PKCδ Mediates NF-κB Inflammatory Response and Downregulates SIRT1 Expression in Liver Fibrosis

Lee, Su Jin; Kim, Su Ji; Lee, Hyun‐Shik; Kwon, Oh Nam

doi:10.3390/ijms20184607

Cited by 27 publications

(22 citation statements)

References 41 publications

(41 reference statements)

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“…It has been reported that mitochondrial Ca 2+ overload rapidly increased protein acetylation via a buildup of NADH and the inhibition of sirtuin enzymatic activity ( Marcu et al, 2014 ). In addition, the increase of Ca 2+ concentration in cytosol activated protein kinase Cδ (PKCδ) which negatively regulated SIRT1 expression ( Lee et al, 2019 ). Our previous study revealed that the quaternary ammonium salt derivative of haloperidol, N-n-Butyl haloperidol iodide (F 2 ), a new calcium antagonist that reduced cytosolic calcium level, inhibited the Ca 2+ -dependent translation of PKCα ( Wang et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Verapamil Alleviates Myocardial Ischemia/Reperfusion Injury by Attenuating Oxidative Stress via Activation of SIRT1

et al. 2022

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Myocardial ischemia/reperfusion (I/R) injury is a potential complication of ischemic heart disease after recanalization. One of the primary reasons for I/R injury is the excessive accumulation of reactive oxygen species (ROS) in cardiomyocytes. Verapamil, a classic calcium channel blocker, has the potential to mitigate I/R-evoked oxidative stress. However, the underlying mechanisms have not been fully elucidated. SIRT1 is an essential regulator of I/R and offers resistance to oxidative stress arising from I/R. It is still inconclusive if verapamil can reduce myocardial I/R-triggered oxidative damage through modulating SIRT1 antioxidant signaling. To verify our hypothesis, the H9c2 cardiomyocytes and the mice were treated with verapamil and then exposed to hypoxia/reoxygenation (H/R) or I/R in the presence or absence of the SIRT1 inhibitor EX527. As expected, verapamil stimulated SIRT1 antioxidant signaling evidenced by upregulation of SIRT1, FoxO1, SOD2 expressions and downregulation of Ac-FoxO1 expression in vitro and in vivo. In addition, verapamil remarkably suppressed H/R and I/R-induced oxidative stress proven by declined ROS level and MDA content. The cardioprotective actions of verapamil via SIRT1 were further confirmed in the experiments with the presence of the specific SIRT1 inhibitor EX527. We demonstrated that verapamil alleviated myocardial I/R-evoked oxidative stress partially via activation of SIRT1 antioxidant signaling. Subsequently, verapamil protected against cardiac dysfunction and myocardial infarction accompanied by oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Verapamil Alleviates Myocardial Ischemia/Reperfusion Injury by Attenuating Oxidative Stress via Activation of SIRT1

et al. 2022

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“…A series of research results have confirmed that the overexpression of SIRT1 can significantly inhibit the expression of inflammatory genes. Currently, it is believed that this factor plays an anti-inflammatory effect mainly by down-regulating the acetylated modification levels of NF-KB, AP-1 and histone (37)(38)(39). Meanwhile, BOTH AMPK and SIRT1 are enzymes sensitive to energy metabolism in the body, so they usually play a synergistic effect to jointly maintain energy homeostasis in the body.…”

Section: Discussionmentioning

confidence: 99%

Effect and mechanism of Angelic Shaoyaosan mediated AMPK/SIRT1 positive feedback loop to promote autophagy and regulate the systemic inflammatory response in acute pancreatitis

Sun

Nie

2021

Cell Mol Biol (Noisy-le-grand)

