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Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 8416

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Prof. Dr. Jun Kobayashi

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Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, 1-1 Keyakidai, Sakado 350-0295, Japan
Interests: nitric oxide; nitrate/nitrite; crush syndrome; ischemia/reperfusion injury; reactive oxygen species
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Dear Colleagues,

Ischemia–reperfusion (I/R) injury is caused by a temporary restriction of blood supply to a particular organ, such as the heart, brain, kidney, liver and skeletal muscle. Subsequent reperfusion to these hypoxic or anoxic organs causes organ dysfunction and tissue cell death, sometimes leading to systemic circulatory shock. Although the organ type, as well as magnitude and duration of the interruption in the blood supply are critical determinants of whether the organ becomes necrotic or not, organ damage is essentially caused by oxidative stress following reperfusion, which induces cell membrane lipid peroxidation, mitochondrial dysfunction and subsequent inflammatory responses, such as neutrophil activation and the release of reactive oxygen species and other inflammatory mediators, including adhesion molecules and various cytokines. Effective pharmacological agents and methods to combat I/R injury have recently been developed. Nevertheless, we are far from establishing the treatment for this disease. I, therefore, look forward to fruitful discussions on this theme, particularly from the standpoint of molecular biology, and call for original articles and reviews focusing on the pathophysiology of I/R injury, development of animal models, and development of new pharmacological and interventional strategies. This Special Issue will provide a key resource to the readers of CIMB, including new findings related to I/R injury with the potential to lead to novel treatment strategies.

Prof. Dr. Jun Kobayashi
Guest Editor

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Keywords

ischemia–reperfusion injury
myocardial infarction
cerebral infarction
renal infarction
crush syndrome
oxidative stress
reactive oxygen species

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Published Papers (8 papers)

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Research

14 pages, 1663 KiB

Open AccessArticle

Inflammatory Monocytes Are Rapidly Recruited to the Post-Ischaemic Liver in Patients Undergoing Liver Transplantation and Cytokines Associated with Their Activation Correlate with Graft Outcomes

by Francis P. Robertson, Antonia O. Cuff, Victoria Male, Graham P. Wright, Laura J. Pallett, Barry J. Fuller and Brian R. Davidson

Curr. Issues Mol. Biol. 2025, 47(1), 49; https://doi.org/10.3390/cimb47010049 - 14 Jan 2025

Viewed by 489

Abstract

Liver ischaemia–reperfusion (IR) injury remains a major cause of morbidity and mortality following liver transplantation and resection. CD4+ T cells have been shown to play a key role in murine models; however, there is currently a lack of data that support their role in human patients. Methods: Data on clinical outcomes and complications were documented prospectively in 28 patients undergoing first elective liver transplant surgery. Peripheral blood samples were collected at baseline (pre-op), 2 h post graft reperfusion, immediately post-op, and 24 h post-op. A post-reperfusion biopsy was analysed in all patients, and in five patients, a donor liver biopsy was available pre-implantation. Circulating cytokines were measured, and T cells were analysed for activation markers and cytokine production. Results: Circulating levels of cytokines associated with innate immune cell recruitment and activation were significantly elevated in the peri-transplant period. High circulating IL-10 levels corresponded with the development of graft-specific complications. The proportion of CD4+ T cells in the peripheral circulation fell throughout the peri-operative period, suggesting CD4+ T cell recruitment to the graft. Although TNFα was the predominant cytokine produced by CD4+ T cells in the intrahepatic environment, the production of IFNγ was significantly upregulated by circulating CD4+ T cells. Furthermore, we demonstrated clear recruitment of inflammatory monocytes in the peri-operative period. In donor-and-recipient pairs with a mismatch at the HLA-A2 or A3 allele, we demonstrated that inflammatory monocytes in the liver are recipient-derived. Discussion: This is the first study to our knowledge that tracks early immune cell responses in humans undergoing liver transplantation. The recruitment of inflammatory monocytes from the recipient and their cytokine release is associated with liver-specific complications. Inflammatory monocytes would be an attractive target to ameliorate ischaemia–reperfusion injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

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10 pages, 3222 KiB

Open AccessArticle

MIF Inhibition by ISO-1 Decreased Autophagic Activity in Primary Astrocytes During Cobalt Chloride-Induced Hypoxia

by Ji-Hyun Park, Hye-Ji Cho, Dae-Yong Song, Jung-Ho Lee and Hong-Il Yoo

Curr. Issues Mol. Biol. 2024, 46(12), 13607-13616; https://doi.org/10.3390/cimb46120813 - 29 Nov 2024

