Developing targeted antioxidant nanomedicines for ischemic penumbra: Novel strategies in treating brain ischemia-reperfusion injury.

During cerebral ischemia-reperfusion conditions, the excessive reactive oxygen species in the ischemic penumbra region, resulting in neuronal oxidative stress, constitute the main pathological mechanism behind ischemia-reperfusion damage. Swiftly reinstating blood perfusion in the ischemic penumbra zone and suppressing neuronal oxidative injury are key to effective treatment. Presently, antioxidants in clinical use suffer from low bioavailability, a singular mechanism of action, and substantial side effects, severely restricting their therapeutic impact and widespread clinical usage. Recently, nanomedicines, owing to their controllable size and shape and surface modifiability, have demonstrated good application potential in biomedicine, potentially breaking through the bottleneck in developing neuroprotective drugs for ischemic strokes. This manuscript intends to clarify the mechanisms of cerebral ischemia-reperfusion injury and provides a comprehensive review of the design and synthesis of antioxidant nanomedicines, their action mechanisms and applications in reversing neuronal oxidative damage, thus presenting novel approaches for ischemic stroke prevention and treatment.

[Indications and techniques for endovascular revascularization of visceral arteries in mesenteric ischemia]. / Indikation und Technik der endovaskulären Revaskularisation der Viszeralarterien bei mesenterialer Ischämie.

Endovascular revascularization of visceral arteries is an important cornerstone of an interdisciplinary treatment concept for both acute and chronic forms of mesenteric ischemia. The advantages lie in the minimally invasive procedure and the speed of restoration of perfusion. This article provides an overview of the indications, techniques and current state of the clinical literature with respect to endovascular revascularization.

Propolis ameliorates ischemia/reperfusion-induced testicular damage by reducing oxidative stress / El propóleo mejora el daño testicular inducido por isquemia/reperfusión al reducir el estrés oxidativo

Purpose: This study was performed to evaluate the effect of ethanolic extract of Turkish propolis (EEP) on testicular ischemia/reperfusion (I/R) damage in rats in terms of biochemistry and histopathology, for the first time. Methods: A total of 18 male Sprague-Dawley rats were divided into three groups with six rats in each group: control, torsion/detorsion (T/D), and T/D+EEP (100mg/kg). Testicular torsion was performed by 720° rotating the left testicle in a clockwise direction. The duration of ischemia was 4h and orchiectomy was performed after 2h of detorsion. EEP was applied only once 30min before detorsion. Tissue malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant status (TAS) levels were determined using colorimetric methods. Oxidative stress index (OSI) was calculated by proportioning tissue TOS and TAS values to each other. Tissue glutathione (GSH) and glutathione peroxidase (GPx) levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. Johnsen's testicle scoring system was used for histological evaluation. Results: In the T/D group, it was determined that statistically significant decreasing in TAS, GSH, GPx levels and Johnsen score, and increasing in TOS, OSI and MDA levels (p<0.05) compared with control group. EEP administration statistically significantly restored this I/R damage (p<0.05). Conclusion: This is the first study to show that propolis prevent I/R-induced testicular damage through its antioxidant activity. More comprehensive studies are needed to see the underlying mechanisms. (AU)

