information

Enhanced Anti-Inflammatory Effects of Silibinin and Capsaicin Combination in Lipopolysaccharide-Induced RAW264.7 Cells by Inhibiting NF-κB and MAPK Activation.

Publications

Enhanced Anti-Inflammatory Effects of Silibinin and Capsaicin Combination in Lipopolysaccharide-Induced RAW264.7 Cells by Inhibiting NF-κB and MAPK Activation.

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