MITOCHONDRIAL FUNCTION AND TISSUE VIABILITY IN VIVO:FROM ANIMAL EXPERIMENTS TO CLINICAL APPLICATIONS.FORTY YEARS OF FRUITFUL COLLABORATION WITH BRITTON CHANCE

The involvement of mitochondrial dysfunction in many pathophysiological conditions and human diseases is well documented.In order to evaluate mitochondrial function in vitro,many experimental systems have been developed.Nevertheless the number of in vivo monitoring systems for the evaluation of mitochondrial activities in intact animals and patients is relatively limited.The pioneering development of the conceptual and technological aspects ofmitochondrial monitoring,in vitro and in vivo,was done by the late Prof.Britton Chance(July 24,1913
November 16,2010)since the early 1950s.It was my privilege to join his laboratory in 1972 and collaborate with him for almost four decades.The main achievements of our collaboration are presented in this paper.Our activities included cycles of technology development,followed by its applications to study various pathophysiological conditions.In the initial stage,thefirstfiber-optic
based NADHfluorometer was developed.This device enabled us to monitor various organs in anesthetized animals aswell as the brain of nonanesthetized small animals.Later on,the addition of various physiological parameters to NADH monitoring enabled us to correlate mitochondrial function with other cellular functions.The application of the developed technology to clinical situations was a major interest of Prof.Chance and indeed this goal was achieved in the last decade.As of today,the basic tool forNADHmonitoring and the large database of results are available for large-scale experimental and clinical applications.

Innate Immunity in the Development of Connective Tissue Dysplasia: Pilot Study in Children with Congenital Hip Dislocation

Introduction: Observing and treatment of hip dysplasia in children have always been in the sphere of interest of modern molecular medicine. The role of molecular factors in the formation of connective tissue dysplasia in children is considered crucial for such multisystem disorders, and connective tissue dysplasia progressing involves immune system parameters and biochemical markers. The aim of this work was to establish the relationship between immune status indicators and biochemical markers of connective tissue using bioinformatics and modeling methods. Materials and Methods: 27 patients with congenital hip dislocation, admitted to the University Clinic of Privolzhsky Research Medical University, Department of children orthopedics for surgical treatment, were examined. Determination of 10 blood parameters was conducted by modern biochemical and immunological methods. Statistica 12.0 software from StatSoft was used for statistical data processing. Methods of nonparametric statistics were used since the samples in the control group partially follow the normal distribution. Correlation methods and regression modeling methods were used to evaluate the relationship of indicators. Results and Conclusion: In our investigation we have shown the presence of statistical and mathematical interactions between the parameters of innate immunity and indicators of connective tissue metabolism. The leading role of the immune system in the development of pathologies associated with connective tissue dysplasia is assumed. In further investigations it is necessary to clarify the role hypoxia in HIF-1 stimulated control of skeletal dysplasia, collagen modification, connective tissue dysplasia development.

Effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury

To study the effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury (sTBI).Methods All 33 patients with sTBI(GCS≤8) were randomly divided into hypothermic group and control group.Microdialysis catheters were inserted into the cerebral cortex of perilesion,relative normal brain tissue and subcutaneous tissue of abdomen in order to analyze the concentrations of lactate/pyruvate (L/P),lactate/glucose (L/G) and the glycerol(Gly) in extracellular fluid (ECF).Results In comparison with the control group,the concentration of L/G,L/P and Gly in periphery and that of L/P in ECF of the “normal brain tissue” were significantly decreased in the hypothermic group.In control group,concentration of L/G,L/P and Gly in periphery were higher than those in relative normal brain.In the hypothermic group,L/P concentration in periphery was higher than that in relative normal brain.Conclusion Mild hypothermia protects brain by decreasing concentrations of L/G,L/P and Gly in periphery and L/P concentration in “normal brain tissue”.The energy crisis and membrane phospholipid breakage in periphery are easier to happen after TBI,where mild hypothermia exerts significant protgective role.12 refs,3 tabs.

Apolipoprotein E in diet-induced obesity:a paradigm shift from conventional perception

Apolipoprotein E（APOE） is a major protein component of peripheral and brain lipoprotein transport systems.APOE in peripheral circulation does not cross the blood brain barrier or blood cerebrospinal fluid barrier. As a result,peripheral APOE expression does not affect brain APOE levels and vice versa. Numerous epidemiological studies suggest a key role of peripherally expressed APOE in the development and progression of coronary heart disease while brain APOE has been associated with dementia and Alzheimer＇s disease. More recent studies, mainly in experimental mice, suggested a link between Apoe and morbid obesity. According to the latest findings, expression of human apolipoprotein E3（APOE3） isoform in the brain of mice is associated with a potent inhibition of visceral white adipose tissue（WAT） mitochondrial oxidative phosphorylation leading to significantly reduced substrate oxidation,increased fat accumulation and obesity. In contrast, hepatically expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity. These novel findings constitute a major paradigm shift from the widely accepted perception that APOE promotes obesity via receptor-mediated postprandial lipid delivery to WAT. Here, we provide a critical review of the latest facts on the role of APOE in morbid obesity.