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New Strategies Protecting from Ischemia/Reperfusion

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 27171

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Dr. Didier F. Pisani

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Laboratory of Molecular PhysioMedicine (LP2M), Faculty of Medicine, University Côte d'Azur, CNRS, Nice, France
Interests: adipocyte; metabolism; nutrition; obesity; oxidative stress; ischemia
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Dr. Thierry Hauet

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Department of Biochemistry, Pole Biospharm, University Hospital Center and Faculty of Medicine, University of Poitiers, INSERM Unit UMR 1082, 86021 Poitiers, France
Interests: organ preservation; preclinical models; cells models; ischemia reperfusion; oxidative stress; metabolism; transplantation models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ischemia/reperfusion (I/R) injuries are the most common causes of debilitating disease and death in stroke, cardiovascular ischemia, organ transplantation, and more. I/R is due to a partial or complete blood flow arrest, characterized by hypoxia or anoxia coupled to a deprivation in energy substrates, and then by an abrupt increase in oxygen supply of the affected region, both inducing critical damages to cells and tissues. Indeed, I/R leads to various deleterious process such as oxidative stress, energy distress, acidification and inflammation, along with the production of stress mediators including cytokines, oxygen and nitrogen species, as well as glucose and fatty acid metabolites. In recent decades, we have profoundly advanced in our comprehension of the biological and molecular pathways influencing I/R effects. Nevertheless, no clinical protocols or pharmacological approaches are completely satisfying and effective to protect tissues and organs from the deleterious consequences of I/R.

This Special Issue is dedicated to highlighting all new avenues allowing for a better management of I/R outcome. We invite investigators from all fields involving ischemia and reperfusion to present recent advances in the comprehension of the molecular pathways leading to I/R, as well as the development of new pharmacological and clinical approaches to prevent adverse consequences of I/R.

Dr. Didier F. Pisani
Dr. Thierry Hauet
Guest Editors

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Keywords

hypoxia
anoxia
stroke
transplantation
infarct
oxidative stress
metabolism
inflammation

Published Papers (11 papers)

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Editorial

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2 pages, 191 KiB

Open AccessEditorial

New Strategies Protecting from Ischemia/Reperfusion

by Thierry Hauet and Didier F. Pisani

Int. J. Mol. Sci. 2022, 23(24), 15867; https://doi.org/10.3390/ijms232415867 - 14 Dec 2022

Cited by 4 | Viewed by 1194

Abstract

This Special Issue aims to highlight new avenues in the management of Ischemia/Reperfusion (I/R) injury [...] Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

Research

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15 pages, 2018 KiB

Open AccessArticle

N-Acetylcysteine Administration Attenuates Sensorimotor Impairments Following Neonatal Hypoxic-Ischemic Brain Injury in Rats

by Evangelia Kesidou, Christina Bitsina, Athanasios Chatzisotiriou, Paschalis Theotokis, Evgenia Dandi, Despina A. Tata and Evangelia Spandou

Int. J. Mol. Sci. 2022, 23(24), 16175; https://doi.org/10.3390/ijms232416175 - 19 Dec 2022

Cited by 3 | Viewed by 1530

Abstract

Hypoxic ischemic (HI) brain injury that occurs during neonatal period has been correlated with severe neuronal damage, behavioral deficits and infant mortality. Previous evidence indicates that N-acetylcysteine (NAC), a compound with antioxidant action, exerts a potential neuroprotective effect in various neurological disorders including injury induced by brain ischemia. The aim of the present study was to investigate the role of NAC as a potential therapeutic agent in a rat model of neonatal HI brain injury and explore its long-term behavioral effects. To this end, NAC (50 mg/kg/dose, i.p.) was administered prior to and instantly after HI, in order to evaluate hippocampal and cerebral cortex damage as well as long-term functional outcome. Immunohistochemistry was used to detect inducible nitric oxide synthase (iNOS) expression. The results revealed that NAC significantly alleviated sensorimotor deficits and this effect was maintained up to adulthood. These improvements in functional outcome were associated with a significant decrease in the severity of brain damage. Moreover, NAC decreased the short-term expression of iNOS, a finding implying that iNOS activity may be suppressed and that through this action NAC may exert its therapeutic action against neonatal HI brain injury. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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22 pages, 4914 KiB

