scholarly journals PEG35 and Glutathione Improve Mitochondrial Function and Reduce Oxidative Stress in Cold Fatty Liver Graft Preservation

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 158
Author(s):  
Raquel G. Bardallo ◽  
Idoia Company-Marin ◽  
Emma Folch-Puy ◽  
Joan Roselló-Catafau ◽  
Arnau Panisello-Rosello ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Liver ◽  
Uncoupling Protein ◽  
Ischemia Reperfusion ◽  
Liver Graft ◽  
Zucker Rats ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Atp Production ◽  
Preservation Solutions

The need to meet the demand for transplants entails the use of steatotic livers, more vulnerable to ischemia-reperfusion (IR) injury. Therefore, finding the optimal composition of static cold storage (SCS) preservation solutions is crucial. Given that ROS regulation is a therapeutic strategy for liver IR injury, we have added increasing concentrations of PEG35 and glutathione (GSH) to the preservation solutions (IGL-1 and IGL-2) and evaluated the possible protection against energy depletion and oxidative stress. Fatty livers from obese Zücker rats were isolated and randomly distributed in the control (Sham) preserved (24 h at 4 °C) in IGL-0 (without PEG35 and 3 mmol/L GSH), IGL-1 (1 g/L PEG35, and 3 mmol/L GSH), and IGL-2 (5 g/L PEG35 and 9 mmol/L GSH). Energy metabolites (ATP and succinate) and the expression of mitochondrial oxidative phosphorylation complexes (OXPHOS) were determined. Mitochondrial carrier uncoupling protein 2 (UCP2), PTEN-induced kinase 1 (PINK1), nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the inflammasome (NLRP3) expressions were analyzed. As biomarkers of oxidative stress, protein oxidation (AOPP) and carbonylation (DNP derivatives), and lipid peroxidation (malondialdehyde (MDA)–thiobarbituric acid (TBA) adducts) were measured. In addition, the reduced and oxidized glutathione (GSH and GSSG) and enzymatic (Cu–Zn superoxide dismutase (SOD), CAT, GSH S-T, GSH-Px, and GSH-R) antioxidant capacities were determined. Our results showed that the cold preservation of fatty liver graft depleted ATP, accumulated succinate and increased oxidative stress. In contrast, the preservation with IGL-2 solution maintained ATP production, decreased succinate levels and increased OXPHOS complexes I and II, UCP2, and PINK-1 expression, therefore maintaining mitochondrial integrity. IGL-2 also protected against oxidative stress by increasing Nrf2 and HO-1 expression and GSH levels. Therefore, the presence of PEG35 in storage solutions may be a valuable option as an antioxidant agent for organ preservation in clinical transplantation.

scholarly journals Identification of MicroRNA-92a-3p as an Essential Regulator of Tubular Epithelial Cell Pyroptosis by Targeting Nrf1 via HO-1

2021 ◽  
Vol 11 ◽  
Author(s):  
Renhe Wang ◽  
Haijun Zhao ◽  
Yingyu Zhang ◽  
Hai Zhu ◽  
Qiuju Su ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cell ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tubular Epithelial Cell ◽  
Heme Oxygenase 1 ◽  
Related Factor

Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and has no effective treatment. Exploring the molecular mechanisms of renal IRI is critical for the prevention of AKI and its evolution to chronic kidney disease and end-stage renal disease. The aim of the present study was to determine the biological function and molecular mechanism of action of miR-92a-3p in tubular epithelial cell (TEC) pyroptosis. We investigated the relationship between nuclear factor-erythroid 2-related factor 1 (Nrf1) and TEC pyroptosis induced by ischemia–reperfusion in vivo and oxygen–glucose deprivation/reoxygenation (OGD/R) in vitro. MicroRNAs (miRNAs) are regulators of gene expression and play a role in the progression of renal IRI. Nrf1 was confirmed as a potential target for miRNA miR-92a-3p. In addition, the inhibition of miR-92a-3p alleviated oxidative stress in vitro and decreased the expression levels of NLRP3, caspase-1, GSDMD-N, IL-1β, and IL-18 in vitro and in vivo. Moreover, Zn-protoporphyrin-IX, an inhibitor of heme oxygenase-1, reduced the protective effect of Nrf1 overexpression on OGD/R-induced TEC oxidative stress and pyroptosis. The results of this study suggest that the inhibition of miR-92a-3p can alleviate TEC oxidative stress and pyroptosis by targeting Nrf1 in renal IRI.

