Dataset Information

Kaempferol-induced mitochondrial damage promotes NF-κB-NLRP3-caspase-1 signaling axis-mediated pyroptosis in gastric cancer cells.

ABSTRACT: GC is a gastrointestinal tumor with high morbidity and mortality. Owing to the high rate of postoperative recurrence associated with GC, the effectiveness of radiotherapy and chemotherapy may be compromised by the occurrence of severe undesirable side effects. In light of these circumstances, KP, a flavonoid abundantly present in diverse herbal and fruit sources, emerges as a promising therapeutic agent with inherent anti-tumor properties. This study endeavors to demonstrate the therapeutic potential of KP in the context of GC while unraveling the intricate underlying mechanisms. Notably, our investigations unveil that KP stimulation effectively promotes the activation of NLRP3 inflammatory vesicles within AGS cells by engaging the NF-κB signaling pathway. Consequently, the signal cascade triggers the cleavage of Caspase-1, culminating in the liberation of IL-18. Furthermore, we ascertain that KP facilitate AGS cell pyroptosis by inducing mitochondrial damage. Collectively, our findings showcase KP as a compelling candidate for the treatment of GC-related diseases, heralding new possibilities for future therapeutic interventions.

SUBMITTER: Qi X

PROVIDER: S-EPMC11002587 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Kaempferol-induced mitochondrial damage promotes NF-κB-NLRP3-caspase-1 signaling axis-mediated pyroptosis in gastric cancer cells.

Qi Xiafei X Liu Jiatong J Wang Liuxiang L Gu Peixing P Song Siyuan S Shu Peng P

Heliyon 20240323 7

GC is a gastrointestinal tumor with high morbidity and mortality. Owing to the high rate of postoperative recurrence associated with GC, the effectiveness of radiotherapy and chemotherapy may be compromised by the occurrence of severe undesirable side effects. In light of these circumstances, KP, a flavonoid abundantly present in diverse herbal and fruit sources, emerges as a promising therapeutic agent with inherent anti-tumor properties. This study endeavors to demonstrate the therapeutic pote ...[more]

PMID: 38596072

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Project description:IntroductionOsteoarthritis (OA) is a prevalent chronic degenerative disease, marked by a complex interplay of mechanical stress, inflammation, and metabolic imbalances. Recent studies have highlighted the potential of spermidine (SPD), a naturally occurring polyamine known for its anti-inflammatory and antioxidant properties, as a promising therapeutic agent for OA. This study delves into the therapeutic efficacy and mechanistic pathways of SPD in mitigating OA symptoms.MethodsForty Sprague-Dawley rats were randomly assigned to four groups, including the CG (sham operation), model (anterior cruciate ligament transection [ACLT], and treatment (ACLT + two different doses of SPD) groups. In vivo, correlations between OA severity and different interventions were assessed by ELISA, X-rays, CT imaging, histological staining, and immunohistochemistry. In vitro, IL-1β was used to trigger chondrocyte inflammation, and SPD's cytotoxicity was assessed in primary rat chondrocytes. Next, inflammatory markers, extracellular matrix (ECM) proteins, and pathway marker proteins were detected in chondrocytes administered IL-1β alone, SPD, or aryl hydrocarbon receptor (AhR) silencing, by qRT-PCR, Griess reaction, ELISA, Western blot, and immunofluorescence. Morphological alterations and pyroptosis in chondrocytes were examined by transmission electron microscopy (TEM) and flow cytometry.ResultsOur research reveals that SPD exerts significant anti-inflammatory and antipyroptotic effects on IL-1β-treated chondrocytes and in anterior cruciate ligament transection (ACLT) rat models of OA, primarily through interaction with the Aryl hydrocarbon receptor (AhR). Specifically, SPD's binding to AhR plays a crucial role in modulating the inflammatory response and cellular pyroptosis by inhibiting both the AhR/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways. Furthermore, the knockdown of AhR was found to negate the beneficial effects of SPD, underscoring the centrality of the AhR pathway in SPD's action mechanism. Additionally, SPD was observed to promote the preservation of cartilage integrity and suppress ECM degradation, further supporting its potential as an effective intervention for OA.DiscussionCollectively, our findings propose SPD as a novel therapeutic approach for OA treatment, targeting the AhR pathway to counteract the disease's progression and highlighting the need for further clinical evaluation to fully establish its therapeutic utility.

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-κB 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-κB, and NLRP3: cleaved Caspase-1, IL-1β, and GSDMD-N: and elevated the concentration of IL-1β, IL-6, and TNF-α, 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-κB, NLRP3; cleaved Caspase-1, IL-1β, 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-κB axis controlled decrease of pyroptosis via NLRP3 cascade.

Project description:Trillium tschonoskii Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via the induction of apoptosis and autophagy in vitro and in vivo. In this study, we further found that the NLRP3 inflammasome was activated in PPVI administrated A549-bearing athymic nude mice. As is known to us, pyroptosis is an inflammatory form of caspase-1-dependent programmed cell death that plays an important role in cancer. By using A549 and H1299 cells, the in vitro effect and action mechanism by which PPVI induces activation of the NLRP3 inflammasome in NSCLC were investigated. The anti-proliferative effect of PPVI in A549 and H1299 cells was firstly measured and validated by MTT assay. The activation of the NLRP3 inflammasome was detected by using Hoechst33324/PI staining, flow cytometry analysis and real-time live cell imaging methods. We found that PPVI significantly increased the percentage of cells with PI signal in A549 and H1299, and the dynamic change in cell morphology and the process of cell death of A549 cells indicated that PPVI induced an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. In addition, belnacasan (VX-765), an inhibitor of caspase-1, could remarkably decrease the pyroptotic cell death of PPVI-treated A549 and H1299 cells. Moreover, by detecting the expression of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD in A549 and h1299 cells using Western blotting, immunofluorescence imaging and flow cytometric analysis, measuring the caspase-1 activity using colorimetric assay, and quantifying the cytokines level of IL-1β and IL-18 using ELISA, the NLRP3 inflammasome was found to be activated in a dose manner, while VX-765 and necrosulfonamide (NSA), an inhibitor of GSDMD, could inhibit PPVI-induced activation of the NLRP3 inflammasome. Furthermore, the mechanism study found that PPVI could activate the NF-κB signaling pathway via increasing reactive oxygen species (ROS) levels in A549 and H1299 cells, and N-acetyl-L-cysteine (NAC), a scavenger of ROS, remarkably inhibited the cell death, and the activation of NF-κB and the NLRP3 inflammasome in PPVI-treated A549 and H1299 cells. Taken together, these data suggested that PPVI-induced, caspase-1-mediated pyroptosis via the induction of the ROS/NF-κB/NLRP3/GSDMD signal axis in NSCLC, which further clarified the mechanism of PPVI in the inhibition of NSCLC, and thereby provided a possibility for PPVI to serve as a novel therapeutic agent for NSCLC in the future.

Dataset Information

Kaempferol-induced mitochondrial damage promotes NF-κB-NLRP3-caspase-1 signaling axis-mediated pyroptosis in gastric cancer cells.

Publications

Kaempferol-induced mitochondrial damage promotes NF-κB-NLRP3-caspase-1 signaling axis-mediated pyroptosis in gastric cancer cells.

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