International Journal of Molecular Sciences

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26 pages, 26078 KiB

Open AccessArticle

The Effects of a Meldonium Pre-Treatment on the Course of the Faecal-Induced Sepsis in Rats

by Siniša Đurašević, Aleksandra Ružičić, Iva Lakić, Tomislav Tosti, Saša Đurović, Sofija Glumac, Slađan Pavlović, Slavica Borković-Mitić, Ilijana Grigorov, Sanja Stanković, Nebojša Jasnić, Jelena Đorđević and Zoran Todorović

Int. J. Mol. Sci. 2021, 22(18), 9698; https://doi.org/10.3390/ijms22189698 - 8 Sep 2021

Cited by 5 | Viewed by 3324

Abstract

Sepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by an exaggerated pro-inflammatory state and lipid metabolism disturbance leading to sequential organ failure. Meldonium is an anti-ischemic and anti-inflammatory agent which negatively interferes with lipid metabolism by [...] Read more.

Sepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by an exaggerated pro-inflammatory state and lipid metabolism disturbance leading to sequential organ failure. Meldonium is an anti-ischemic and anti-inflammatory agent which negatively interferes with lipid metabolism by shifting energy production from fatty acid oxidation to glycolysis, as a less oxygen-demanding pathway. Thus, we investigated the effects of a four-week meldonium pre-treatment on faecal-induced sepsis in Sprague-Dawley male rats. Surprisingly, under septic conditions, meldonium increased animal mortality rate compared with the meldonium non-treated group. However, analysis of the tissue oxidative status did not provide support for the detrimental effects of meldonium, nor did the analysis of the tissue inflammatory status showing anti-inflammatory, anti-apoptotic, and anti-necrotic effects of meldonium. After performing tissue lipidomic analysis, we concluded that the potential cause of the meldonium harmful effect is to be found in the overall decreased lipid metabolism. The present study underlines the importance of uninterrupted energy production in sepsis, closely drawing attention to the possible harmful effects of lipid-mobilization impairment caused by certain therapeutics. This could lead to the much-needed revision of the existing guidelines in the clinical treatment of sepsis while paving the way for discovering new therapeutic approaches. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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16 pages, 3943 KiB

Open AccessArticle

Preconditioning-Activated AKT Controls Neuronal Tolerance to Ischemia through the MDM2–p53 Pathway

by Emilia Barrio, Rebeca Vecino, Irene Sánchez-Morán, Cristina Rodríguez, Alberto Suárez-Pindado, Juan P. Bolaños, Angeles Almeida and Maria Delgado-Esteban

Int. J. Mol. Sci. 2021, 22(14), 7275; https://doi.org/10.3390/ijms22147275 - 6 Jul 2021

Cited by 11 | Viewed by 3224

Abstract

One of the most important mechanisms of preconditioning-mediated neuroprotection is the attenuation of cell apoptosis, inducing brain tolerance after a subsequent injurious ischemia. In this context, the antiapoptotic PI3K/AKT signaling pathway plays a key role by regulating cell differentiation and survival. Active AKT [...] Read more.

One of the most important mechanisms of preconditioning-mediated neuroprotection is the attenuation of cell apoptosis, inducing brain tolerance after a subsequent injurious ischemia. In this context, the antiapoptotic PI3K/AKT signaling pathway plays a key role by regulating cell differentiation and survival. Active AKT is known to increase the expression of murine double minute-2 (MDM2), an E3-ubiquitin ligase that destabilizes p53 to promote the survival of cancer cells. In neurons, we recently showed that the MDM2–p53 interaction is potentiated by pharmacological preconditioning, based on subtoxic stimulation of NMDA glutamate receptor, which prevents ischemia-induced neuronal apoptosis. However, whether this mechanism contributes to the neuronal tolerance during ischemic preconditioning (IPC) is unknown. Here, we show that IPC induced PI3K-mediated phosphorylation of AKT at Ser⁴⁷³, which in turn phosphorylated MDM2 at Ser¹⁶⁶. This phosphorylation triggered the nuclear stabilization of MDM2, leading to p53 destabilization, thus preventing neuronal apoptosis upon an ischemic insult. Inhibition of the PI3K/AKT pathway with wortmannin or by AKT silencing induced the accumulation of cytosolic MDM2, abrogating IPC-induced neuroprotection. Thus, IPC enhances the activation of PI3K/AKT signaling pathway and promotes neuronal tolerance by controlling the MDM2–p53 interaction. Our findings provide a new mechanistic pathway involved in IPC-induced neuroprotection via modulation of AKT signaling, suggesting that AKT is a potential therapeutic target against ischemic injury. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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16 pages, 4513 KiB

Open AccessArticle

Evaluating the Effects of Subnormothermic Perfusion with AP39 in a Novel Blood-Free Model of Ex Vivo Kidney Preservation and Reperfusion

by Smriti Juriasingani, Ashley Jackson, Max Yulin Zhang, Aushanth Ruthirakanthan, George J. Dugbartey, Emrullah Sogutdelen, Max Levine, Moaath Mandurah, Matthew Whiteman, Patrick Luke and Alp Sener

Int. J. Mol. Sci. 2021, 22(13), 7180; https://doi.org/10.3390/ijms22137180 - 2 Jul 2021

Cited by 19 | Viewed by 3826

Abstract

The use of blood for normothermic and subnormothermic kidney preservation hinders the translation of these approaches and promising therapeutics. This study evaluates whether adding hydrogen sulfide donor AP39 to Hemopure, a blood substitute, during subnormothermic perfusion improves kidney outcomes. After 30 min of [...] Read more.