Gastrodin Pretreatment Protects Liver Against Ischemia-Reperfusion Injury via Activation of the Nrf2/HO-1 Pathway

2020 ◽  
Vol 48 (05) ◽  
pp. 1159-1178
Author(s):  
Bo Yuan ◽  
Hanfei Huang ◽  
Siming Qu ◽  
Hongbin Zhang ◽  
Jie Lin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Damage ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
Alanine Transaminase ◽  
Heterozygous Mutation ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner

Hepatic ischemia-reperfusion (IR) injury remains the major cause of liver damage post-liver surgery or transplantation. Diminishing oxidative stress and inflammatory responses is a powerful channel to reduce the rate of morbidity and mortality. Gastrodin (GSTD), a bioactive compound extracted from the traditional Chinese herbal agent with a long history of clinical application in nervous system diseases, is suggested to possess anti-oxidative effects on liver diseases, such as nonalcoholic fatty liver disease. However, the therapeutic potential of GSTD in liver IR injury remains unclear. In this paper, we performed surgery to set up the 70% hepatic IR injury models in mice after a three-day pretreatment of GSTD. We found the administration of GSTD reduced liver damage, which correlated with lower histological Suzuki’s score, lower serum alanine transaminase (AST) and alanine transaminase (ALT) levels, less oxidative stress, and cell apoptosis in a dose-responsive manner, as compared to the parallel control. Meanwhile, we observed a great induction of heme oxygenase-1 (HO-1) and an activation of the p38 mitogen-activated protein kinases/nuclear factor erythroid 2-related factor 2 (p38MAPK/Nrf2) pathway in response to the GSTD pretreatment, while the protective effects upon GSTD diminished in mice with HO-1 heterozygous mutation. In addition, GSTD inhibited IR induced toll-like receptor (TLR) 4, but not TLR2 in a HO-1 dependent manner, leading to a down-regulation of cytokines, such as interleukin (IL)-6 and TNF-[Formula: see text]. Collectively, our findings revealed GSTD attenuated liver IR injury via activation of the HO-1 pathway, providing a novel therapeutic strategy to minimize the IR induced oxidative stress in the process of liver transplantation.

scholarly journals Melatonin attenuates acute kidney ischemia/reperfusion injury in diabetic rats by activation of the SIRT1/Nrf2/HO-1 signaling pathway

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Si Shi ◽  
Shaoqing Lei ◽  
Chaoliang Tang ◽  
Kai Wang ◽  
Zhongyuan Xia
Keyword(s):  
Oxidative Stress ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Selective Inhibition ◽  
Diabetic Rats ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Beneficial Effects ◽  
Antioxidative Effects

AbstractBackground and aims: Diabetic kidney is more sensitive to ischemia/reperfusion (I/R) injury, which is associated with increased oxidative stress and impaired nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Melatonin, a hormone that is secreted with the rhythm of the light/dark cycle, has antioxidative effects in reducing acute kidney injury (AKI). However, the molecular mechanism of melatonin protection against kidney I/R injury in the state of diabetes is still unknown. In the present study, we hypothesized that melatonin attenuates renal I/R injury in diabetes by activating silent information regulator 2 associated protein 1 (SIRT1) expression and Nrf2/HO-1 signaling. Methods: Control or streptozotocin (STZ)-induced Type 1 diabetic rats were treated with or without melatonin for 4 weeks. Renal I/R injury was achieved by clamping both left and right renal pedicles for 30 min followed by reperfusion for 48 h. Results: Diabetic rats that were treated with melatonin undergoing I/R injury prevented renal injury from I/R, in aspects of the histopathological score, cell apoptosis, and oxidative stress in kidney, accompanied with decreased expressions of SIRT1, Nrf2, and HO-1 as compared with those in control rats. All these alterations were attenuated or prevented by melatonin treatment; but these beneficial effects of melatonin were abolished by selective inhibition of SIRT1 with EX527. Conclusion: These findings suggest melatonin could attenuate renal I/R injury in diabetes, possibly through improving SIRT1/Nrf2/HO-1 signaling.

scholarly journals Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Qianqian Zhang ◽  
Yanqiu Lai ◽  
Jielin Deng ◽  
Menglong Wang ◽  
Zhenya Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vagus Nerve ◽  
Nerve Stimulation ◽  
Vagus Nerve Stimulation ◽  
Ischemia Reperfusion ◽  
Heme Oxygenase 1 ◽  
Sham Operation ◽  
Related Factor ◽  
Hepatic Ischemia ◽  
Sham Operation Group

