scholarly journals Metabotropic Glutamate Receptor Blockade Reduces Preservation Damage in Livers from Donors after Cardiac Death

2021 ◽  
Vol 22 (5) ◽  
pp. 2234
Author(s):  
Laura Giuseppina Di Pasqua ◽  
Clarissa Berardo ◽  
Marta Cagna ◽  
Roberta Verta ◽  
Debora Collotta ◽  
...  
Keyword(s):  
Cardiac Death ◽  
Caspase 3 ◽  
Metabotropic Glutamate Receptor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Warm Ischemia ◽  
Related Factor ◽  
Caspase 9 ◽  
Uw Solution ◽  
Tnf Α

We previously demonstrated that the blockade of mGluR5 by 2-methyl-6(phenylethynyl)pyridine (MPEP) reduces both cold and warm ischemia/reperfusion injury. Here we evaluated whether MPEP reduces the hepatic preservation injury in rat livers from cardiac-death-donors (DCDs). Livers from DCD rats were isolated after an in situ warm ischemia (30 min) and preserved for 22 h at 4 °C with UW solution. Next, 10 mg/Kg MPEP or vehicle were administered 30 min before the portal clamping and added to the UW solution (3 µM). LDH released during washout was quantified. Liver samples were collected for iNOS, eNOS, NO, TNF-α, ICAM-1, caspase-3 and caspase-9 protein expression and nuclear factor-erythroid-2-related factor-2 (Nrf2) gene analysis. Lower LDH levels were detected in control grafts versus DCD groups. An increase in eNOS and NO content occurred after MPEP treatment; iNOS and TNF-α content was unchanged. ICAM-1 expression was reduced in the MPEP-treated livers as well as the levels of caspase-3 and caspase-9. Nrf2, oxidative stress-sensitive gene, was recovered to control value by MPEP. These results suggest that MPEP can be used to reclaim DCD livers subjected to an additional period of cold ischemia during hypothermic storage. MPEP protects against apoptosis and increased eNOS, whose overexpression has been previously demonstrated to be protective in hepatic ischemia/reperfusion damage.

scholarly journals Tubeimoside-1 Protects Against Renal Ischemia Reperfusion Injury In Vivo and In Vitro

2020 ◽  
Vol 15 (12) ◽  
pp. 1934578X2097764
Author(s):  
Xiaoli Yuan ◽  
Jing Wang ◽  
Yun Zhang
Keyword(s):  
Reperfusion Injury ◽  
Cell Apoptosis ◽  
Renal Cell ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Caspase 9 ◽  
Tnf Α ◽  
Renal Ischemia Reperfusion Injury

Renal ischemia reperfusion injury (RIRI) is one of the main causes of acute kidney injury. This study aimed to explore whether tubeimoside-1 (TBMS1) could protect against RIRI. RIRI mice model and hypoxia/reoxygenation (H/R)-induced NRK-52E cells were used in this study. The renal pathology was observed by hematoxylin and eosin staining to calculate the tubular injury score. The levels of serum creatinine and blood urine nitrogen were analyzed by a Hitachi model 7180 automatic analyzer. The expressions of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin 6 (IL-6), Bax, cleaved caspase-3, cleaved caspase-9, total caspase-3, and total caspase-9 in renal tissues and NRK-52E cells were detected by western blot analysis. The levels of TNF-α, IL-1β, and IL-6 in serum and NRK-52E cells were measured by a commercial enzyme-linked immunosorbent assay kit. The renal cell apoptosis in renal tissues was analyzed by TUNEL assay, and NRK-52E cell apoptosis was detected by flow cytometry analysis. CCK-8 assay was used to analyze the viability of NRK-52E cells after the indicated treatment. As a result, the renal tissues that were seriously damaged in mice with RIRI could be alleviated by TBMS1. Therefore, 50 mg/kg TBMS1 was chosen for the animal experiment. Renal cell apoptosis was increased in renal tissues of mice with RIRI. These changes could be partially reversed by TBMS1 treatment. TBMS1 improved the viability, and reduced the inflammation and apoptosis of H/R-induced NRK-52E cells. In conclusion, TBMS1 ameliorates RIRI by promoting viability and suppressing apoptosis and inflammation of renal cells.

scholarly journals Activation of Nrf2 by Ischemic Preconditioning and Sulforaphane in Renal Ischemia/Reperfusion Injury: a Comparative Experimental Study

