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New Molecular Insights into Ischemia/Reperfusion: 2nd Edition

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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: 20 June 2026 | Viewed by 12008

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Prof. Dr. Moo-Ho Won

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Department of Emergency Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 24289, Republic of Korea
Interests: ischemia/reperfusion; neurodegeneration; neurogenesis; cerebral ischemia; aging in CNS
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Dear Colleagues,

Ischemia/reperfusion (IR) causes a complex pathophysiological process, called IR injury, defined as the paradoxical exacerbation of cellular dysfunction and death following the restoration of blood flow to previously ischemic tissues. IR injury happens in a wide range of organs, including the heart, brain, spinal cord, gut, kidney, and skeletal muscle. IR injury not only involves the ischemic organ itself but also induces systemic damage to distant organs. Huge efforts have been made to develop potential treatments for IR injury, but the molecular and cellular mechanisms of IR injury are not fully understood regarding organs. Therefore, many researchers have been investigating the mechanisms of IR injury in diverse organs using various experimental animal models of IR injury (i.e., different methods of the occlusion of blood vessels and different periods of occlusion time). Principally, the mechanisms of IR injury include excitotoxicity, oxidative stress, and inflammation. Nevertheless, the mechanisms are significantly different depending on the organs. For instance, blood–brain (spinal cord) barrier damage is one of the mechanisms of IR injury in the central nervous system. Therefore, investigation into the molecular mechanisms of IR injury in various organs is warranted so that we can treat or protect against IR injury. Thus, this Special Issue will focus ischemia/reperfusion in various organs, including the heart, brain, spinal cord, liver, and kidneys.

Prof. Dr. Moo-Ho Won
Guest Editor

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Keywords

vital organs
ischemic injury
cell and organ dysfunction
oxidative stress
inflammation
excitotoxicity

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New Molecular Insights into Ischemia/Reperfusion in International Journal of Molecular Sciences (8 articles)

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Research

Jump to: Review

18 pages, 2995 KB

Open AccessArticle

Enhanced Retinal Ganglion Cell Survival via Autophagy Activation in a Novel Retinal Ischemia/Reperfusion Rat Model

by Si Hyung Lee, Jung Woo Han, Su-ah Yoon, Hun Soo Chang and Tae Kwann Park

Int. J. Mol. Sci. 2026, 27(2), 1031; https://doi.org/10.3390/ijms27021031 - 20 Jan 2026

Viewed by 609

Abstract

Autophagy is a fundamental catabolic process that degrades and recycles intracellular components, serving as a key survival mechanism in neurons. In glaucomatous optic neuropathy, autophagy has been linked to both protection of retinal ganglion cells (RGCs) and their accelerated loss, yet its precise impact remains unresolved. In this study, we established and validated a straightforward rat model of retinal ischemia/reperfusion (I/R) using double circumlimbal sutures, which reliably produced RGC apoptosis, retinal thinning, and axonal degeneration compared with controls. Early after reperfusion (1–6 h), robust induction of the autophagy marker LC3B was observed, but this activation diminished within 48 h. Other autophagy-related proteins, including ATG4, ATG7, Beclin-1, and p62, followed similar temporal patterns, while components of the mammalian target of rapamycin (mTOR) pathway displayed an inverse time course. Pharmacologic suppression of mTOR with intravitreal rapamycin administered prior to ischemia provided the most significant neuroprotection, whereas post-injury treatment yielded minimal benefit. Collectively, these findings indicate that timely stimulation of autophagy before retinal ischemic injury can enhance RGC survival and may represent a therapeutic potential for glaucoma management. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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11 pages, 2189 KB

Open AccessArticle

Assessment of Anxiety- and Depression-like Behaviors and Local Field Potential Changes in a Cryogenic Lesion Model of Traumatic Brain Injury

by Yeon Hee Yu, Yu Ran Lee, Dae-Kyoon Park, Beomjong Song and Duk-Soo Kim

Int. J. Mol. Sci. 2026, 27(2), 597; https://doi.org/10.3390/ijms27020597 - 7 Jan 2026

Viewed by 608

Abstract

Patients with traumatic brain injury (TBI) have an elevated risk of developing chronic psychiatric and behavioral disorders, including impairments in motor function, memory deficits, anxiety, and depression. Although a substantial body of work has addressed the treatment and rehabilitation of sensory, motor, and cognitive symptoms after TBI, there is a relative scarcity of comprehensive behavioral assessments targeting neuropsychiatric manifestations in preclinical models. This study aims to investigate the connections between emotional sequelae after TBI and modifications in local field potentials (LFPs). Following cryogenic lesion-induced TBI, animals exhibited anxiety-like behaviors as assessed by the open field test (p < 0.001), light/dark box test (p < 0.001), and elevated plus maze test (p < 0.01). Depression-like behavior was observed using the forced swim test (p < 0.001). LFP analysis demonstrated a marked elevation in neural oscillatory activity associated with anxiety and depression in the contralateral hemisphere relative to the ipsilateral side (p < 0.001). These results indicate that the emotional consequences triggered by TBI may be linked to dysregulated synchronous neural activity between the ipsilateral and contralateral hemispheres. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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17 pages, 2190 KB

