Reperfusion Damage Research Articles

Features of blood pressure in mice with a genetic defect of different subtypes of α1-adrenoreceptors

To identify the effects of different subtypes of α1-adrenoreceptors on the level of systemic blood pressure in laboratory mice. Features of blood pressure of 36 laboratory mice older than 18 months having a genetic defect (lines ADRA-1A, ADRA-1D and ADRA-1D) of one of the subtypes of α1-adrenoreceptors (α1a, α1b, α1d) were studied. The control group included ten healthy laboratory mice of the same age. The blood pressure of mice was measured with modern high-precision and noninvasive method using the CodaTM Standard system (Kent Scientific Corporation, U.S.A.). The mice of the ADRA-1A line were revealed to have reduced systolic and diastolic blood pressure and maximum level of pulse pressure, as well as the greatest fluctuations of pulse pressure; for the ADRA-1B line - the highest levels of systolic and diastolic blood pressure; for the ADRA-1D line - the smallest systolic and diastolic blood pressure and the minimum values of pulse pressure. The obtained results show the specific contribution of α1a, α1b and α1d subtypes of the adrenoreceptors in the maintenance of normal hemodynamic of an organism, which should be considered when studying pathogenesis of primary open-angle glaucoma.

Progranulin Protects Rat Testis From Ischaemic Reperfusion Injury

Abstract Background: Ischemic reperfusion (I/R) damage of the testis is a common problem, it is mainly caused by testicular torsion and detorsion. Progranulin (PGRN) has been reported to have prominent anti-inflammatory and protective effects on I/R injury in the heart, brain and kidney, however, its effects on testicular I/R lesion have not been evaluated. Aim of Study: To examine the effects of progranulin on rat testicular ischaemia/reperfusion induced by torsion/ detor-sion and the possible underlying mechanisms. Material and Methods: In this study, rats were divided into 4 groups: (i) Sham; (ii) Testicular ischemia/reperfusion (I/R), 2h of ischemia followed by 6 h of reperfusion; (iii) I/R treated by PGRN (0.01mg/rat) administered 1.5h after the induction of ischaemia. (iv) I/R treated by PGRN (0.1mg/rat) administered 1.5h after development of ischemia. At the end of the study, some testicular oxidative stress markers, inflam-matory, apoptotic markers and serum testosterone were meas-ured, in addition to histopathologic study. Results: Significant decreases in serum testosterone levels, testicular superoxide dismutase (SOD) and glutathione per-oxidase (Gpx) activity with increase in tissue malondialdehyde (MDA) were observed in I/R group when compared with controls. These antioxidant levels were increased in PGRN treated groups with significant decrease in MDA levels. While an increase in tumor necrosis factor-alpha (TNF-a), IL-1b, caspase-8 and caspase-3 levels were found in the torsion/ detorsion group, significant decrease in the levels of these inflammatory cytokines and apoptotic markers were observed in PRGR treated groups in a dose dependent maner. Conclusion: These results demonstrate that PGRN signif-icantly produced protective effects on testicular tissue damage through antioxidant, anti-inflammatory and antiapoptotic mechanisms.

Changes in the Stoichiometry of Uniplex Decrease Mitochondrial Calcium Overload and Contribute to Tolerance of Cardiac Ischemia/Reperfusion Injury in Hypothyroidism.

Background: Thyroid hormone status in hypothyroidism (HT) downregulates key elements in Ca2+ handling within the heart, reducing contractility, impairing the basal energetic balance, and increasing the risk of cardiovascular disease. Mitochondrial Ca2+ transport is reduced in HT, and tolerance to reperfusion damage has been documented, but the precise mechanism is not well understood. Therefore, we aimed to determine the stoichiometry and activity of the mitochondrial Ca2+ uniporter or uniplex in an HT model and the relevance to the opening of the mitochondrial permeability transition pores (mPTP) during ischemia/reperfusion (I/R) injury.Methods: An HT model was established in Wistar rats by treatment with 6-propylthiouracil for 28 days. Uniplex composition and activity were determined in cardiac mitochondria. Hearts were perfused ex vivo to induce I/R injury, and functional parameters related to contractility and tissue viability were evaluated.Results: The cardiac stoichiometry between two subunits of the uniplex (MICU1/MCU) increased by 25% in animals with HT. The intramitochondrial Ca2+ content was reduced by 40% and was less prone to the mPTP opening. After I/R injury, ischemic contracture and the onset of ventricular fibrillation were delayed in animals with HT, concomitant with a reduction in oxidative damage and mitochondrial dysfunction.Conclusions: Our results suggest that HT is associated with an increase in the cardiac MICU1/MCU ratio, thereby changing the stoichiometry between these subunits to increase the threshold to cytosolic Ca2+ and reduce mitochondrial Ca2+ overload. Our results also demonstrate that this HT model can be used to explore the role of mitochondrial Ca2+ transport in cardiac diseases due to its induced tolerance to cardiac damage.