The use of blood for normothermic and subnormothermic kidney preservation hinders the translation of these approaches and promising therapeutics. This study evaluates whether adding hydrogen sulfide donor AP39 to Hemopure, a blood substitute, during subnormothermic perfusion improves kidney outcomes. After 30 min of renal pedicle clamping, porcine kidneys were treated to 4 h of static cold storage (SCS-4 °C) or subnormothermic perfusion at 21 °C with Hemopure (H-21 °C), Hemopure + 200 nM AP39 (H200nM-21 °C) or Hemopure + 1 µM AP39 (H1µM-21 °C). Then, kidneys were reperfused with Hemopure at 37 °C for 4 h with metabolic support. Perfusate composition, tissue oxygenation, urinalysis and histopathology were analyzed. During preservation, the H200nM-21 °C group exhibited significantly higher urine output than the other groups and significantly higher tissue oxygenation than the H1µM-21 °C group at 1 h and 2h. During reperfusion, the H200nM-21 °C group exhibited significantly higher urine output and lower urine protein than the other groups. Additionally, the H200nM-21 °C group exhibited higher perfusate pO₂ levels than the other groups and significantly lower apoptotic injury than the H-21 °C and the H1µM-21 °C groups. Thus, subnormothermic perfusion at 21 °C with Hemopure + 200 nM AP39 improves renal outcomes. Additionally, our novel blood-free model of ex vivo kidney preservation and reperfusion could be useful for studying other therapeutics. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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14 pages, 10723 KiB

Open AccessArticle

Behavioral and Neuronal Effects of Inhaled Bromine Gas: Oxidative Brain Stem Damage

by Shazia Shakil, Juan Xavier Masjoan Juncos, Nithya Mariappan, Iram Zafar, Apoorva Amudhan, Archita Amudhan, Duha Aishah, Simmone Siddiqui, Shajer Manzoor, Cristina M. Santana, Wilson K. Rumbeiha, Samina Salim, Aftab Ahmad and Shama Ahmad

Int. J. Mol. Sci. 2021, 22(12), 6316; https://doi.org/10.3390/ijms22126316 - 12 Jun 2021

Cited by 5 | Viewed by 3074

Abstract

The risk of accidental bromine (Br₂) exposure to the public has increased due to its enhanced industrial use. Inhaled Br₂ damages the lungs and the heart; however, adverse effects on the brain are unknown. In this study, we examined the [...] Read more.

The risk of accidental bromine (Br₂) exposure to the public has increased due to its enhanced industrial use. Inhaled Br₂ damages the lungs and the heart; however, adverse effects on the brain are unknown. In this study, we examined the neurological effects of inhaled Br₂ in Sprague Dawley rats. Rats were exposed to Br₂ (600 ppm for 45 min) and transferred to room air and cage behavior, and levels of glial fibrillary acidic protein (GFAP) in plasma were examined at various time intervals. Bromine exposure resulted in abnormal cage behavior such as head hitting, biting and aggression, hypervigilance, and hyperactivity. An increase in plasma GFAP and brain 4-hydroxynonenal (4-HNE) content also was observed in the exposed animals. Acute and delayed sympathetic nervous system activation was also evaluated by assessing the expression of catecholamine biosynthesizing enzymes, tryptophan hydroxylase (TrpH1 and TrpH2), and tyrosine hydroxylase (TyrH), along with an assessment of catecholamines and their metabolites. TyrH was found to be increased in a time-dependent manner. TrpH1 and TrpH2 were significantly decreased upon Br₂ exposure in the brainstem. The neurotransmitter content evaluation indicated an increase in 5-HT and dopamine at early timepoints after exposure; however, other metabolites were not significantly altered. Taken together, our results predict brain damage and autonomic dysfunction upon Br₂ exposure. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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13 pages, 2899 KiB

Open AccessArticle

Role of PEG35, Mitochondrial ALDH2, and Glutathione in Cold Fatty Liver Graft Preservation: An IGL-2 Approach

by Raquel G. Bardallo, Rui Teixeira da Silva, Teresa Carbonell, Emma Folch-Puy, Carlos Palmeira, Joan Roselló-Catafau, Jacques Pirenne, René Adam and Arnau Panisello-Roselló

Int. J. Mol. Sci. 2021, 22(10), 5332; https://doi.org/10.3390/ijms22105332 - 19 May 2021

Cited by 18 | Viewed by 2910

Abstract

The total damage inflicted on the liver before transplantation is associated with several surgical manipulations, such as organ recovery, washout of the graft, cold conservation in organ preservation solutions (UW, Celsior, HTK, IGL-1), and rinsing of the organ before implantation. Polyethylene glycol 35 [...] Read more.