2015 ◽  
pp. 313-323 ◽  
Author(s):  
A. A. SHOKEIR ◽  
N. BARAKAT ◽  
A. M. HUSSEIN ◽  
A. AWADALLA ◽  
A. M. HARRAZ ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Intercellular Adhesion Molecule ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Antioxidant Genes ◽  
Tnf Α

Objectives of the study were to investigate impact of ischemic preconditioning (Ipre) and sulforaphane (SFN) and combination of them on nuclear factor 2 erythroid related factor 2 (Nrf2) gene and its dependent genes, heme oxygenase-1 (HO1) and NADPH-quinone oxidoreductase1 (NQO-1) and inflammatory cytokines TNF-α, IL1β, and intercellular adhesion molecule-1 (ICAM1) and caspase-3 in renal ischemia/reperfusion (I/R) injury. Ninety male Sprague Dawely rats were classified into 5 groups (each consists of 18 rats): sham, control, Ipre, sulforaphane and Sulfo+Ipre. Each group was subdivided into 3 subgroups each containing 6 rats according to time of harvesting kidney and taking blood samples; 24 h, 48 h, and 7 days subgroups. Renal functions including serum creatinine, BUN were measured at basal conditions and by the end of experiment. Expression of Nrf2, HO-1, NQO-1, TNF-α, IL-1β, and ICAM-1 was measured by real time PCR in kidney tissues by the end of experiment. Also, immunohistochemical localization of caspase-3 and chemical assay of malondialdehyde (MDA), GSH and SOD activity were measured in kidney tissues. Both Ipre and SFN improved kidney functions, enhanced the expression of Nrf2, HO-1, and NQO-1, attenuated the expression of inflammatory (TNF-α, IL-1, and ICAM-1) and apoptotic (caspase-3) markers. However, the effect of sulforaphane was more powerful than Ipre. Also, a combination of them caused more improvement in antioxidant genes expression and more attenuation in inflammatory genes but not caspase-3 than each one did separately. Sulforaphane showed more powerful effect in renoprotection against I/R injury than Ipre as well as there might be a synergism between them at the molecular but not at the function level.

scholarly journals Orexin-A Alleviates Astrocytic Apoptosis and Inflammation via Inhibiting OX1R-mediated NF-κB and MAPK Signaling Pathways in Cerebral Ischemia/reperfusion Injury

2021 ◽  
Author(s):  
Dandan Xu ◽  
Tingting Kong ◽  
Ziqi Shao ◽  
Rumin Zhang ◽  
Shengnan Zhang ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Caspase 9 ◽  
Astrocyte Activation ◽  
Tnf Α ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Pro Inflammatory Cytokines

Abstract Background: Orexin-A (OXA) is a neuropeptide with neuroprotective effect by reducing cerebral ischemia/reperfusion injury (CIRI). Inflammation and apoptosis mediated by astrocyte activation are the key pathological mechanisms for CIRI. We thus attempted to confirm neuroprotective effects of OXA on astrocytic inflammation and apoptosis in CIRI and clarify the relative mechanisms. Methods: A middle cerebral artery occlusion and reperfusion (MCAO/R) rat model and U251 glioma cells model subjected to oxygen glucose deprivation and reperfusion (OGD/R) were established, with or without OXA treatment. Neurological deficit score was determined, and cerebral infarct volume was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Western Blot was used to detect the expressions of NF-κB p65, p-ERK, p-p38, GFAP, OX1R, IL-1β, TNF-α, IL-6, iNOS, Bcl-2, Bax, CytC, cleaved caspase-9 and cleaved caspase-3 in vivo and vitro. Pro-inflammatory cytokines in cell supernatant IL-1β, TNF-α and IL-6 were determined by ELISA. Hoechst 33342 staining was used to detect the apoptosis of astrocyte. Immunofluorescent staining was performed to assess the nuclear translocation of p65 and the expression of GFAP. Results: The results showed that OXA significantly improved neurological deficit score and decreased the volume of infarct area in brain. OXA decreased inflammatory mediators, inhibited astrocyte activation and nuclear translocation of NF-κB and phosphorylation of MAPK/ERK and MAPK/p38. Besides, OXA suppressed apoptosis via upregulating the ratio of Bcl-2/Bax and downregulating cytochrome C, cleaved-caspase-9 and cleaved caspase-3. Conclusions: Overall, it was concluded that OXA exerts neuroprotective effect during CIRI through attenuating astrocytes apoptosis, astrocytes activation and pro-inflammatory cytokines production, by Inhibiting OX1R-mediated NF-κB, MAPK/ERK and MAPK/p38 signaling pathways. The progress in our study are helpful to elucidate the molecular mechanisms of OXA neuroprotection, which could lead to the development of new treatment strategies for ischemic stroke.

