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Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics

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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 (31 January 2024) | Viewed by 14662

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Special Issue Editors

Prof. Dr. Joan Roselló-Catafau

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Guest Editor

Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain
Interests: organ (liver, pancreas, small intestine, kidney) transplantation; cell signaling molecular mechanisms in organ transplantation; graft therapeutics; preservation and preservation solutions
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. René Adam

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Guest Editor

Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, 94800 Paris, France
Interests: liver cancer; liver metastases; liver surgery; liver transplantation; ischemia–reperfusion; liver preservation; machine perfusion; liver graft dysfunction
Special Issues, Collections and Topics in MDPI journals

Dr. Teresa Carbonell Camós

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Guest Editor

Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
Interests: oxidants and antioxidants in physiology; intermittent hypoxia and neuroprotection in postischemic processes; molecular mechanisms induced by hypothermia in isolated rat liver
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ischemia–reperfusion injury (IRI) is inherent to surgery and organ resection and transplantation (TX). The cumulative damage due to ischemia and reperfusion associated with organ transplantation compromises the viability of the organ and its successful transplantation outcome. The present knowledge of underlying IRI pathophysiological mechanisms reveals a complex cell signaling crossroads that makes further therapeutic strategies difficult and justifies the in-depth investigation of the cell signaling pathways involved in IRI to prevent its adverse consequences more effectively and improve organ transplantation outcomes.

The advances in the study of IRI pathophysiology mechanisms are poor when compared to the development of immunosuppressive strategies in TX. For this reason, and continuing with the core idea of previous Special Issues, it is necessary to explore new insights into the molecular pathways involved in the complex pathophysiology of IRI, covering different perspectives, including different organs (heart, liver, kidney, pancreas, small intestine), with a special emphasis on the underlying mechanisms, including but not limited to the involvement of inflammatory mediators, mitochondrial dysfunction, apoptosis, and other potential markers associated with IRI.

This Special Issue calls for original research, full reviews, and perspectives that address the progress and current knowledge on the pathophysiological mechanisms of IRI in different organs. This includes protective graft preservation strategies with MP, surgical intervention, ischemic preconditioning/postconditioning, and pharmacological strategies including clinical and experimental settings. We welcome studies on the pathophysiological mechanisms involved in warm and cold ischemia and the inherent reperfusion and any strategy aimed at the prevention of IRI. Contributions are not limited to the fields that are mentioned in the keywords.

Prof. Dr. Joan Roselló-Catafau
Prof. Dr. René Adam
Dr. Teresa Carbonell Camós
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

ischemia–reperfusion injury
transplantation
liver
pancreas
small intestine
HOPE
glycocalyx
inflammation
oxidative and endoplasmic reticulum stress
pharmacological treatments

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Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics 2.0 in International Journal of Molecular Sciences (1 article)

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23 pages, 11243 KiB

Open AccessArticle

The CaMK Family Differentially Promotes Necroptosis and Mouse Cardiac Graft Injury and Rejection

by Haitao Lu, Jifu Jiang, Jeffery Min, Xuyan Huang, Patrick McLeod, Weihua Liu, Aaron Haig, Lakshman Gunaratnam, Anthony M. Jevnikar and Zhu-Xu Zhang

Int. J. Mol. Sci. 2024, 25(8), 4428; https://doi.org/10.3390/ijms25084428 - 17 Apr 2024