Objetivo: Este estudio se realizó para evaluar por primera vez el efecto del extracto etanólico de propóleo turco (EEP) sobre el daño por isquemia/reperfusión (I/R) testicular en ratas en términos de bioquímica e histopatología. Métodos: Un total de 18 ratas macho Sprague-Dawley se dividieron en 3 grupos con 6 ratas en cada grupo: control, torsión/detorsión (T/D) y T/D+EEP (100mg/kg). La torsión testicular se realizó con una rotación de 720° del testículo izquierdo en el sentido de las agujas del reloj. La duración de la isquemia fue de 4h y la orquiectomía se realizó a las 2h de la detorsión. EEP se aplicó solo una vez 30min antes de la detorsión. Los niveles de malondialdehído tisular (MDA), estado oxidante total (TOS) y estado antioxidante total (TAS) se determinaron mediante métodos colorimétricos. El índice de estrés oxidativo (OSI) se calculó proporcionando los valores de TOS y TAS del tejido entre sí. Los niveles de glutatión tisular (GSH) y glutatión peroxidasa (GPx) se determinaron utilizando kits de ensayo inmunoabsorbente ligado a enzimas (ELISA). Se utilizó el sistema de puntuación de testículos de Johnsen para la evaluación histológica. Resultados: En el grupo T/D, se determina una disminución estadísticamente significativa en los niveles de TAS, GSH, GPx y puntuación de Johnsen y un aumento en los niveles de TOS, OSI y MDA (p<0,05) en comparación con el grupo control. La administración de EEP restauró de forma estadísticamente significativa este daño I/R (p<0,05). Conclusión: Este es el primer estudio que demuestra que el propóleo previene el daño testicular inducido por I/R a través de su actividad antioxidante. Se necesitan estudios más completos para ver los mecanismos subyacentes. (AU)

Propolis ameliorates ischemia/reperfusion-induced testicular damage by reducing oxidative stress.

PURPOSE: This study was performed to evaluate the effect of ethanolic extract of Turkish propolis (EEP) on testicular ischemia/reperfusion (I/R) damage in rats in terms of biochemistry and histopathology, for the first time. METHODS: A total of 18 male Sprague-Dawley rats were divided into three groups with six rats in each group: control, torsion/detorsion (T/D), and T/D+EEP (100mg/kg). Testicular torsion was performed by 720° rotating the left testicle in a clockwise direction. The duration of ischemia was 4h and orchiectomy was performed after 2h of detorsion. EEP was applied only once 30min before detorsion. Tissue malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant status (TAS) levels were determined using colorimetric methods. Oxidative stress index (OSI) was calculated by proportioning tissue TOS and TAS values to each other. Tissue glutathione (GSH) and glutathione peroxidase (GPx) levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. Johnsen's testicle scoring system was used for histological evaluation. RESULTS: In the T/D group, it was determined that statistically significant decreasing in TAS, GSH, GPx levels and Johnsen score, and increasing in TOS, OSI and MDA levels (p<0.05) compared with control group. EEP administration statistically significantly restored this I/R damage (p<0.05). CONCLUSION: This is the first study to show that propolis prevent I/R-induced testicular damage through its antioxidant activity. More comprehensive studies are needed to see the underlying mechanisms.

Optimization of green extraction process with natural deep eutectic solvent and comparative in vivo pharmacokinetics of bioactive compounds from Astragalus-Safflower pair.

INTRODUCTION: Natural deep eutectic solvents (NaDESs) are promising not only in componential extraction, but also in drug delivery system due to their green and safe features. In this work, NaDESs were applied to extract bioactive components from Astragalus-Safflower pair, a classic traditional Chinese medicine combination. Furthermore, ready-to-use crude extracts were administrated to SD rats. METHODS: Total 9 NaDESs composed of food grade ingredients were screened for the extraction of representative 9 components (hydroxysafflor yellow A, anhydrosafflor yellow B, eleutheroside B, calycosin-7-O-glucoside, kaempferol-3-O-rutinoside, ononin, calycosin, astraganoside, and carthamin) from Astragalus-Safflower pair. Afterwards, genetic artificial neural network (GNN) was adopted for optimizing the ultrasound-assisted extraction process. After SD rats were orally administrated with the ready-to-use crude extracts extracted under the optimized conditions, the in vivo pharmacokinetic characteristics of 5 components were evaluated comprehensively from weight, gender, solvent and modeling surgery, under a well-established UPLC-MS/MS method. RESULTS: Betaine-Lactic acid (Bet-Lac) was eventually determined as the optimal extraction solvent for subsequent experiments. The optimal ultrasound assisted extraction process was as follows: 90 min of extraction time, 65 °C of temperature, 80% of Bet-Lac content and 50 mg/ml of solid-liquid ratio. Bet-Lac enhanced to varying degrees the bioavailability of analytes in normal and cerebral ischemia/reperfusion injured (CI/RI) rats in contrast with corresponding rats administrated with water extract groups (p < 0.05). Besides, the bioavailability of active components in CI/RI rat plasma was significantly lower than that in normal rats (p < 0.05), indicating pathological damage of CI/R had a significant impact on pharmacokinetic profile of compounds in rats. However, gender and body weight had no significant effects on the pharmacokinetic profile of bioactive components. CONCLUSIONS: NaDESs exhibited higher extraction efficiency than conventional solvents. And GNN is reliable to optimize the ultrasound assisted extraction process. This study supported the potential of non-toxic NaDESs as solvents for extraction process and drug delivery systems at the same time.

