Physiological and ethnogenetic risk factors for cardiovascular thrombosis

An analysis of publications on the polymorphism of enzymes, receptors, and other systems of lipid and lipoprotein metabolism critical for the formation of vascular lipoprotein plaques and thrombi revealed the importance of certain genetic factors for the development of cardiovascular disorders. However, because of the polygenic nature of these disorders, the assessment of the corresponding hereditary risk factors requires multivariablecorrelation analysis. Population studies show that the polymorphism of individual genes manifests itself in the difference in incidence rates between ethnic groups.     

Neurodegenerative Disorders: The Role of Genetic Factors in Their Origin and the Efficiency of Treatment

The review considers the main molecular physiological causes of neurodegenerative disorders. The genetic factors involved in Parkinson’s and Alzheimer’s diseases are conventionally divided into pharmacodynamic and pharmacokinetic. The former are analyzed at the levels of dopamine (DA) neurons and polymorphism of the D₁, D₂, and D₃ DA receptors. The role of polymorphisms of some proteins such as parkin (PARK1-PARK10) and α-synuclein in generation of Lewy bodies is described. The pharmacokinetic factors play a role in Parkinson’s disease (PD) at the level of metabolism of DA, dioxyphenylalanine, and tyrosine and include polymorphisms of enzymes and proteins involved in the relevant metabolic reactions. The profile of DA metabolites may contribute to neurotoxicity and the development of PD. Prospects of drug therapy of PD and the risk of adverse drug effects such as mental disorders and dyskinesia are considered in terms of polymorphisms of enzymes and transport proteins.__________Translated from Fiziologiya Cheloveka, Vol. 31, No. 4, 2005, pp. 119–130.Original Russian Text Copyright © 2005 by Sukhanov, Ionov, Piruzyan.     

Characteristics of endocrine disorders in the early stages of the development of chronic experimental pancreatitis

The experiments on normal mongrel dogs and those with chronic experimental pancreatitis were performed to reveal the early changes of the endocrine pancreas function. The concentration of immunoreactive insulin and glucagon were studied in afferent vessels of the organ after intraarterial glucose-loading during pancreatic perfusion in situ. The data obtained have shown that in chronic pancreatitis the maximum secretion of insulin is decreased and delayed, as compared to normal animals. At the same time insulin-glucagon secretion ratio remains unchanged. That was indicative of the normal alpha-cell function at the early stages of the disease.     

Antibody dynamics of carnivorous mammals and corvine birds infected with Francisella tularensis

The time course of antibody formation in carnivorous mammals and corvine birds infected with a single injection of F. tularensis has been experimentally studied in the agglutination test and the passive hemagglutination test. In carnivorous mammals the allergic transformation of the body has been established by means of the leukocytolysis test.     

Specific Inter-residue Interactions as Determinants of Human Monoacylglycerol Lipase Catalytic Competency: A ROLE FOR GLOBAL CONFORMATIONAL CHANGES*

The serine hydrolase monoacylglycerol lipase (MGL) functions as the main metabolizing enzyme of 2-arachidonoyl glycerol, an endocannabinoid signaling lipid whose elevation through genetic or pharmacological MGL ablation exerts therapeutic effects in various preclinical disease models. To inform structure-based MGL inhibitor design, we report the direct NMR detection of a reversible equilibrium between active and inactive states of human MGL (hMGL) that is slow on the NMR time scale and can be modulated in a controlled manner by pH, temperature, and select point mutations. Kinetic measurements revealed that hMGL substrate turnover is rate-limited across this equilibrium. We identify a network of aromatic interactions and hydrogen bonds that regulates hMGL active-inactive state interconversion. The data highlight specific inter-residue interactions within hMGL modulating the enzymes function and implicate transitions between active (open) and inactive (closed) states of the hMGL lid domain in controlling substrate access to the enzymes active site.     

Thiamine deficiency caused by thiamine antagonists triggers upregulation of apoptosis inducing factor gene expression and leads to caspase 3-mediated apoptosis in neuronally differentiated rat PC-12 cells

Recent evidence suggests that alterations in oxidative metabolism induced by thiamine deficiency lead to neuronal cell death. However, the molecular mechanisms underlying this process are still under extensive investigation. Here, we report that rat pheochromocytoma PC-12 cells differentiated in the presence of NGF into neurons undergo apoptosis due to thiamine deficiency caused by antagonists of thiamine - amprolium, pyrithiamine and oxythiamine. Confocal laser scanning fluorescence microscopy revealed that annexin V binds to PC-12 cells in presence of thiamine antagonists after 72 h incubation. Results also show that thiamine antagonists trigger upregulation of gene expression of mitochondrial-derived apoptosis inducing factor, DNA fragmentation, cleavage of caspase 3 and translocation of active product to the nucleus. We therefore propose that apoptosis induced by amprolium, pyrithiamine or oxythiamine occurs via the mitochondria-dependent caspase 3-mediated signaling pathway. In addition, our data indicate that pyrithiamine and oxythiamine are more potent inducers of apoptosis than amprolium.     

Entropy capacity determines protein folding

Search and study of the general principles that govern kinetics and thermodynamics of protein folding generate a new insight into the factors controlling this process. Here, based on the known experimental data and using theoretical modeling of protein folding, we demonstrate that there exists an optimal relationship between the average conformational entropy and the average energy of contacts per residue-that is, an entropy capacity-for fast protein folding. Statistical analysis of conformational entropy and number of contacts per residue for 5829 protein structures from four general structural classes (all-alpha, all-beta, alpha/beta, alpha+beta) demonstrates that each class of proteins has its own class-specific average number of contacts (class alpha/beta has the largest number of contacts) and average conformational entropy per residue (class all-alpha has the largest number of rotatable angles phi, psi, and chi per residue). These class-specific features determine the folding rates: alpha proteins are the fastest folding proteins, then follow beta and alpha+beta proteins, and finally alpha/beta proteins are the slowest ones. Our result is in agreement with the experimental folding rates for 60 proteins. This suggests that structural and sequence properties are important determinants of protein folding rates.