Electroacupuncture stimulation at Yanglingquan acupoint ameliorates hepatic ischemia-reperfusion injury by down-regulating ET-1 to inhibit TAK1-JNK/p38 pathway

2021 ◽  
Author(s):  
Lai Wei ◽  
Yinyin Su ◽  
Siyou Tan ◽  
Yi Zou ◽  
Yixun Tang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Expression Patterns ◽  
Hepatic Ischemia ◽  
Tnf Α ◽  
Hepatic Ischemia Reperfusion ◽  
Liver Tissues

The current study set out to investigate the molecular mechanism of electroacupuncture (EA) stimulation at Yanglingquan acupoint (GB34) in hepatic ischemia-reperfusion injury (HIRI) in rats via regulation of the endothelin-1 (ET-1) mediated transforming growth factor-β-activated kinase-1 (TAK1)-c-Jun NH2-terminal kinase (JNK)/p38 signaling pathway. First, EA stimulation was applied to the constructed rat model of HIRI at GB34. Subsequently, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and myeloperoxidase (MPO) in liver tissues were measured. Apoptotic changes in liver tissues in rats with HIRI were observed using TUNEL staining. Western blot assay was employed to determine the expression patterns of Bcl-2, Bax, c-caspase-3 and the activation of TAK1-JNK/p38 signaling pathway, and immunohistochemistry was conducted to determine the protein expression patterns of c-caspase-3 and ET-1. In addition, ELISA was performed to determine the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in serum. The results demonstrated a significant decline in the activities of AST and ALT and hepatocyte apoptosis in rats with HIRI following EA stimulation. Meanwhile, EA stimulation brought about decreases in the expression levels of Bcl-2, Bax and c-caspase-3, MPO activity, TNF-α, IL-1β and IL-6 in serum, and diminished those of ET-1 in liver tissues, in addition to inhibiting the TAK1-JNK/p38 signaling pathway. Over-expression of ET-1 could counter the inhibitory effects of EA stimulation of HIRI in rats. Together, our findings indicate that EA stimulation at GB34 down-regulates the expression of ET-1, which inhibits the TAK1-JNK/p38 signaling pathway, consequently alleviating HIRI in rats.

Analyzing the anti-ischemia–reperfusion injury effects of ginsenoside Rb1 mediated through the inhibition of p38α MAPK

2016 ◽  
Vol 94 (1) ◽  
pp. 97-103 ◽  
Author(s):  
Gonghao Li ◽  
Wenhao Qian ◽  
Changyun Zhao
Keyword(s):  
P38 Mapk ◽  
Caspase 3 ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitogen Activated Protein Kinase ◽  
Ginsenoside Rb1 ◽  
Group I ◽  
Tnf Α ◽  
P38α Mapk

Recent studies have demonstrated that ginsenoside Rb1 protects the myocardium from ischemia–reperfusion (I/R) injury. However, the precise mechanisms for this protection have not been determined. This study aimed to determine whether the attenuation of I/R-induced myocardial injury by ginsenoside Rb1 (GS Rb1) is due to inhibition of p38α mitogen-activated protein kinase (MAPK). Sprague–Dawley rats were distributed among 6 treatment groups: sham group; I/R group; p38 MAPK inhibitor SB203580 group (SB + I/R); GS Rb1 group (GS + I/R); p38 MAPK agonist anisomycin group (Ani + I/R); and the GS Rb1 + Ani group (GS + Ani + I/R). All of the anaesthetized rats, except those in the sham group, underwent an open-chest procedure that involved 30 min of myocardial ischemia followed by 2 h of reperfusion. Myocardial infarction size (MIS), caspase-3 activity, and levels of the cytokine tumor necrosis factor alpha (TNF-α) in the myocardium were monitored. The expressions of p38α MAPK, caspase-3, and TNF-α in the myocardium were assayed. GS Rb1 reduced MIS and attenuated caspase-3 activity and the levels of TNF-α in the myocardium. Protein expression of total p38α MAPK was not significantly altered. In the Ani + I/R and I/R groups, the levels of phospho-p38α MAPK were significantly increased compared with the sham group, and these increased levels were reduced with GS Rb1. Hemodynamic parameters were not significantly different between the GS + I/R and SB + I/R groups. GS Rb1 exerts an anti-apoptotic effect that protects against I/R injury by inhibiting p38α MAPK phosphorylation, suggesting that GS Rb1-mediated protection requires the inhibition of p38α MAPK.