Viewed by 340

Abstract

Organ transplantation is associated with various forms of programmed cell death which can accelerate transplant injury and rejection. Targeting cell death in donor organs may represent a novel strategy for preventing allograft injury. We have previously demonstrated that necroptosis plays a key role in promoting transplant injury. Recently, we have found that mitochondria function is linked to necroptosis. However, it remains unknown how necroptosis signaling pathways regulate mitochondrial function during necroptosis. In this study, we investigated the receptor-interacting protein kinase 3 (RIPK3) mediated mitochondrial dysfunction and necroptosis. We demonstrate that the calmodulin-dependent protein kinase (CaMK) family members CaMK1, 2, and 4 form a complex with RIPK3 in mouse cardiac endothelial cells, to promote trans-phosphorylation during necroptosis. CaMK1 and 4 directly activated the dynamin-related protein-1 (Drp1), while CaMK2 indirectly activated Drp1 via the phosphoglycerate mutase 5 (PGAM5). The inhibition of CaMKs restored mitochondrial function and effectively prevented endothelial cell death. CaMKs inhibition inhibited activation of CaMKs and Drp1, and cell death and heart tissue injury (n = 6/group, p < 0.01) in a murine model of cardiac transplantation. Importantly, the inhibition of CaMKs greatly prolonged heart graft survival (n = 8/group, p < 0.01). In conclusion, CaMK family members orchestrate cell death in two different pathways and may be potential therapeutic targets in preventing cell death and transplant injury. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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18 pages, 1722 KiB

Open AccessArticle

Targeting Mitochondrial Dynamics during Lower-Limb Ischemia Reperfusion in Young and Old Mice: Effect of Mitochondrial Fission Inhibitor-1 (mDivi-1)

by Stéphanie Paradis, Anne-Laure Charles, Margherita Giannini, Alain Meyer, Anne Lejay, Samy Talha, Gilles Laverny, Anne Charloux and Bernard Geny

Int. J. Mol. Sci. 2024, 25(7), 4025; https://doi.org/10.3390/ijms25074025 - 04 Apr 2024

Viewed by 558

Abstract

Peripheral arterial disease (PAD) strikes more than 200 million people worldwide and has a severe prognosis by potentially leading to limb amputation and/or death, particularly in older patients. Skeletal muscle mitochondrial dysfunctions and oxidative stress play major roles in this disease in relation with ischemia-reperfusion (IR) cycles. Mitochondrial dynamics through impairment of fission–fusion balance may contribute to skeletal muscle pathophysiology, but no data were reported in the setting of lower-limb IR despite the need for new therapeutic options. We, therefore, investigated the potential protective effect of mitochondrial division inhibitor-1 (mDivi-1; 50 mg/kg) in young (23 weeks) and old (83 weeks) mice submitted to two-hour ischemia followed by two-hour reperfusion on systemic lactate, muscle mitochondrial respiration and calcium retention capacity, and on transcripts specific for oxidative stress and mitochondrial dynamics. At the systemic levels, an IR-related increase in circulating lactate was still major despite mDivi-1 use (+305.9% p < 0.0001, and +269.4% p < 0.0001 in young and old mice, respectively). Further, IR-induced skeletal muscle mitochondrial dysfunctions (more severely impaired mitochondrial respiration in old mice (OXPHOS CI state, –68.2% p < 0.0001 and −84.9% p < 0.0001 in 23- and 83-week mice) and reduced calcium retention capacity (–46.1% p < 0.001 and −48.2% p = 0.09, respectively) were not corrected by mDivi-1 preconditioning, whatever the age. Further, mDivi-1 treatment did not oppose superoxide anion production (+71.4% p < 0.0001 and +37.5% p < 0.05, respectively). At the transcript level, markers of antioxidant enzymes (SOD 1, SOD 2, catalase, and GPx) and fission markers (Drp1, Fis) remained unchanged or tended to be decreased in the ischemic leg. Fusion markers such as mitofusin 1 or 2 decreased significantly after IR in both groups. In conclusion, aging enhanced the deleterious effects or IR on muscle mitochondrial respiration, and in this setting of lower-limb IR, mDivi-1 failed to protect the skeletal muscle both in young and old mice. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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15 pages, 9890 KiB

Open AccessArticle

Sulforaphane Is Protective against Warm Ischemia/Reperfusion Injury and Partial Hepatectomy in Rats

by Richi Nakatake, Tetsuya Okuyama, Yuki Hashimoto, Morihiko Ishizaki, Hidesuke Yanagida, Hiroaki Kitade, Katsuhiko Yoshizawa, Mikio Nishizawa and Mitsugu Sekimoto