Viewed by 824

Abstract

Ischemic stroke is a leading contributor to death and disability worldwide, driving extensive research into pharmacological treatments beyond thrombolysis. Macrophage migration inhibitory factor (MIF), a cytokine, is implicated in several pathological conditions. In this study, we examined the effects of MIF on autophagy in astrocytes under the condition of chemical hypoxia. Primary astrocytes were treated with cobalt chloride, a well-known drug for inducing chemical hypoxia, followed by Western blot analyses to assess the HIF-1α, MIF, and LC3 protein levels along with a CCK assay. Additionally, cobalt chloride-treated astrocytes were co-treated with the MIF inhibitor ISO-1, and Western blot analyses were performed for MIF and LC3. Cell viability was evaluated using the CCK assay in astrocytes treated with cobalt chloride and ISO-1, with additional rapamycin treatment. Our results show that ISO-1 reduced LC3-II levels in astrocytes exposed to high concentrations of cobalt chloride (1000 μM) for 6 h. Moreover, rapamycin decreased cell viability in astrocytes treated with both 1000 μM cobalt chloride and ISO-1. Our data suggest that MIF plays a role in inducing autophagy in astrocytes under hypoxic conditions and is involved in the regulation of autophagic activity. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

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11 pages, 746 KiB

Open AccessArticle

Synergistic Protection of Vitamin B Complex and Alpha-Lipoic Acid Against Hepatic Ischemia–Reperfusion Injury: Boosting Antioxidant Defenses in Rats

by Fatih Seğmen, Semih Aydemir, Onur Küçük, Ümit Murat Parpucu and Recep Dokuyucu

Curr. Issues Mol. Biol. 2024, 46(12), 13554-13564; https://doi.org/10.3390/cimb46120810 - 28 Nov 2024

Viewed by 754

Abstract

This study aimed to investigate the protective effects of vitamin B complex and alpha-lipoic acid (ALA) pre-treatments on hepatic ischemia–reperfusion injury (IRI) in rats, focusing on their potential to enhance antioxidant defense mechanisms and reduce post-ischemic liver damage. Thirty male Wistar albino rats were divided into four groups: sham group (n = 10), IRI group (n = 10), vitamin B group (n = 10), vitamin B + ALA group (n = 10). In the IRI, vitamin B, and vitamin B + ALA groups, the rats underwent 45 min of hepatic ischemia followed by 60 min of reperfusion. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, and lactate dehydrogenase (LDH) were measured. Additionally, serum total antioxidant status (TAS) and total oxidant status (TOS) were assessed, and the oxidative stress index (OSI) was calculated. Liver tissue samples were collected for morphological evaluation. In the vitamin B and vitamin B + ALA groups, ALT, AST, urea, creatinine and LDH levels were better compared with the IRI group but the difference was statistically significant for only LDH levels in the vitamin B group and ALT, urea, and LDH levels in the vitamin B + ALA group (p < 0.05). The lowest TOS and OSI levels were reported in the vitamin B and vitamin B + ALA groups and these groups had statistically significantly higher TAS compared with the sham and IRI groups (p < 0.05). Our findings suggest that a vitamin B complex alone or a vitamin B complex + ALA combination reduces post-ischemic hepatic injury by enhancing the anti-oxidative status. The low dose of ALA may be a co-factor in these results and studies with larger doses of ALA are required to determine its effects on IRI of the liver. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

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15 pages, 22286 KiB

Open AccessArticle

Overexpression of miR-451a Aggravates Renal Ischemia–Reperfusion Injury by Targeting KLF1-ACSL4 to Promote Ferroptosis

by Haitao Yu and Xin Gou

Curr. Issues Mol. Biol. 2024, 46(11), 11853-11867; https://doi.org/10.3390/cimb46110704 - 23 Oct 2024