scholarly journals Administration of minocycline ameliorates damage in a renal ischemia/reperfusion injury model

2011 ◽  
Vol 34 (1) ◽  
pp. 55 ◽  
Author(s):  
Dan Xia ◽  
Kezhen Shen ◽  
Weidr Zhong ◽  
Hao Pan
Keyword(s):  
Oxidative Stress ◽  
Renal Dysfunction ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Intercellular Adhesion Molecule ◽  
Caspase 8 ◽  
Intercellular Adhesion Molecule 1 ◽  
Caspase 9

Purpose: The purpose of this study was to investigate the effects of minocycline on the renal dysfunction and injury caused by bilateral ischemia/reperfusion (I/R) of murine kidneys in vivo. Methods: Male C57BL/6 mice were administered minocycline (45 mg/kg i.v.) or saline (0.9%, v/v, NaCl) 36 hours prior to I/R. Mice were subjected to bilateral renal ischemia (35 min) followed by reperfusion (6 hours). Serum creatinine (sCr) and blood urea nitrogen (BUN) levels were measured. Additionally, renal superoxide dismutase (SOD) levels, malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity were determined. The expression of intercellular adhesion molecule-1 (ICAM-1), caspase-3, caspase-8 and caspase-9 was determined using real time RT-PCR and Western blot analysis. Results: Minocycline administration significantly reduced the increases in sCr and BUN caused by I/R, indicating attenuation of renal dysfunction and injury, and reduced histological evidence of renal damage caused by I/R. Minocycline administration also markedly reduced the evidence of oxidative stress (MPO activity, SOD and MDA levels), inflammation (ICAM-1 expression and MPO activity) and apoptosis (caspase-3, caspase-8 and caspase-9 expression) in mouse kidneys subjected to I/R. Conclusion: These findings provide good evidence that minocycline can reduce the renal dysfunction and injury caused by I/R of the kidney. Its mechanism may involve suppression of apoptosis, inflammatory response and oxidative stress.

Nitric Oxide Modulation as a Potential Molecular Mechanism Underlying the Protective Role of NaHS in Liver Ischemia Reperfusion Injury

2021 ◽  
Vol 14 ◽  
Author(s):  
Salwa A. Ibrahim ◽  
Seham A. Abdel-Gaber ◽  
Mohamed A. Ibrahim ◽  
Entesar F. Amin ◽  
Rehab K. Mohammed ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Histopathological Examination ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Albino Rats ◽  
High Morbidity ◽  
Tissue Samples ◽  
Sodium Hydrosulfide ◽  
Tnf Α

Background and aim: Liver IR is a frequent clinical complication with high morbidity and mortality. The present study evaluated the possible protective effect of sodium hydrosulfide (NaHS), a H2S donor, in IR-induced hepatic injury and explored the mechanisms of actions of the investigated drug. Methods: Male albino rats (200-230 g) were divided into the following groups: group 1:Sham-operated non treated rats, group 2: IR non treated rats, group 3: L-NNA + IR rats, group 4: NaHS + IR rats, group 5: L-NNA + NaHS + IR rats. Blood samples were collected for ALT determination. Liver tissue samples were used for the assessment of GPx, catalase, SOD, MDA, total nitrites and TNF-α. Parts from the liver were fixed in 10% formalin solution for histopathological examination and immunohistochemical examination of iNOS, eNOS and caspase-3. Results: NaHS protected the liver against IR. This hepatoprotection was associated with normalization of antioxidant enzyme activity and decrease in hepatic MDA, TNF-α and expression of caspase-3 and iNOS. Conclusion: NaHS is hepatoprotective in IR injury. The hepatoprotective effects of NaHS are associated with antioxidant, anti-inflammatory and antiapoptotic effects. These effects are probably mediated via NO modulation.