Int. J. Mol. Sci. 2024, 25(1), 579; https://doi.org/10.3390/ijms25010579 - 01 Jan 2024

Viewed by 1094

Abstract

Sulforaphane (SFN) has various beneficial effects on organ metabolism. However, whether SFN affects inflammatory mediators induced by warm hepatic ischemia/reperfusion injury (HIRI) is unclear. To investigate the hepatoprotective effects of SFN using an in vivo model of HIRI and partial hepatectomy (HIRI + PH), rats were subjected to 15 min of hepatic ischemia with blood inflow occlusion, followed by 70% hepatectomy and release of the inflow occlusion. SFN (5 mg/kg) or saline was randomly injected intraperitoneally 1 and 24 h before ischemia. Alternatively, ischemia was prolonged for 30 min to evaluate the effect on mortality. The influence of SFN on the associated signaling pathways was analyzed using the interleukin 1β (IL-1β)-treated primary cultured rat hepatocytes. In the HIRI + PH-treated rats, SFN reduced serum liver enzyme activities and the frequency of pathological liver injury, such as apoptosis and neutrophil infiltration. SFN suppressed tumor necrosis factor-alpha (TNF-α) mRNA expression and inhibited nuclear factor-kappa B (NF-κB) activation by HIRI + PH. Mortality was significantly reduced by SFN. In IL-1β-treated hepatocytes, SFN suppressed the expression of inflammatory cytokines and NF-κB activation. Taken together, SFN may have hepatoprotective effects in HIRI + PH in part by inhibiting the induction of inflammatory mediators, such as TNF-α, via the suppression of NF-κB in hepatocytes. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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17 pages, 2605 KiB

Open AccessArticle

INT-767—A Dual Farnesoid-X Receptor (FXR) and Takeda G Protein-Coupled Receptor-5 (TGR5) Agonist Improves Survival in Rats and Attenuates Intestinal Ischemia Reperfusion Injury

by Emilio Canovai, Ricard Farré, Alison Accarie, Mara Lauriola, Gert De Hertogh, Tim Vanuytsel, Jacques Pirenne and Laurens J. Ceulemans

Int. J. Mol. Sci. 2023, 24(19), 14881; https://doi.org/10.3390/ijms241914881 - 04 Oct 2023

Cited by 2 | Viewed by 1143

Abstract

Intestinal ischemia is a potentially catastrophic emergency, with a high rate of morbidity and mortality. Currently, no specific pharmacological treatments are available. Previous work demonstrated that pre-treatment with obeticholic acid (OCA) protected against ischemia reperfusion injury (IRI). Recently, a more potent and water-soluble version has been synthesized: Intercept 767 (INT-767). The aim of this study was to investigate if intravenous treatment with INT-767 can improve outcomes after IRI. In a validated rat model of IRI (60 min ischemia + 60 min reperfusion), three groups were investigated (n = 6/group): (i) sham: surgery without ischemia; (ii) IRI + vehicle; and (iii) IRI + INT-767. The vehicle (0.9% NaCl) or INT-767 (10 mg/kg) were administered intravenously 15 min after start of ischemia. Endpoints were 7-day survival, serum injury markers (L-lactate and I-FABP), histology (Park–Chiu and villus length), permeability (transepithelial electrical resistance and endotoxin translocation), and cytokine expression. Untreated, IRI was uniformly lethal by provoking severe inflammation and structural damage, leading to translocation and sepsis. INT-767 treatment significantly improved survival by reducing inflammation and preserving intestinal structural integrity. This study demonstrates that treatment with INT-767 15 min after onset of intestinal ischemia significantly decreases IRI and improves survival. The ability to administer INT-767 intravenously greatly enhances its clinical potential. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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15 pages, 3503 KiB

Open AccessArticle

The Distinct Innate Immune Response of Warm Ischemic Injured Livers during Continuous Normothermic Machine Perfusion

by Joris Blondeel, Nicholas Gilbo, Veerle Heedfeld, Tine Wylin, Louis Libbrecht, Ina Jochmans, Jacques Pirenne, Hannelie Korf and Diethard Monbaliu

