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.

The Sturgeon Ovarian Liquid and the Perch Roe Extract are Able to Enhance the Recovery of the Fibroblasts after their Stress-induced Premature Senescence

“…Содержащийся в кожуре и косточках красного винограда ресвератрол в концентрациях, ингибирующих mTOR, также тормозит клеточное старение [22]. Исследования, проведённые in vitro и in vivo, показывают, что соединения, содержащиеся в растениях (полифенолы, флавоноиды, терпеноиды, витамины), способны активировать редокс-чувствительную Nrf2-сигнальную систему, которая усиливает экспрессию антиоксидантных генов и, тем самым, улучшает защиту от окислительного стресса и старения [2]. Например, активаторы Nrf2 обнаружены в экстрактах брокколи [8].…”

“…Например, активаторы Nrf2 обнаружены в экстрактах брокколи [8]. Широко используемый в традиционной китайской медицине камфорный гриб (Antrodia cinnamomea) содержит тритерпеноиды, способные препятствовать преждевременному старению фибробластов, активируя Nrf2-зависимые антиоксидантные гены и усиливая экспрессию SIRT-1 (NAD + -зависимую гистондезацетилазу), которая взаимодействует также с рядом молекул, включая p53 и FoxO1 [2]. Экспрессию SIRT-1 усиливают и не содержащие спирт экстракты красного вина, которые защищают клетки эндотелия от индуцированного окислительным стрессом старения на 26-40% [23].…”

“…Клеточным старением называется явление необратимой остановки пролиферации клеток [1,2]. Различают репликативное и стресс-индуцированное преждевременное старение (stress-induced premature senescence, SIPS), которые имеют целый ряд общих свойств.…”

Regenerative and protective effects of calcium silicate on senescent fibroblasts induced by high glucose

“…Defects in any biological property of fibroblasts may affect the healing process. Numerous studies have shown that HG stimulation results in premature cellular senescence . This impairs cell proliferation and migration and inhibits fibroblast differentiation into myofibroblasts, thus blocking up wound repair .…”

“…The G 1 phase is the restriction point of the cell cycle. Kumar et al have found that HG induced cell cycle arrest at the G 0 /G 1 phase in fibroblasts . In addition, HG stimulation upregulates the expression of p21 and p16, both of which are cyclin‐dependent kinase inhibitors and potent negative regulators of cell cycle progression.…”