Open AccessArticle

Mild Therapeutic Hypothermia Protects from Acute and Chronic Renal Ischemia-Reperfusion Injury in Mice by Mitigated Mitochondrial Dysfunction and Modulation of Local and Systemic Inflammation

by Maxime Schleef, Fabrice Gonnot, Bruno Pillot, Christelle Leon, Stéphanie Chanon, Aurélie Vieille-Marchiset, Maud Rabeyrin, Gabriel Bidaux, Fitsum Guebre-Egziabher, Laurent Juillard, Delphine Baetz and Sandrine Lemoine

Int. J. Mol. Sci. 2022, 23(16), 9229; https://doi.org/10.3390/ijms23169229 - 17 Aug 2022

Cited by 8 | Viewed by 1606

Abstract

Renal ischemia-reperfusion (IR) injury can lead to acute kidney injury, increasing the risk of developing chronic kidney disease. We hypothesized that mild therapeutic hypothermia (mTH), 34 °C, applied during ischemia could protect the function and structure of kidneys against IR injuries in mice. In vivo bilateral renal IR led to an increase in plasma urea and acute tubular necrosis at 24 h prevented by mTH. One month after unilateral IR, kidney atrophy and fibrosis were reduced by mTH. Evaluation of mitochondrial function showed that mTH protected against IR-mediated mitochondrial dysfunction at 24 h, by preserving CRC and OX-PHOS. mTH completely abrogated the IR increase of plasmatic IL-6 and IL-10 at 24 h. Acute tissue inflammation was decreased by mTH (IL-6 and IL1-β) in as little as 2 h. Concomitantly, mTH increased TNF-α expression at 24 h. One month after IR, mTH increased TNF-α mRNA expression, and it decreased TGF-β mRNA expression. We showed that mTH alleviates renal dysfunction and damage through a preservation of mitochondrial function and a modulated systemic and local inflammatory response at the acute phase (2–24 h). The protective effect of mTH is maintained in the long term (1 month), as it diminished renal atrophy and fibrosis, and mitigated chronic renal inflammation. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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11 pages, 4238 KiB

Open AccessArticle

Relaxin and Erythropoietin Significantly Reduce Uterine Tissue Damage during Experimental Ischemia–Reperfusion Injury

by Lina Jakubauskiene, Matas Jakubauskas, Gintare Razanskiene, Bettina Leber, Jennifer Weber, Lisa Rohrhofer, Diana Ramasauskaite, Kestutis Strupas, Philipp Stiegler and Peter Schemmer

Int. J. Mol. Sci. 2022, 23(13), 7120; https://doi.org/10.3390/ijms23137120 - 27 Jun 2022

Cited by 3 | Viewed by 1422

Abstract

Successful uterus transplantation, a potential treatment method for women suffering from absolute uterine infertility, is negatively affected by ischemia–reperfusion injury (IRI). The aim of this study is to investigate the protective effect of relaxin (RLX) or/and erythropoietin (EPO) on experimental uterus IRI. Eighty rats, randomly assigned into eight groups (n = 10/group), were pretreated with either saline, 5 μg/kg human relaxin-2, 4000 IU/kg recombinant human erythropoietin or their combination. Ischemia was achieved by clamping the aorta and ovarian arteries for 60 min, following 120 min of reperfusion and tissue sampling. For sham animals, clamping was omitted during surgery. There were no differences in tissue histological score, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, myeloperoxidase (MPO) and TUNEL-positive cell count between all sham-operated rats. Pretreatment with RLX preserved normal tissue morphology, reduced MDA levels, MPO and TUNEL-positive cell count, preserved SOD activity and upregulated NICD and HES1 gene expression when compared to the control group. Pretreatment with EPO reduced MDA levels. In conclusion, pretreatment with RLX, EPO or a combination of both EPO and RLX significantly alleviates uterine tissue damage caused by IRI. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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15 pages, 2963 KiB

