Poligapolide, a PI3K/Akt Inhibitor in Immunodeficiency Virus Type 1 TAT-Transduced CHME5 Cells, Isolated from the Rhizome of <i>Polygala tenuifolia</i>

Abstract

The rhizome of Polygala tenuifolia WILLD (PT, family Polygalaceae) has been used in traditional Chinese medicine for inflammation, dementia, amnesia, neurasthenia and cancer. The phosphoinositide 3-kinase (PI3K)/Akt inhibitor(s) was isolated from PT by using the cytoprotective phenotype of human immunodeficiency virus type 1 (HIV-1) Tat-transduced CHME5 cells against lipopolysaccharide/cycloheximide. We isolated 9 constituents (1)- (9) The phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway is particularly activated by several key human pathogenic viruses such as human immunodeficiency virus type 1 (HIV-1) 1) and human papillomavirus (HPV).2) This virusinduced activation of PI3K/Akt pathway involves specific viral proteins such as E6/E7 of HPV, NS5A of hepatitis C virus (HCV), Tax of human T-lymphotrophic virus type (HTLV) and Tat of HIV-1. Of them, HIV-1 Tat appears to inactivate phosphatase and tensin homology (PTEN), a negative regulator of the PI3K/Akt pathway.3,4) For example, the transfection of HIV-1 Tat into CHME5 cells, a human microglial cell line, and human primary macrophages elevates their cytoprotective phenotypes against cellular stresses. 4,5) More specifically, the HIV-1 Tat-expressing CHME5 cells activate the PI3K/Akt pathway upon exposure to cellular stresses by reducing the level of PTEN. 3,5) These cells render strong resistance to extracellular stresses such as lipopolysaccharide (LPS) or nitric oxide. Tat-expressing human microglia and macrophages play important roles in the establishment of long-living HIV-1 reservoirs in the central nervous system, 6,7) which in turn induces neuronal death and HIV-1 associated neurodegenerative diseases. 8)Also the PI3K/Akt pathway is also highly activated in many cancer cells. 9) Therefore, PI3K/Akt inhibitors have been extensively searched as potential anti-cancer and anti-HIV-1 dementia agents. Nevertheless, the studies on the isolation of PI3K/Akt inhibitors from natural products have not been thoroughly.The rhizome of Polygala tenuifolia WILLD (PT, Polygalaceae), which contains xanthones, and triterpenoid saponin, has been used in traditional Chinese medicine for inflammation, dementia, amnesia, neurasthenia and cancer. 10,11) As a part of our studies on anti-PI3K/Akt constituents from natural medicines, we isolated 4 anti-cytoprotective compounds, clionasterol, ethyl cholestan-22-en-3-ol, 3-O-β-D-glucosyl ethyl cholestan-22-en-3-ol, and 3-O-β-D-glucopyranosyl clionasterol from EtOAc fraction of PT against HIV-1 Tat-transduced CHME5 cells by inhibiting PDK1 phosphorylation, in the previous study. 12)In the present study, we continuously screened PI3K/Akt inhibitory constituents from PT, isolated a novel constituent named poligapolide and investigated its inhibitory effect against the activation of PI3K, pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK1), Akt and glycogen synthase kinase-3 beta (GSK3β) in HIV-1 Tat-transduced CHME5 cells. Results and DiscussionTo search PI3K/Akt inhibitors from PT, first we isolated 9 compounds in EtOAc...

The human microglial HMC3 cell line: where do we stand? A systematic literature review

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“…Glycyrrhetinic acid protects H9c2 cells from oxygen glucose deprivation-induced injury, and the potential underlying mechanism might be related to the PI3K/Akt signaling pathway [15]. The rhizome of Polygala tenuifolia WILLD has been used in Traditional Chinese Medicine to treat inflammation, dementia, amnesia, neurasthenia, and cancer [16]. A novel polysaccharide from Acorus tatarinowii has been found to exert anti-neuroinflammatory and neuroprotective effects through modulation of the PI3K/Akt signaling pathway [17].…”

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