Open AccessArticle

Lidocaine Attenuates miRNA Dysregulation and Kinase Signaling Activation in a Porcine Model of Lung Ischemia/Reperfusion Injury

by Alberto Alonso, Sergio D. Paredes, Agustín Turrero, Lisa Rancan, Ignacio Garutti, Carlos Simón and Elena Vara

Int. J. Mol. Sci. 2025, 26(21), 10385; https://doi.org/10.3390/ijms262110385 - 25 Oct 2025

Viewed by 692

Abstract

Ischemia/reperfusion (I/R) injury is a major complication in lung transplantation. Recent evidence suggests that mitogen-activated protein kinases (MAPKs) such as p-38 mitogen-activated protein kinase (p-38 MAPK) and extracellular signal-regulated kinase (ERK), along with functionally related kinases like phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), contribute to I/R pathophysiology by mediating inflammatory and stress-response signaling. MicroRNAs (miRNAs) also play a regulatory role in these processes. Lidocaine has demonstrated anti-inflammatory activity in several tissues; however, its ability to modulate miRNA expression and kinase activation in the lung is not yet fully understood. This study investigated the involvement of these signaling molecules in lung I/R injury and evaluated the modulatory effect of intravenous lidocaine in a porcine lung auto-transplantation model. Eighteen large white pigs were assigned to sham-operated (n = 6), control (lung auto-transplantation, n = 6), or lidocaine-treated (n = 6) groups. Lidocaine was administered as a 1.5 mg/kg bolus followed by a continuous infusion (1.5 mg·kg⁻¹·h⁻¹). Lung biopsies were collected before ischemia, before reperfusion, and at 30- and 60-min post-reperfusion to assess total and phosphorylated levels of p-38 MAPK, ERK, PI3K, and AKT (Thr308, Ser473), along with miR-126, miR-142-5p, miR-152, and miR-155 expression. I/R increased p-38 MAPK and AKT, and enhanced phosphorylation of all four kinases. miRNA levels were also upregulated. Lidocaine partially or completely attenuated these changes. These findings support a role for these molecular pathways in lung I/R injury and suggest that lidocaine may offer protective effects through their modulation. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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10 pages, 2454 KB

Open AccessArticle

Glibenclamide Serves as a Potent Vasopressor to Treat Vasoplegia After Cardiopulmonary Bypass and Reperfusion in a Porcine Model

by Andreas Winter, Pascal Nepper, Marcus Hermann, Franziska Bayer, Stephanie Riess, Razan Salem, Jan Hlavicka, Anatol Prinzing, Florian Hecker, Tomas Holubec, Kai Zacharowski, Thomas Walther and Fabian Emrich

Int. J. Mol. Sci. 2025, 26(9), 4040; https://doi.org/10.3390/ijms26094040 - 24 Apr 2025

Cited by 2 | Viewed by 1083

Abstract

The hemodynamic stabilization of patients after complex cardiac surgery is a daily challenge. The use of high doses of catecholamines is common but has potential adverse effects. Glibenclamide, a K_ATP blocker, seems to attenuate vasoplegia in different animal models of septic shock. Therefore, the aim of this study was to investigate the impact of Glibenclamide on the vasoplegic syndrome after cardiopulmonary bypass in a porcine model. In this experimental study, 20 landrace pigs were randomized into two groups and examined: In the control group, standard medical therapy, including norepinephrine, was used, and in the study group standard medical therapy plus additional Glibenclamide was administered. Following general anesthesia, prolonged cardiopulmonary bypass and aortic cross-clamping was performed. In the study group, Glibenclamide was administered 45 min after weaning from cardiopulmonary bypass. The dosage used was 10 mg/kg as a bolus, followed by a continuous infusion of 10 mg/kg/h. Hemodynamic and laboratory measurements were performed. Glibenclamide had a relevant effect on circulatory parameters. With increasing vascular resistance and blood pressure, norepinephrine was able to be reduced. While the heart rate dropped to physiological levels, the cardiac index decreased as well. The results lead to the conclusion that Glibenclamide was able to break through vasoplegic syndrome and could therefore serve as a potent drug to stabilize patients after cardiac surgery. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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Review

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14 pages, 1229 KB

Open AccessReview

Myocardial Ischemia–Reperfusion Injury—Mechanistic Insights and Novel Therapeutics

by Dong-Yeon Han, Hyo-Suk Ahn and Hun-Jun Park

Int. J. Mol. Sci. 2026, 27(5), 2106; https://doi.org/10.3390/ijms27052106 - 24 Feb 2026

