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

Abstract

Sipjeondaebo-tang (SDT) is used frequently as a herbal prescription to treat deficiency syndromes in traditional Korean medicine. We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachidonic acid (AA) plus iron-mediated cytotoxicity in a concentration-dependent manner and prevented changes in apoptosis-related protein expression. In addition, SDT pretreatment significantly reduced glutathione depletion, hydrogen peroxide production, and mitochondrial dysfunction via treatment with AA plus iron. SDT increased the phosphorylation of AMP-activated protein kinase (AMPK) in accordance with the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Experiments using an AMPK chemical inhibitor (Compound C) or CaMKK2 chemical inhibitor (STO-609) suggested that the CaMKK2-AMPK signaling pathway contributes to SDT-mediated protection of mitochondria and cells. Moreover, administration of SDT for 4 consecutive days to mice significantly reduced the alanine aminotransferase and aspartate aminotransferase activities induced by carbon tetrachloride, and the numbers of degenerated hepatocytes, infiltrated inflammatory cells, nitrotyrosine-positive cells, and 4-hydroxynonenal-positive cells in liver tissue. Therefore, SDT protects hepatocytes from oxidative stress via CaMKK2-dependent AMPK activation and has the therapeutic potential to prevent or treat oxidative stress-related liver injury.

Melanocortin 1 receptor attenuates early brain injury following subarachnoid hemorrhage by controlling mitochondrial metabolism via AMPK/SIRT1/PGC-1α pathway in rats

“…Many other studies have found that AMPK suppresses inflammation and plays an important role in cellular oxidative stress and apoptosis. For example, Park et al has suggested that Sipjeondaebo-tang can reduce oxidative stress by activating the CaMKK2/AMPK signaling pathway, thereby reducing liver damage 57 ; In addition, Gui et al has reported that Salidroside can inhibit smooth muscle by regulating the AMPK/mTOR/ULK1 signaling pathway. It should be noted that ROS increases the expression of AMPK as well 58 .…”

Heat shock protein 22 modulates NRF1/TFAM-dependent mitochondrial biogenesis and DRP1-sparked mitochondrial apoptosis through AMPK-PGC1α signaling pathway to alleviate the early brain injury of subarachnoid hemorrhage in rats

“…Previous findings have indicated that hsp22 directly binds to AMPK and promotes its nuclear translocation and phosphorylation at Thr172, which results in a stimulation of survival mechanisms [ 27 ]. Additionally, activators and suppressants of AMPK have been employed to verify that AMPK exerts a protective role in mitochondrial dynamics imbalance and oxidative stress-mediated myocardium [ [50] , [51] , [52] ], brain [ 28 , 53 , 54 ] and liver injury [ 25 ]. But, it is still little known whether hsp22-induced upregulation of p-AMPK is answerable for its protective properties on mitochondrial dysfunction in SAH.…”

“…Adenosine 5'monophosphate-activated protein kinase (AMPK), as a cellular energy sensor, is a trimer composed of α, β and γ subunit units. Potent evidence displayed that activation of AMPK at the site of Thr172 could modulate mitochondrial biogenesis and fission [ 22 , 23 ], reduce ROS [ 24 , 25 ] and mitigate cell apoptosis [ 26 ] in various pathological processes. Moreover, the co-immunoprecipitation assay substantiated that hsp22 can diminish myocardial ischemia injury by promoting the Thr172 phosphorylation of AMPK [ 27 ].…”

Remedying the Mitochondria to Cure Human Diseases by Natural Products

“…Solanum melongena extract [46] Ganoderma lucidum [47] α-Arbutin [51] Auraptene [54] Oxidative stress Solanum melongena extract [46] Linalool [48] α-Arbutin [51] Naringenin [52] Apigenin [53] Auraptene [54] Apoptosis Ganoderma lucidum [47] Cinnamic acid derivatives [49] Proanthocyanidins [50] Naringenin [52] Apigenin [53] Naringenin [55] Ulmoside A [56] Mitochondrial membrane potential imbalance [59] Polygonatum kingianum [61] Betaine [63] Nicotinamide riboside [64] Puerarin [65] Punica granatum L. [62] Silybin [67] Salvianolic acid B [68] Oxidative stress Cimicifuga racemosa extract [59] Sipjeondaebo-tang [60] Polygonatum kingianum [61] 11 Oxidative Medicine and Cellular Longevity…”

“…Nicotinamide riboside [64] Diosgenin [66] Silybin [67] NecroX-7 [69] Apoptosis Cimicifuga racemosa extract [59] Polygonatum kingianum [61] Betaine [63] Silybin [67] Salvianolic acid B [68] Mitochondrial membrane potential imbalance Cimicifuga racemosa extract [59] Sipjeondaebo-tang [60] Diosgenin [66] Salvianolic acid B [68] NecroX-7 [69] Fatty acid oxidation Silybin [67] NecroX-7 [69] T2DM…”