The total damage inflicted on the liver before transplantation is associated with several surgical manipulations, such as organ recovery, washout of the graft, cold conservation in organ preservation solutions (UW, Celsior, HTK, IGL-1), and rinsing of the organ before implantation. Polyethylene glycol 35 (PEG35) is the oncotic agent present in the IGL-1 solution, which is an alternative to UW and Celsior solutions in liver clinical transplantation. In a model of cold preservation in rats (4 °C; 24 h), we evaluated the effects induced by PEG35 on detoxifying enzymes and nitric oxide, comparing IGL-1 to IGL-0 (which is the same as IGL-1 without PEG). The benefits were also assessed in a new IGL-2 solution characterized by increased concentrations of PEG35 (from 1 g/L to 5 g/L) and glutathione (from 3 mmol/L to 9 mmol/L) compared to IGL-1. We demonstrated that PEG35 promoted the mitochondrial enzyme ALDH2, and in combination with glutathione, prevented the formation of toxic aldehyde adducts (measured as 4-hydroxynonenal) and oxidized proteins (AOPP). In addition, PEG35 promoted the vasodilator factor nitric oxide, which may improve the microcirculatory disturbances in steatotic grafts during preservation and revascularization. All of these results lead to a reduction in damage inflicted on the fatty liver graft during the cold storage preservation. In this communication, we report on the benefits of IGL-2 in hypothermic static preservation, which has already been proved to confer benefits in hypothermic oxygenated dynamic preservation. Hence, the data reported here reinforce the fact that IGL-2 is a suitable alternative to be used as a unique solution/perfusate when hypothermic static and preservation strategies are used, either separately or combined, easing the logistics and avoiding the mixture of different solutions/perfusates, especially when fatty liver grafts are used. Further research regarding new therapeutic and pharmacological insights is needed to explore the underlying mitochondrial mechanisms exerted by PEG35 in static and dynamic graft preservation strategies for clinical liver transplantation purposes. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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17 pages, 4479 KiB

Open AccessArticle

In Vivo Transcutaneous Monitoring of Hemoglobin Derivatives Using a Red-Green-Blue Camera-Based Spectral Imaging Technique

by Fahima Khatun, Yoshihisa Aizu and Izumi Nishidate

Int. J. Mol. Sci. 2021, 22(4), 1528; https://doi.org/10.3390/ijms22041528 - 3 Feb 2021

Cited by 5 | Viewed by 2997

Abstract

Cyanosis is a pathological condition that is characterized by a bluish discoloration of the skin or mucous membranes. It may result from a number of medical conditions, including disorders of the respiratory system and central nervous system, cardiovascular diseases, peripheral vascular diseases, deep [...] Read more.

Cyanosis is a pathological condition that is characterized by a bluish discoloration of the skin or mucous membranes. It may result from a number of medical conditions, including disorders of the respiratory system and central nervous system, cardiovascular diseases, peripheral vascular diseases, deep vein thrombosis, and regional ischemia. Cyanosis can also be elicited from methemoglobin. Therefore, a simple, rapid, and simultaneous monitoring of changes in oxygenated hemoglobin and deoxygenated hemoglobin is useful for protective strategies against organ ischemic injury. We previously developed a red-green-blue camera-based spectral imaging method for the measurements of melanin concentration, oxygenated hemoglobin concentration (C_HbO), deoxygenated hemoglobin concentration (C_Hb_R), total hemoglobin concentration (C_HbT) and tissue oxygen saturation (StO₂) in skin tissues. We leveraged this approach in this study and extended it to the simultaneous quantifications of methemoglobin concentration (C_metHb), C_HbO, C_Hb_R, and StO₂. The aim of the study was to confirm the feasibility of the method to monitor C_metHb, C_HbO, C_Hb_R, C_HbT, and StO₂. We performed in vivo experiments using rat dorsal skin during methemoglobinemia induced by the administration of sodium nitrite (NaNO₂) and changing the fraction of inspired oxygen (FiO₂), including normoxia, hypoxia, and anoxia. Spectral diffuse reflectance images were estimated from an RGB image by the Wiener estimation method. Multiple regression analysis based on Monte Carlo simulations of light transport was used to estimate C_HbO, C_HbR, C_metHb, C_HbT, and StO₂. C_metHb rapidly increased with a half-maximum time of less than 30 min and reached maximal values nearly 60 min after the administration of NaNO₂, whereas StO₂ dramatically dropped after the administration of NaNO₂, indicating the temporary production of methemoglobin and severe hypoxemia during methemoglobinemia. Time courses of C_HbT and StO₂, while changing the FiO₂, coincided with well-known physiological responses to hyperoxia, normoxia, and hypoxia. The results indicated the potential of this method to evaluate changes in skin hemodynamics due to loss of tissue viability and vitality. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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14 pages, 2941 KiB

