ABSTRACT
Grifola frondosa (GF), a species of Basidiomycotina, is widely distributed across Asia and has been used as an immunomodulatory, anti-bacterial, and anti-cancer agent. In the present study, the pharmacological activity of the GF extract against an ecotoxicological industrial chemical, bisphenol A (BPA) in normal human dermal fibroblasts (NHDFs), was investigated. GF extract containing naringin, hesperidin, chlorogenic acid, and kaempferol showed an inhibitory effect on cell death and inflammation induced by BPA in the NHDFs. For the cell death caused by BPA, GF extract inhibited the production of reactive oxygen species responsible for the unique activation of the extracellular signal-regulated kinase. In addition, GF extract attenuated the expression of apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase-3) and the pro-inflammatory cytokine IL-1ß by the suppression of the redox-sensitive transcription factor, nuclear factor-kappa B (NF-κB) in BPA-treated NHDFs. For the inflammation triggered by BPA, GF extract blocked the inflammasome-mediated caspase-1 activation that leads to the secretion of IL-1ß protein. These results indicate that the GF extract is a functional antioxidant that prevents skin fibroblastic pyroptosis induced by BPA.
Subject(s)
Endocrine Disruptors , Grifola , Hesperidin , Antioxidants/pharmacology , Benzhydryl Compounds , Caspase 3 , Chlorogenic Acid , Cytokines/metabolism , Extracellular Signal-Regulated MAP Kinases , Fibroblasts/metabolism , Humans , Inflammasomes , Inflammation/chemically induced , Kaempferols , NF-kappa B/metabolism , Phenols , Plant Extracts/pharmacology , Proto-Oncogene Proteins c-bcl-2 , Reactive Oxygen Species/metabolism , bcl-2-Associated X Protein/metabolismABSTRACT
Kaempferol, a bioflavonoid present in fruits and vegetables, has a variety of antioxidant and anti-inflammatory capacities, but the functional role of kaempferol in oxidative skin dermal damage has yet to be well studied. In this study, we examine the role of kaempferol during the inflammation and cell death caused by 12-O-tetradecanoylphorbol-13-acetate (TPA) in normal human dermal fibroblasts (NHDF). TPA (5 µM) significantly induced cytotoxicity of NHDF, where a robust increase in the interleukin (IL)-1ß mRNA among the various pro-inflammatory cytokines. The skin fibroblastic cytotoxicity and IL-1ß expression induced by TPA were significantly ameliorated by a treatment with 100 nM of kaempferol. Kaempferol blocked the production of the intracellular reactive oxygen species (ROS) responsible for the phosphorylation of c-Jun N-terminal kinase (JNK) induced by TPA. Interestingly, we found that kaempferol inhibited the phosphorylation of nuclear factor-kappa B (NF-κB) and the inhibitor NF-κB (IκBα), which are necessary for the expression of cleaved caspase-3 and the IL-1ß secretion in TPA-treated NHDF. These results suggest that kaempferol is a functional agent that blocks the signaling cascade of the skin fibroblastic inflammatory response and cytotoxicity triggered by TPA.
Subject(s)
Dermatologic Agents/pharmacology , Fibroblasts/drug effects , Interleukin-1beta/metabolism , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Kaempferols/pharmacology , Skin/drug effects , Tetradecanoylphorbol Acetate/pharmacology , Blotting, Western , Cell Line , Enzyme-Linked Immunosorbent Assay , Fibroblasts/metabolism , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , Skin/metabolismABSTRACT
Astaxanthin, a natural antioxidant carotenoid, is a nutrient with diverse health benefits, given that it decreases the risk of oxidative stress-related diseases. In the present study, we investigate the functional role of astaxanthin during autophagic cell death induced by the estrogenic endocrine-disrupting chemical bisphenol A (BPA) in normal human dermal fibroblasts (NHDF). BPA significantly induced apoptotic cell death and autophagy in NHDF. Autophagic cell death evoked by BPA was significantly restored upon a treatment with astaxanthin (10 µM) via the inhibition of intracellular reactive oxygen species (ROS) production. Astaxanthin inhibited the phosphorylation of extracellular signal-regulated kinases (ERK) stimulated by ROS production, but it did not influence the activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in BPA-treated NHDF. Astaxanthin abrogated the ERK-mediated activation of nuclear factor-kappa B (NF-κB), which is responsible for the mRNA expression of LC3-II, Beclin-1, Atg12, and Atg14 during apoptotic cell death induced by BPA. These results indicate that astaxanthin is a pharmacological and nutritional agent that blocks the skin fibroblastic autophagic cell death induced by BPA in human dermal fibroblasts.
