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
Journal
Oncotarget
Journal Volume
7
Journal Issue
39
Pages
62836-62861
Date Issued
2016
Author(s)
K.J. Senthil Kumar
M. Gokila Vani
Jeng-Leun Mau
Chin-Chung Lin
Fang-Hua Chu
VivianHsiu-Chuan Liao
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.
Other Subjects
antcin M; beta galactosidase; biological marker; cyclin D; cyclin dependent kinase 2; cyclin dependent kinase 4; cyclin dependent kinase 6; cyclin dependent kinase inhibitor 1; cyclin dependent kinase inhibitor 2A; cyclin E; glucose; mitogen activated protein kinase p38; plant medicinal product; protein SMP30; reactive oxygen metabolite; retinoblastoma protein; sirtuin 1; stress activated protein kinase; transcription factor FKHR; transcription factor Nrf2; unclassified drug; acetylcysteine; antcin B; antioxidant; cholest 4 en 3 one; NFE2L2 protein, human; phytochemical; reactive oxygen metabolite; resveratrol; retinoblastoma protein; SIRT1 protein, human; sirtuin 1; stilbene derivative; transcription factor Nrf2; triterpene; antiaging activity; Antrodia cinnamomea; Article; Caenorhabditis elegans; cell proliferation; cell protection; controlled study; deacetylation; drug activity; endothelium cell; enzyme activation; enzyme activity; enzyme degradation; enzyme inhibition; enzyme phosphorylation; enzyme repression; G1 phase cell cycle checkpoint; gene; gene silencing; growth inhibition; HO 1 gene; human; human cell; hyperglycemia; IC50; in vitro study; in vivo study; NQO 1 gene; oxidative stress; pharmacological blocking; phytochemistry; protein acetylation; protein depletion; protein expression; senescence; skin fibroblast; survival rate; transcription initiation; upregulation; Antrodia; apoptosis; cell aging; cell cycle; cell survival; chemistry; Chinese medicine; cytology; drug effect; fibroblast; hyperglycemia; metabolism; phosphorylation; skin; Acetylcysteine; Antioxidants; Antrodia; Apoptosis; Cell Cycle; Cell Proliferation; Cell Survival; Cellular Senescence; Cholestenones; Endothelial Cells; Fibroblasts; Gene Silencing; Glucose; Humans; Hyperglycemia; Medicine, Chinese Traditional; NF-E2-Related Factor 2; Oxidative Stress; Phosphorylation; Phytochemicals; Reactive Oxygen Species; Retinoblastoma Protein; Sirtuin 1; Skin; Stilbenes; Triterpenes
Publisher
Impact Journals LLC
Type
journal article