Open AccessArticle

Akt Inhibition as Preconditioning Treatment to Protect Kidney Cells against Anoxia

by Nicolas Melis, Romain Carcy, Isabelle Rubera, Marc Cougnon, Christophe Duranton, Michel Tauc and Didier F. Pisani

Int. J. Mol. Sci. 2022, 23(1), 152; https://doi.org/10.3390/ijms23010152 - 23 Dec 2021

Cited by 1 | Viewed by 2635

Abstract

Lesions issued from the ischemia/reperfusion (I/R) stress are a major challenge in human pathophysiology. Of human organs, the kidney is highly sensitive to I/R because of its high oxygen demand and poor regenerative capacity. Previous studies have shown that targeting the hypusination pathway of eIF5A through GC7 greatly improves ischemic tolerance and can be applied successfully to kidney transplants. The protection process correlates with a metabolic shift from oxidative phosphorylation to glycolysis. Because the protein kinase B Akt is involved in ischemic protective mechanisms and glucose metabolism, we looked for a link between the effects of GC7 and Akt in proximal kidney cells exposed to anoxia or the mitotoxic myxothiazol. We found that GC7 treatment resulted in impaired Akt phosphorylation at the Ser473 and Thr308 sites, so the effects of direct Akt inhibition as a preconditioning protocol on ischemic tolerance were investigated. We evidenced that Akt inhibitors provide huge protection for kidney cells against ischemia and myxothiazol. The pro-survival effect of Akt inhibitors, which is reversible, implied a decrease in mitochondrial ROS production but was not related to metabolic changes or an antioxidant defense increase. Therefore, the inhibition of Akt can be considered as a preconditioning treatment against ischemia. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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15 pages, 3529 KiB

Open AccessArticle

JAK Inhibition Prevents DNA Damage and Apoptosis in Testicular Ischemia-Reperfusion Injury via Modulation of the ATM/ATR/Chk Pathway

by Farah Khashab, Farah Al-Saleh, Nora Al-Kandari, Fatemah Fadel and May Al-Maghrebi

Int. J. Mol. Sci. 2021, 22(24), 13390; https://doi.org/10.3390/ijms222413390 - 13 Dec 2021

Cited by 10 | Viewed by 2513

Abstract

Testicular ischemia reperfusion injury (tIRI) causes oxidative stress-induced DNA damage leading to germ cell apoptosis (GCA). The aim of the study is to establish a direct link between JAK2 activation and the DNA damage response (DDR) signaling pathways and their role in tIRI-induced GCA using AG490, a JAK2 specific inhibitor. Male Sprague Dawley rats (n = 36) were divided into three groups: sham, unilateral tIRI and tIRI + AG490 (40 mg/kg). During tIRI, augmentation in the phosphorylation levels of the JAK2/STAT1/STAT3 was measured by immunohistochemistry. Observed spermatogenic arrest was explained by the presence of considerable levels of DSB, AP sites and 8OHdG and activation of caspase 9, caspase 3 and PARP, which were measured by colorimetric assays and TUNEL. The ATM/Chk2/H2AX and ATR/Chk1 pathways were also activated as judged by their increased phosphorylation using Western blot. These observations were all prevented by AG490 inhibition of JAK2 activity. Our findings demonstrate that JAK2 regulates tIRI-induced GCA, oxidative DNA damage and activation of the ATM/Chk2/H2AX and ATR/Chk1 DDR pathways, but the cell made the apoptosis decision despite DDR efforts. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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14 pages, 2531 KiB

Open AccessArticle

Pantoprazole Attenuates MAPK (ERK1/2, JNK, p38)–NF-κB and Apoptosis Signaling Pathways after Renal Ischemia/Reperfusion Injury in Rats

by Michael A. Fawzy, Sherif A. Maher, Sally M. Bakkar, Mahmoud A. El-Rehany and Moustafa Fathy