Open AccessArticle

Hyperbaric Oxygen Preconditioning Upregulates Heme OxyGenase-1 and Anti-Apoptotic Bcl-2 Protein Expression in Spontaneously Hypertensive Rats with Induced Postischemic Acute Kidney Injury

by Jelena Nesovic Ostojic, Milan Ivanov, Nevena Mihailovic-Stanojevic, Danijela Karanovic, Sanjin Kovacevic, Predrag Brkic, Maja Zivotic, Una Jovana Vajic, Djurdjica Jovovic, Rada Jeremic, Senka Ljubojevic-Holzer and Zoran Miloradovic

Int. J. Mol. Sci. 2021, 22(3), 1382; https://doi.org/10.3390/ijms22031382 - 30 Jan 2021

Cited by 14 | Viewed by 2854

Abstract

Renal ischemia and reperfusion (I/R) injury is the most common cause of acute kidney injury (AKI). Pathogenesis of postischemic AKI involves hemodynamic changes, oxidative stress, inflammation process, calcium ion overloading, apoptosis and necrosis. Up to date, therapeutic approaches to treat AKI are extremely [...] Read more.

Renal ischemia and reperfusion (I/R) injury is the most common cause of acute kidney injury (AKI). Pathogenesis of postischemic AKI involves hemodynamic changes, oxidative stress, inflammation process, calcium ion overloading, apoptosis and necrosis. Up to date, therapeutic approaches to treat AKI are extremely limited. Thus, the aim of this study was to evaluate the effects of hyperbaric oxygen (HBO) preconditioning on citoprotective enzyme, heme oxygenase-1 (HO-1), pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins expression, in postischemic AKI induced in normotensive Wistar and spontaneously hypertensive rats (SHR). The animals were randomly divided into six experimental groups: SHAM-operated Wistar rats (W-SHAM), Wistar rats with induced postischemic AKI (W-AKI) and Wistar group with HBO preconditioning before AKI induction (W-AKI + HBO). On the other hand, SHR rats were also divided into same three groups: SHR-SHAM, SHR-AKI and SHR-AKI + HBO. We demonstrated that HBO preconditioning upregulated HO-1 and anti-apoptotic Bcl-2 protein expression, in both Wistar and SH rats. In addition, HBO preconditioning improved glomerular filtration rate, supporting by significant increase in creatinine, urea and phosphate clearances in both rat strains. Considering our results, we can also say that even in hypertensive conditions, we can expect protective effects of HBO preconditioning in experimental model of AKI. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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17 pages, 3388 KiB

Open AccessArticle

P2Y11 Agonism Prevents Hypoxia/Reoxygenation- and Angiotensin II-Induced Vascular Dysfunction and Intimal Hyperplasia Development

by Marie Piollet, Adrian Sturza, Stéphanie Chadet, Claudie Gabillard-Lefort, Lauriane Benoist, Danina-Mirela Muntean, Oana-Maria Aburel, Denis Angoulvant and Fabrice Ivanes

Int. J. Mol. Sci. 2021, 22(2), 855; https://doi.org/10.3390/ijms22020855 - 16 Jan 2021

Cited by 7 | Viewed by 2694

Abstract

Vascular dysfunction in cardiovascular diseases includes vasomotor response impairments, endothelial cells (ECs) activation, and smooth muscle cells (SMCs) proliferation and migration to the intima. This results in intimal hyperplasia and vessel failure. We previously reported that activation of the P2Y11 receptor (P2Y11R) in [...] Read more.

Vascular dysfunction in cardiovascular diseases includes vasomotor response impairments, endothelial cells (ECs) activation, and smooth muscle cells (SMCs) proliferation and migration to the intima. This results in intimal hyperplasia and vessel failure. We previously reported that activation of the P2Y11 receptor (P2Y11R) in human dendritic cells, cardiofibroblasts and cardiomyocytes was protective against hypoxia/reoxygenation (HR) lesions. In this study, we investigated the role of P2Y11R signaling in vascular dysfunction. P2Y11R activity was modulated using its pharmacological agonist NF546 and antagonist NF340. Rat aortic rings were exposed to angiotensin II (AngII) and evaluated for their vasomotor response. The P2Y11R agonist NF546 reduced AngII-induced vascular dysfunction by promoting EC-dependent vasorelaxation, through an increased nitric oxide (NO) bioavailability and reduced AngII-induced H₂O₂ release; these effects were prevented by the use of the P2Y11R antagonist NF340. Human vascular SMCs and ECs were subjected to AngII or H/R simulation in vitro. P2Y11R agonist modulated vasoactive factors in human ECs, that is, endothelial nitric oxide synthase (eNOS) and endothelin-1, reduced SMC proliferation and prevented the switch towards a synthetic phenotype. H/R and AngII increased ECs secretome-induced SMC proliferation, an effect prevented by P2Y11R activation. Thus, our data suggest that P2Y11R activation may protect blood vessels from HR-/AngII-induced injury and reduce vascular dysfunctions. These results open the way for new vasculoprotective interventions. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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17 pages, 5589 KiB

