title: A steroid like phytochemical Antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1.
abstract: The present study revealed the anti-aging properties of antcin M (ANM) and elucidated the molecular mechanism underlying the effects. We found that exposure of human normal dermal fibroblasts (HNDFs) to high-glucose (HG, 30 mM) for 3 days, accelerated G0/G1 phase arrest and senescence. Indeed, co-treatment with ANM (10 µM) significantly attenuated HG-induced growth arrest and promoted cell proliferation. Further molecular analysis revealed that ANM blocked the HG-induced reduction in G1-S transition regulatory proteins such as cyclin D, cyclin E, CDK4, CDK6, CDK2 and protein retinoblastoma (pRb). In addition, treatment with ANM eliminated HG-induced reactive oxygen species (ROS) through the induction of anti-oxidant genes, HO-1 and NQO-1 via transcriptional activation of Nrf2. Moreover, treatment with ANM abolished HG-induced SIPS as evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity. This effect was further confirmed by reduction in senescence-associated marker proteins including, p21CIP1, p16INK4A, and p53/FoxO1 acetylation. Also, the HG-induced decline in aging-related marker protein SMP30 was rescued by ANM. Furthermore, treatment with ANM increased SIRT-1 expression, and prevented SIRT-1 depletion. This protection was consistent with inhibition of SIRT-1 phosphorylation at Ser47 followed by blocking its upstream kinases, p38 MAPK and JNK/SAPK. Further analysis revealed that ANM partially protected HG-induced senescence in SIRT-1 silenced cells. A similar effect was also observed in Nrf2 silenced cells. However, a complete loss of protection was observed in both Nrf2 and SIRT-1 knockdown cells suggesting that both induction of Nrf2-mediated anti-oxidant defense and SIRT-1-mediated deacetylation activity contribute to the anti-aging properties of ANM in vitro. Result of in vivo studies shows that ANM-treated C. elegens exhibits an increased survival rate during HG-induced oxidative stress insult. Furthermore, ANM significantly extended the life span of C. elegans. Taken together, our results suggest the potential application of ANM in age-related diseases or as a preventive reagent against aging process.
authors.affiliation: Department of Forestry, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Kumar K J
authors.initials: KK
authors.lastname: Senthil
authors.affiliation: Department of Forestry, National Chung Hsing University, Taichung, Taiwan.|National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Vani M
authors.initials: VM
authors.lastname: Gokila
authors.affiliation: National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.|Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Jeng-Leun
authors.initials: JL
authors.lastname: Mau
authors.affiliation: Taiwan Leader Biotech Company, Taipei, Taiwan.
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Lin
authors.affiliation: School of Forestry and Resource Conservation, National Taiwan University, Taipei, Taiwan.
authors.forename: Fang-Hua
authors.initials: FH
authors.lastname: Chu
authors.affiliation: Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Wei
authors.affiliation: Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Vivian Hsiu-Chuan
authors.initials: VH
authors.lastname: Liao
authors.affiliation: Department of Forestry, National Chung Hsing University, Taichung, Taiwan.|National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.|Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Sheng-Yang
authors.initials: SY
authors.lastname: Wang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D055491:Antrodia / Q000378:metabolism; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D002783:Cholestenones / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects*; D020868:Gene Silencing; D005947:Glucose / Q000737:chemistry; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D008516:Medicine, Chinese Traditional; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D064209:Phytochemicals / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D016160:Retinoblastoma Protein / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D012867:Skin / Q000166:cytology*; D013267:Stilbenes / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D002783:Cholestenones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D064209:Phytochemicals; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein; D013267:Stilbenes; D014315:Triterpenes; C570347:antcin B; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005947:Glucose; D000077185:Resveratrol; D000111:Acetylcysteine
keywords: Antcin M; Gerotarget; SIRT-1; antrodia salmonea; hyperglycemia; stress-induced premature senescence