Actin-Cytoskeleton Drives Caveolae Signaling to Mitochondria during Postconditioning.

Caveolae-associated signaling toward mitochondria contributes to the cardioprotective mechanisms against ischemia-reperfusion (I/R) injury induced by ischemic postconditioning. In this work, we evaluated the role that the actin-cytoskeleton network exerts on caveolae-mitochondria communication during postconditioning. Isolated rat hearts subjected to I/R and to postconditioning were treated with latrunculin A, a cytoskeleton disruptor. Cardiac function was compared between these hearts and those exposed only to I/R and to the cardioprotective maneuver. Caveolae and mitochondria structures were determined by electron microscopy and maintenance of the actin-cytoskeleton was evaluated by phalloidin staining. Caveolin-3 and other putative caveolae-conforming proteins were detected by immunoblot analysis. Co-expression of caveolin-3 and actin was evaluated both in lipid raft fractions and in heart tissue from the different groups. Mitochondrial function was assessed by respirometry and correlated with cholesterol levels. Treatment with latrunculin A abolishes the cardioprotective postconditioning effect, inducing morphological and structural changes in cardiac tissue, reducing F-actin staining and diminishing caveolae formation. Latrunculin A administration to post-conditioned hearts decreases the interaction between caveolae-forming proteins, the co-localization of caveolin with actin and inhibits oxygen consumption rates in both subsarcolemmal and interfibrillar mitochondria. We conclude that actin-cytoskeleton drives caveolae signaling to mitochondria during postconditioning, supporting their functional integrity and contributing to cardiac adaption against reperfusion injury.

Histopathological effects of ß-hCG and vitamin C on the detorsioned testicle in rats with unilateral testicular torsion.

BACKGROUND: Testicular torsion is still an urgent surgical condition and without any treatment it can cause infertility. The main pathophysiology of testicular torsion ischaemic injury however; the main sequalae of detorsion is reperfusion injury. Furthermore; treatments to prevent ischemic reperfusion injury due to decreased blood flow are important to preserve testicular function. AIMS: Human chorionic gonadotropin ß (ß-hCG) is an anabolic hormone that supports steroidogenesis and spermatogenesis. Vitamin C (Vit-C) is one of the water-soluble vitamins and is also a potent antioxidant in ischemic damage. Moreover, it has protective effects by increasing blood and lymph flow in the testicles. The aim of this study is to investigate the effects of ß-hCG, Vit-C and their combination on ischemic reperfusion injury occurring after surgical treatment of testicular torsion. STUDY DESIGN: Animal research studies. METHODS: The study was performed on 25 male Wistar albino rats. The animals were divided equally into 5 groups. In the first group "Control Group," left orchiectomy was performed. In the second group "Sham Group," a 720° clockwise torsion was created and after 4 h of left testicular torsion it was detorsioned for 4 h and then left orchiectomy was performed. In the third group same procedure was applied with 30 mg vitamin C was administered via intraperitoneal route once a week for 3 weeks. In the fourth group after same surgical procedures 75 IU ß-hCG was administered via intraperitoneal route once a week for 3 weeks. In the fifth group after 4 h left testicle torsion it was detorsioned for 4 h then, 75 IU ß-hCG and vitamin C together were administered via intraperitoneal route once a week for 3 weeks. Left orchiectomy was performed after 3 weeks in the third, fourth and fifth groups. Specimens were evaluated histologically. RESULTS: Testicular tissue histopathological evaluations were performed. A high histopathological stage indicates more testicular damage, and a low one was indicated less testicular damage. The average histopathological grade of vitamin C + ß-hCG group was significantly higher than the average histopathological grade of the control, the sham group and vitamin C group. The average histopathological grade of the vitamin C group was significantly lower than the average histopathological grade of sham and ß-hCG groups. The ratio of the testicular atrophy of the Vitamin C + ß-hCG group (100%) was higher than sham (40%) and ß-hCG (40%) groups with a significant difference. A significant statistical difference was found among all groups histopathological grades of testicular tissue. CONCLUSION: In animals taking vitamin C, an improvement of histopathological findings and a significant decrease in histological stages has been provided. However, it was observed that the histological findings of ß-hCG and ß-hCG + vitamin C groups worsened. It was found that ß-hCG increased oxidative damage in the testicles and this damage can be so severe that exceeding the capacity of potent antioxidants such as Vitamin C. We believe that ß-hCG can be harmful to testicles exposed to oxidative damage.

