Protective Effects the Akt Activator SC79 in Hepatic Ischemia-Reperfusion Injury

Zhou, Huaiyu; Yu, Ying; Zhang, Jinna; Zhang, Yunfang; Luan, Qi; Wang, Gongming

doi:10.12659/msm.911178

Cited by 8 publications

(7 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, PI3K and their downstream target Akt are family of signal transduction enzymes incorporated in regulation of cellular activation, inflammation, and apoptosis. It has been reported that PI3K/Akt/mTOR signal is involved in the process of liver IR injury (Covington et al, ; Liu et al, ; Zhou et al, ). In accordance with these previous studies, we reported a decrease in protein expression of PI3K, Akt, and mTOR in hepatic IR group as compared with sham control group.…”

Section: Discussionmentioning

confidence: 99%

Perindopril Ameliorates Hepatic Ischemia Reperfusion Injury Via Regulation of NF‐κB‐p65/TLR‐4, JAK1/STAT‐3, Nrf‐2, and PI3K/Akt/mTOR Signaling Pathways

Kamel

Hassanein

Ahmed

et al. 2019

The Anatomical Record

View full text Add to dashboard Cite

Hepatic ischemia reperfusion (IR) is an inevitable clinical problem for surgical procedures such as liver transplantation and liver resection. This study was designed to evaluate the protective effect of perindopril (PER) against hepatic IR injury. Thirty‐two rats were used and randomly allocated into four groups. Sham control group was subjected to sham operation and received saline only, IR group was subjected to IR and received vehicle, PER group was pretreated with PER (one milligram per kilogram per day i.p. for 10 consecutive days), and IR+PER group was pretreated with PER then subjected to IR. Liver function biomarkers (aspartate aminotransferase and alanine aminotransferase), oxidative stress (glutathione, malondialdehyde, myeloperoxidase, and superoxide dismutase) and inflammation markers (tumor necrosis factor‐alpha, interferon‐gamma, and inteleukin‐10 [IL‐10]), mRNA expression of NF‐κB‐p65 and TLR‐4, as well as protein expression of JAK1, STAT‐3, PI3K, mTOR, Akt, and Nrf‐2 were investigated concomitantly with histopathological examination. The results indicated that, hepatic IR induced a significant alteration in liver function biomarkers and structure, oxidative stress, and inflammation. At the molecular level, up‐regulation of NF‐κB‐p65, TLR‐4, JAK1, and STAT‐3 concomitantly with down‐regulation of Nrf‐2, IL‐10, PI3K, Akt, and mTOR were observed. These disturbances were alleviated by pretreatment of IR rats with PER in concomitant with hepatic structural improvement. Conclusively, the protective effect of PER presumably may be relevant to its ability to reduce oxidative stress, ameliorate the inflammatory processes, and modify the related signaling pathways. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1935–1949, 2020. © 2019 American Association for Anatomy

show abstract

Section: Discussionmentioning

confidence: 99%

Perindopril Ameliorates Hepatic Ischemia Reperfusion Injury Via Regulation of NF‐κB‐p65/TLR‐4, JAK1/STAT‐3, Nrf‐2, and PI3K/Akt/mTOR Signaling Pathways

Kamel

Hassanein

Ahmed

et al. 2019

The Anatomical Record

View full text Add to dashboard Cite

show abstract

“…Despite a great demand for Akt activators for various therapeutic applications, efforts to identify the true Akt activators were not successful until recently when a smallmolecule SC79 was discovered to be a selective, potent, and cell-permeable Akt activator, which enables cytosolic activation of Akt that recapitulates the primary function of Akt signaling (21). The cytoprotective effects afforded by SC79 have been observed in various experimental settings (8,21,59,61) For example, SC79 shielded neurons from ischemia-elicited cell death (21), protected against early brain injury following subarachnoid hemorrhage (59), protected retinal pigment epithelium cells from UV radiation (8), and provided protective effects on the hepatic I/R injury (61). We have recently shown that SC79 prevented lethal hepatic failure induced by Fas-mediated apoptosis of hepatocytes (31).…”

Section: G392mentioning

confidence: 99%

AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury

Jing

Liu

Xue

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-α can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-α-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-α-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-α-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-α act through both AKT-mediated activation of NF-κB and upregulation of FLIPL/S.

show abstract

“…SC 79-mediated Akt activation rescues ischemia-induced neuronal death in rodents [165,166]. It also protects rodents from bacterial lipopolysaccharide-induced liver injury [167,168] and hepatic [169], renal [170] and cerebral ischemia [166]. Determining effects of SC 79 in metabolic diseases, either alone or in combination with IP6K inhibitor of AMPK activator will be of interest.…”

Section: Bone Marrow Stem Cellsmentioning

confidence: 99%

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

2020

View full text Add to dashboard Cite

In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans.

show abstract

Protective Effects the Akt Activator SC79 in Hepatic Ischemia-Reperfusion Injury

Cited by 8 publications

References 22 publications

Perindopril Ameliorates Hepatic Ischemia Reperfusion Injury Via Regulation of NF‐κB‐p65/TLR‐4, JAK1/STAT‐3, Nrf‐2, and PI3K/Akt/mTOR Signaling Pathways

Perindopril Ameliorates Hepatic Ischemia Reperfusion Injury Via Regulation of NF‐κB‐p65/TLR‐4, JAK1/STAT‐3, Nrf‐2, and PI3K/Akt/mTOR Signaling Pathways

AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

Contact Info

Product

Resources

About