Int. J. Mol. Sci. 2023, 24(16), 12831; https://doi.org/10.3390/ijms241612831 - 16 Aug 2023

Cited by 1 | Viewed by 933

Abstract

Although normothermic machine perfusion (NMP) provides superior preservation of liver grafts compared to static cold storage and allows for viability testing of high-risk grafts, its effect on the liver immune compartment remains unclear. We investigated the innate immune response during 6 h of continuous NMP (cNMP) of livers that were directly procured (DP, n = 5) or procured after 60 min warm ischemia (WI, n = 5), followed by 12 h of whole blood (WB) reperfusion. WI livers showed elevated transaminase levels during cNMP but not after WB reperfusion. Perfusate concentrations of TNF-α were lower in WI livers during cNMP and WB reperfusion, whereas IL-8 concentrations did not differ significantly. TGF-β concentrations were higher in WI livers during NMP but not after WB reperfusion, whereas IL-10 concentrations were similar. Endoplasmic stress and apoptotic signaling were increased in WI livers during cNMP but not after WB reperfusion. Additionally, neutrophil mobilization increased to a significantly lesser extent in WI livers at the end of NMP. In conclusion, WI livers exhibit a distinct innate immune response during cNMP compared to DP livers. The cytokine profile shifted towards an anti-inflammatory phenotype during cNMP and WB reperfusion, and pro-apoptotic signaling was stronger during cNMP. During WB reperfusion, livers exhibited a blunted cytokine release, regardless of ischemic damage, supporting the potential reconditioning effect of cNMP. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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13 pages, 2305 KiB

Open AccessArticle

Intravenous Polyethylene Glycol Alleviates Intestinal Ischemia-Reperfusion Injury in a Rodent Model

by Mathias Clarysse, Alison Accarie, Arnau Panisello-Roselló, Ricard Farré, Emilio Canovai, Diethard Monbaliu, Gert De Hertogh, Tim Vanuytsel, Jacques Pirenne and Laurens J. Ceulemans

Int. J. Mol. Sci. 2023, 24(13), 10775; https://doi.org/10.3390/ijms241310775 - 28 Jun 2023

Viewed by 952

Abstract

Intestinal ischemia-reperfusion injury (IRI) is a common clinical entity, and its outcome is unpredictable due to the triad of inflammation, increased permeability and bacterial translocation. Polyethylene glycol (PEG) is a polyether compound that is extensively used in pharmacology as an excipient in various products. More recently, this class of products have shown to have potent anti-inflammatory, anti-apoptotic, immunosuppressive and cell-membrane-stabilizing properties. However, its effects on the outcome after intestinal IRI have not yet been investigated. We hypothesized that PEG administration would reduce the effects of intestinal IRI in rodents. In a previously described rat model of severe IRI (45 min of ischemia followed by 60 min of reperfusion), we evaluated the effect of IV PEG administration at different doses (50 and 100 mg/kg) before and after the onset of ischemia. In comparison to control animals, PEG administration stabilized the endothelial glycocalyx, leading to reduced reperfusion edema, bacterial translocation and inflammatory reaction as well as improved 7-day survival. These effects were seen both in a pretreatment and in a treatment setting. The fact that this product is readily available and safe should encourage further clinical investigations in settings of intestinal IRI, organ preservation and transplantation. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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12 pages, 1945 KiB

Open AccessArticle

Heat Shock Protein 70 Is Involved in the Efficiency of Preconditioning with Cyclosporine A in Renal Ischemia Reperfusion Injury by Modulating Mitochondrial Functions

by Maxime Schleef, Margaux Rozes, Bruno Pillot, Gabriel Bidaux, Fitsum Guebre-Egziabher, Laurent Juillard, Delphine Baetz and Sandrine Lemoine

Int. J. Mol. Sci. 2023, 24(11), 9541; https://doi.org/10.3390/ijms24119541 - 31 May 2023