Viewed by 1317

Abstract

Myocardial ischemia–reperfusion (I/R) injury remains a major contributor to infarct expansion and adverse cardiac remodeling despite advances in timely reperfusion therapy. Although restoration of blood flow is essential for myocardial salvage, the abrupt transition from ischemia to reperfusion paradoxically exacerbates cardiomyocyte injury through profound metabolic, ionic, and mitochondrial disturbances. Reperfusion should be viewed not simply as restoration of blood flow, but as a critical biological transition that converts ischemic stress into a self-amplifying injury network. Reperfusion induces excessive reactive oxygen species generation, calcium overload, endothelial barrier disruption, and dysregulated innate immune activation, which converge on mitochondrial dysfunction and diverse forms of cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Emerging evidence highlights that these pathological processes are tightly interconnected through damage-associated molecular pattern signaling, microvascular leakage, and inflammatory amplification, underscoring the limitations of single-target therapeutic approaches. This review summarizes the molecular and cellular mechanisms underlying myocardial I/R injury with a particular focus on oxidative stress, immune modulation, vascular integrity, and ferroptosis. We further discuss current and emerging cardioprotective strategies, including antioxidant therapies, modulation of neutrophil recruitment, microvascular leakage blockade, and anti-ferroptotic interventions. Finally, we address key translational challenges and future perspectives for developing integrated cardioprotective therapies aimed at improving clinical outcomes in acute myocardial infarction. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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25 pages, 1898 KB

Open AccessReview

Molecular Mechanisms, Dynamic Lesions, and Therapeutic Targets in Intestinal Ischemia–Reperfusion Injury: A Systematic Review

by Julia Marton, Răzvan Alexandru Ciocan, Ioana Bâldea, Mădălina Luciana Gherman, Dan Gheban, Adriana Filip, Ionuț Răzvan Pașcalău, Florin Vasile Mihăileanu, Raluca Maria Pop and Claudia Diana Gherman

Int. J. Mol. Sci. 2026, 27(4), 1763; https://doi.org/10.3390/ijms27041763 - 12 Feb 2026

Cited by 1 | Viewed by 760

Abstract

Intestinal ischemia–reperfusion injury (IRI) represents a major cause of morbidity and mortality in abdominal surgery, trauma, and intestinal transplantation. The pathophysiological process involves a biphasic cascade that begins with ischemic hypoxia and progresses to amplified cellular and molecular injury upon reperfusion. This review synthesizes recent mechanistic insights regarding endothelial and microvascular dysfunction, epithelial barrier breakdown, microbiota-driven systemic propagation, and the involvement of oxidative/nitrosative stress and inflammatory signaling. The novelty of our review’s approach is the focus on experimental and translational studies and correlation of the data with future directions for mechanistic research and clinical implementation. Despite promising preclinical results, heterogeneity in study protocols or/and model limitations make clinical translation challenging. Recent studies have demonstrated that mitochondria, tight junction proteins, adhesion molecules and innate immune receptors are critical determinants of lesion evolution. Based on these, the current therapeutic strategies include antioxidants, adenosine pathway modulators, dexmedetomidine, ischemic conditioning, hyperbaric oxygen therapy, and microbiota-targeted interventions. Since each mechanism is acting on distinct molecular pathways, a multimodal therapy that integrates redox modulation, endothelial protection, microbiome regulation, and the identification and employment of precision biomarkers is likely to improve outcomes. Beyond summarizing established molecular mechanisms, this review critically reassesses why decades of promising experimental strategies for intestinal ischemia–reperfusion injury has largely failed to translate into effective clinical therapies. By distinguishing context-dependent mechanisms from pathways with consistent translational relevance, we highlight key methodological and biological barriers limiting clinical applicability. Furthermore, we propose a temporally structured, multimodal therapeutic framework that integrates phase-specific pathophysiology with targeted interventions, aiming to inform future experimental design and improve translational success. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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19 pages, 1548 KB

Open AccessReview

Oxygen-Mediated Molecular Mechanisms Involved in Intestinal Ischemia and Reperfusion Injury

by Paraschos Archontakis-Barakakis, Theodoros Mavridis and Athanasios Chalkias

Int. J. Mol. Sci. 2025, 26(17), 8398; https://doi.org/10.3390/ijms26178398 - 29 Aug 2025