Int. J. Mol. Sci. 2021, 22(19), 10669; https://doi.org/10.3390/ijms221910669 - 01 Oct 2021

Cited by 27 | Viewed by 2319

Abstract

Ischemia/reperfusion injury (IRI) in the kidney is the most common cause of acute renal dysfunction through different cell damage mechanisms. This study aimed to investigate, on molecular basics for the first time, the effect of pantoprazole on renal IRI in rats. Different biochemical parameters and oxidative stress markers were assessed. ELISA was used to estimate proinflammatory cytokines. qRT-PCR and western blot were used to investigate the gene and protein expression. Renal histopathological examination was also performed. IRI resulted in tissue damage, elevation of serum levels of creatinine, urea nitrogen, malondialdehyde, TNF-α, IL-6, IL-1β, up-regulation of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins. Furthermore, it up-regulated the expression of the Bax gene and down-regulated the expression of the Bcl-2 gene. Treatment of the injured rats with pantoprazole, either single dose or multiple doses, significantly alleviated IRI-induced biochemical and histopathological changes, attenuated the levels of proinflammatory cytokines, down-regulated the expression of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins, and the Bax gene, and up-regulated Bcl-2 gene expression. Moreover, treatment with pantoprazole multiple doses has an ameliorative effect that is greater than pantoprazole single-dose. In conclusion, pantoprazole diminished renal IRI via suppression of apoptosis, attenuation of the pro-inflammatory cytokines’ levels, and inhibition of the intracellular signaling pathway MAPK (ERK1/2, JNK, p38)–NF-κB. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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Review

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11 pages, 1726 KiB

Open AccessReview

Quest for Quality in Translational Stroke Research—A New Dawn for Neuroprotection?

by Matteo Haupt, Stefan T. Gerner, Mathias Bähr and Thorsten R. Doeppner

Int. J. Mol. Sci. 2022, 23(10), 5381; https://doi.org/10.3390/ijms23105381 - 11 May 2022

Cited by 6 | Viewed by 2682

Abstract

Despite tremendous progress in modern-day stroke therapy, ischemic stroke remains a disease associated with a high socioeconomic burden in industrialized countries. In light of demographic change, these health care costs are expected to increase even further. The current causal therapeutic treatment paradigms focus on successful thrombolysis or thrombectomy, but only a fraction of patients qualify for these recanalization therapies because of therapeutic time window restrictions or contraindications. Hence, adjuvant therapeutic concepts such as neuroprotection are urgently needed. A bench-to-bedside transfer of neuroprotective approaches under stroke conditions, however, has not been established after more than twenty years of research, albeit a great many data have demonstrated several neuroprotective drugs to be effective in preclinical stroke settings. Prominent examples of substances supported by extensive preclinical evidence but which failed clinical trials are tirilazad and disodium 2,4-sulphophenyl-N-tert-butylnitrone (NXY-059). The NXY-059 trial, for instance, was retrospectively shown to have a seriously weak study design, a trial of insufficient quality and a poor statistical analysis, although it initially met the recommendations of the STAIR committee. In light of currently ongoing novel neuroprotective stroke trials, such as ESCAPE-NA, and to avoid the mistakes made in the past, an improvement in study quality in the field of stroke neuroprotection is urgently needed. In the present review, animal models closely reflecting the “typical” stroke patient, occlusion techniques and the appropriate choice of time windows are discussed. In this context, the STAIR recommendations could provide a useful orientation. Taking all of this into account, a new dawn for neuroprotection might be possible. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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13 pages, 1165 KiB

Open AccessReview

Roles of Nitric Oxide in Brain Ischemia and Reperfusion

by Yijie Wang, Fenfang Hong and Shulong Yang

Int. J. Mol. Sci. 2022, 23(8), 4243; https://doi.org/10.3390/ijms23084243 - 11 Apr 2022