Rapid postmortem ventilation improves donor lung viability by extending the tolerable warm ischemic time after cardiac death in mice

2021 ◽  
Author(s):  
Junyi Yu ◽  
Che Xu ◽  
Janet S. Lee ◽  
Jonathan K. Alder ◽  
Zongmei Wen ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Cardiac Death ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Warm Ischemia ◽  
Warm Ischemia Time ◽  
Lung Injury Score ◽  
Ischemic Time ◽  
Ischemia Time ◽  
Donor Lung

Uncontrolled donation after cardiac death (uDCD) contributes little to ameliorating donor lung shortage due to rapidly progressive warm ischemia after circulatory arrest. Here, we demonstrated non-hypoxia improves donor lung viability in a novel uDCD lung transplant model undergoing rapid ventilation after cardiac death and compared the evolution of ischemia-reperfusion injury in mice that underwent pulmonary artery ligation (PAL). The tolerable warm ischemia time at 37ºC was initially determined in mice using a modified PAL model. The donor lung following PAL was also transplanted into syngeneic mice and compared to those that underwent rapid ventilation or no ventilation at 37ºC prior to transplantation. Twenty-four hours following reperfusion, lung histology, PaO2/FIO2 ratio, and inflammatory mediators were measured. Four hours of PAL had little impact on PaO2/FIO2 ratio and acute lung injury score in contrast to significant injury induced by 5 hours of PAL. Four-hour PAL lungs showed an early myeloid-dominant inflammatory signature when compared to naïve lungs and substantially injured five-hour PAL lungs. In the context of transplantation, unventilated donor lungs showed severe injury after reperfusion, whereas ventilated donor lungs showed minimal changes in PaO2/FIO2 ratio, histologic score, and expression of inflammatory markers. Taken together, the tolerable warm ischemia time of murine lungs at 37oC can be extended by maintaining alveolar ventilation for up to 4 hours. Non-hypoxic lung warm ischemia-reperfusion injury shows an early transcriptional signature of myeloid cell recruitment and extracellular matrix proteolysis prior to blood-gas barrier dysfunction and significant tissue damage.

Prostacyclin-induced peroxisome proliferator-activated receptor-α translocation attenuates NF-κB and TNF-α activation after renal ischemia-reperfusion injury

2009 ◽  
Vol 297 (4) ◽  
pp. F1109-F1118 ◽  
Author(s):  
Hsi-Hsien Chen ◽  
Tzen-Wen Chen ◽  
Heng Lin
Keyword(s):  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Cell Number ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nitrogen Levels ◽  
Tnf Α

Prostacyclin and peroxisome proliferator-activated receptors (PPAR) protect against ischemia-reperfusion (I/R) injury by the induction of an anti-inflammatory pathway. In this study, we examined the prostacyclin-enhanced protective effect of PPARα in I/R-induced kidney injury. PPAR-α reduced the NF-κB-induced overexpression of TNF-α and apoptosis in cultured kidney cells. In a murine model, pretreating wild-type (WT) mice with a PPAR-α activator, docosahexaenoic acid (DHA), significantly reduced I/R-induced renal dysfunction (lowered serum creatinine and urea nitrogen levels), apoptotic responses (decreased apoptotic cell number and caspase-3, -8 activation), and NF-κB activation. By comparison, I/R-induced injury was exacerbated in PPAR-α knockout mice. This indicated that PPAR-α attenuated renal I/R injury via NF-κB-induced TNF-α overexpression. Overexpression of prostacyclin using an adenovirus could also induce PPAR-α translocation from the cytosol into the nucleus to inhibit caspase-3 activation. This prostacyclin/PPAR-α pathway attenuated TNF-α promoter activity by binding to NF-κB. Using a cAMP inhibitor (CAY10441) and a prostacyclin receptor antibody, we also found that there was another prostacyclin/IP receptor/cAMP pathway that could inhibit TNF-α production. Taken together, our results demonstrate for the first time that prostacyclin induces the translocation of PPAR-α from the cytosol into the nucleus and attenuates NF-κB-induced TNF-α activation following renal I/R injury. Treatments that can augment prostacyclin, PPAR-α, or the associated signaling pathways may ameliorate conditions associated with renal I/R injury.

Sign in / Sign up

Export Citation Format

Share Document