Association study of sporadic Parkinson's disease genetic risk factors in patients from Russia by APEX technology

Most patients with Parkinson's disease (PD) have sporadic form of the disease with a multifactorial etiology due to interactions between environmental conditions and the genetic constitution of the individuals. We have analyzed by APEX technology 50 single nucleotide polymorphisms (SNPs) in 19 genes related to cholecystokinin, serotonin, dopamine and opioid neurotransmission. Significant differences in the allele and genotype frequencies between the controls and PD patients were detected for four SNPs from three genes (serotonin 2A receptor (rs6311, P = 0.043), Wolfram syndrome 1 (rs1801211, P = 0.007), proopiomelanocortin (rs28930368, P = 0.026 and rs2071345, P = 0.027) genes). Two SNPs in proopiomelanocortin (POMC) gene were also associated with different clinical forms of PD. Our data suggest that at least three genes involved in neurotransmitter systems may have more specific role in genetic predisposition to PD.     

Polyfluoroalkylated antipyrines in Pd-catalyzed transformations

In the direct C–H arylation with arylhalogenides in the presence of Pd(OAc)₂, trifluoromethyl-containing antipyrine reacts very slowly and incompletely owing to the low nucleophilicity of its C4 center. However, it was effective in modifying polyfluoroalkyl-substituted 4-bromo- and 4-iodo antipyrines by the Suzuki and Sonogashira reactions. It was established that using Pd₂(dba)₃ as catalyst and XPhos as phosphine ligand was the optimal catalytic system for the synthesis of 4-aryl- and 4-phenylethynyl-3-polyfluoroalkyl-antipyrines. Moreover, iodo-derivatives as the initial reagents were found to be more advantageous compared to bromo-containing analogs. It was found that 4-phenylethynyl-5-CF₃-antipyrine has a moderate activity against the influenza virus A/Puerto Rico/8/34 (H1N1) and 4-iodo-5-CF₃-antipyrine reveals a weak activity against the vaccine virus (strain Copenhagen) and bovine diarrhea virus (strain VC-1).

Peculiarities of heterocyclic systems with electron-withdrawing groups (polyfluoroalkyl-containing antipyrines) in Pd-catalyzed C–H arylation and cross-coupling reactions.     

Time course of the expression of genes of brain-derived neurotrophic factor and nerve growth factor in the hippocampus and frontal cortex induced by semax in rats

Semax is a synthetic peptide consisting of the ACTH fragment (4–7) and the C-terminal Pro-Gly-Pro peptide. It promotes neuron survival during hypoxia and increases selcective attention and memory consolidation. It has been shown that semax influences the expression of some genes, particularly nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). In the present study, we performed an analysis of the time course of the expression of NGF and BDNF genes in the hippocampus and frontal cortex in rats after a single intranasal administration of semax at a dose of 50 μg/kg. We found that semax administration resulted in a rapid long-term activation of the NGF and BDNF genes expression, which was specific for different rat brain structures investigated.     

The temporary dynamics of inflammation-related genes expression under tuftsin analog Selank action

Previous studies have shown that synthetic tuftsin analogue Selank and its fragments cause a number of alterations in the expression of certain genes involved in inflammation in mouse spleen. In this work we studied the effect of Selank and its short fragment Gly-Pro on the temporary dynamics of C3, Casp1, Il2rg, and Xcr1 genes expression in mouse spleen after single intraperitoneal injection (100 μg/kg) of peptides using real-time PCR method. We found a significant 3-fold decrease in the C3 mRNA level just 30 min after Selank injection and similar alteration this gene mRNA level after Gly-Pro administration. A wave-like alteration in the Casp1 mRNA level was observed after Selank injection. We found a significant alteration in the mRNA level of the Il2rg gene at early time points after Selank and Gly-Pro administration and an almost equal reduction in the Xcr1 mRNA level 90 min after the administration of Selank and its fragment. Our results showed that, Selank and its short fragment Gly-Pro influence the expression of genes that mediate different types of immune responses, thereby maintaining the balance of the immune system. It should be noted that in most cases, there was a coincidence in the expression profiles of the studied genes after Selank and Gly-Pro administration. This might indicate an active contribution of the dipeptide to the final effect of Selank.     

Associations of greenness with diabetes mellitus and glucose-homeostasis markers: The 33 Communities Chinese Health Study

Background

Residing in greener places may be protective against diabetes mellitus (DM) but evidence is scarce and comes mainly from developed countries.

HFE p.C282Y gene variant is associated with varicose veins in Russian population

Clinical and Experimental Medicine - Recently, the association of polymorphism rs1800562 (p.C282Y) in the hemochromatosis (HFE) gene with the increased risk of venous ulceration was shown. We...     

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model

Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbb^th3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbb^th3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in β-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing β-thalassemia–related liver iron overload. In ex vivo studies on erythroid precursors from patients with β-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for β-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.     

Comparison of standard renal denervation procedure versus novel distal and branch vessel procedure with brachial arterial access

Objectives

We assessed a novel approach to percutaneous renal denervation for uncontrolled hypertension consisting of ablation beyond the proximal main renal artery (Y-pattern), including the primary branches, and compared it to the standard procedure applied only within the main vessel. We also assessed the safety and practicality of a brachial access approach.