Cited by 23 | Viewed by 2937

Abstract

Brain ischemia and reperfusion (I/R) is one of the most severe clinical manifestations of ischemic stroke, placing a significant burden on both individuals and society. The only FDA-approved clinical treatment for ischemic stroke is tissue plasminogen activator (t-PA), which rapidly restores cerebral blood flow but can have severe side effects. The complex pathological process of brain I/R has been well-established in the past few years, including energy metabolism disorders, cellular acidosis, doubling of the synthesis or release of excitotoxic amino acids, intracellular calcium homeostasis, free radical production, and activation of apoptotic genes. Recently, accumulating evidence has shown that NO may be strongly related to brain I/R and involved in complex pathological processes. This review focuses on the role of endogenous NO in pathological processes in brain I/R, including neuronal cell death and blood brain barrier disruption, to explore how NO impacts specific signaling cascades and contributes to brain I/R injury. Moreover, NO can rapidly react with superoxide to produce peroxynitrite, which may also mediate brain I/R injury, which is discussed here. Finally, we reveal several therapeutic approaches strongly associated with NO and discuss their potential as a clinical treatment for ischemic stroke. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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21 pages, 1323 KiB

Open AccessReview

Neuroelectric Mechanisms of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage

by Hidenori Suzuki, Fumihiro Kawakita and Reona Asada

Int. J. Mol. Sci. 2022, 23(6), 3102; https://doi.org/10.3390/ijms23063102 - 13 Mar 2022

Cited by 19 | Viewed by 3314

Abstract

Delayed cerebral ischemia (DCI) remains a challenging but very important condition, because DCI is preventable and treatable for improving functional outcomes after aneurysmal subarachnoid hemorrhage (SAH). The pathologies underlying DCI are multifactorial. Classical approaches to DCI focus exclusively on preventing and treating the reduction of blood flow supply. However, recently, glutamate-mediated neuroelectric disruptions, such as excitotoxicity, cortical spreading depolarization and seizures, and epileptiform discharges, have been reported to occur in high frequencies in association with DCI development after SAH. Each of the neuroelectric disruptions can trigger the other, which augments metabolic demand. If increased metabolic demand exceeds the impaired blood supply, the mismatch leads to relative ischemia, resulting in DCI. The neuroelectric disruption also induces inverted vasoconstrictive neurovascular coupling in compromised brain tissues after SAH, causing DCI. Although glutamates and the receptors may play central roles in the development of excitotoxicity, cortical spreading ischemia and epileptic activity-related events, more studies are needed to clarify the pathophysiology and to develop novel therapeutic strategies for preventing or treating neuroelectric disruption-related DCI after SAH. This article reviews the recent advancement in research on neuroelectric disruption after SAH. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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18 pages, 2017 KiB

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Role of Mitochondrial Pathways in Cell Apoptosis during He-Patic Ischemia/Reperfusion Injury

by Sen Zhang, Sijing Rao, Meiwen Yang, Chen Ma, Fengfang Hong and Shulong Yang

Int. J. Mol. Sci. 2022, 23(4), 2357; https://doi.org/10.3390/ijms23042357 - 21 Feb 2022

Cited by 22 | Viewed by 3503

Abstract

Hepatic ischemia-reperfusion injury is a major cause of post-operative hepatic dysfunction and liver failure after transplantation. Mitochondrial pathways can be either beneficial or detrimental to hepatic cell apoptosis during hepatic ischemia/reperfusion injury, depending on multiple factors. Hepatic ischemia/reperfusion injury may be induced by opened mitochondrial permeability transition pore, released apoptosis-related proteins, up-regulated B-cell lymphoma-2 gene family proteins, unbalanced mitochondrial dynamics, and endoplasmic reticulum stress, which are integral parts of mitochondrial pathways. In this review, we discuss the role of mitochondrial pathways in apoptosis that account for the most deleterious effect of hepatic ischemia/reperfusion injury. Full article

(This article belongs to the Special Issue New Strategies Protecting from Ischemia/Reperfusion)

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