The effects of Ginsenosides on PI3K/AKT signaling pathway

Abstract

Ginsenosides belong to a group of steroid glycosides that are extracted from the plant genus Panax (ginseng). This plant has been used for a long time for the treatment of a variety of disorders in traditional medicine. Recent studies have assessed the biological impact of Ginsenosides in cell culture or animal models. Animal studies have shown their beneficial impacts in the remedy of pathological conditions in different tissues. The ameliorating effects of Ginsenosides in diverse pathogenic conditions can be attributed to their effects on the production of reactive oxygen species. These substances mainly affect the activity of AMPK/AKT and PI3K/AKT pathways. The beneficial effects of Ginsenosides have been appraised in diabetes-related complications, spinal cord injury, cerebral ischemia, myocardial ischemia, and other disorders which are associated with oxidative stress. Moreover, these substances have been shown to interfere with the pathologic conditions during carcinogenesis. In the current study, we explain these impacts in two distinct sections including non-neoplastic conditions and neoplastic conditions.

Keywords: Gene expression; Ginsenoside; Signaling pathway.

Fig. 1

Chemical structure of some ginsenosides studied in this paper. Ginsenosides are the major constituents found in the plant ginseng. It has been reported that they have unique biological activities such as anti-aging, anti-oxidant, anti-tumor, anti-diabetic, and organ-protective impacts

Fig. 2

Ginsenosides can affect the activity of PI3K/AKT, GSK-3β, and AMPK pathways resulting in decreasing oxidative stress [4], inflammation, gluconeogenesis, glucose production, lipid accumulation, as well as insulin resistance [12]. There are three types of AKT substrates, GSK-3β, FOXO1, and PGC-1α, that could be involved in liver glucose production. The activated PI3K/AKT pathway could participate in insulin metabolism and glucose uptake improvement via translocating GLUTs (glucose transporters, especially GLUT4) to the cell membrane and/or through enhancing glycogen synthesis that happens by phosphorylation of glycogen synthase kinase 3 (GSK-3β) [12, 13]. On the one hand, FOXO could regulate insulin responsiveness and glucose homeostasis [12]. Moreover, AMPK could decrease fat and cholesterol synthesis. Ginsenosides can also decrease insulin resistance. In addition, ginsenosides can inhibit ROS production via activating Nrf-2, HO-1, and AKT [–16]. They can also inhibit the NF-кB signaling pathway and decrease inflammation via blocking the mRNA expression of pro-inflammatory mediators as well as cytokines, including TNF-α, IL-1β, iNOS, and COX-2 [14]

Fig. 3

Several studies have shown that ginsenosides have anti-tumor activity. In tumor cells, ginsenosides could induce exogenous apoptosis via enhancing the expression of TRAILs, p53, Fas/FasL, resulting in the activation of caspase cascades (Pro-caspase-8-caspase-3) [61]. Ginsenosides could regulate the JAK/STAT pathway involved in immune regulatory processes. They have regulatory roles on P53, Fas/FasL, and Bax [62]. Indeed, ginsenosides via blocking JAK1/STAT3 could decrease the expression of STAT3 target genes, including survivin, Bcl-2, Bcl-xL. Therefore, they could increase apoptosis in tumor cells via inhibiting the mentioned pathway [62, 63]. Interestingly, they could inhibit NF-кB signaling by regulating Bax/Bcl-2 expression, resulting in the inhibition of angiogenesis [64]. Ginsenosides also via blocking the PI3K/AKT/mTOR could inhibit the proliferation of cancer cells and induce apoptosis [48, 65]. Ginsenosides by decreasing the expression of some cell cycle proteins including Cyclin-B1 could block tumor cell cycles [66, 67]. Ginsenosides by upregulating the expression of LC3-II, Beclin-1, and Atg7 could also induce autophagy, resulting in tumor cell death [68, 69]