It has been demonstrated that vagus nerve stimulation (VNS) plays a protective role in ischemia/reperfusion (I/R) injury of various organs. The present study investigates the protective effect of VNS on hepatic I/R injury and the potential mechanisms. Male Sprague-Dawley rats were randomly allocated into three groups: the sham operation group (Sham; n=6, sham surgery with sham VNS); the I/R group (n=6, hepatic I/R surgery with sham VNS); and the VNS group (n=6, hepatic I/R surgery plus VNS). The I/R model was established by 1 hour of 70% hepatic ischemia. Tissue samples and blood samples were collected after 6 hours of reperfusion. The left cervical vagus nerve was separated and stimulated throughout the whole I/R process. The stimulus intensity was standardized to the voltage level that slowed the sinus rate by 10%. VNS significantly reduced the necrotic area and cell death in I/R tissues. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were also decreased by VNS. In addition, VNS suppressed inflammation, oxidative stress, and apoptosis in I/R tissues. VNS significantly increased the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) in the liver. These data indicated that VNS may attenuate hepatic I/R injury by inhibiting inflammation, oxidative stress, and apoptosis possibly via the Nrf2/HO-1 pathway.

scholarly journals Epigallocatechin 3-Gallate Has a Neuroprotective Effect in Retinas of Rabbits with Ischemia/Reperfusion through the Activation of Nrf2/HO-1

2020 ◽  
Vol 21 (10) ◽  
pp. 3716 ◽  
Author(s):  
Josué Rivera-Pérez ◽  
Martín Martínez-Rosas ◽  
César A. Conde-Castañón ◽  
Julia D. Toscano-Garibay ◽  
Nancy J. Ruiz-Pérez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Protective Effect ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion ◽  
Neuronal Cells ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mrna Levels ◽  
Neuroprotective Efficacy

Retinal ischemia-reperfusion (rI/R) generates an oxidative condition causing the death of neuronal cells. Epigallocatechin 3-gallate (EGCG) has antioxidant and anti-inflammatory properties. Nonetheless, its correlation with the pathway of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) for the protection of the retina is unknown. We aimed to evaluate the neuroprotective efficacy of single-doses of EGCG in rI/R and its association with Nrf2/Ho-1 expression. In albino rabbits, rI/R was induced and single-doses of EGCG in saline (0–30 mg/kg) were intravenously administered to select an optimal EGCG concentration that protects from retina damage. To reach this goal, retinal structural changes, gliosis by glial fibrillary acidic protein (GFAP) immunostaining, and lipid peroxidation level by TBARS (thiobarbituric acid reactive substance) assay were determined. EGCG in a dose of 15 mg/kg (E15) presented the lowest levels of histological damage, gliosis, and oxidative stress in the studied groups. To determine the neuroprotective efficacy of E15 in a timeline (6, 24, and 48 h after rI/R), and its association with the Nrf2/HO-1 pathway, the following assays were done by immunofluorescence: apoptosis (TUNEL assay), necrosis (high-mobility group box-1; HMGB1), Nrf2, and HO-1. In addition, the Ho-1 mRNA (qPCR) and lipid peroxidation levels were evaluated. E15 showed a protective effect during the first 6 h, compared to 24 and 48 h after rI/R, as revealed by a decrease in the levels of all damage markers. Nuclear translocation Nrf2 and HO-1 staining were increased, including Ho-1 mRNA levels. In conclusion, a single dose of E15 decreases the death of neuronal cells induced by oxidative stress during the first 6 h after rI/R. This protective effect is associated with the nuclear translocation of Nrf2 and with an elevation of Ho-1 expression.

scholarly journals Pharmacological Protection against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 823
Author(s):  
Bercis Imge Ucar ◽  
Gulberk Ucar ◽  
Sarmistha Saha ◽  
Brigitta Buttari ◽  
Elisabetta Profumo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Therapeutic Strategy ◽  
Membrane Lipids ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Membrane Integrity ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Wide Range

Ischemia/reperfusion (I/R) injury is associated with substantial clinical implications, including a wide range of organs such as the brain, kidneys, lungs, heart, and many others. I/R injury (IRI) occurs due to the tissue injury following the reestablishment of blood supply to ischemic tissues, leading to enhanced aseptic inflammation and stimulation of oxidative stress via reactive oxygen and nitrogen species (ROS/RNS). Since ROS causes membrane lipids’ peroxidation, triggers loss of membrane integrity, denaturation of proteins, DNA damage, and cell death, oxidative stress plays a critical part in I/R pathogenesis. Therefore, ROS regulation could be a promising therapeutic strategy for IRI. In this context, Nrf2 (NF-E2-related factor 2) is a transcription factor that regulates the expression of several factors involved in the cellular defense against oxidative stress and inflammation, including heme oxygenase-1 (HO-1). Numerous studies have shown the potential role of the Nrf2/HO-1 pathway in IRI; thus, we will review the molecular aspects of Nrf2/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response element (ARE) signaling pathway in I/R, and we will also highlight the recent insights into targeting this pathway as a promising therapeutic strategy for preventing IRI.

scholarly journals Role of PEG35, Mitochondrial ALDH2, and Glutathione in Cold Fatty Liver Graft Preservation: An IGL-2 Approach

