scholarly journals TNFα-Mediated Necroptosis Aggravates Ischemia-Reperfusion Injury in the Fatty Liver by Regulating the Inflammatory Response

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Faji Yang ◽  
Longcheng Shang ◽  
Shuai Wang ◽  
Yang Liu ◽  
Haozhen Ren ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Fatty Liver ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Production ◽  
Ischemia And Reperfusion Injury ◽  
Nonalcoholic Fatty Liver ◽  
Neutralizing Monoclonal Antibody

Nonalcoholic fatty liver disease (NAFLD) is more sensitive to ischemia and reperfusion injury (IRI), while there are no effective methods to alleviate IRI. Necroptosis, also known as “programmed necrosis,” incorporates features of necrosis and apoptosis. However, the role of necroptosis in IRI of the fatty liver remains largely unexplored. In the present study, we aimed to assess whether necroptosis was activated in the fatty liver and whether such activation accelerated IRI in the fatty liver. In this study, we found that the liver IRI was enhanced in HFD-fed mice with more release of TNFα. TNFα and supernatant of macrophages could induce necroptosis of hepatocytes in vitro. Necroptosis was activated in NAFLD, leading to more severe IRI, and such necroptosis could be inhibited by TN3-19.12, the neutralizing monoclonal antibody against TNFα. Pretreatment with Nec-1 and GSK′872, two inhibitors of necroptosis, significantly reduced the liver IRI and ROS production in HFD-fed mice. Moreover, the inhibition of necroptosis could decrease ROS production of hepatocytes in vitro. Inflammatory response was activated during IRI, and necroptosis inhibitors could suppress signaling pathways of inflammation and the soakage of inflammation cells. In conclusion, TNFα-induced necroptosis played an important role during IRI in the fatty liver. Our findings demonstrated that necroptosis might be a potential target to reduce the fatty liver-associated IRI.

scholarly journals CYP2J2 and EETs Protect Against Pulmonary Hypertension with Lung Ischemia-Reperfusion Injury In Vivo and In Vitro

2021 ◽  
Author(s):  
Yun Ding ◽  
Pengjie Tu ◽  
Yiyong Chen ◽  
Yangyun Huang ◽  
Xiaojie Pan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Reperfusion Injury ◽  
Lung Tissue ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Background Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert anti-inflammatory, anti-apoptotic, pro-proliferative, and antioxidant effects on the cardiovascular system. However, the role of CYP2J2 and EETs in pulmonary arterial hypertension (PAH) with lung ischemia-reperfusion injury (LIRI) remains unclear. In the present study, we investigated the effects of CYP2J2 overexpression and exogenous EETs on PAH with LIRI in vitro and in vivo.Methods CYP2J2 gene was transfected into rat lung tissue by recombinant adeno-associated virus (rAAV) to increase the levels of EETs in serum and lung tissue. A rat model of PAH with LIRI was constructed by tail vein injection of monocrotaline (50 mg/kg) for 4 weeks, followed by clamping of the left pulmonary hilum for 1 h and reperfusion for 2 h. In addition, we established a cellular model of human pulmonary artery endothelial cells (HPAECs) with TNF-α combined with hypoxic reoxygenation (anoxia for 8 h and reoxygenation for 16 h) to determine the effect and mechanism of exogenous EETs.Results CYP2J2 overexpression significantly reduced the inflammatory response, oxidative stress and apoptosis associated with lung injury in PAH with LIRI. In addition, exogenous EETs suppressed inflammatory response and reduced intracellular reactive oxygen species (ROS) production and inhibited apoptosis in a tumor necrosis factor alpha (TNF-α) combined hypoxia-reoxygenation model of HPAECs. Our further studies revealed that the anti-inflammatory effects of CYP2J2 overexpression and EETs might be mediated by PPARγ pathway; the anti-apoptotic effects might be mediated by the PI3K/Ak pathway.Conclusions CYP2J2 overexpression and EETs protect against PAH with LIRI via anti-inflammation, anti-oxidative stress and anti-apoptosis, suggesting that increased levels of EETs may be a promising strategy for the prevention and treatment of PAH with LIRI.

scholarly journals Renalase Attenuates Mouse Fatty Liver Ischemia/Reperfusion Injury through Mitigating Oxidative Stress and Mitochondrial Damage via Activating SIRT1

2019 ◽  
Vol 2019 ◽  
pp. 1-21 ◽  
Author(s):  
Tao Zhang ◽  
Jian Gu ◽  
Jianrong Guo ◽  
Ke Chen ◽  
Huili Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Liver ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Control Diet ◽  
Liver Ischemia ◽  
Portal Triad ◽  
Nonalcoholic Fatty Liver

Liver ischemia/reperfusion (IR) injury is a severe complication of liver surgery. Moreover, nonalcoholic fatty liver disease (NAFLD) patients are particularly vulnerable to IR injury, with higher rates of postoperative morbidity and mortality after liver surgeries. Our previous study found that renalase (RNLS) was highly sensitive and responsive to oxidative stress, which may be a promising biomarker for the evaluation of the severity of liver IR injury. However, the role of RNLS in liver IR injury remains unclear. In the present study, we intensively explored the role and mechanism of RNLS in fatty liver IR injury in vivo and in vitro. C57BL/6 mice were divided into 2 groups feeding with high-fat diet (HFD) and control diet (CD), respectively. After 20 weeks’ feeding, they were suffered from portal triad blockage and reflow to induce liver IR injury. Additionally, oleic acid (OA) and tert-butyl hydroperoxide (t-BHP) were used in vitro to induce steatotic hepatocytes and to simulate ROS burst and mimic cellular oxidative stress following portal triad blockage and reflow, respectively. Our data showed that RNLS was downregulated in fatty livers, and RNLS administration effectively attenuated IR injury by reducing ROS production and improving mitochondrial function through activating SIRT1. Additionally, the downregulation of RNLS in the fatty liver was mediated by a decrease of signal transduction and activator of transcription 3 (STAT3) expression under HFD conditions. These findings make RNLS a promising therapeutic strategy for the attenuation of liver IR injury.