Therapeutic Properties of Mesenchymal Stem Cell on Organ Ischemia-Reperfusion Injury.

The shortage of donor organs is a major global concern. Organ failure requires the transplantation of functional organs. Donor’s organs are preserved for variable periods of warm and cold ischemia time, which requires placing them into a preservation device. Ischemia and reperfusion damage the organs, due to the lack of oxygen during the ischemia step, as well as the oxidative stress during the reperfusion step. Different methodologies are developed to prevent or to diminish the level of injuries. Preservation solutions were first developed to maximize cold static preservation, which includes the addition of several chemical compounds. The next chapter of organ preservation comes with the perfusion machine, where mechanical devices provide continuous flow and oxygenation ex vivo to the organs being preserved. In the addition of inhibitors of mitogen-activated protein kinase and inhibitors of the proteasome, mesenchymal stem cells began being used 13 years ago to prevent or diminish the organ’s injuries. Mesenchymal stem cells (e.g., bone marrow stem cells, adipose derived stem cells and umbilical cord stem cells) have proven to be powerful tools in repairing damaged organs. This review will focus upon the use of some bone marrow stem cells, adipose-derived stem cells and umbilical cord stem cells on preventing or decreasing the injuries due to ischemia-reperfusion.

P2711Prevalence of collateral circulation and its importance on the development of reperfusion injury in patients with acute myocardial infarction with ST-segment elevation

Abstract Prevalence of collateral circulation and its importance on the development of reperfusion injury in patients with acute myocardial infarction with st segment elevation treated with primary percutaneous coronary angioplasty Introduction In myocardial infarction with ST-segment elevation, early restoration of flow is the most important objective, but there is a possibility that reperfusion may induce ischemia-reperfusion injury. There is little information about the relationship of collateral circulation and reperfusion damage in patients with infarction, which is the reason for our study. Objective: To determine the prevalence of collateral circulation and its importance in the development of microvascular occlusion and intramyocardial hemorrhage evaluated by magnetic resonance imaging in patients with acute myocardial infarction with ST-segment elevation. Methods Observational, analytical study, retrospective cohort. Methods From March 2008 to April 2017, 359 patients were included and they were over 18 years of age with acute myocardial infarction with ST-segment elevation undergoing primary angioplasty who had magnetic resonance imaging. It was classified into 2 groups of patients: Group 1 (309 patients, without collateral circulation) and group 2 (50 patients, with collateral circulation). The presence or absence of collateral circulation was determined by coronary angiography and reperfusion injury (microvascular obstruction and intramyocardial hemorrhage) was evaluated by magnetic resonance. The x2 test was used to compare the categorical variables and the Mann-Whitney U test for continuous numerical variables. Results Of 359 patients, 50 (13.9%) patients had collateral circulation. The presence of reperfusion damage by magnetic resonance was compared. Patients in group 1 had reperfusion injury in 73.8% and group 2, 70.0% (p: 0.57). Presence or absence of reperfusion injury in patients with and without collateral circulation No Collateral circulation Collateral circulation “p” value n=309 (%) n=50 (%) Reperfusion inury 0.57 No 81 (26.2%) 15 (30.0%) Yes 228 (73.8%) 35 (70.0%) Microvascular Obstruction 0.59 No 81 (26.4%) 15 (30.0%) Yes 226 (73.6%) 35 (70.0%) Myocardial Hemorrhage 0.24 No 189 (61.4%) 35 (70.0%) Yes 119 (38.6%) 15 (30.0%) Conclusions In the present study it is demonstrated that the presence of collateral circulation did not influence the reperfusion damage, so the collateral circulation does not protect the myocardium from reperfusion injury. Prospective studies were needed to confirm this results. Acknowledgement/Funding Carlos Slim Fundation