A Primeval Mechanism of Tolerance to Desiccation Based on Glycolic Acid Saves Neurons in Mammals from Ischemia by Reducing Intracellular Calcium-Mediated Excitotoxicity.

Stroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, reopen occluded arteries but do not protect against ischemia-induced damage that occurs before reperfusion or neuronal damage induced by ischemia/reperfusion. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis in Caenorhabditis elegans dauer larva and that GA itself can rescue this phenotype. During the process of desiccation/rehydration, a metabolic stop/start similar to the one observed during ischemia/reperfusion occurs. In this study, the protective effect of GA is tested in different ischemia models, i.e., in commonly used stroke models in mice and swine. The results show that GA, given during reperfusion, strongly protects against ischemic damage and improves functional outcome. Evidence that GA exerts its effect by counteracting the glutamate-dependent increase in intracellular calcium during excitotoxicity is provided. These results suggest that GA treatment has the potential to reduce mortality and disability in stroke patients.

Stamp2 Protects From Maladaptive Structural Remodeling and Systolic Dysfunction in Post-Ischemic Hearts by Attenuating Neutrophil Activation.

The six-transmembrane protein of prostate 2 (Stamp2) acts as an anti-inflammatory protein in macrophages by protecting from overt inflammatory signaling and Stamp2 deficiency accelerates atherosclerosis in mice. Herein, we describe an unexpected role of Stamp2 in polymorphonuclear neutrophils (PMN) and characterize Stamp2's protective effects in myocardial ischemic injury. In a murine model of ischemia and reperfusion (I/R), echocardiography and histological analyses revealed a pronounced impairment of cardiac function in hearts of Stamp2-deficient- (Stamp2-/- ) mice as compared to wild-type (WT) animals. This difference was driven by aggravated cardiac fibrosis, as augmented fibroblast-to-myofibroblast transdifferentiation was observed which was mediated by activation of the redox-sensitive p38 mitogen-activated protein kinase (p38 MAPK). Furthermore, we observed increased production of reactive oxygen species (ROS) in Stamp2-/- hearts after I/R, which is the likely cause for p38 MAPK activation. Although myocardial macrophage numbers were not affected by Stamp2 deficiency after I/R, augmented myocardial infiltration by polymorphonuclear neutrophils (PMN) was observed, which coincided with enhanced myeloperoxidase (MPO) plasma levels. Primary PMN isolated from Stamp2-/- animals exhibited a proinflammatory phenotype characterized by enhanced nuclear factor (NF)-κB activity and MPO secretion. To prove the critical role of PMN for the observed phenotype after I/R, antibody-mediated PMN depletion was performed in Stamp2-/- mice which reduced deterioration of LV function and adverse structural remodeling to WT levels. These data indicate a novel role of Stamp2 as an anti-inflammatory regulator of PMN and fibroblast-to-myofibroblast transdifferentiation in myocardial I/R injury.

Implications of Oxidative and Nitrosative Post-Translational Modifications in Therapeutic Strategies against Reperfusion Damage.