Viewed by 995

Abstract

Cyclosporine A (CsA) preconditioning is known to target mitochondrial permeability transition pore and protect renal function after ischemia reperfusion (IR). The upregulation of heat-shock protein 70 (Hsp70) expression after CsA injection is thought to be associated with renal protection. The aim of this study was to test the effect of Hsp70 expression on kidney and mitochondria functions after IR. Mice underwent a right unilateral nephrectomy and 30 min of left renal artery clamping, performed after CsA injection and/or administration of the Hsp70 inhibitor. Histological score, plasma creatinine, mitochondrial calcium retention capacity, and oxidative phosphorylation were assessed after 24 h of reperfusion. In parallel, we used a model of hypoxia reoxygenation on HK2 cells to modulate Hsp70 expression using an SiRNA or a plasmid. We assessed cell death after 18 h of hypoxia and 4 h of reoxygenation. CsA significantly improved renal function, histological score, and mitochondrial functions compared to the ischemic group but the inhibition of Hsp70 repealed the protection afforded by CsA injection. In vitro, Hsp70 inhibition by SiRNA increased cell death. Conversely, Hsp70 overexpression protected cells from the hypoxic condition, as well as the CsA injection. We did not find a synergic association between Hsp70 expression and CsA use. We demonstrated Hsp70 could modulate mitochondrial functions to protect kidneys from IR. This pathway may be targeted by drugs to provide new therapeutics to improve renal function after IR. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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22 pages, 8174 KiB

Open AccessArticle

The Landscape of Aberrant Alternative Splicing Events in Steatotic Liver Graft Post Transplantation via Transcriptome-Wide Analysis

by Hui Liu, Yueqin Zhu, Kevin Tak-Pan Ng, Chung-Mau Lo and Kwan Man

Int. J. Mol. Sci. 2023, 24(9), 8216; https://doi.org/10.3390/ijms24098216 - 04 May 2023

Viewed by 1894

Abstract

The application of steatotic liver graft has been increased significantly due to the severe donor shortage and prevalence of non-alcoholic fatty liver disease. However, steatotic donor livers are vulnerable to acute phase inflammatory injury, which may result in cancer recurrence. Alternative splicing events (ASEs) are critical for diverse transcriptional variants in hepatocellular carcinoma (HCC). Here, we aimed to depict the landscape of ASEs, as well as to identify the differential ASEs in steatotic liver graft and their association with tumor recurrence after transplantation. The overall portrait of intragraft transcripts and ASEs were elucidated through RNA sequencing with the liver graft biopsies from patients and rat transplant models. Various differential ASEs were identified in steatotic liver grafts. CYP2E1, ADH1A, CYP2C8, ADH1C, and HGD, as corresponding genes to the common pathways involved differential ASEs in human and rats, were significantly associated with HCC patients’ survival. The differential ASEs related RNA-binding proteins (RBPs) were enriched in metabolic pathways. The altered immune cell distribution, particularly macrophages and neutrophils, were perturbated by differential ASEs. The cancer hallmarks were enriched in steatotic liver grafts and closely associated with differential ASEs. Our work identified the differential ASE network with metabolic RBPs, immune cell distribution, and cancer hallmarks in steatotic liver grafts. We verified the link between steatotic liver graft injury and tumor recurrence at post-transcriptional level, offered new evidence to explore metabolism and immune responses, and provided the potential prognostic and therapeutic markers for tumor recurrence. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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16 pages, 3680 KiB

Open AccessArticle

DUSP6 Deficiency Attenuates Neurodegeneration after Global Cerebral Ischemia

by Yi-Chinn Weng, Yu-Ting Huang, I-Chen Chiang, Huai-Chia Chuang, Tsong-Hai Lee, Tse-Hua Tan and Wen-Hai Chou

Int. J. Mol. Sci. 2023, 24(9), 7690; https://doi.org/10.3390/ijms24097690 - 22 Apr 2023

