Ganoderic Acid D Protects Human Amniotic Mesenchymal Stem Cells against Oxidative Stress-Induced Senescence through the PERK/NRF2 Signaling Pathway

Abstract

Aging is an important risk factor in the occurrence of many chronic diseases. Senescence and exhaustion of adult stem cells are considered as a hallmark of aging in organisms. In this study, a senescent human amniotic mesenchymal stem cell (hAMSC) model subjected to oxidative stress was established in vitro using hydrogen peroxide. We investigated the effects of ganoderic acid D (GA-D), a natural triterpenoid compound produced from Ganoderma lucidum, on hAMSC senescence. GA-D significantly inhibited β-galactosidase (a senescence-associated marker) formation, in a dose-dependent manner, with doses ranging from 0.1 μM to 10 μM, without inducing cytotoxic side-effects. Furthermore, GA-D markedly inhibited the generation of reactive oxygen species (ROS) and the expression of p21 and p16 proteins, relieved the cell cycle arrest, and enhanced telomerase activity in senescent hAMSCs. Furthermore, GA-D upregulated the expression of phosphorylated protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK), peroxidase III (PRDX3), and nuclear factor-erythroid 2-related factor (NRF2) and promoted intranuclear transfer of NRF2 in senescent cells. The PERK inhibitor GSK2656157 and/or the NRF2 inhibitor ML385 suppressed the PERK/NRF2 signaling, which was activated by GA-D. They induced a rebound for the generation of ROS and β-galactosidase-positive cells and attenuated the differentiation capacity. These findings suggest that GA-D retards hAMSC senescence through activation of the PERK/NRF2 signaling pathway and may be a promising candidate for the discovery of antiaging agents.

The Keap1‐Nrf2 System: A Mediator between Oxidative Stress and Aging

“…Similarly, extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinases, such as p38, both promote Nrf2 activation and upregulate Nrf2 target genes [ 140 , 141 ]. In particular, p38 phosphorylates Nrf2 at three serine residues (Ser 215 , Ser 408 , and Ser 577 ), facilitating a decrease in Nrf2 nuclear accumulation [ 142 ].…”

“…Some triterpenoids also have obvious antioxidant and antiaging activity. For instance, Xu et al demonstrated that ganoderic acid D exhibits potent antisenescence effects against H 2 O 2 -induced premature senescence of human amniotic mesenchymal stem cells through the activation of PERK/Nrf2 signals [ 141 ]. Additionally, Lefaki and colleagues demonstrated that 18 α -glycyrrhetinic acid can activate the Nrf2/SKN-1 pathway against DNA damage [ 207 ].…”

“…Phosphorylated Nrf2 translocates into the nucleus and binds to ARE/sMaf, promoting the transcription of ARE-driven genes and thereby alleviating oxidative stress-mediated damage [ 187 , 191 , 194 ]. Similarly, dietary components can also activate AMPK, CK2, PKC, ERK, and p38 signaling pathways to cause Nrf2 phosphorylation and nuclear translocation, thus promoting the transcription of antioxidant genes [ 141 , 204 , 206 , 208 ]. Additionally, certain dietary phytochemicals such as resveratrol can react with the cysteine residues of Keap1 (i.e., Cys151, Cys257, Cys273, Cys288, and Cys297) via oxidation or alkylation to dissociate Nrf2 from Keap1 [ 208 , 209 ].…”

Medicinal Mushrooms: Bioactive Compounds, Use, and Clinical Trials

“…An antiaging action of G . lucidum was shown in a recent study [ 26 ] by assaying the effects of ganoderic acid D on oxidative stress-induced stem cell senescence, using an H 2 O 2 -induced stem cell senescent model using human amniotic mesenchymal cells (hAMSCs) with a high expression of β-galactosidase, a senescence-associated marker. Ganoderic acid D inhibited the generation of reactive oxygen species (ROS) and senescence-associated markers, such as β-galactosidase, p21, and p16INK4a, and enhanced telomerase activity through the activation of the PERK/NRF2 signaling pathway.…”

Mesenchymal Stem Cells Transplantation in Intracerebral Hemorrhage: Application and Challenges

“…Oxidative stress preconditioning could protect the MSCs vitality through activating the Nrf2 pathway and upregulating its downstream target of the superoxide dismutase, catalase, and HO-1 ( Zhang F. et al, 2019 ). Moreover, many strategies had been explored to avoid cell apoptosis and senescence initiated by oxidative stress, including pioglitazone, vaspin, ganoderic acid D, and vitamin E ( Bhatti et al, 2018 ; Hu et al, 2019 ; Zhu et al, 2019 ; Xu et al, 2020 ). Taken together, before MSCs could be reliably and effectively used as hemorrhage stroke therapy, it is necessary to better understand the multiple microenvironmental regulatory mechanisms driving transplanted MSCs to form repair effect.…”