Post-translational modifications based on redox reactions "switch on-off" the biological activity of different downstream targets, modifying a myriad of processes and providing an efficient mechanism for signaling regulation in physiological and pathological conditions. Such modifications depend on the generation of redox components, such as reactive oxygen species and nitric oxide. Therefore, as the oxidative or nitrosative milieu prevailing in the reperfused heart is determinant for protective signaling, in this review we defined the impact of redox-based post-translational modifications resulting from either oxidative/nitrosative signaling or oxidative/nitrosative stress that occurs during reperfusion damage. The role that cardioprotective conditioning strategies have had to establish that such changes occur at different subcellular levels, particularly in mitochondria, is also presented. Another section is devoted to the possible mechanism of signal delivering of modified proteins. Finally, we discuss the possible efficacy of redox-based therapeutic strategies against reperfusion damage.

PET-MRI nanoparticles imaging of blood-brain barrier damage and modulation after stroke reperfusion.

In an acute ischaemic stroke, understanding the dynamics of blood-brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood-brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood-brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood-brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischaemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (<1 nm) and AGuIX® nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced magnetic resonance imaging, the baseline transfer constant K trans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] ×10-3 min-1, respectively, in the normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] ×10-3 min-1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, K trans for both Gd-DOTA and AGuIX® nanoparticles was significantly higher within the ischaemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] ×10-3 min-1 for Gd-DOTA and AGuIX® nanoparticles, respectively. With AGuIX® nanoparticles, K trans also increased within the ischaemic growth areas, suggesting added value for AGuIX®. Finally, K trans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n = 7) compared to placebo (n = 5). K trans quantification with AGuIX® nanoparticles can monitor early blood-brain barrier damage and treatment effect in ischaemic stroke after reperfusion.

Hepatic consequences of COVID-19 infection. Lapping or biting?

The outbreak of coronavirus disease 2019 (COVID-19) starting last December in China placed emphasis on liver involvement during infection. This review discusses the underlying mechanisms linking COVID-19 to liver dysfunction, according to recent available information, while waiting further studies. The manifestations of liver damage are usually mild (moderately elevated serum aspartate aminotransferase activities), and generally asymptomatic. Few patients can still develop severe liver problems, and therapeutic options can be limited. Liver dysfunction may affect about one-third of the patients, with prevalence greater in men than women, and in elderly. Mechanisms of damage are complex and include direct cholangiocyte damage and other coexisting conditions such as the use of antiviral drugs, systemic inflammatory response, respiratory distress syndrome-induced hypoxia, sepsis, and multiple organ dysfunction. During new COVID-19 infections, liver injury may be observed. If liver involvement appears during COVID-19 infection, however, attention is required. This is particularly true if patients are older or have a pre-existing history of liver diseases. During COVID-19 infection, the onset of liver damage impairs the prognosis, and hospital stay is longer.

Leptin affects the inflammatory response after STEMI.

Leptin is an adipose tissue-derived hormone primarily involved in the regulation of food intake. Leptine has been shown to have a much broader role than just regulating body weight and appetite in response to food intake: among the others, it has been associated with increased ROS production and inflammation, factors involved in the restoration of an effective myocardial reperfusion after myocardial revascularization. Our study, to our best knowledge, is the first showing a direct relationship between leptin serum levels, inflammatory mediators of the ischemia reperfusion damage and effective myocardial reperfusion in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention. Our findings suggest that leptin serum levels are directly associated with the inflammatory response during an acute myocardial infarction and may have a role in risk stratification in this clinical setting.

Differential expression of miR-142-3p protects cardiomyocytes from myocardial ischemia-reperfusion via TLR4/NFkB axis.