Cited by 2 | Viewed by 1213

Abstract

Transient global cerebral ischemia (tGCI) resulting from cardiac arrest causes selective neurodegeneration in hippocampal CA1 neurons. Although the effect is clear, the underlying mechanisms directing this process remain unclear. Previous studies have shown that phosphorylation of Erk1/2 promotes cell survival in response to tGCI. DUSP6 (also named MKP3) serves as a cytosolic phosphatase that dephosphorylates Erk1/2, but the role of DUSP6 in tGCI has not been characterized. We found that DUSP6 was specifically induced in the cytoplasm of hippocampal CA1 neurons 4 to 24 h after tGCI. DUSP6-deficient mice showed normal spatial memory acquisition and retention in the Barnes maze. Impairment of spatial memory acquisition and retention after tGCI was attenuated in DUSP6-deficient mice. Neurodegeneration after tGCI, revealed by Fluoro-Jade C and H&E staining, was reduced in the hippocampus of DUSP6-deficient mice and DUSP6 deficiency enhanced the phosphorylation and nuclear translocation of Erk1/2 in the hippocampal CA1 region. These data support the role of DUSP6 as a negative regulator of Erk1/2 signaling and indicate the potential of DUSP6 inhibition as a novel therapeutic strategy to treat neurodegeneration after tGCI. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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14 pages, 5207 KiB

Open AccessArticle

Effects of Aloe-Emodin on the Expression of Brain Aquaporins and Secretion of Neurotrophic Factors in a Rat Model of Post-Stroke Depression

by Yang Liu, Jing Peng, Qinjie Leng, Yang Tian, Xiaoqing Wu and Rui Tan

Int. J. Mol. Sci. 2023, 24(6), 5206; https://doi.org/10.3390/ijms24065206 - 08 Mar 2023

Cited by 1 | Viewed by 1601

Abstract

Post-stroke depression (PSD) is a common complication of stroke that can damage patients’ brains. More and more studies have been conducted on PSD in recent years, but the exact mechanism is still not understood. Currently, animal models provide an alternative approach to better understand the pathophysiology of PSD and may also pave the way for the discovery of new treatments for depression. This study investigated the therapeutic effect and mechanism of aloe-emodin (AE) on PSD rats. Previous studies have shown that AE positively affects PSD in rats by improving depression, increasing their activities and curiosities, enhancing the number of neurons, and ameliorating damage to brain tissue. Meanwhile, AE could up-regulate the expression of brain-derived neurotrophic factor (BDNF) and neurotrophic 3 (NTF3), but it could also down-regulate the expression of aquaporins (AQP3, AQP4, and AQP5), glial fibrillary acidic protein (GFAP), and transient receptor potential vanilloid 4 (TRPV4), which is helpful in maintaining homeostasis and alleviating encephaledema. AE may be a prospective solution in the future for the treatment of PSD patients. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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Review

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13 pages, 2688 KiB

Open AccessReview

Ischemia–Reperfusion Injury in Kidney Transplantation: Mechanisms and Potential Therapeutic Targets

by Francesco Lasorsa, Monica Rutigliano, Martina Milella, Antonio d’Amati, Felice Crocetto, Savio Domenico Pandolfo, Biagio Barone, Matteo Ferro, Marco Spilotros, Michele Battaglia, Pasquale Ditonno and Giuseppe Lucarelli

Int. J. Mol. Sci. 2024, 25(8), 4332; https://doi.org/10.3390/ijms25084332 - 14 Apr 2024