Open AccessArticle

Evaluation of Liver Quality after Circulatory Death versus Brain Death: A Comparative Preclinical Pig Model Study

by Jérôme Danion, Raphael Thuillier, Géraldine Allain, Patrick Bruneval, Jacques Tomasi, Michel Pinsard, Thierry Hauet and Thomas Kerforne

Int. J. Mol. Sci. 2020, 21(23), 9040; https://doi.org/10.3390/ijms21239040 - 27 Nov 2020

Cited by 4 | Viewed by 2195

Abstract

The current organ shortage in hepatic transplantation leads to increased use of marginal livers. New organ sources are needed, and deceased after circulatory death (DCD) donors present an interesting possibility. However, many unknown remains on these donors and their pathophysiology regarding ischemia reperfusion [...] Read more.

The current organ shortage in hepatic transplantation leads to increased use of marginal livers. New organ sources are needed, and deceased after circulatory death (DCD) donors present an interesting possibility. However, many unknown remains on these donors and their pathophysiology regarding ischemia reperfusion injury (IRI). Our hypothesis was that DCD combined with abdominal normothermic regional recirculation (ANOR) is not inferior to deceased after brain death (DBD) donors. We performed a mechanistic comparison between livers from DBD and DCD donors in a highly reproducible pig model, closely mimicking donor conditions encountered in the clinic. DCD donors were conditioned by ANOR. We determined that from the start of storage, pro-lesion pathways such as oxidative stress and cell death were induced in both donor types, but to a higher extent in DBD organs. Furthermore, pro-survival pathways, such as resistance to hypoxia and regeneration showed activation levels closer to healthy livers in DCD-ANOR rather than in DBD organs. These data highlight critical differences between DBD and DCD-ANOR livers, with an apparent superiority of DCD in terms of quality. This confirms our hypothesis and further confirms previously demonstrated benefits of ANOR. This encourages the expended use of DCD organs, particularly with ANOR preconditioning. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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16 pages, 3674 KiB

Open AccessArticle

Tissue Expression of Atrial and Ventricular Myosin Light Chains in the Mechanism of Adaptation to Oxidative Stress

by Marta Banaszkiewicz, Anna Krzywonos-Zawadzka, Agnieszka Olejnik and Iwona Bil-Lula

Int. J. Mol. Sci. 2020, 21(21), 8384; https://doi.org/10.3390/ijms21218384 - 9 Nov 2020

Cited by 5 | Viewed by 2560

Abstract

Ischemia/reperfusion (I/R) injury induces post-translational modifications of myosin light chains (MLCs), increasing their susceptibility to degradation by matrix metalloproteinase 2 (MMP-2). This results in the degradation of ventricular light chains (VLC1) in heart ventricles. The aim of the study was to investigate changes [...] Read more.

Ischemia/reperfusion (I/R) injury induces post-translational modifications of myosin light chains (MLCs), increasing their susceptibility to degradation by matrix metalloproteinase 2 (MMP-2). This results in the degradation of ventricular light chains (VLC1) in heart ventricles. The aim of the study was to investigate changes in MLCs content in the mechanism of adaptation to oxidative stress during I/R. Rat hearts, perfused using the Langendorff method, were subjected to I/R. The control group was maintained in oxygen conditions. Lactate dehydrogenase (LDH) activity and reactive oxygen/nitrogen species (ROS/RNS) content were measured in coronary effluents. Atrial light chains (ALC1) and ventricular light chains (VLC1) gene expression were examined using RQ-PCR. ALC1 and VLC1 protein content were measured using ELISA tests. MMP-2 activity was assessed by zymography. LDH activity as well as ROS/RNS content in coronary effluents was higher in the I/R group (p = 0.01, p = 0.04, respectively), confirming heart injury due to increased oxidative stress. MMP-2 activity in heart homogenates was also higher in the I/R group (p = 0.04). ALC1 gene expression and protein synthesis were significantly increased in I/R ventricles (p < 0.01, 0.04, respectively). VLC1 content in coronary effluents was increased in the I/R group (p = 0.02), confirming the increased degradation of VLC1 by MMP-2 and probably an adaptive production of ALC1 during I/R. This mechanism of adaptation to oxidative stress led to improved heart mechanical function. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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Review

Jump to: Research

24 pages, 1073 KiB

Open AccessReview

The Antioxidant Transcription Factor Nrf2 in Cardiac Ischemia–Reperfusion Injury

by Ana Mata and Susana Cadenas

Int. J. Mol. Sci. 2021, 22(21), 11939; https://doi.org/10.3390/ijms222111939 - 3 Nov 2021

Cited by 42 | Viewed by 3601

Abstract

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that controls cellular defense responses against toxic and oxidative stress by modulating the expression of genes involved in antioxidant response and drug detoxification. In addition to maintaining redox homeostasis, Nrf2 is also [...] Read more.