Viewed by 1020

Abstract

Ischemia–reperfusion injury (IRI) is a predominant factor leading to delayed graft function (DGF) following kidney transplantation. MicroRNAs (miRNAs) play a pivotal role in the pathogenesis of renal IRI, with ferroptosis being a critical driving force throughout the process. In this study, we utilized bioinformatics methods to construct a network diagram of differentially expressed miRNAs, transcription factors (TFs), and ferroptosis-related genes. An I/R-induced renal injury model in mice and an in vitro H/R-induced HK-2 cell injury model were established. Quantitative real-time PCR (qRT-PCR) and Western blot analysis were used to measure the mRNA and miRNA levels in cells and tissues. The MDA concentration, iron levels, and GSH concentration were measured to evaluate the ferroptosis levels. CCK-8 assays were performed to assess cell viability. Luciferase reporter assays were conducted to validate the downstream targets of miRNA, and chromatin immunoprecipitation assays were performed to verify the interaction between TFs and mRNAs. Both the in vivo and in vitro results demonstrate that miR-451a was significantly enriched in the IRI renal tissues and cells, exacerbating ferroptosis. MiR-451a was found to reduce the expression of Kruppel-like factor 1 (KLF1) by directly binding to the 3′UTR of KLF1 mRNA. Additionally, KLF1 was identified as a negative transcription factor for acyl-CoA synthetase long-chain family member 4 (ACSL4). We demonstrated that IRI induced the upregulation of miR-451a, which reduced KLF1 expression, thereby promoting ferroptosis by upregulating ACSL4 expression, ultimately aggravating IRI-induced renal damage. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

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11 pages, 1993 KiB

Open AccessArticle

The Role of Mannitol and Vitamin D in Ovarian Ischemia/Reperfusion Injury in Rats with Acute Abdominal

by Faruk Karateke, Atilla Karateke, Basak Topdagi, Merve Atilgan and Recep Dokuyucu

Curr. Issues Mol. Biol. 2024, 46(8), 8903-8913; https://doi.org/10.3390/cimb46080526 - 15 Aug 2024

Cited by 2 | Viewed by 1489

Abstract

This study was designed to investigate the effects of vitamin D and mannitol in an experimental rat ovarian torsion model. Thirty-two female Wistar albino rats were randomly classified as group 1: (sham), group 2: (detorsion), group 3: (detorsion + mannitol), group 4: (detorsion + vitamin D) and group 5: (detorsion + mannitol + vitamin D) (for each group n = 8). All groups were subjected to bilateral adnexal torsion for 2 h except for group 1. Bilateral adnexal detorsion was performed in all groups except for group 1. Groups 3 and 5 intraperitoneally received the injection of mannitol at a dose of 0.3 mg/kg 30 min before detorsion. Also, the group’s 4 and 5 orally received vitamin D in a dose of 500 IU/kg/day for two weeks before torsion. Total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI) and proliferating cell nuclear antigen (PCNA) levels were analyzed. According to the histopathological analyses, ovarian tissue damage and follicle counting were evaluated. TOS, OSI and histopathologic score values of ovarian tissue were significantly lower in group 5 than groups 2, 3 and 4 (p < 0.05). The PCNA level was significantly higher in group 5 than in groups 2, 3 and 4 (p < 0.05). A strong negative correlation was found between OSI and PCNA in groups 2, 3, 4 and 5 (r = −0.92, p = 0.01; r = −0.98, p < 0.0001; r = −0.98, p < 0.0001 and r = −0.96, p = 0.0002, respectively). The numbers of primordial follicles in group 5 (p < 0.001) and primary follicles in group 4 (p < 0.001) were significantly higher when compared to group 2. Based on the results of this study, it could be suggested that combination treatment of mannitol with vitamin D is more effective in reversing tissue damage induced by ischemia–reperfusion (I/R) injury in the ovarian torsion model than administration of only an agent. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

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16 pages, 6733 KiB

Open AccessArticle

The Combined Delivery of the Vegf, Ang, and Gdnf Genes Stimulates Angiogenesis and Improves Post-Ischemic Innervation and Regeneration in Skeletal Muscle

by Igor Valerievich Samatoshenkov, Alexander Maazovich Aimaletdinov, Elena Yurievna Zakirova, Yuri Alexandrovich Chelyshev, Julia Maratovna Samatoshenkova, Marat Salimovich Kadyrov, Evgeny Alekseevich Kniazev, Bulat Ilgamovich Salakhov and Yana Olegovna Mukhamedshina

Curr. Issues Mol. Biol. 2024, 46(8), 8611-8626; https://doi.org/10.3390/cimb46080507 - 5 Aug 2024

Viewed by 1032

Abstract

In this study, the effects of different combinations of the genes Vegf, Ang, and Gdnf injected both using direct virus-mediated injection (adenovirus, Ad5) and umbilical cord blood mononuclear cells (UCBCs) on the processes of stimulation of post-ischemic innervation, angiogenesis, and regeneration in skeletal muscle were investigated in a rat hindlimb chronic ischemia model. It was shown that more pronounced stimulation of angiogenesis and restoration of post-ischemic innervation were achieved both in the early (28 days post-ischemia, dpi) and late (42 dpi) terms of the experiment in the calf muscle when UCBCs delivered the combination of Ad5-Vegf and Ad5-Ang compared to the direct injection of the same vector combination into the area of ischemia. At the same time, the inclusion of Ad5-Gdnf in the combination of Ad5-Vegf and Ad5-Ang directly injected or administered by UCBCs provided a significant increase in the number of centronuclear muscle fibers, indicating stimulation of post-ischemic reparative myogenesis. This study allowed us to determine the most effective gene combinations for angiogenesis and neurogenesis, which, in the future, may serve as the basis for the development of gene and gene cell products for the treatment of chronic lower limb ischemia. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