Viewed by 433

Abstract

Kidney transplantation offers a longer life expectancy and a better quality of life than dialysis to patients with end-stage kidney disease. Ischemia–reperfusion injury (IRI) is thought to be a cornerstone in delayed or reduced graft function and increases the risk of rejection by triggering the immunogenicity of the organ. IRI is an unavoidable event that happens when the blood supply is temporarily reduced and then restored to an organ. IRI is the result of several biological pathways, such as transcriptional reprogramming, apoptosis and necrosis, innate and adaptive immune responses, and endothelial dysfunction. Tubular cells mostly depend on fatty acid (FA) β-oxidation for energy production since more ATP molecules are yielded per substrate molecule than glucose oxidation. Upon ischemia–reperfusion damage, the innate and adaptive immune system activates to achieve tissue clearance and repair. Several cells, cytokines, enzymes, receptors, and ligands are known to take part in these events. The complement cascade might start even before organ procurement in deceased donors. However, additional experimental and clinical data are required to better understand the pathogenic events that take place during this complex process. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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19 pages, 5700 KiB

Open AccessReview

Extracellular Vesicles in Liver Transplantation: Current Evidence and Future Challenges

by Nicola De Stefano, Alberto Calleri, Angelo Corso Faini, Victor Navarro-Tableros, Silvia Martini, Silvia Deaglio, Damiano Patrono and Renato Romagnoli

Int. J. Mol. Sci. 2023, 24(17), 13547; https://doi.org/10.3390/ijms241713547 - 31 Aug 2023

Cited by 1 | Viewed by 1159

Abstract

Extracellular vesicles (EVs) are emerging as a promising field of research in liver disease. EVs are small, membrane-bound vesicles that contain various bioactive molecules, such as proteins, lipids, and nucleic acids and are involved in intercellular communication. They have been implicated in numerous physiological and pathological processes, including immune modulation and tissue repair, which make their use appealing in liver transplantation (LT). This review summarizes the current state of knowledge regarding the role of EVs in LT, including their potential use as biomarkers and therapeutic agents and their role in graft rejection. By providing a comprehensive insight into this emerging topic, this research lays the groundwork for the potential application of EVs in LT. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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Other

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15 pages, 515 KiB

Open AccessPerspective

Ischemia-Reperfusion Programming of Alzheimer’s Disease-Related Genes—A New Perspective on Brain Neurodegeneration after Cardiac Arrest

by Ryszard Pluta and Stanisław J. Czuczwar

Int. J. Mol. Sci. 2024, 25(2), 1291; https://doi.org/10.3390/ijms25021291 - 20 Jan 2024

Viewed by 1086

Abstract

The article presents the latest data on pathological changes after cerebral ischemia caused by cardiac arrest. The data include amyloid accumulation, tau protein modification, neurodegenerative and cognitive changes, and gene and protein changes associated with Alzheimer’s disease. We present the latest data on the dysregulation of genes related to the metabolism of the amyloid protein precursor, tau protein, autophagy, mitophagy, apoptosis, and amyloid and tau protein transport genes. We report that neuronal death after cerebral ischemia due to cardiac arrest may be dependent and independent of caspase. Moreover, neuronal death dependent on amyloid and modified tau protein has been demonstrated. Finally, the results clearly indicate that changes in the expression of the presented genes play an important role in acute and secondary brain damage and the development of post-ischemic brain neurodegeneration with the Alzheimer’s disease phenotype. The data indicate that the above genes may be a potential therapeutic target for brain therapy after ischemia due to cardiac arrest. Overall, the studies show that the genes studied represent attractive targets for the development of new therapies to minimize ischemic brain injury and neurological dysfunction. Additionally, amyloid-related genes expression and tau protein gene modification after cerebral ischemia due to cardiac arrest are useful in identifying ischemic mechanisms associated with Alzheimer’s disease. Cardiac arrest illustrates the progressive, time- and area-specific development of neuropathology in the brain with the expression of genes responsible for the processing of amyloid protein precursor and the occurrence of tau protein and symptoms of dementia such as those occurring in patients with Alzheimer’s disease. By carefully examining the common genetic processes involved in these two diseases, these data may help unravel phenomena associated with the development of Alzheimer’s disease and neurodegeneration after cerebral ischemia and may lead future research on Alzheimer’s disease or cerebral ischemia in new directions. Full article

(This article belongs to the Special Issue Ischemia Reperfusion Injury: A Cell Signaling Crossroads and Therapeutics)

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