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that controls cellular defense responses against toxic and oxidative stress by modulating the expression of genes involved in antioxidant response and drug detoxification. In addition to maintaining redox homeostasis, Nrf2 is also involved in various cellular processes including metabolism and inflammation. Nrf2 activity is tightly regulated at the transcriptional, post-transcriptional and post-translational levels, which allows cells to quickly respond to pathological stress. In the present review, we describe the molecular mechanisms underlying the transcriptional regulation of Nrf2. We also focus on the impact of Nrf2 in cardiac ischemia–reperfusion injury, a condition that stimulates the overproduction of reactive oxygen species. Finally, we analyze the protective effect of several natural and synthetic compounds that induce Nrf2 activation and protect against ischemia–reperfusion injury in the heart and other organs, and their potential clinical application. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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53 pages, 775 KiB

Open AccessReview

Combating Ischemia-Reperfusion Injury with Micronutrients and Natural Compounds during Solid Organ Transplantation: Data of Clinical Trials and Lessons of Preclinical Findings

by Christina Mauerhofer, Lukas Grumet, Peter Schemmer, Bettina Leber and Philipp Stiegler

Int. J. Mol. Sci. 2021, 22(19), 10675; https://doi.org/10.3390/ijms221910675 - 1 Oct 2021

Cited by 8 | Viewed by 2988

Abstract

Although extended donor criteria grafts bear a higher risk of complications such as graft dysfunction, the exceeding demand requires to extent the pool of potential donors. The risk of complications is highly associated with ischemia-reperfusion injury, a condition characterized by high loads of [...] Read more.

Although extended donor criteria grafts bear a higher risk of complications such as graft dysfunction, the exceeding demand requires to extent the pool of potential donors. The risk of complications is highly associated with ischemia-reperfusion injury, a condition characterized by high loads of oxidative stress exceeding antioxidative defense mechanisms. The antioxidative properties, along with other beneficial effects like anti-inflammatory, antiapoptotic or antiarrhythmic effects of several micronutrients and natural compounds, have recently emerged increasing research interest resulting in various preclinical and clinical studies. Preclinical studies reported about ameliorated oxidative stress and inflammatory status, resulting in improved graft survival. Although the majority of clinical studies confirmed these results, reporting about improved recovery and superior organ function, others failed to do so. Yet, only a limited number of micronutrients and natural compounds have been investigated in a (large) clinical trial. Despite some ambiguous clinical results and modest clinical data availability, the vast majority of convincing animal and in vitro data, along with low cost and easy availability, encourage the conductance of future clinical trials. These should implement insights gained from animal data. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

15 pages, 859 KiB

Open AccessReview

Methods of Attenuating Ischemia-Reperfusion Injury in Liver Transplantation for Hepatocellular Carcinoma

by Łukasz Masior and Michał Grąt

Int. J. Mol. Sci. 2021, 22(15), 8229; https://doi.org/10.3390/ijms22158229 - 30 Jul 2021

Cited by 15 | Viewed by 5206

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent indications for liver transplantation. However, the transplantation is ultimately associated with the occurrence of ischemia-reperfusion injury (IRI). It affects not only the function of the graft but also significantly worsens the oncological results. Various [...] Read more.

Hepatocellular carcinoma (HCC) is one of the most frequent indications for liver transplantation. However, the transplantation is ultimately associated with the occurrence of ischemia-reperfusion injury (IRI). It affects not only the function of the graft but also significantly worsens the oncological results. Various methods have been used so far to manage IRI. These include the non-invasive approach (pharmacotherapy) and more advanced options encompassing various types of liver conditioning and machine perfusion. Strategies aimed at shortening ischemic times and better organ allocation pathways are still under development as well. This article presents the mechanisms responsible for IRI, its impact on treatment outcomes, and strategies to mitigate it. An extensive review of the relevant literature using MEDLINE (PubMed) and Scopus databases until September 2020 was conducted. Only full-text articles written in English were included. The following search terms were used: “ischemia reperfusion injury”, “liver transplantation”, “hepatocellular carcinoma”, “preconditioning”, “machine perfusion”. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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17 pages, 1170 KiB

Open AccessReview

New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation

by Hui Liu and Kwan Man

Int. J. Mol. Sci. 2021, 22(15), 8210; https://doi.org/10.3390/ijms22158210 - 30 Jul 2021

Cited by 57 | Viewed by 5546

Abstract

Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, [...] Read more.

Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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13 pages, 296 KiB

Open AccessReview

How Machine Perfusion Ameliorates Hepatic Ischaemia Reperfusion Injury

by George Clarke, Hynek Mergental, Angus Hann, M. Thamara P. R. Perera, Simon C. Afford and Darius F. Mirza

Int. J. Mol. Sci. 2021, 22(14), 7523; https://doi.org/10.3390/ijms22147523 - 14 Jul 2021

Cited by 14 | Viewed by 2651

Abstract

The increasing disparity between the number of patients listed for transplantation and the number of suitable organs has led to the increasing use of extended criteria donors (ECDs). ECDs are at increased risk of developing ischaemia reperfusion injury and greater risk of post-transplant [...] Read more.

The increasing disparity between the number of patients listed for transplantation and the number of suitable organs has led to the increasing use of extended criteria donors (ECDs). ECDs are at increased risk of developing ischaemia reperfusion injury and greater risk of post-transplant complications. Ischaemia reperfusion injury is a major complication of organ transplantation defined as the inflammatory changes seen following the disruption and restoration of blood flow to an organ—it is a multifactorial process with the potential to cause both local and systemic organ failure. The utilisation of machine perfusion under normothermic (37 degrees Celsius) and hypothermic (4–10 degrees Celsius) has proven to be a significant advancement in organ preservation and restoration. One of the key benefits is its ability to optimise suboptimal organs for successful transplantation. This review is focused on examining ischaemia reperfusion injury and how machine perfusion ameliorates the graft’s response to this. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

16 pages, 270 KiB

Open AccessReview

Ischemia-Reperfusion Injuries Assessment during Pancreas Preservation

by Thomas Prudhomme, John F. Mulvey, Liam A. J. Young, Benoit Mesnard, Maria Letizia Lo Faro, Ann Etohan Ogbemudia, Fungai Dengu, Peter J. Friend, Rutger Ploeg, James P. Hunter and Julien Branchereau

Int. J. Mol. Sci. 2021, 22(10), 5172; https://doi.org/10.3390/ijms22105172 - 13 May 2021

Cited by 17 | Viewed by 4384

Abstract

Maintaining organ viability between donation and transplantation is of critical importance for optimal graft function and survival. To date in pancreas transplantation, static cold storage (SCS) is the most widely practiced method of organ preservation. The first experiments in ex vivo perfusion of [...] Read more.

Maintaining organ viability between donation and transplantation is of critical importance for optimal graft function and survival. To date in pancreas transplantation, static cold storage (SCS) is the most widely practiced method of organ preservation. The first experiments in ex vivo perfusion of the pancreas were performed at the beginning of the 20th century. These perfusions led to organ oedema, hemorrhage, and venous congestion after revascularization. Despite these early hurdles, a number of factors now favor the use of perfusion during preservation: the encouraging results of HMP in kidney transplantation, the development of new perfusion solutions, and the development of organ perfusion machines for the lung, heart, kidneys and liver. This has led to a resurgence of research in machine perfusion for whole organ pancreas preservation. This review highlights the ischemia-reperfusion injuries assessment during ex vivo pancreas perfusion, both for assessment in pre-clinical experimental models as well for future use in the clinic. We evaluated perfusion dynamics, oedema assessment, especially by impedance analysis and MRI, whole organ oxygen consumption, tissue oxygen tension, metabolite concentrations in tissue and perfusate, mitochondrial respiration, cell death, especially by histology, total cell free DNA, caspase activation, and exocrine and endocrine assessment. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

14 pages, 1068 KiB

Open AccessReview

The Endothelial Glycocalyx and Organ Preservation—From Physiology to Possible Clinical Implications for Solid Organ Transplantation

by Simon Mathis, Gabriel Putzer, Stefan Schneeberger and Judith Martini

Int. J. Mol. Sci. 2021, 22(8), 4019; https://doi.org/10.3390/ijms22084019 - 13 Apr 2021

Cited by 15 | Viewed by 2965

Abstract

The endothelial glycocalyx is a thin layer consisting of proteoglycans, glycoproteins and glycosaminoglycans that lines the luminal side of vascular endothelial cells. It acts as a barrier and contributes to the maintenance of vascular homeostasis and microperfusion. During solid organ transplantation, the endothelial [...] Read more.

The endothelial glycocalyx is a thin layer consisting of proteoglycans, glycoproteins and glycosaminoglycans that lines the luminal side of vascular endothelial cells. It acts as a barrier and contributes to the maintenance of vascular homeostasis and microperfusion. During solid organ transplantation, the endothelial glycocalyx of the graft is damaged as part of Ischemia Reperfusion Injury (IRI), which is associated with impaired organ function. Although several substances are known to mitigate glycocalyx damage, it has not been possible to use these substances during graft storage on ice. Normothermic machine perfusion (NMP) emerges as an alternative technology for organ preservation and allows for organ evaluation, but also offers the possibility to treat and thus improve organ quality during storage. This review highlights the current knowledge on glycocalyx injury during organ transplantation, presents ways to protect the endothelial glycocalyx and discusses potential glycocalyx protection strategies during normothermic machine perfusion. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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18 pages, 2057 KiB

Open AccessReview

Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia—Reperfusion Injury

by Zoran Todorović, Siniša Đurašević, Maja Stojković, Ilijana Grigorov, Slađan Pavlović, Nebojša Jasnić, Tomislav Tosti, Jelica Bjekić Macut, Christoph Thiemermann and Jelena Đorđević

Int. J. Mol. Sci. 2021, 22(6), 2798; https://doi.org/10.3390/ijms22062798 - 10 Mar 2021

Cited by 15 | Viewed by 3624

Abstract

Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until [...] Read more.

Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until cell death. The critical event in such a series of harmful events in the cell is the unwanted accumulation of fatty acids that leads to lipotoxicity. Lipid analysis provides additional insight into the pathogenesis of ischemia/reperfusion (I/R) disorders and reveals new targets for drug action. The profile of changes in the composition of fatty acids in the cell, as well as the time course of these changes, indicate both the mechanism of damage and new therapeutic possibilities. A therapeutic approach to reperfusion lipotoxicity involves attenuation of fatty acids overload, i.e., their transport to adipose tissue and/or inhibition of the adverse effects of fatty acids on cell damage and death. The latter option involves using PPAR agonists and drugs that modulate the transport of fatty acids via carnitine into the interior of the mitochondria or the redirection of long-chain fatty acids to peroxisomes. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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16 pages, 592 KiB

Open AccessReview

Assessing Kidney Graft Viability and Its Cells Metabolism during Machine Perfusion

by Maria Irene Bellini, Francesco Tortorici, Maria Ida Amabile and Vito D’Andrea

Int. J. Mol. Sci. 2021, 22(3), 1121; https://doi.org/10.3390/ijms22031121 - 23 Jan 2021

Cited by 18 | Viewed by 4189

Abstract

Kidney transplantation is the golden treatment for end-stage renal disease. Static cold storage is currently considered the standard method of preservation, but dynamic techniques, such as machine perfusion (MP), have been shown to improve graft function, especially in kidneys donated by extended criteria [...] Read more.

Kidney transplantation is the golden treatment for end-stage renal disease. Static cold storage is currently considered the standard method of preservation, but dynamic techniques, such as machine perfusion (MP), have been shown to improve graft function, especially in kidneys donated by extended criteria donors and donation after circulatory death. With poor organ quality being a major reason for kidneys not being transplanted, an accurate, objective and reliable quality assessment during preservation could add value and support to clinicians’ decisions. MPs are emerging technologies with the potential to assess kidney graft viability and quality, both in the hypothermic and normothermic scenarios. The aim of this review is to summarize current tools for graft viability assessment using MP prior to implantation in relation to the ischemic damage. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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15 pages, 1202 KiB

Open AccessReview

Oxygen Transport during Ex Situ Machine Perfusion of Donor Livers Using Red Blood Cells or Artificial Oxygen Carriers

by Silke B. Bodewes, Otto B. van Leeuwen, Adam M. Thorne, Bianca Lascaris, Rinse Ubbink, Ton Lisman, Diethard Monbaliu, Vincent E. De Meijer, Maarten W. N. Nijsten and Robert J. Porte

Int. J. Mol. Sci. 2021, 22(1), 235; https://doi.org/10.3390/ijms22010235 - 28 Dec 2020

Cited by 32 | Viewed by 5162

Abstract

Oxygenated ex situ machine perfusion of donor livers is an alternative for static cold preservation that can be performed at temperatures from 0 °C to 37 °C. Organ metabolism depends on oxygen to produce adenosine triphosphate and temperatures below 37 °C reduce the [...] Read more.

Oxygenated ex situ machine perfusion of donor livers is an alternative for static cold preservation that can be performed at temperatures from 0 °C to 37 °C. Organ metabolism depends on oxygen to produce adenosine triphosphate and temperatures below 37 °C reduce the metabolic rate and oxygen requirements. The transport and delivery of oxygen in machine perfusion are key determinants in preserving organ viability and cellular function. Oxygen delivery is more challenging than carbon dioxide removal, and oxygenation of the perfusion fluid is temperature dependent. The maximal oxygen content of water-based solutions is inversely related to the temperature, while cellular oxygen demand correlates positively with temperature. Machine perfusion above 20 °C will therefore require an oxygen carrier to enable sufficient oxygen delivery to the liver. Human red blood cells are the most physiological oxygen carriers. Alternative artificial oxygen transporters are hemoglobin-based oxygen carriers, perfluorocarbons, and an extracellular oxygen carrier derived from a marine invertebrate. We describe the principles of oxygen transport, delivery, and consumption in machine perfusion for donor livers using different oxygen carrier-based perfusion solutions and we discuss the properties, advantages, and disadvantages of these carriers and their use. Full article

(This article belongs to the Special Issue Protective Strategies against Organ Ischemic Injury)

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