2021 ◽  
Vol 22 (10) ◽  
pp. 5332
Author(s):  
Raquel G. Bardallo ◽  
Rui Teixeira da Silva ◽  
Teresa Carbonell ◽  
Emma Folch-Puy ◽  
Carlos Palmeira ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Fatty Liver ◽  
Liver Graft ◽  
Suitable Alternative ◽  
Graft Preservation ◽  
Preservation Solutions ◽  
Microcirculatory Disturbances ◽  
Organ Recovery ◽  
Surgical Manipulations

The total damage inflicted on the liver before transplantation is associated with several surgical manipulations, such as organ recovery, washout of the graft, cold conservation in organ preservation solutions (UW, Celsior, HTK, IGL-1), and rinsing of the organ before implantation. Polyethylene glycol 35 (PEG35) is the oncotic agent present in the IGL-1 solution, which is an alternative to UW and Celsior solutions in liver clinical transplantation. In a model of cold preservation in rats (4 °C; 24 h), we evaluated the effects induced by PEG35 on detoxifying enzymes and nitric oxide, comparing IGL-1 to IGL-0 (which is the same as IGL-1 without PEG). The benefits were also assessed in a new IGL-2 solution characterized by increased concentrations of PEG35 (from 1 g/L to 5 g/L) and glutathione (from 3 mmol/L to 9 mmol/L) compared to IGL-1. We demonstrated that PEG35 promoted the mitochondrial enzyme ALDH2, and in combination with glutathione, prevented the formation of toxic aldehyde adducts (measured as 4-hydroxynonenal) and oxidized proteins (AOPP). In addition, PEG35 promoted the vasodilator factor nitric oxide, which may improve the microcirculatory disturbances in steatotic grafts during preservation and revascularization. All of these results lead to a reduction in damage inflicted on the fatty liver graft during the cold storage preservation. In this communication, we report on the benefits of IGL-2 in hypothermic static preservation, which has already been proved to confer benefits in hypothermic oxygenated dynamic preservation. Hence, the data reported here reinforce the fact that IGL-2 is a suitable alternative to be used as a unique solution/perfusate when hypothermic static and preservation strategies are used, either separately or combined, easing the logistics and avoiding the mixture of different solutions/perfusates, especially when fatty liver grafts are used. Further research regarding new therapeutic and pharmacological insights is needed to explore the underlying mitochondrial mechanisms exerted by PEG35 in static and dynamic graft preservation strategies for clinical liver transplantation purposes.

scholarly journals Sanghuangporus sanghuang Mycelium Prevents Paracetamol-Induced Hepatotoxicity through Regulating the MAPK/NF-κB, Keap1/Nrf2/HO-1, TLR4/PI3K/Akt and CaMKKβ/LKB1/AMPK Pathways and Suppressing Oxidative Stress and Inflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 897
Author(s):  
Wen-Ping Jiang ◽  
Jeng-Shyan Deng ◽  
Shyh-Shyun Huang ◽  
Sheng-Hua Wu ◽  
Chin-Chu Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Mitogen Activated Protein Kinase ◽  
Heme Oxygenase 1 ◽  
Molecular Evidence ◽  
Related Factor ◽  
Serum Aminotransferase ◽  
Compound C

Liver damage induced by paracetamol overdose is the main cause of acute liver failure worldwide. In order to study the hepatoprotective effect of Sanghuangporus sanghuang mycelium (SS) on paracetamol-induced liver injury, SS was administered orally every day for 6 days in mice before paracetamol treatment. SS decreased serum aminotransferase activities and the lipid profiles, protecting against paracetamol hepatotoxicity in mice. Furthermore, SS inhibited the lipid peroxidation marker malondialdehyde (MDA), hepatic cytochrome P450 2E1 (CYP2E1), and the histopathological changes in the liver and decreased inflammatory activity by inhibiting the production of proinflammatory cytokines in paracetamol-induced acute liver failure. Moreover, SS improved the levels of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase in the liver. Significantly, SS diminished mitogen-activated protein kinase (MAPK), Toll-like receptor 4 (TLR4), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and the nuclear factor-kappa B (NF-κB) axis, as well as upregulated the Kelch-like ECH-associated protein 1 (Keap1)/erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, in paracetamol-induced mice. SS mainly inhibited the phosphorylation of the liver kinase B1 (LKB1), Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ), and AMP-activated protein kinase (AMPK) protein expression. Furthermore, the protective effects of SS on paracetamol-induced hepatotoxicity were abolished by compound C, an AMPK inhibitor. In summary, we provide novel molecular evidence that SS protects liver cells from paracetamol-induced hepatotoxicity by inhibiting oxidative stress and inflammation.

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