Sulforaphane protects from myocardial ischemia-reperfusion damage through the balanced activation of Nrf2/AhR

The activation of the transcription factor Nrf2 and the consequent increment in the antioxidant response might be a powerful strategy to contend against reperfusion damage. In this study we compared the effectiveness between sulforaphane (SFN), a well known activator of Nrf2 and the mechanical maneuver of post-conditioning (PostC) to confer cardioprotection in an in vivo cardiac ischemia-reperfusion model. We also evaluated if additional mechanisms, besides Nrf2 activation contribute to cardioprotection. Our results showed that SFN exerts an enhanced protective response as compared to PostC. Bot, strategies preserved cardiac function, decreased infarct size, oxidative stress and inflammation, through common protective pathways; however, the aryl hydrocarbon receptor (AhR) also participated in the protection conferred by SFN. Our data suggest that SFN-mediated cardioprotection involves transient Nrf2 activation, followed by phase I enzymes upregulation at the end of reperfusion, as a long-term protection mechanism.

Коррекция ишемических-реперфузионных повреждений сетчатки у крыс с использованием агонистов имидазолиновых рецепторов I, II типов

Коррекция ишемических-реперфузионных повреждений сетчатки у крыс с использованием агонистов имидазолиновых рецепторов I, II типов

T follicular helper cell recruitment to the ischemic brain

Abstract Stroke is one of the leading causes of death and disability worldwide. Both clinical and preclinical studies suggest the importance of inflammation in acute and long-term neuronal tissue damage following ischemic stroke. However, the mechanisms of how components of the adaptive immune system contribute to neuroinflammation after stroke are still not fully understood. Previous work in our lab demonstrated that CD4+ T cells accumulate in the brain after cerebral ischemia and Interleukin-21 (IL-21) plays a significant role in T cell-mediated reperfusion damage following ischemic stroke. Given that the major producer of IL-21 is follicular helper T (TFH) cells, we sought to delineate the contribution of these IL-21 producing cells to ischemic damage. Here, we identify that pro-inflammatory CD4+CXCR5+IL21+ TFH cells are recruited to the ischemic brain during the reperfusion phase of transient middle cerebral artery occlusion (tMCAO) in mice. We also show that in human stroke tissue, CD4+CXCR5+ cells adhere to CXCL13-expressing inflamed vessel within the stroke lesions. Additionally, we found that inflamed endothelial cells in mice upregulate CXCL13 following tMCAO, indicating a possible mechanism contributing to TFH cell recruitment to the ischemic brain. Most importantly, administration of blocking antibodies against CXCL13 or BCL6, a TFH cell transcription factor, after tMCAO resulted in a significant decrease in infarct volume and TFH cell frequency in the brain. Overall, these data identify a novel mechanism for how pro-inflammatory T cells are recruited to the ischemic brain to propagate stroke damage and identify potential novel targets for stroke therapy.

The development of an extended normothermic ex vivo reperfusion model of the sheep uterus to evaluate organ quality after cold ischemia in relation to uterus transplantation.