Cited by 3 | Viewed by 2200

Abstract

The gastrointestinal tract is affected by multiple ailments that manifest with similar chemical, subcellular, and cellular changes, such as those in intestinal ischemia–reperfusion injury (IRI). The main chemical changes that are described under IRI conditions include the depletion of oxygen available for normal metabolism and the abundant production and increase in intracellular and extracellular concentrations of hydrogen peroxide and other reactive oxygen species (ROS). The enzymes causing this accumulation are xanthine dehydrogenase turning into xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase, and nitric oxide synthase. The cellular changes revolve around an oxygen-sensing system that is responsive to varying oxygen levels, which has Hypoxia-Inducible Factors (HIFs) at its base. HIFs are transcription factors, the intracellular concentrations of which significantly increase under hypoxic conditions. Upon activation, they alter the expression of gene sets to ensure appropriate cellular adjustment to the hypoxic and IRI environment. Despite the primary regulation of the system involving oxygen, it is interconnected with multiple other subcellular and cellular functions. Thus, it represents a linchpin control mechanism of cellular adaptation. The effect of HIF activation in intestinal cells aims at preserving the structural integrity of the intestinal lining. The effect in different subtypes of leucocytes aims at immune system activation to protect against previously luminally located and subsequently invading pathogens and toxins. All in all, the HIF system is an integral part of cellular and tissue compensation against intestinal IRI. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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22 pages, 757 KB

Open AccessReview

Carbon Monoxide as a Molecular Modulator of Ischemia–Reperfusion Injury: New Insights for Translational Application in Organ Transplantation

by Zhouyu Li, Kazuhiro Takeuchi, Yuichi Ariyoshi, Akira Kondo, Takehiro Iwanaga, Yurika Ichinari, Akiyuki Iwamoto, Kenya Shimizu, Kohei Miura, Shiori Miura, Lina Ma, Mitsuhiro Sekijima, Masayoshi Okumi and Hisashi Sahara

Int. J. Mol. Sci. 2025, 26(16), 7825; https://doi.org/10.3390/ijms26167825 - 13 Aug 2025

Cited by 2 | Viewed by 1771

Abstract

Carbon monoxide (CO) is generally recognized as a toxic gas; however, it has recently been identified as an endogenous gasotransmitter with significant cytoprotective properties. CO modulates key molecular pathways, including anti-inflammatory, anti-apoptotic, antioxidant, and vasodilatory signaling pathways, by targeting heme- and non-heme-containing proteins. These proteins include soluble guanylate cyclase, cytochrome P450 enzymes, MAPKs, and NLRP3. This review summarizes recent advances in understanding the molecular mechanisms associated with the protective effects of CO, particularly in the context of ischemia–reperfusion injury relevant to organ transplantation. We discuss preclinical data from rodent and large animal models, as well as therapeutic delivery strategies, such as inhalation, CO-releasing molecules, and gas-entrapping materials. We also reviewed early-phase clinical trials. The objective of this review is to provide a thorough exploration of CO as a potential therapeutic gas, with special emphasis on its application in transplantation. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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16 pages, 1400 KB

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Factors Contributing to Resistance to Ischemia-Reperfusion Injury in Olfactory Mitral Cells

by Choong-Hyun Lee, Ji Hyeon Ahn and Moo-Ho Won

Int. J. Mol. Sci. 2025, 26(11), 5079; https://doi.org/10.3390/ijms26115079 - 25 May 2025

Cited by 1 | Viewed by 1944

Abstract

Brain ischemia-reperfusion (IR) injury is a critical pathological process that leads to extensive neuronal death, with hippocampal pyramidal cells, particularly those in the cornu Ammonis 1 (CA1) subfield, being highly vulnerable. Until now, human olfactory mitral cell resistance to IR injury has not been directly studied, but olfactory dysfunction in humans is frequently reported in systemic vascular conditions such as ischemic heart failure and may serve as an early clinical marker of neurological or cardiovascular disease. Mitral cells, the principal neurons of the olfactory bulb (OB), exhibit remarkable resistance to IR injury, suggesting the presence of unique molecular adaptations that support their survival under ischemic stress. Several factors may contribute to the resilience of mitral cells. They have a lower susceptibility to excitotoxicity, mitigating the harmful effects of excessive glutamate signaling. Additionally, they maintain efficient calcium homeostasis, preventing calcium overload—a major trigger for cell death in vulnerable neurons. Mitral cells may also express high baseline levels of antioxidant enzymes and their activities, counteracting oxidative stress. Their robust mitochondrial function enhances energy production and reduces susceptibility to metabolic failure. Furthermore, neuroprotective signaling pathways, including phosphatidylinositol-3-kinase (PI3K)/Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated antioxidative responses, further bolster their resistance. In addition to these intrinsic mechanisms, the unique microvascular architecture and metabolic support within the olfactory bulb provide an extra layer of protection. By comparing mitral cells to ischemia-sensitive neurons, key vulnerabilities—such as oxidative stress, excitotoxicity, calcium dysregulation, and mitochondrial dysfunction—can be identified and potentially mitigated in other brain regions. Understanding these molecular determinants of neuronal survival may offer valuable insights for developing novel neuroprotective strategies to combat IR injury in highly vulnerable areas, such as the hippocampus and cortex. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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