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This research was carried out to investigate the effect and mechanism of Angelic Shaoyaosan mediated AMPK/SIRT1 positive feedback loop to promote autophagy and regulate systemic inflammatory response in acute pancreatitis. In this study, the rat pancreatic acini AR42J cells were chosen as the research object, the application of hyla induced pancreatic acinar cells made model for acute pancreatitis, application of different concentrations of angelica peony spread effect on building cells, thus divided into control group, built in the module, the low concentration group, concentration and high concentration groups, determined by MTT method was applied to explore the above categories in cell proliferation, cell apoptosis was measured by flow cytometry, the expression of inflammatory factors in cell supernatant was determined by enzyme-linked immunoassay, and the expression of autophagy marker proteins LC3- ? and P62 was determined by Western-Bolt method. In order to explore the relationship between AMPK and SIRT1, immunoco-precipitation method was used to determine the interaction between AMPK and SIRT1, and dual luciferase experiment was used to explore the effect of AMPK on SIRT1. The AICAR group, BLM-275 group and negative control group were established. To explore the effect of SIRT1 on AMPK, we established SRT 1720 group, EX-527 group and control group. Direct binding between AMPK and SIRT1 should be determined by chromatin co-precipitation assay. In order to further explore the effect of AMPK/SIRT1 positive feedback loop on the systemic inflammatory response of acute pancreatitis, this study selected the medium-concentration Danggui Shaoyajiao SAN group as the control group (group C), and applied AMPK inhibitor BLM-275 and SIRT1 inhibitor EX 527 to the effect of medium-concentration Danggui Shaoyajiao SAN cells, respectively. The expression of autophagy marker proteins LC3- ? and P62 in groups A and B were determined by the Western-Bolt method. Results showed that compared with the control group, the cell survival rate, the expression of AMPK, SIRT1 and LC3-II in the model group were decreased, and the apoptosis rate of iNOS, IL-2, TNF-?, P62 and apoptosis were increased in the model group (P<0.05). the levels of iNOS, IL-2, TNF-?, P62 and cell survival rate in low, medium and high concentration groups decreased gradually, while the expressions of AMPK, SIRT1, LC3-II and cell apoptosis rate increased (P<0.05). The levels of iNOS, IL-2 and TNF-? in the three groups were gradually decreased with the increase of the concentration (P<0.05). Immunoprecipitation showed that AMPK and SIRT1 could bind to each other in cells. The double luciferase experiment indicated that the reporter gene containing the SIRT1 binding site was constructed. The luciferase activity was increased in THE AICAR group and decreased in the BLM-275 group (P<0.05). The reporter gene containing the AMPK promoter binding site was constructed. The luciferase activity in SRT1720 group was increased, while that in EX-527 group was decreased. SIRT1 could directly bind to the AMPK promoter. SIRT1 and LC3- ? protein expressions in group A were down-regulated, and P62 protein was increased (P<0.05). The protein expressions of AMPK and LC3- ? in group B were down-regulated, and the protein expression of P62 was increased (P<0.05). It concluded that AMPK can directly bind to activate SIRT1 expression, and SIRT1 expression can also activate AMPK, forming a positive feedback loop between the two. Therefore, Angelic Shaoyaodong decoction can mediate AMPK/SIRT1 positive feedback pathway to promote autophagy and regulate systemic inflammatory response in acute pancreatitis.

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“…Liver damage has been reported to induce inflammation and PKCδ translocation to the plasma membrane[ 44 , 45 ]. PKCδ activation has been observed in the tissues of patients with non-alcoholic steatohepatitis and non-alcoholic fatty liver disease and in a mouse model of hepatic cirrhosis[ 46 - 49 ].…”

Section: Subcellular Localizations and Functions Of Pkcδmentioning

confidence: 99%

Multiple subcellular localizations and functions of protein kinase Cδ in liver cancer

Yamada¹,

Yoshida²

2022

WJG

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Protein kinase Cδ (PKCδ) is a member of the PKC family, and its implications have been reported in various biological and cancerous processes, including cell proliferation, cell death, tumor suppression, and tumor progression. In liver cancer cells, accumulating reports show the bi-functional regulation of PKCδ in cell death and survival. PKCδ function is defined by various factors, such as phosphorylation, catalytic domain cleavage, and subcellular localization. PKCδ has multiple intracellular distribution patterns, ranging from the cytosol to the nucleus. We recently found a unique extracellular localization of PKCδ in liver cancer and its growth factor-like function in liver cancer cells. In this review, we first discuss the structural features of PKCδ and then focus on the functional diversity of PKCδ based on its subcellular localization, such as the nucleus, cell surface, and extracellular space. These findings improve our knowledge of PKCδ involvement in the progression of liver cancer.

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PKCδ Mediates NF-κB Inflammatory Response and Downregulates SIRT1 Expression in Liver Fibrosis

Cited by 27 publications

References 41 publications

Verapamil Alleviates Myocardial Ischemia/Reperfusion Injury by Attenuating Oxidative Stress via Activation of SIRT1

Verapamil Alleviates Myocardial Ischemia/Reperfusion Injury by Attenuating Oxidative Stress via Activation of SIRT1

Effect and mechanism of Angelic Shaoyaosan mediated AMPK/SIRT1 positive feedback loop to promote autophagy and regulate the systemic inflammatory response in acute pancreatitis

Multiple subcellular localizations and functions of protein kinase Cδ in liver cancer

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