Kaji-Ichigoside F1 and Rosamultin Protect Vascular Endothelial Cells against Hypoxia-Induced Apoptosis via the PI3K/AKT or ERK1/2 Signaling Pathway

Abstract

As a pair of differential isomers, Kaji-ichigoside F1 and Rosamultin are both pentacyclic triterpenoids isolated from the subterranean root of Potentilla anserina L., a plant used in folk medicine in western China as antihypoxia and anti-inflammatory treatments. We demonstrated that Kaji-ichigoside F1 and Rosamultin effectively prevented hypoxia-induced apoptosis in vascular endothelial cells. We established a hypoxia model, using EA.hy926 cells, to further explore the mechanisms. Hypoxia promoted the phosphorylation of AKT, ERK1/2, and NF-κB. In hypoxic cells treated with Kaji-ichigoside F1, p-ERK1/2 and p-NF-κB levels were increased, while the level of p-AKT was decreased. Treatment with Rosamultin promoted phosphorylation of ERK1/2, NF-κB, and AKT in hypoxic cells. Following the addition of LY294002, the levels of p-AKT, p-ERK1/2, and p-NF-κB decreased significantly. Addition of PD98059 resulted in reduced levels of p-ERK1/2 and p-NF-κB, while p-AKT levels were increased. Pharmacodynamic analysis demonstrated that both LY294002 and PD98059 significantly inhibited the positive effects of Kaji-ichigoside F1 on cell viability during hypoxia, consistent with the results of hematoxylin-eosin (H&E) staining, DAPI staining, and flow cytometry. The antihypoxia effects of Rosamultin were remarkably inhibited by LY294002 but promoted by PD98059. In Kaji-ichigoside F1- and Rosamultin-treated cells, Bcl2 expression was significantly upregulated, while expression of Bax and cytochrome C and levels of cleaved caspase-9 and cleaved caspase-3 were reduced. Corresponding to pharmacodynamic analysis, LY294002 inhibited the regulatory effects of Kaji-ichigoside F1 and Rosamultin on the above molecules, while PD98059 inhibited the regulatory effects of Kaji-ichigoside F1 but enhanced the regulatory effects of Rosamultin. In conclusion, Kaji-ichigoside F1 protected vascular endothelial cells against hypoxia-induced apoptosis by activating the ERK1/2 signaling pathway, which positively regulated the NF-κB signaling pathway and negatively regulated the PI3K/AKT signaling pathway. Rosamultin protected vascular endothelial cells against hypoxia-induced apoptosis by activating the PI3K/AKT signaling pathway and positively regulating ERK1/2 and NF-κB signaling pathways.

Assessing the Potential Value and Mechanism of Kaji-Ichigoside F1 on Arsenite-Induced Skin Cell Senescence

“…Oxidative stress deepens the understanding of the cellular senescence process and provides promising tools for the development of new therapeutic strategies [ 31 ]. Rosa roxburghii is a natural medicinal and edible plant that is unique to the mountainous area of southwest China, in which its main active ingredients are flavonoid of Rosa roxburghii Tratt and triterpenoids of Rosa roxburghii Tratt , and has antioxidant and antihypoxia effects [ 29 , 30 ]. Recent study has shown that Rosa roxburghii can attenuate arsenic poisoning by regulating element balance and oxidative stress [ 27 ].…”

“…However, there are very limited effective targeted prevention and treatment measures for skin cell senescence caused by arsenic. Rosa roxburghii is a natural medicinal and edible plant that is unique to the mountainous area of southwest China and has antioxidant and antihypoxia effects [ 29 , 30 ]. Its main active ingredients include polysaccharides, flavonoids, superoxide dismutase, vitamin C, and triterpenes.…”

Assessing the Association of Element Imbalances With Arsenism and the Potential Application Value of Rosa roxburghii Tratt Juice

“…Some studies ( Chen et al, 2007 ; Mahata et al, 2008 ; Zablotska et al, 2008 ; Xu et al, 2016 ; Xia et al, 2020 ; Xu et al, 2021b ) have shown that vitamins, trace elements, and natural medicinal plants can be used to prevent and treat endemic arsenism. RRT , a traditional Chinese health food that is unique to the mountainous area of southwest China ( An et al, 2011 ; Shi et al, 2020 ), contains a variety of biologically active metabolites (such as pentacyclic triterpenoids and flavonoids) and rich nutrients (including trace elements, vitamins, polysaccharides, dietary fiber, unsaturated fatty acids, and superoxide dismutase) ( Wu et al, 2020 ). Our previous animal study found that RRT can attenuate liver damage in arsenic-poisoned rats by regulating element balance and oxidative stress ( Xu et al, 2021b ).…”

“…Natural medicinal and edible plants have contributed extensively towards the development of modern medicine ( Kushiro et al, 2003 ); however, a large number of natural products are yet to be developed and applied ( Sen and Samanta, 2015 ). Rosa roxburghii Tratt ( RRT ) juice is the original juice of Rosa roxburghii Tratt fruit, which is a traditional Chinese health food that is unique to the mountainous area of southwest China ( Shi et al, 2020 ). RRT contains a variety of biologically active metabolites (such as pentacyclic triterpenoids and flavonoids) and rich nutrients (including trace elements, vitamins, polysaccharides, dietary fiber, unsaturated fatty acids, and superoxide dismutase) ( Wu et al, 2020 ).…”

FAT10 Combined with Miltefosine Inhibits Mitochondrial Apoptosis and Energy Metabolism in Hypoxia-Induced H9C2 Cells by Regulating the PI3K/AKT Signaling Pathway

“…Moreover, AKT refers to a downstream effector of phosphoinositide 3-kinase (PI3K); therefore, PI3K/AKT represents a critical pathway of cellular processes that are responsible for cell survival [ 13 , 14 ]. A study indicated that the activation of PI3K/AKT signaling inhibited hypoxia-induced apoptosis in vascular endothelial cells [ 15 ]. Apart from that, the PI3K/AKT pathway was related to the apoptosis of cardiomyocytes subjected to ischemic hypoxia [ 4 ].…”