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13 pages, 11373 KiB

Open AccessArticle

Skimmianine Showed Neuroprotection against Cerebral Ischemia/Reperfusion Injury

by Hayat Ayaz, Fırat Aşır and Tuğcan Korak

Curr. Issues Mol. Biol. 2024, 46(7), 7373-7385; https://doi.org/10.3390/cimb46070437 - 12 Jul 2024

Cited by 2 | Viewed by 1068

Abstract

The aim of this study was to investigate the antioxidant and anti-inflammatory effects of skimmianine on cerebral ischemia–reperfusion (IR) injury. Twenty-four female Wistar albino rats were randomly divided into three groups: Sham, Ischemia–Reperfusion (IR), and IR + Skimmianine (40 mg/kg Skimmianine). Cerebral ischemia was induced using a monofilament nylon suture to occlude the middle cerebral artery for 60 min. Following 23 h of reperfusion, the animals were sacrificed 14 days later. The effects of skimmianine on brain tissue post-IR injury were examined through biochemical and immunochemical analyses. In silico analysis using the Enrichr platform explored skimmianine’s potential biological processes involving IBA-1, IL-6, and NF-κB proteins. In the IR group, MDA levels increased, while SOD and CAT antioxidant enzyme activities decreased. In the IR + Skimmianine group, skimmianine treatment resulted in decreased MDA levels and increased SOD and CAT activities. Significant increases in IBA-1 expression were observed in the IR group, which skimmianine treatment significantly reduced, modulating microglial activation. High levels of IL-6 expression were noted in pyramidal neurons, vascular structures, and neuroglial cells in the IR group; skimmianine treatment reduced IL-6 expression, demonstrating anti-inflammatory effects. Increased NF-κB expression was observed in neurons and blood vessels in the gray and white matter in the IR group; skimmianine treatment reduced NF-κB expression. Gene Ontology results suggest skimmianine impacts immune and inflammatory responses via IBA-1 and IL-6, with potential effects on estrogen mechanisms mediated by NF-κB. Skimmianine may be a potential therapeutic strategy due to its antioxidant and anti-inflammatory effects on cerebral IR injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

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20 pages, 2641 KiB

Open AccessArticle

The Autophagic and Apoptotic Death of Forebrain Neurons of Rats with Global Brain Ischemia Is Diminished by the Intranasal Administration of Insulin: Possible Mechanism of Its Action

by Irina O. Zakharova, Liubov V. Bayunova, Daria K. Avrova, Alina D. Tretyakova, Alexander O. Shpakov and Natalia F. Avrova

Curr. Issues Mol. Biol. 2024, 46(7), 6580-6599; https://doi.org/10.3390/cimb46070392 - 27 Jun 2024

Cited by 3 | Viewed by 857

Abstract

Insulin is a promising neuroprotector. To better understand the mechanism of insulin action, it was important to show its ability to diminish autophagic neuronal death in animals with brain ischemic and reperfusion injury. In forebrain ischemia and reperfusion, the number of live neurons in the hippocampal CA1 region and frontal cortex of rats decreased to a large extent. Intracerebroventricular administration of the autophagy and apoptosis inhibitors to ischemic rats significantly increased the number of live neurons and showed that the main part of neurons died from autophagy and apoptosis. Intranasal administration of 0.5 IU of insulin per rat (before ischemia and daily during reperfusion) increased the number of live neurons in the hippocampal CA1 region and frontal brain cortex. In addition, insulin significantly diminished the level of autophagic marker LC3B-II in these forebrain regions, which markedly increased during ischemia and reperfusion. Our studies demonstrated for the first time the ability of insulin to decrease autophagic neuronal death, caused by brain ischemia and reperfusion. Insulin administered intranasally activated the Akt-kinase (activating the mTORC1 complex, which inhibits autophagy) and inhibited the AMP-activated protein kinase (which activates autophagy) in the hippocampus and frontal cortex of rats with brain ischemia and reperfusion. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Ischemia–Reperfusion Injury)

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