Our research aims to explore the impact of miR-142 on myocardial apoptosis in the mouse ischemia and reperfusion (IR) model and investigate the underlying mechanisms at the molecular level. A considerable downregulation of miR-142 was observed in the cardiac area of mice post IR modeling. To understand the regulatory function of IR-induced miR-142 downregulation, the animals were categorized into four groups: IR model group; IR + agomir-142 group (IR mice treated with agomir-142); IR + antagomir-142 group (IR mice treated with antagomir-142); IR + agomir-142 + negative control (NC) group (IR mice processed with agomir-NC). The results indicated that agomir-142 upregulation was capable of shrinking IR damage-triggered infarction of the ventriculus sinister, strengthening myocardial function, and guarding against cardiomyocyte apoptosis, whereas further decreased miR-142 with antagomir-142 infection displayed negative influence of miR-142 against mice IR damage. In the cellular assay, miR-142 overexpression significantly improved proliferation and inhibited the apoptosis of neonatal rat cardiomyocytes (NRCs). Moreover, we found that miR-142 reduced the Bcl-2/Bax ratio and upregulated hydrogen peroxide (H2 O2 )-induced caspase-3 expression. Furthermore, transfection with an miR-142 mimic prevented the upregulation of TLR4/NFkB expression and activation in H2 O2 -treated NRCs. Our findings also revealed that miR-142 is linked to the 3'-untranslated area of the TLR4 gene. In addition, TLR4 overexpression considerably ablated the protective effects of miR-142 in terms of the cell viability of H2 O2 -treated NRCs. Taken together, miR-142 agomir injection in mice and miR-142 mimic transfection in NRCs plays a role in protecting the heart from IR damage and malfunction via the TLR4/NFkB axis both in vivo and in vitro.

The Role of GLP1 in Rat Steatotic and Non-Steatotic Liver Transplantation from Cardiocirculatory Death Donors.

In liver transplantation (LT), organ shortage has led to the use of steatotic and non-steatotic grafts from donors after cardiocirculatory death (DCD). However, these grafts, especially those with steatosis, exhibit poor post-operative outcomes. To address this problem, we investigated the roles of gut-derived glucagon-like peptide 1 (GLP1) and dipeptidyl peptidase 4 (DPP4), the serine protease that cleaves it, in steatotic and non-steatotic LT from DCDs. Using Zucker rats, liver grafts from DCDs were cold stored and transplanted to recipients. GLP1 was administered to donors. The levels of GLP1 in intestine and of both GLP1 and DDP4 in circulation were unaltered following cardiocirculatory death (CD). In steatotic livers from DCD, increased GLP1 and decreased DPP4 were recorded, and administration of GLP1 caused a rise in hepatic GLP1 and a reduction in DDP4. This protected against inflammation, damage, and proliferation failure. Conversely, low GLP1 and high DDP4 were observed in non-steatotic livers from DCD. The exogenous GLP1 did not modify hepatic DDP4, and the accumulated GLP1 exerted harmful effects, increasing damage, inflammation, and regeneration failure. Herein, we show that there are differences in GLP1/DDP4 regulation depending on the type of liver implanted, suggesting that GLP1 can be used as a novel and effective therapy in steatotic grafts from DCDs but that it is not appropriate for non-steatotic DCDs.

The Effect of Fibroblast Growth Factor 15 Signaling in Non-Steatotic and Steatotic Liver Transplantation from Cardiocirculatory Death.

We elucidate the relevance of fibroblast growth factor 15 (FGF15) in liver transplantation (LT) using rats with both steatotic and non-steatotic organs from donors after cardiocirculatory death (DCD). Compared to LT from non-DCDs, the induction of cardiocirculatory death (CD) increases hepatic damage, proliferation, and intestinal and circulatory FGF15. This is associated with high levels of FGF15, bilirubin and bile acids (BAs), and overexpression of the enzyme involved in the alternative BA synthesis pathway, CYP27A1, in non-steatotic livers. Furthermore, CD activates the proliferative pathway, Hippo/YAP, in these types of liver. Blocking FGF15 action in LT from DCDs does not affect CYP27A1 but causes an overexpression of CYP7A, an enzyme from the classic BA synthesis pathway, and this is related to further accumulation of BAs and exacerbated damage. FGF15 inhibition also impairs proliferation without changing Hippo/YAP. In spite of worse damage, steatosis prevents a proliferative response in livers from DCDs. In steatotic grafts, CD does not modify CYP7A1, CYP27A1, BA, or the Hippo/YAP pathway, and FGF15 is not involved in damage or proliferation. Thus, endogenous FGF15 protects against BA accumulation and damage and promotes regeneration independently of the Hippo/YAP pathway, in non-steatotic LT from DCDs. Herein we show a minor role of FGF15 in steatotic LT from DCDs.