Uterus transplantation has recently proved that infertility in women with uterine factor infertility can be cured. It is still an experimental procedure with numerous critical details remaining to be established, including tolerance to warm and cold ischemic insults. In preparation for human uterus transplantation trials, most teams use the sheep as a model system for research and team training, since the vasculature and the uterus is of similar size as in the human. We, therefore, aimed to develop an ex vivo sheep uterus reperfusion platform that mimics the reperfusion situation so that initial assessments and comparisons can be performed without the need for costly and labor-intensive in vivo transplantation experiments. Isolated sheep uteri were perfused with the preservation solution IGL-1 and were then exposed to cold ischemia for either 4(n=6) or 48hours (n=7). Uteri were then reperfused for 48hours under normothermic conditions with an oxygenated recirculating perfusate containing growth factors and synthetic oxygen carriers. Histological and biochemical analysis of the perfusate was conducted to assess reperfusion injury. Quantification of cell density indicated no significant edema in the myometrium or in the endometrium of uteri exposed to 4hours cold ischemia and then a normothermic ex vivo reperfusion for 48hours. Only the outer serosa layer and the inner columnar luminal epithelial cells were affected by the reperfusion. However, a much faster and severe reperfusion damage of all uterine layers were evident during the reperfusion experiment following 48hours of cold ischemia. This was indicated by major accumulation of extracellular fluid, presence of apoptotic-labeled glandular epithelial layer and vascular endothelium. A significant accumulation of lactate was measured in the perfusate with a subsequent decrease in pH. We developed a novel ex vivo sheep uterus model for prolonged perfusion. This model proved to be able to distinguish reperfusion injury-related differences associated to organ preservation. The experimental setup is a platform that can be used to conduct further studies on uterine ischemia- and reperfusion injury that may lead to improved human uterus transplantation protocols.

Neuroprotective effect of neuregulin-1β on spinal cord ischemia reperfusion injury

Objective: This study was designed to see if neuregulin-1β (NRG-1β) plays a protective role in spinal cord ischemia and reperfusion injury (SCII). Design: Animal research. Setting: China. Participants: NA. Interventions: Forty-eight SD rats were randomly divided into control group (n = 16), SCII model group (n = 16) and NRG-1β-treated group (n = 16). In control group, the abdominal aorta was isolated but not clipped. The rats in NRG-1β-treated group were treated with 10μg/kg NRG-1β during developing SCII model. Outcome Measures: Neurological scores were evaluated. At 3, 6, 12 and 24 h after the reperfusion, rats were killed. Pathological changes of spinal cord were assessed with HE staining, and immunohistochemical staining of matrix metalloproteinases-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). MMP-9 and TIMP-1 mRNA levels were assessed using real-time PCR. Results: NRG-1β reduced the damage of SCII in the rats. The expression of MMP-9 protein and mRNA in NRG-1β treatment group was significantly lower than the model group (P < 0.05) at 6 h, 12 h and 24 h after the perfusion. The expression of TIMP-1 protein and mRNA in the treatment group was significantly higher than the model group at 12 h and 24 h after the perfusion. Conclusion: NRG-1β reduced the reperfusion damage in rat model of SCII, in which process MMP-9 and TIMP-1 were probably involved.

Exogenous GDF11 attenuates non-canonical TGF-β signaling to protect the heart from acute myocardial ischemia-reperfusion injury.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-β1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after myocardial ischemia-reperfusion (I-R). No investigations have as yet explored the cardioprotective effect of exogenous recombinant GDF11 in acute I-R injury, despite the convenience of its clinical application. We sought to determine whether exogenous recombinant GDF11 protects against acute myocardial I-R injury and investigate the underlying mechanism in Sprague-Dawley rats. We found that GDF11 reduced arrhythmia severity and successfully attenuated myocardial infarction; GDF11 also increased cardiac function after I-R, enhanced HO-1 expression and decreased oxidative damage. GDF11 activated the canonical TGF-β signaling pathway and inactivated the non-canonical pathways, ERK and JNK signaling pathways. Moreover, administration of GDF11 prior to reperfusion protected the heart from reperfusion damage. Notably, pretreatment with the activin-binding protein, follistatin (FST), inhibited the cardioprotective effects of GDF11 by blocking its activation of Smad2/3 signaling and its inactivation of detrimental TGF-β signaling. Our data suggest that exogenous GDF11 has cardioprotective effects and may have morphologic and functional recovery in the early stage of myocardial I-R injury. GDF11 may be an innovative therapeutic approach for reducing myocardial I-R injury.

