Tryptanthrin prevents oxidative stress-mediated apoptosis through AMP-activated protein kinase-dependent p38 mitogen-activated protein kinase activation

Abstract

Tryptanthrin (6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline) has been reported to have a variety of pharmacological activities. Present study investigated the cytoprotective effects of tryptanthrin on arachidonic acid (AA) + iron-mediated oxidative stress and the molecular mechanisms responsible. In HepG2 cells, pretreatment with tryptanthrin inhibited the cytotoxic effect of AA + iron in a concentration-dependent manner. In addition, tryptanthrin prevented the changes in the levels of apoptosis-related proteins, and attenuated reactive oxygen species production, glutathione depletion, and mitochondrial membrane impairment induced by AA + iron. Mechanistic investigations showed that tryptanthrin increased the phosphorylations of AMP-activated protein kinase (AMPK) and of p38 mitogen-activated protein kinase (p38). Furthermore, inhibition of AMPK or p38 reduced the ability of tryptanthrin to prevent AA + iron-induced cell death and mitochondrial dysfunction. Transfection experiments using AMPK mutants indicated that p38 phosphorylation by tryptanthrin was dependent on AMPK activation. In a phenylhydrazine-induced acute liver injury model, tryptanthrin decreased serum levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin in mice. Additionally, tryptanthrin reduced numbers of degenerating hepatocytes, infiltrating inflammatory cells, 4-hydroxynonenal-, and nitrotyrosine-positive cells in hepatic tissues. Thus, these results suggest tryptanthrin has therapeutic potential to protect cells from oxidative injury via AMPK-dependent p38 activation.

Sipjeondaebo-tang Alleviates Oxidative Stress‐Mediated Liver Injury through Activation of the CaMKK2‐AMPK Signaling Pathway

“…Because we and others have reported several medicinal herbs and natural products that prevent oxidative stress via AMPK activation [ 4 , 7 – 10 ], we first monitored the effect of SDT (300 μ g/mL) on the temporal responses of AMPK and ACC (a representative downstream substrate of AMPK) phosphorylation. Based on immunoblot results, maximal increases in AMPK and ACC phosphorylation were observed at 0.5 h after SDT treatment, after which the levels gradually decreased.…”

“…We previously reported that eupatilin, tryptanthrin, isorhamnetin, Paeonia obovata , and Buddleja officinalis protect cells from the effects of AA plus iron via AMPK activation [ 4 , 7 – 9 , 32 ]. AMPK is regarded as a master regulator of cellular homeostasis related to oxidative and metabolic stress [ 5 ].…”

“…AMPK is regarded as a master regulator of cellular homeostasis related to oxidative and metabolic stress [ 5 ]. In our previous study, blockage of AMPK activation by a chemical inhibitor (e.g., compound C) or dominant negative mutant of AMPK failed to reduce the H 2 O 2 generation, mitochondrial membrane impairment, and cytotoxicity induced by AA plus iron [ 4 , 7 , 9 , 32 ]. Similarly, the present results showed that SDT increased AMPK and ACC phosphorylation.…”

“…Because the mitochondrion is an essential subcellular organelle for accelerating oxidative stress, maintaining mitochondrial integrity and homeostasis via AMPK provides a prosurvival signal against oxidative stress. Several medicinal herbs and isolated natural products that protect against oxidative stress via AMPK activation have been identified [ 4 , 7 – 10 ].…”

Antiviral Action of Tryptanthrin Isolated from Strobilanthes cusia Leaf against Human Coronavirus NL63

“…Tryptanthrin exhibited anti-neuroinflammatory action by inactivating NF-κB pathway to suppress TLR4-MyD88-mediated inflammation [38]. Additionally, tryptanthrin exerted a hepatoprotective effect on oxidative stress through the activation of AMP-activated protein kinase and p38 mitogenactivated protein kinase in HepG2 cells [39]. Therefore, such pharmacological activities improved the antiviral potential of tryptanthrin against HCoV-NL63 and other viruses.…”