Механизмы повреждения и защиты клетки при ишемии/реперфузии и экспериментальное обоснование применения препаратов на основе лития в анестезиологии

Pharmaceuticals based on lithium ions have been already used in clinical practice for over 60 years for the treatment of bipolar disorders and remain a basic pharmacological therapy for patients with this disease. In spite of this, the therapeutic mechanisms of action of lithium ions have not been fully investigated. In the past decade, in vitro and in vivo experiments have provided a good deal of data suggesting that lithium ions have previously undescribed neuro-, cardio-, and nephro-protective properties. Numerous investigations have demonstrated that glycogen synthase kinase-3/3, the key enzyme of different pathological and protective signaling pathways, is the target of lithium ions in displaying these effects. This review deals with just these new properties of lithium ions, which make them utterly promising for clinical use in circulatory arrest-associated conditions, which is particularly relevant for anesthesiology and resuscitation. Key words: lithium ions, brain, heart, kidney, postresuscitation disease.Фармакологические препараты на основе ионов лития уже более 60 лет используются в клинической практике для лечения биполярных расстройств и остаются основой фармакотерапии пациентов с этой группой заболеваний. Несмотря на это, терапевтические механизмы действия ионов лития изучены не в полной мере. В течение последних 10 лет в экспериментах in vitro и in vivo было получено множество данных, свидетельствующих о наличии у ионов лития ранее не описанных нейро-, кардио- и нефропротекторных свойств. Основной мишенью ионов лития при реализации этих эффектов является киназа гликогенсинтазы-3в, ключевой фермент различных патологических и защитных сигнальных путей. Данный обзор посвящен новым свойствам ионов лития, делающих их чрезвычайно перспективными для клинического применения при состояниях, связанных с остановкой кровообращения, что особенно актуально для анестезиологии и реаниматологии. Ключевые слова: ионы лития, мозг, сердце, почка, постреанимационная болезнь

Decreased renal expression of PAQR5 is associated with the absence of a nephroprotective effect of progesterone in a rat UUO model

Abstract Fibrosis is a severe complication of chronic kidney disease (CKD). Progesterone, like other sex hormones, plays an important role in renal physiology, but its role in CKD is poorly understood. We investigated progesterone effect on renal fibrosis progression in the rat model of unilateral ureteral obstruction (UUO). Female rats were exposed to UUO, ovariectomy and progesterone administration after UUO with ovariectomy. Expression of key fibrosis markers, proinflammatory cytokines, levels of membrane-bound (PAQR5) and nuclear (PGR) progesterone receptors, and matrix metalloproteinase (MMP) activity were analyzed in the obstructed and intact rat kidney. In all groups exposed to UUO, decreased PAQR5 expression was observed in the obstructed kidney while in the contralateral kidney, it remained unaffected. We found increased mRNA levels for profibrotic COL1A1, FN1, MMP2, TIMP1, TIMP2, proinflammatory IL1α, IL1β, and IL18, as well as elevated α-SMA and MMP9 proteins, collagen deposition, and MMP2 activity in all UUO kidneys. Progesterone had slight or no effect on the change in these markers. Thus, we demonstrate for the first time diminished sensitivity of the kidney to progesterone associated with renal fibrosis due to a severe decrease in PAQR5 expression that was accompanied by the lack of nephroprotection in a rat UUO model

Synthetic and natural polyanions induce cytochrome c release from mitochondria in vitro and in situ

A synthetic polyanion composed of styrene, maleic anhydride, and methacrylic acid (molar ratio 56:37:7) significantly inhibited the respiration of isolated rat liver mitochondria in a time-dependent fashion that correlated with 1) collapse of the mitochondrial membrane potential and 2) high amplitude mitochondrial swelling. The process is apparently Ca2+ dependent. Since it is blocked by cyclosporin A, the process is ascribed to induction of the mitochondrial permeability transition. In mitoplasts, i.e., mitochondria lacking their outer membranes, the polyanion rapidly blocked respiration. After incubation of rat liver mitochondria with the polyanion, cytochrome c was released into the incubation medium. In solution, the polyanion modified by conjugation with fluorescein formed a complex with cytochrome c. Addition of the polyanion to cytochrome c-loaded phosphatidylcholine/cardiolipin liposomes induced the release of the protein from liposomal membrane evidently due to coordinated interplay of Coulomb and hydrophobic interactions of the polymer with cytochrome c. We conclude that binding of the polyanion to cytochrome c renders it inactive in the respiratory chain due to exclusion from its native binding sites. Apparently, the polyanion interacts with cytochrome c in mitochondria and releases it to the medium through breakage of the outer membrane as a result of severe swelling. Similar properties were demonstrated for the natural polyanion, tobacco mosaic virus RNA. An electron microscopy study confirmed that both polyanions caused mitochondrial swelling. Exposure of cerebellar astroglial cells in culture to the synthetic polyanion resulted in cell death, which was associated with nuclear fragmentation

Effect of MSCs and MSC-Derived Extracellular Vesicles on Human Blood Coagulation

Mesenchymal stem cells (MSCs) have emerged as a potent therapeutic tool for the treatment of a number of pathologies, including immune pathologies. However, unwelcome effects of MSCs on blood coagulation have been reported, motivating us to explore the thrombotic properties of human MSCs from the umbilical cord. We revealed strong procoagulant effects of MSCs on human blood and platelet-free plasma using rotational thromboelastometry and thrombodynamic tests. A similar potentiation of clotting was demonstrated for MSC-derived extracellular vesicles (EVs). To offer approaches to avoid unwanted effects, we studied the impact of a heparin supplement on MSC procoagulative properties. However, MSCs still retained procoagulant activity toward blood from children receiving a therapeutic dose of unfractionated heparin. An analysis of the mechanisms responsible for the procoagulant effect of MSCs/EVs revealed the presence of tissue factor and other proteins involved in coagulation-associated pathways. Also, we found that some MSCs and EVs were positive for annexin V, which implies the presence of phosphatidylserine on their surfaces, which can potentiate clot formation. Thus, we revealed procoagulant activity of MSCs/EVs associated with the presence of phosphatidylserine and tissue factor, which requires further analysis to avoid adverse effects of MSC therapy in patients with a risk of thrombosis