Interferon regulatory factor-1 activates autophagy to aggravate hepatic ischemia-reperfusion injury via the P38/P62 pathway in mice

Yu, Yu; Li, Shipeng; Wang, Zhen; He, Jun; Ding, Yijie; Zhang, Haiming; Yu, Wenli; Shi, Yiwei; Z, Cui; Wang, Ximo; Wang, Zhiliang; Sun, Li‐Ying; Zhang, Rongxin; Du, Haiyan; Zhu, Zhi‐Jun

doi:10.1038/srep43684

Cited by 22 publications

(26 citation statements)

References 47 publications

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“…Our previous research was directed toward examining the role of IRF-1 in regulating autophagy to aggravation on hepatic IRI as coupled with IRF-1. We also found that IRF-1 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling [17]. In this study, we report that IRF-1 was …”

Section: Discussionsupporting

confidence: 57%

Interferon Regulatory Factor 1 Activates Autophagy to Aggravate Hepatic Ischemia-Reperfusion Injury by Increasing High Mobility Group Box 1 Release

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Interferon regulatory factor 1(IRF-1) and high mobility group box 1(HMGB1) have been independently identified as being key players in hepatic ischemia-reperfusion injury (IRI). We attempted to determine whether IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release. Methods: The hepatic IRI model was generated in C57BL/6 mice, euthanized at 2, 6, 12 or 24 h after reperfusion. To examine the effects of HMGB1 release inhibition, Glycyrrhiza acid (GA) was administered to the mice and at six hours after injectiont. AML12 cells were immersed in mineral oil for 90 min and then cultured in complete Dulbecco’s Modified Eagle’s Medium (DMEM)/F12 to simulate IRI. AML12 cells were treated with IRF-1 siRNA, Ad-IRF-1 or GA. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Next, autophagic vacuoles were detected by transmission electron microscopy (TEM) or LC3 dots. The expression of IRF-1 and HMGB1 mRNA were measured by real-time polymerase chain reaction. The expression of IRF-1, microtubule-associated protein 1 light chain 3 (LC3), Bcl-2, Beclin 1, HMGB1 were detected by western blotting or immunohistochemistry. Results: The levels of hepatic IRF-1, mRNA and protein were significantly increased in livers after exposure to IRI, together with, IRI-induced increase of HMGB1 mRNA and release of HMGB1 in liver tissue. Knockout of IRF-1 decreased expression and release of HMGB1 in liver, and inhibiting the release of HMGB1 could alleviate hepatic IRI. In addition, knockout of IRF-1 downregulated LC3II and Beclin1, while number of autophagosomes or LC3 dots were increased. Up-regulating IRF-1 expression could increase the levels of LC3Ⅱ expression in AML12 cells after exposure to IRI. The levels of HMGB1 in Ad-IRF-1 transfected AML12 cell supernatants increased, together with number of LC3 dots increasing. However, GA could inhibit both Ad-IRF-1 induced HMGB1 release and the increase in the number of LC3 dots. Conclusions: IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release.

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Section: Discussionsupporting

confidence: 57%

Interferon Regulatory Factor 1 Activates Autophagy to Aggravate Hepatic Ischemia-Reperfusion Injury by Increasing High Mobility Group Box 1 Release

Liu

et al. 2018

Cell Physiol Biochem

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“…Each sample was blindly analyzed to measure the extent of liver damage based on the technique outlined by Yu et al 43 Briefly, 24 regions of the liver were graded for the degree of injury based on each of the following parameters: cytoplasmic discoloration, vacuolation formation, nuclear pyknosis, nuclear fragmentation, nuclear discoloration and red cell stasis. Specifically, one whole deep coronal section was …”

Section: Histopathological Assessmentmentioning

confidence: 99%

“…43 Blood was collected after reperfusion for 12 h and centrifuged at 3,600× g for 15 min to get the sera, following which AST and ALT activities were measured by a standard automatic biochemistry analyzer.…”

Section: Liver Function Assessmentmentioning

confidence: 99%

In vitro and in vivo protein release and anti-ischemia/<br />reperfusion injury properties of bone morphogenetic protein-2-loaded glycyrrhetinic acid-poly(ethylene glycol)-b-poly(L-lysine) nanoparticles