scholarly journals RTA-408 Protects Kidney from Ischemia-Reperfusion Injury in Mice via Activating Nrf2 and Downstream GSH Biosynthesis Gene

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Peng Han ◽  
Zhiqiang Qin ◽  
Jingyuan Tang ◽  
Zhen Xu ◽  
Ran Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Function ◽  
Reperfusion Injury ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Ros Production ◽  
Antioxidant Genes

Acute kidney injury (AKI) induced by ischemia-reperfusion is a critical conundrum in many clinical settings. Here, this study aimed to determine whether and how RTA-408, a novel oleanane triterpenoid, could confer protection against renal ischemia-reperfusion injury (IRI) in male mice. Mice treated with RTA-408 undergoing unilateral ischemia followed by contralateral nephrectomy had improved renal function and histological outcome, as well as decreased apoptosis, ROS production, and oxidative injury marker compared with vehicle-treated mice. Also, we had found that RTA-408 could strengthen the total antioxidant capacity by increasing Nrf2 nuclear translocation and subsequently increased Nrf2 downstream GSH-related antioxidant gene expression and activity. In vitro study demonstrated that GSH biosynthesis enzyme GCLc could be an important target of RTA-408. Furthermore, Nrf2-deficient mice treated with RTA-408 had no significant improvement in renal function, histology, ROS production, and GSH-related gene expression. Thus, by upregulating Nrf2 and its downstream antioxidant genes, RTA-408 presents a novel and potential approach to renal IRI prevention and therapy.

scholarly journals Ischemia reperfusion injury promotes recurrence of hepatocellular carcinoma in fatty liver via ALOX12-12HETE-GPR31 signaling axis

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Faji Yang ◽  
Yuheng Zhang ◽  
Haozhen Ren ◽  
Jinglin Wang ◽  
Longcheng Shang ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Reperfusion Injury ◽  
Epithelial Mesenchymal Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mesenchymal Transition ◽  
Functional Changes ◽  
Fatty Livers ◽  
Hcc Recurrence

Abstract Background Ischemia reperfusion injury (IRI) has been shown to increase the risk of tumor recurrence after liver surgery. Also, nonalcoholic fatty liver disease (NAFLD) is associated with increased HCC recurrence. ALOX12–12-HETE pathway is activated both in liver IRI and NASH. Also, ALOX12–12-HETE has been shown to mediate tumorigenesis and progression. Therefore, our study aims to investigate whether the ALOX12–12-HETE-GPR31 pathway involved in IRI induced HCC recurrence in NAFLD. Methods HCC mouse model was used to mimic the HCC recurrence in NAFLD. Western Blot, qPCR, Elisa and Immunofluorescence analysis were conducted to evaluate the changes of multiple signaling pathways during HCC recurrence, including ALOX12–12-HETE axis, EMT, MMPs and PI3K/AKT/NF-κB signaling pathway. We also measured the expression and functional changes of GPR31 by siRNA. Results ALOX12–12-HETE pathway was activated in liver IRI and its activation was further enhanced in NAFLD, which induced more severe HCC recurrence in fatty livers than normal livers. Inhibition of ALOX12–12-HETE by ML355 reduced the HCC recurrence in fatty livers. In vitro studies showed that 12-HETE increased the expression of GPR31 and induced epithelial-mesenchymal transition (EMT) and matrix metalloprotein (MMPs) by activating PI3K/AKT/NF-κB pathway. Furthermore, knockdown of GPR31 in cancer cells inhibited the HCC recurrence in NAFLD. Conclusions ALOX12–12-HETE-GPR31 played an important role in HCC recurrence and might be a potential therapeutic target to reduce HCC recurrence after surgery in fatty livers.

A hydrolyzed whey peptide-based diet ameliorates hepatic ischemia–reperfusion injury in the rat nonalcoholic fatty liver

Surgery Today ◽  
2014 ◽  
Vol 44 (12) ◽  
pp. 2354-2360 ◽  
Author(s):  
Akira Nii ◽  
Tohru Utsunomiya ◽  
Mitsuo Shimada ◽  
Toru Ikegami ◽  
Hiroki Ishibashi ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Ischemia Reperfusion

scholarly journals Activity of renal organic anion transporters in a model of ischemia and reperfusion injury in vitro

2018 ◽  
pp. 25-27
Author(s):  
V. A. Evteev ◽  
R. E. Kazakov ◽  
A. B. Prokof'ev ◽  
I. A. Mazerkina ◽  
N. D. Bunyatyan
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Organic Anion ◽  
Dicarboxylic Acids ◽  
Organic Anion Transporters ◽  
Ischemia And Reperfusion Injury ◽  
Anion Transporters ◽  
Slc Transporters

The aim of the work is to study the functional characteristics of SLC transporters of organic anions: OAT1 and OAT3 in normal conditions and in model ischemia/reperfusion injury.Materials and methods. The HEK293 cell line was used as a model for the study. Conditions of ischemia/reperfusion injury were created by the previously described method. The activity of the transporters was assessed by the capture of the marker substrate - fluorescein. The concentration of fluorescein was measured using a plate fluorimeter. The results were normalized by the amount of total protein.Results. In condition of ischemia/reperfusion injury, the activity of organic anion transporters decreased in comparison with the norm. The data obtained allow us to conclude that in conditions of ischemia/reperfusion injury, the concentration of dicarboxylic acids in the cell is low, which in turn can lead to a decrease activity of transporters.

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