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

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.

Изменение функциональной активности тромбоцитов при длительном световом воздействии в эксперименте

We studied the effect of intensive light exposure on the aggregation activity of white male rats' platelets using the experimental Light-Dark (18:6) lighting model. Analysis of platelet aggregation activity was carried out using a computerized 230LA "Biola" aggregation analyzer using the method of V.A. Gabbasov. It was established that in case of prolonged light exposure in the body of laboratory animals there was a disturbance of aggregation activity accompanied by an increase in the parameters of the curve of the average weighted radius of platelets and the parameters of the light transmittance curve. Violation of the daytime regime in the form of artificial prolongation of illumination causes increase of platelet aggregation activity and provokes development of microcirculatory disturbances. Forming changes in the hemostasis system increase in proportion to the duration of the experiment. The most pronounced changes in the vascular-platelet mechanism of hemostasis are formed on the 21st day of the experiment, indicating the development of processes of maladaptation followed by exhaustion of the organism.

Bone stump formation against the background of post-amputation pain syndrome

Introduction: Bone is the basis of the stump. Aim: To study the impact of post-amputation pain syndrome on the nature of reparative processes in the bone residual limb. Material and methods: Three series of experiments were performed on 45 rabbits, 15 in each with mid-third thigh amputation and muscular plasty. In series 1, 2, a perineural catheter was attached to the sciatic nerve stump during amputation, and mechanical irritation of the nerve was performed daily for 20 minutes in series 1 for 20 days. In series 2, 0.3 mL of lidocaine (1%) was injected through the catheter into the circumference of the nerve twice daily for 20 days. Series 3 is a control. The follow-up periods were 1, 3, 6 months. The study method was histological with infusion of the vessels with ink-gelatin mixture. Results and discussion: In series 1, there was a sharp disturbance of the reparative process, which consisted in shape changes, resorption of the cortical diaphyseal plate, fractures, stump deformity, absence of bone closure plate formation, and microcirculatory disturbances. In the overall majority of experiments of series 2, the stumps retained the shape and structure characteristic of diaphysis with normalization of microcirculation. In series 3, the results of the residual limb formation were better than in series1, but worse than in series 2. Conclusions: When the pain syndrome is resolved within 20 days after amputation, a bone stump is formed with an organotypic shape and structure characteristic of the diaphysis, the formation of a compact closure plate of mature bone tissue, normalization of the medullary tissues and blood circulation. In post-amputation pain syndrome, organotypic formation of the residual limb does not occur.

Imaging of the Intestinal Microcirculation during Acute and Chronic Inflammation

Because of its unique microvascular anatomy, the intestine is particularly vulnerable to microcirculatory disturbances. During inflammation, pathological changes in blood flow, vessel integrity and capillary density result in impaired tissue oxygenation. In severe cases, these changes can progress to multiorgan failure and possibly death. Microcirculation may be evaluated in superficial tissues in patients using video microscopy devices, but these techniques do not allow the assessment of intestinal microcirculation. The gold standard for the experimental evaluation of intestinal microcirculation is intravital microscopy, a technique that allows for the in vivo examination of many pathophysiological processes including leukocyte-endothelial interactions and capillary blood flow. This review provides an overview of changes in the intestinal microcirculation in various acute and chronic inflammatory conditions. Acute conditions discussed include local infections, severe acute pancreatitis, necrotizing enterocolitis and sepsis. Inflammatory bowel disease and irritable bowel syndrome are included as examples of chronic conditions of the intestine.

