Fisetin attenuates hydrogen peroxide-induced cell damage by scavenging reactive oxygen species and activating protective functions of cellular glutathione system
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Fisetin
Cell damage
Fisetin
Lewis lung carcinoma
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The morbidity and fatality rates of non-small-cell lung cancer (NSCLC) were high, although a combination of multiple treatments was used. Fisetin, a small flavonoid compound, had shown anticancer activities. Thus, we aimed at exploring the mechanisms of Fisetin in the treatment of NSCLC.TCMSP and Swiss target tools were used to screen the targets of Fisetin, and GeneCards was used to collect the genes related to NSCLC. The genes common to Fisetin and NSCLC were obtained by Venn analysis, whose possible functions were further annotated. A "Compound-Target-Disease" network was then constructed and hub genes were filtered. Also, molecular docking was performed to predict the binding abilities between Fisetin and the hub genes. Then, the effects of Fisetin on the expression of hub genes in lung adenocarcinoma cells were preliminarily evaluated in vitro.A total of 131 genes common to Fisetin and NSCLC were filtered out, which might be enriched in several biological processes including antioxidation, cell proliferation, and various signaling pathways, such as PI3K-Akt and IL-17 signaling pathways. Among them, PIK3R1, CTNNB1, JUN, EGFR, and APP might be the hub genes. Molecular docking indicated the close bond between Fisetin and them. Experiments implied a possible effect of Fisetin on the expression of hub genes in A549 cells.The present study found a series of novel targets and pathways for Fisetin treating NSCLC. Multiple angles, targets, and pathways were involved in the biological processes, which need to be verified in further experiments.
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플라보노이드(flavonoid)는 식물 등의 대사체에서 유래한 폴리페놀 계열의 화합물이며, 다양한 인체생리작용을 조절할 수 있는 것으로 알려져 있다. 이중 3,3’,3’,7-tetrahydroxyflavone (fisetin)은 다양한 과일과 채소에서 발견되며, 최근 노쇠용해(senolytic) 활성을 통해 특정 조직의 기능을 회복시킨다는 것이 알려졌다. 본 연구에서는 인간 표피 각질세포를 대상으로 하여 fisetin의 피부장벽 유전자 발현 조절 및 항노화 효능을 분석하였다. Fisetin은 말단소립 역전사효소(telomerase)의 활성을 증가시켰으며, CDKN1B 유전자의 발현을 감소시켰다. 또한 피부장벽을 구성하는 주요 유전자인 KRT1, FLG, IVL, DSP의 발현을 증가시켰으며, 세라마이드 합성효소의 일종인 CerS3, CerS4 유전자의 발현을 증가시켰다. 이러한 결과는 fisetin의 효능이 노쇠용해에 국한되지 않고 인간 각질세포의 다양한 생리학적 조절에도 관여함을 보여준다. 따라서 fisetin은 화장품 및 의약품 등의 생리활성 조절물질로 활용될 수 있다고 사료된다.
Fisetin
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Fisetin
Cell damage
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Peroxide
Hydroxyl radical
Pro-oxidant
Reactive intermediate
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Abstract Fisetin, a natural flavonoid, possesses numerous biological activities that have been extensively studied in various diseases. When it comes to cancer, fisetin exhibits a range of biological effects, such as suppressing cell growth, triggering programmed cell death, reducing the formation of new blood vessels, protecting against oxidative stress, and inhibiting cell migration. Moreover, fisetin has the ability to enhance the effectiveness of chemotherapy. The anticancer properties of fisetin can be attributed to a diverse array of molecules and signaling pathways, including vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), PI3K/Akt/mTOR, and Nrf2/HO-1. Consequently, fisetin holds promise as a therapeutic agent for anticancer treatment. In this review, we place emphasis on the biological functions and various molecular targets of fisetin in anticancer therapy.
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Ionizing radiation can induce cellular oxidative stress through the generation of reactive oxygen species, resulting in cell damage and cell death. The aim of this study was to determine whether the antioxidant effects of the flavonoid fisetin (3,7,3',4'-tetrahydroxyflavone) included the radioprotection of cells exposed to γ-irradiation. Fisetin reduced the levels of intracellular reactive oxygen species generated by γ-irradiation and thereby protected cells against γ-irradiation-induced membrane lipid peroxidation, DNA damage, and protein carbonylation. In addition, fisetin maintained the viability of irradiated cells by partially inhibiting γ-irradiation-induced apoptosis and restoring mitochondrial membrane potential. These effects suggest that the cellular protective effects of fisetin against γ-irradiation are mainly due to its inhibition of reactive oxygen species generation.
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The present data show that freshly explanted BCG-activated mouse peritoneal macrophages release large quantities of hydrogen peroxide upon initial contact with a foreign substratum, without the requirement for other membrane stimuli such as phorbol diesters. The hydrogen peroxide detected under these conditions does not originate from extracellularly released superoxide, since 2 x 10(5) BCG-activated macrophages spontaneously released 1.6 nmol hydrogen peroxide but only 0.2 nmol superoxide. Thus, more than 90% of the hydrogen peroxide detected was not derived from extracellular superoxide dismutation. The dissociation between hydrogen peroxide and superoxide release was further demonstrated in cytochalasin B- or lidocaine-treated cells or in the absence of glucose. Under these conditions, hydrogen peroxide release was markedly inhibited while superoxide release was unaffected. These observations provide evidence that another metabolic pathway is involved in the generation and release of hydrogen peroxide during adherence and spreading of freshly explanted activated macrophages onto a substratum.
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Peroxide
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Fisetin (3,3',4',7-tetrahydroxyflavone), a flavonoid abundant in various fruits and vegetables, including apple, strawberry, and onion, shows several beneficial effects such as anti-oxidant, anti-inflammatory, and anti-tumor effects. The free radical theory of aging suggests that age-related accumulation of oxidative damage is the major cause of aging and that decreasing cellular oxidative stress can regulate aging. Here, we investigated the effects of dietary supplementation with fisetin on the stress response, aging, and age-related diseases. Fisetin reduced the cellular ROS levels and increased the resistance to oxidative stress. However, the response to UV irradiation was not affected by fisetin. Both the mean and maximum lifespans were significantly extended by fisetin; lifespan extension by fisetin was accompanied by reduced fertility as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin. Amyloid beta-induced toxicity was markedly decreased by fisetin, which required DAF-16 and SKN-1. Reduced motility induced by a high-glucose diet was completely recovered by supplementation with fisetin, which was dependent on SKN-1. Using a Parkinson's disease model, we showed that degeneration of dopaminergic neurons was significantly inhibited by treatment with fisetin. Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy. These findings support the free radical theory of aging and suggest that fisetin can be a strong candidate for use in novel anti-aging anti-oxidant nutraceuticals.
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Malondialdehyde
Cell damage
Lucigenin
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