Protective Effects of Butyrate on Renal Ischemia-Reperfusion Injury in Rats

Background: Renal ischemia-reperfusion injury (IRI) usually causes acute kidney injury. There is an urgent need to develop an effective agent to prevent renal IRI. This study aimed to examine the effect of butyrate on renal IRI in rats. Materials and Methods: Rats were randomly assigned into 3 groups (10 rats in each group): the sham group, the IRI group, and the butyrate group. Rats were injected intravenously with 300 mg/kg of sodium butyrate in the butyrate group and with a saline solution in the sham group and IRI group 30 min before renal ischemia. After 24 h of reperfusion, renal function and histologic damage were examined. Myeloperoxidase (MPO) activity assay, in situ apoptosis examination, enzyme-linked immunosorbent assay, immunohistochemical assay, and Western blot were performed as well. Results: Butyrate pretreatment significantly reduced renal dysfunction and histologic damage induced by renal IRI. Butyrate pretreatment caused a significant attenuation of neutrophil infiltration, which was reflected by the reduction of renal MPO activity. Butyrate also reduced apoptotic tubular cell death and improved caspase-3 activation. The expression of TNF-α was decreased following butyrate pretreatment. Conclusions: Butyrate pretreatment protects rats from renal IRI by inhibiting inflammation and apoptosis. Therefore, butyrate may be a potential therapeutic agent for preventing renal IRI.

VEGF Antagonism Attenuates Cerebral Ischemia/Reperfusion-Induced Injury via Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis.

Endoplasmic reticulum (ER) stress-mediated apoptosis pathway is considered to play a vital role in mediating stroke and other cerebrovascular diseases. Previous studies have showed that vascular endothelial growth factor (VEGF) antagonism reduced cerebral ischemic-reperfusion (CI/R) damage, but whether attenuation of ER stress-induced apoptosis is contributing to its mechanisms remains elusive. Our study aimed to investigate the protective effect of VEGF antagonism on CI/R-induced injury. First, oxygen-glucose deprivation and re-oxygenation (OGD/R) BEND3 cell model was constructed to estimate small interfering RNA (siRNA)-VEGF on damage of endothelial cells. Next, in animal model, CI/R mice were induced by middle cerebral artery occlusion (MCAO) for 2 h followed by 24 h reperfusion to investigate cerebral tissue damage. For treatment group, mice received 100 µg/kg anti-VEGF antibodies at 30 min before MCAO, followed by 24 h reperfusion. Our findings demonstrated that pre-administration of siRNA-VEGF before OGD/R changed the biological characteristics of BEND3 cells, reversed the levels of X-box binding protein-1 (XBP-1) and glucose-regulated protein 78 (GRP78), showing siRNA-VEGF attenuated, at least in part, the oxidative damage in OGD/R cell by down-regulating ER stress. In mice experiment, pre-administration of anti-VEGF antibody reduced the brain infarct volume and edema extent and improved neurological scores outcome of CI/R injury mice. Pathological and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining results also confirmed this protective effect. The expressions of VEGF, CATT/EBP homologous protein (CHOP), inositol requiring enzyme 1α (IRE-1α), and cleaved-caspase12 and c-jun N-terminal kinase (JNK) phosphorylation were also prominently decreased. These results suggested that inhibition of endogenous VEGF attenuates CI/R-induced injury via inhibiting ER stress-mediated apoptosis.

Chrysin attenuates global cerebral ischemic reperfusion injury via suppression of oxidative stress, inflammation and apoptosis

Global cerebral ischemia is a leading cause of mortality worldwide. Several biomechanisms play a role in the pathology of cerebral ischemia reperfusion damage, such as oxidative stress, inflammation, apoptosis and excitotoxicity. Chrysin, a natural flavonoid with many important biological activities, was investigated in the present study for its possible neuroprotective properties in a rat model of global ischemia reperfusion. Male Wistar rats were allocated into three groups: sham-operated, ischemia/reperfusion, and chrysin (30 mg/kg) groups. All animals were subjected to ischemia for 15 min followed by reperfusion for 60 min, except for the sham-operated group. Rats were decapitated, then both hippocampi were rapidly excised to evaluate several biomarkers that reflect ischemic injury. The obtained results showed that pre-treatment with chrysin attenuated ischemia-induced oxidative stress by: (i) restoring the glutathione level; and (ii) depressing the levels/activities of thiobarbituric acid reactive substances, the hippocampal NADPH, as well as the xanthine oxidase. Exposure to chrysin also suppressed the inflammation accompanying the ischemia/reperfusion (I/R) damage, through increasing the interleukin-10 level, while decreasing the levels of both interleukin-6 and tumour necrosis factor-alpha. Moreover, an increase in Bcl2 and a decrease in both BAX and Hsp90 levels were recorded following chrysin exposure, which was also accompanied with elevated glutamate and aspartate levels. In conclusion, chrysin has demonstrated an anti-ischemic potential, through attenuation of the mechanisms underlying I/R injury. These data add to the knowledge on the significance of natural flavonoids as neuroprotective agents.