Complete Restitution of the Ischemic Penumbra after Successful Thrombectomy : A Pilot Study Using Quantitative MRI.

PURPOSE: Endovascular thrombectomy is highly effective in patients with proximal large artery occlusion but the relevance of reperfusion injury after recanalization is a matter of debate. The aim of this study was to investigate potential residual metabolic distress and microstructural tissue damage or edema after reperfusion using quantitative oxygen-sensitive T2' and T2-mapping in patients successfully treated by thrombectomy. METHODS: Included in this study were 11 patients (mean age 70 ± 11.4 years) with acute ischemic stroke due to internal carotid artery and/or middle cerebral artery occlusion. Quantitative T2 and T2' (1/T2' = 1/T2* - 1/T2) were determined within the ischemic core and hypoperfused but salvaged tissue with delayed time-to-peak (TTP) in patients before and after successful thrombectomy and compared to a control region within the unaffected hemisphere. RESULTS: Decreased T2' values within hypoperfused tissue before thrombectomy showed a normalization after recanalization (p < 0.01). In formerly hypoperfused but salvaged tissue, T2 values increased significantly after thrombectomy (p < 0.05) but did not differ from reference values in the control region. In salvaged tissue, increases of quantitative T2' and T2 to follow-up were more pronounced in areas with severe TTP delay. CONCLUSION: After successful recanalization, T2' re-increased back to normal in formerly hypoperfused areas as a sign of prompt normalization of oxygen metabolism. Furthermore, quantitative T2 in the formerly hypoperfused tissue did not differ from reference values in unaffected tissue. These results indicate complete restitution of salvaged tissue after reperfusion and support the overall safety of endovascular thrombectomy with respect to microstructural tissue integrity.

Neutrophil Gelatinase-associated Lipocalin Significantly Correlates with Ischemic Damage in Patients Undergoing Laparoscopic Partial Nephrectomy

Background: Laparoscopic partial nephrectomy, which minimizes renal function loss due to its nephron sparing nature, has become a standard technique among many experienced centers worldwide for surgical treatment of localized kidney tumors. Although partial nephrectomy will remain the gold standard, we need to improve perioperative management and surgical method to prevent postoperative acute kidney injury. Aims: To demonstrate the frequency of the development of postoperative acute kidney injury following laparoscopic partial nephrectomy in patients with healthy contralateral kidney and determine the early predictive effects of serum neutrophil gelatinase-associated lipocalin on ischemia-reperfusion injury and its association with warm ischemia time. Study Design: Cross-sectional study. Methods: Eighty patients were included. We analyzed tumor size, operating time, duration of anesthesia, and warm ischemia time. Serum samples were obtained for measurement of serum creatinine, estimated glomerular filtration rate, and neutrophil gelatinase-associated lipocalin level preoperatively, at the postoperative 2nd hour, and on postoperative days 1 and 2. We used receiver operating characteristic curve for determining the cut-off point of neutrophil gelatinase-associated lipocalin to detect postoperative acute kidney injury. Correlation analysis was performed using Spearman's test. Results: Twenty-seven patients developed acute kidney injury on postoperative day 2, and the neutrophil gelatinase-associated lipocalin level increased significantly at the postoperative 2nd hour in the acute kidney injury group (p=0.048). For a cut-off of 129.375 ng/mL neutrophil gelatinase-associated lipocalin, the test showed 70.0% sensitivity and 68.3% specificity for the detection of acute kidney injury at the postoperative 2nd hour. For a cut-off of 184.300 ng/mL neutrophil gelatinase-associated lipocalin, the test exhibited 73.3% sensitivity and 63.3% specificity for the detection of acute kidney injury on postoperative day 1. A significant correlation was found between warm ischemia time and neutrophil gelatinase-associated lipocalin level at the postoperative 2nd hour (r=0.398, p=0.003). The creatinine values were significantly higher and the estimated glomerular filtration rates were significantly lower on postoperative days 1 and 2 in the acute kidney injury group compared with those in the non-acute kidney injury group (p<0.001). Conclusion: The neutrophil gelatinase-associated lipocalin may be used as an alternative biomarker to serum creatinine in differentiation of ischemic damage in patients undergoing laparoscopic partial nephrectomy.

Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury.

BACKGROUND: Establishing sustained reoxygenation/reperfusion ensures not only the recovery, but may initiate a reperfusion injury in which oxidative stress plays a major role. This study offers the mechanism and this mechanism-specific therapeutic strategy against excessive release of reactive oxygen species (ROS) associated with reperfusion-driven recovery of mitochondrial metabolism. AIMS AND METHODS: In neonatal mice subjected to cerebral hypoxia-ischaemia (HI) and reperfusion, we examined conformational changes and activity of mitochondrial complex I with and without post-HI administration of S-nitrosating agent, MitoSNO. Assessment of mitochondrial ROS production, oxidative brain damage, neuropathological and neurofunctional outcomes were used to define neuroprotective strength of MitoSNO. A specificity of reperfusion-driven mitochondrial ROS production to conformational changes in complex I was examined in-vitro. RESULTS: HI deactivated complex I, changing its conformation from active form (A) into the catalytically dormant, de-active form (D). Reperfusion rapidly converted the D-form into the A-form and increased ROS generation. Administration of MitoSNO at the onset of reperfusion, decelerated D→A transition of complex I, attenuated oxidative stress, and significantly improved neurological recovery. In cultured neurons, after simulated ischaemia-reperfusion injury, MitoSNO significantly reduced ROS generation and neuronal mortality. In isolated mitochondria subjected to anoxia-reoxygenation, MitoSNO restricted ROS release during D→A transitions. CONCLUSION: Rapid D→A conformation in response to reperfusion reactivates complex I. This is essential not only for metabolic recovery, but also contributes to excessive release of mitochondrial ROS and reperfusion injury. We propose that the initiation of reperfusion should be followed by pharmacologically-controlled gradual reactivation of complex I.

[Evaluation of the cardioprotective effect of ubiquinol on the model of reperfusion injury of rat myocardium]. / Otsenka kardioprotektornogo deistviia ubikhinola na modeli reperfuzionnogo povrezhdeniia miokarda krys.

The cardioprotective effect of ubiquinol on the model of myocardium reperfusion injury in rats was investigated. The study was carried out using mature males of outbred rats. Myocardial ischemia-reperfusion injury was performed after 30-minute ligation of the left coronary artery followed by reperfusion. The main criteria for assessing the development of pathology included the results of electrocardiography, biochemical analysis of blood plasma, histological and histochemical study of the myocardium. Development of the reperfusion damage of the myocardium caused specific changes in non-treated animals. The best therapeutic effect on biochemical indices was provided by a drug with the known cardioprotective activity - Mexidolâ and the tested object ubiquinol at doses of 2-6 mg/kg. Evaluation of the results of electrocardiography allowed to confirm the development of ischemic myocardial damage in all groups. The results of histochemical and histological examination of the myocardium suggest a high cardioprotective activity of ubiquinol at a dose of 3 mg/kg and a potential cardioprotective effect of ubiquinol in doses closest to the therapeutic doses of 2 and 6 mg/kg. Ubiquinol is a dose 9 mg/kg showed signs of prooxidant activity, manifested in the form of aggravation of reperfusion injury of the myocardium. The most effective in the conditions of experimental pathology is 1% solution of ubiquinol, at a dose of 3 mg/kg, whose cardioprotective effect is comparable or higher than that for the reference drug Mexidolâ at the therapeutic dose. In doses that are greater than therapeutic ubiquinol is able to act as a pro-oxidant.