The Effect of Prophylactic Anticoagulation with Heparin on the Brain Cells of Sprague-Dawley Rats in a Cardiopulmonary-Cerebral Resuscitation Model

After a cardiac arrest (CA) of 5 to 10 min, a marked activation of blood coagulation occurs and microthrombi are found in the cerebral vessels. These microcirculatory disturbances directly affect the outcome on cardiopulmonary resuscitation (CPR). The purpose of this study was to investigate the effects and potential mechanisms of prophylactic anticoagulation on rat brain cells after cerebral CPR. After setting up an asphyxial CA model, we monitored the basic parameters such as the vitals and survival rate of the rats and assessed the respective neurological deficit (ND) and histological damage (HD) scores of their brain tissues. We, furthermore, investigated the influence of heparin on the expressions of TNF-α, IL-1β, CD40, NF-κB, and HIF-1α after asphyxial CA. The results showed that anticoagulation with heparin could obviously improve the outcome and prognosis of brain ischemia, including improvement of neurological function recovery and prevention of morphological and immunohistochemical injury on the brain, while significantly increasing the success rate of CPR. Treatment with heparin significantly inhibited the upregulation of CD40, NF-κB, and HIF-1α induced by asphyxial CA. Thrombolysis treatment may improve the outcome and prognosis of CPR, and future clinical studies need to evaluate the efficacy of early heparin therapy after CA.

Inflammatory Response to Different Toxins in Experimental Sepsis Models

Sepsis is defined as life-threatening organ dysfunction caused by the dysregulated host response to infection. Despite serious mortality and morbidity, no sepsis-specific drugs exist. Endotoxemia is often used to model the hyperinflammation associated with early sepsis. This model classically uses lipopolysaccharide (LPS) from Gram-negative pathogens to activate the immune system, leading to hyperinflammation, microcirculatory disturbances and death. Other toxins may also be used to activate the immune system including Gram-positive peptidoglycan (PG) and lipoteichoic acid (LTA). In addition to these standard toxins, other bacterial components can induce inflammation. These molecules activate different signaling pathways and produce different physiological responses which can be taken advantage of for sepsis modeling. Endotoxemia modeling can provide information on pathways to inflammation in sepsis and contribute to preclinical drug development.

Dipyridamole: the rearguard on proscenium

Антиагрегантная терапия является основой профилактики атеротромбоза и нарушений микроциркуляции при многих видах патологии. Дипиридамол в сочетании с ацетилсалициловой кислотой служит важным компонентом профилактики ишемического инсульта он также доказал свою эффективность в улучшении коронарного кровотока, периферического кровообращения за счет своего антиагрегантного и сосудорасширяющего действия. Синдром обкрадывания является клиническим преувеличением, так как присущ только высоким дозам препарата, вводимым внутривенно. Дипиридамол обладает многими плейотропными эффектами, связанными с его способностью индуцировать синтез интерферона, регулировать оксидативный стресс, активность клеток иммунной системы, матриксных металлопротеиназ и др. Понимание патогенеза различных видов патологии с позиций взаимосвязи гемостаза и воспаления наряду с высокой безопасностью дипиридамола в отношении кровотечений, онкологического роста и его экономической доступностью позволяют применять препарат в ревматологии, акушерстве и гинекологии, нефрологии, гематологии и других областях медицины, проводить актуальные научные исследования. Обзор посвящен обсуждению возможностей коррекции ключевых механизмов патогенеза многих заболеваний с использованием различных свойств дипиридамола и применения данных преимуществ препарата в клинике внутренних болезней. Antiplatelet agents are the main group of drugs using for antiatherothrombotic prophylaxis and correction of microcirculatory disturbances in many fields of medicine. Dipyridamole in combination with acetylsalicylic acid is an important component of stroke prevention. It also demonstrates effectiveness for prevention of cardiovascular complications due to its antiplatelet and vasodilatory effect. Steal phenomenon is clinical exaggeration, because it happens only if high doses of dipyridamole are injected intravenously. Dipyridamole has numerous pleiotropic effects related with its ability to induce interferon synthesis, to regulate oxidative stress, activity of immune cells, matrix metalloproteinases, etc. Understanding of pathogenesis of numerous diseases as the interrelationship between hemostasis and inflammation may leads medical specialists to use dipyridamole in rheumatology, obstetrics, gynecology, nephrology, haematology and other fields of medicine and medical researches. High safety of dipyridamole in regard to hemorrhagic complications, malignant progression and its high economic accessibility are very important features of this wellknown for clinicians drug. Further search of clinical applications for dipyridamole is discussed in this review.