Molecular mechanisms of oxidation damage andlivercell dysfunction in patients withmetastatic colorectal cancer.

Interaction between tumor cells and tumor microenvironment is critical for homeostasis of normal cells and tumor growth. Tumor cell- stroma interaction represents the potent factor able to initiate cancer and affect tumor progression and disease outcome. The tumors vary by their origin and microenvironment (proportion of stromal cells, their composition and activation state). The surgical stress and tumor microenvironment may potentiate acute hepatic failure in the patients with metastatic colorectal cancer(mCRC). Pathological effect of ischemia-reperfusion (I/R) consists in the increased generation of superoxide radicals(SR) and nitrogen oxide(NO) affecting the postresectional regeneration of liver tissue. Redox state of hepatic tissue in I/R setting upon resection of metastases may trigger the aggressiveness of residual cancer cells and regeneration or degradation of hepatic tissue. The aim of the study was to analyze redox state of hepatic tissue following surgery with Pringle maneuver(PM) in the patients with mCRC. mCRC samples from 145patients treated at National Cancer Institute, Ministry of Health of Ukraine, were analyzed. The patients obtained chemotherapy according to the approved international and national standards as well as clinical protocols. Two groups of patients were delineated according to the duration of the interruption of blood inflow due to PM, namely ≤45min and >45min. The activity of FeS proteins in the electron transport chain (ETC) in mitochondria and lactoferrin (LF) level in the tissues were assessed by EPR (77К). The rates of SR and NO generation were determined with spin traps. The activity of matrix metalloproteinase(MMP)-2 and -9was measured by gelatin zymography using SDS-polyacrylamide gel electrophoresis. In tissue of liver resected in the setting of > 45min ischemia, ETC function in mitochondria was impaired (decreased activity of FeS protein of N-2 ETC complex I due to interaction with NO). This results in the hypoxia state and glycolysis with uncontrolled SR generation. In addition, the efficiency of detoxification system in hepatocytes is reduced substantially with increase in semiquinone and LF levels as well as MMP-2and-9 activity as compared with liver without metastatic lesions that was not affected by I/R. The ischemic injury of liver in the setting of metastasis resection results from cell response to interruption of blood flow followed by reperfusion. The key factor in the genesis of reperfusion damage is uncontrolled increase of the levels of SR and their metabolites- reactive oxygen species as well as the increased MMP activity. Also, liver tissue affected by I/R contains high levels of xanthine oxidase metabolizing hypoxanthine and monoamine oxidase deaminizing biogenic amines. Both processes are the sources of SR.

Malondialdehyde level in the patients subjected to open heart surgery in association with lipid profile

Background: Reactive oxygen species are usually produced by the living cell and have different functions in its normal activity and considered as one of the factors that involved in heart disease. Malondialdehyde (MDA) considered as one of the most indictors of oxidative stress and damage produced as a result of lipid peroxidation. Objectives: The main objective is to evaluate serum oxidative stress by measuring the changes in the level of MDA as a marker of oxidative stress and demonstrate the correlation of MDA with lipid profile in patients subjected to open-heart surgery. Methods: A case–control study was carried out in the Department of Chemistry and Biochemistry, College of medicine, Tikrit University, Tikrit, Iraq. The study was carried out for 50 patients subjected to open-heart surgery recruited from the Medical City/Iraqi Center for Heart Disease and Ibn Al-Bitar Cardiac Surgery Center, Department of Cardiac Surgery, Baghdad, Iraq between October 1, 2017 and March 1, 2018. The levels of MDA and lipid profile were measured in the serum of 50 patients, in three different interval preoperative, early postoperative, and late postoperative and compared with 30 age- and gender-matched controls. Results: The results revealed a statistically significant difference in the serum MDA level between patient during preoperative, early postoperative, and late postoperative stage against control group and significant differences in their MDA levels among all patients' stages. Furthermore, there was a significant positive correlation between serum MDA level and total cholesterol in the early postoperative stage. Conclusions: There was an increase in the level of MDA in the early postoperative stage as an indicator of reperfusion damage that occurs immediately after open-heart surgery which then decreases dramatically with decrease in total cholesterol, triglyceride, low-density lipoprotein-cholesterol (LDL-C), and very-LDL-C.