Fang¹,

Liu²,

Jiang³

et al. 2017

IJN

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Here, we describe a bone morphogenetic protein-2 (BMP-2) nanocarrier based on glycyrrhetinic acid (GA)-poly(ethylene glycol) (PEG)-b-poly( l -lysine) (PLL). A protein nanocarrier was synthesized, characterized and evaluated as a BMP-2 delivery system. The designed nanocarrier was synthesized based on the ring-opening polymerization of amino acid N-carboxyanhydride. The final product was measured with 1 H nuclear magnetic resonance. GA-PEG-b-PLL nanocarrier could combine with BMP-2 through electrostatic interaction to form polyion complex (PIC) micelles. BMP-2 could be rapidly and efficiently encapsulated through the GA-PEG-b-PLL nanocarrier under physiological conditions, exhibiting efficient encapsulation and sustained release. In addition, the GA-PEG-b-PLL-mediated BMP-2 delivery system could target the liver against hepatic diseases as it has GA-binding receptors. The anti-hepatic ischemia/reperfusion injury (anti-HI/RI) effect of BMP-2/GA-PEG-b-PLL PIC micelles was investigated in rats using free BMP-2 and BMP-2/PEG-b-PLL PIC micelles as controls, and the results showed that BMP-2/GA-PEG-b-PLL PIC micelles indicated significantly enhanced anti-HI/RI property compared to BMP-2 and BMP-2/PEG-b-PLL. All results suggested that GA-PEG-b-PLL could be used as a potential BMP-2 nanocarrier.

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“…However, we also found that GPR30 activation did not affect the AKT/mTOR, ERK/mTOR, and JNK‐MAPK signaling pathways. p38 MAPK is an mTOR‐independent signaling pathway that has been shown to participate in autophagy (Henson et al, ; Zhong et al, ), with p38 MAPK upregulation inducing autophagy (Matsuzawa et al, ; Qin et al, ; Yu et al, ). Our data revealed that GPR30 activation enhanced p38 phosphorylation in glutamate‐activated astrocytes, indicating that GPR30 activation restored autophagy to basal levels by modulating the p38 MAPK signaling pathway (Figure ).…”

Section: Discussionmentioning

confidence: 99%

Activation of G protein‐coupled receptor 30 protects neurons by regulating autophagy in astrocytes

Wang

Yue

et al. 2019

Glia

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Ischemic stroke leads to neuronal damage induced by excitotoxicity, inflammation, and oxidative stress. Astrocytes play diverse roles in stroke and ischemia‐induced inflammation, and autophagy is critical for maintaining astrocytic functions. Our previous studies showed that the activation of G protein‐coupled receptor 30 (GPR30), an estrogen membrane receptor, protected neurons from excitotoxicity. However, the role of astrocytic GPR30 in maintaining autophagy and neuroprotection remained unclear. In this study, we found that the neuroprotection induced by G1 (GPR30 agonist) in wild‐type mice after a middle cerebral artery occlusion was completely blocked in GPR30 conventional knockout (KO) mice but partially attenuated in astrocytic or neuronal GPR30 KO mice. In cultured primary astrocytes, glutamate exposure induced astrocyte proliferation and decreased astrocyte autophagy by activating mammalian target of rapamycin (mTOR) and c‐Jun N‐terminal kinase (JNK) and inhibiting p38 mitogen‐activated protein kinase (MAPK) pathway. G1 treatment restored autophagy to its basal level by regulating the p38 pathway but not the mTOR and JNK signaling pathways. Our findings revealed a key role of GPR30 in neuroprotection via the regulation of astrocyte autophagy and support astrocytic GPR30 as a potential drug target against ischemic brain damage.

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Interferon regulatory factor-1 activates autophagy to aggravate hepatic ischemia-reperfusion injury via the P38/P62 pathway in mice

Cited by 22 publications

References 47 publications

Interferon Regulatory Factor 1 Activates Autophagy to Aggravate Hepatic Ischemia-Reperfusion Injury by Increasing High Mobility Group Box 1 Release

Interferon Regulatory Factor 1 Activates Autophagy to Aggravate Hepatic Ischemia-Reperfusion Injury by Increasing High Mobility Group Box 1 Release

In vitro and in vivo protein release and anti-ischemia/<br />reperfusion injury properties of bone morphogenetic protein-2-loaded glycyrrhetinic acid-poly(ethylene glycol)-b-poly(L-lysine) nanoparticles

Activation of G protein‐coupled receptor 30 protects neurons by regulating autophagy in astrocytes

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