Роль натрийуретических пептидов и эритропоэтина в регуляции толерантности сердца к действию ишемии и реперфузии. Анализ экспериментальных и клинических данных

Experimental studies show that natriuretic peptides have an infarct-limiting effect both in vitro and in vivo. In studies performed on animals, it was shown that erythropoietin is able to prevent ischemic and reperfusion damage of the heart both in vitro and in vivo by activating a number of kinases and by inactivating GSK-3β kinase. These data suggest that the cardioprotective effect of erythropoietin and natriuretic peptides appears to be associated with the activation of cardiac receptors. Erythropoietin had an anti-apoptotic effect both in vitro and in vivo. In the infarct-limiting effect of the atrial natriuretic peptide, NO synthase, protein kinase C, and the mitoKATP channel are involved. It was found that the in vivo infarct-reducing effect of erythropoietin is associated with the activation of PI3 kinase and ERK1/2 kinase. Brain natriuretic peptide prevents post-infarction cardiac remodeling and increases the survival rate of rats with experimental myocardial infarction. Erythropoietin inhibits post-infarction cardiac remodeling and enhances the process of myocardial neovascularization in rats and dogs. Natriuretic peptides have an infarct-reducing effect in patients with acute myocardial infarction (AMI). Atrial natriuretic peptide prevents post-infarction cardiac remodeling in patients with AMI. Erythropoietin does not affect infarct size in patients with AMI. A single injection of erythropoietin does not affect the post-infarction remodeling of the heart.

Corrigendum to: The role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of myocardial ischemia reperfusion.

Corrigendum to: The role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of myocardial ischemia reperfusion.

Topical hepatic hypothermia associated with ischemic preconditioning. Histopathological and biochemical analysis of ischemia reperfusion damage in a 24 hour model 1.

To develop a new 24 hour extended liver ischemia and reperfusion (LIR) model analyzing the late biochemical and histopathological results of the isolated and combined application of recognized hepatoprotective mechanisms. In addition, we used a new stratification with zoning to classify the histological lesion. A modified animal model of severe hepatic damage produced through 90 minutes of segmental ischemia (70% of the organ) and posterior observation for 24 hours of reperfusion, submitted to ischemic preconditioning (IPC) and topical hypothermia (TH) at 26ºC, in isolation or in combination, during the procedure. Data from intraoperative biometric parameters, besides of late biochemical markers and histopathological findings, both at 24 hours evolution time, were compared with control (C) and normothermic ischemia (NI) groups. All groups were homogeneous with respect to intraoperative physiological parameters. There were no losses once the model was stablished. Animals subjected to NI and IPC had worse biochemical (gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and total bilirubin) and histopathological scores (modified Suzuki score) compared to those of control groups and groups with isolated or associated TH (p < 0.05). The new extended model demonstrates liver ischemia and reperfusion at 24 hour of evolution and, in this extreme scenario, only the groups subjected to topical hypothermia, combined with ischemic preconditioning or alone, had better outcomes than those subjected to only ischemic preconditioning and normothermic ischemia, reaching similar biochemical and histopathological scores to those of the control group.

Myocardial reperfusion injury and oxidative stress: Therapeutic opportunities.

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty (PCA) treatment, which quickly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxically, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species (ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury (MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies (mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weaknesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention, and its continuity may also have some responsibility for the lack of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine (a glutathione donor) and deferoxamine (an iron chelator) could improve the antioxidant cardioprotection by ascorbate, making it even more effective in preventing myocardial reperfusion damage associated with PCA following AMI.