ABSTRACT
Impaired mitophagy is one of the hallmarks of the pathogenesis of Parkinson's disease, which highlights the importance of the proper functioning of mitochondria, as well as the processes of mitochondrial dynamics for the functioning of dopaminergic neurons. At the same time, the main factors leading to disruption of mitophagy in Parkinson's disease are mutations in the Pink1 and Parkin enzymes. Based on the characterized mutant forms, the marked cellular localization, and the level of expression in neurons, these proteins can be considered promising targets for the development of drugs for Parkinson's therapy. This review will consider such class of drug compounds as mitophagy activators and these drugs in the treatment of Parkinson's disease.
ABSTRACT
Anthracosilicosis (AS), a prevalent form of pneumoconiosis among coal miners, results from the accumulation of carbon and silica in the lungs from inhaled coal dust. This study investigated genotoxic effects and certain cytokine genes polymorphic variants in Russian coal miners with ÐS. Peripheral leukocytes were sampled from 129 patients with AS confirmed by X-ray and tissue biopsy and from 164 asymptomatic coal miners. Four single-nucleotide polymorphisms were genotyped in the extracted DNA samples: IL1ß T-511C (rs16944), IL6 C-174G (rs1800795), IL12b A1188C (rs3212227) and VEGFA C634G (rs2010963). Genotoxic effects were assessed by the analysis of chromosome aberrations in cultured peripheral lymphocytes. The mean frequency of chromatid-type aberrations and chromosome-type aberrations, namely, chromatid-type breaks and dicentric chromosomes, was found to be higher in AS patients [3.70 (95% confidence interval {CI}, 3.29-4.10) and 0.28 (95% CI, 0.17-0.38)] compared to the control group [2.41 (95% CI, 2.00-2.82) and 0.09 (95% CI, 0.03-0.15)], respectively. IL1ß gene T/T genotype (rs16944) was associated with AS [17.83% in AS patients against 4.35% in healthy donors, odds ratio = 4.77 (1.88-12.15), P < 0.01]. A significant increase in the level of certain chromosome interchanges among AS donors is of interest because such effects are typical for radiation damage and caused by acute oxidative stress. IL1ß T allele probably may be considered as an AS susceptibility factor among coal miners.
Subject(s)
Anthracosilicosis/genetics , Genetic Association Studies , Interleukin-1beta/genetics , Occupational Exposure , Adult , Anthracosilicosis/etiology , Anthracosilicosis/pathology , Chromosome Aberrations/drug effects , Coal/adverse effects , Coal Mining , DNA Damage/drug effects , Genetic Predisposition to Disease , Genotype , Humans , Interleukin-12 Subunit p40/genetics , Interleukin-6/genetics , Male , Middle Aged , Miners , Polymorphism, Single Nucleotide/genetics , Silicon Dioxide/isolation & purification , Silicon Dioxide/toxicity , Vascular Endothelial Growth Factor A/geneticsABSTRACT
Calcium phosphate bions (CPB) are biomimetic mineralo-organic nanoparticles which represent a physiological mechanism regulating the function, transport and disposal of calcium and phosphorus in the human body. We hypothesised that CPB may be pathogenic entities and even a cause of cardiovascular calcification. Here we revealed that CPB isolated from calcified atherosclerotic plaques and artificially synthesised CPB are morphologically and chemically indistinguishable entities. Their formation is accelerated along with the increase in calcium salts-phosphates/serum concentration ratio. Experiments in vitro and in vivo showed that pathogenic effects of CPB are defined by apoptosis-mediated endothelial toxicity but not by direct tissue calcification or functional changes in anti-calcification proteins. Since the factors underlying the formation of CPB and their pathogenic mechanism closely resemble those responsible for atherosclerosis development, further research in this direction may help us to uncover triggers of this disease.
Subject(s)
Biomimetic Materials/pharmacology , Calcium Phosphates/toxicity , Endothelial Cells/cytology , Plaque, Atherosclerotic/chemistry , Apoptosis , Calcification, Physiologic/drug effects , Endothelial Cells/drug effects , Humans , Phosphates/metabolism , Salts/metabolismABSTRACT
The recombinant producer strain expressing Rhodosporidium toruloides l-phenylalanine ammonia lyase (PAL) has been obtained, and a purification procedure of PAL has been developed. The purified enzyme, PAL, has the following biochemical and catalytic characteristics: Km for l-Phe of 0.49 mM, pH optimum at 8.5, and temperature optimum at 50°C. PAL exhibited a significant cytotoxic effect toward the following cell lines: MCF7 (IC50 = 1.97 U/mL), DU145 (IC50 = 7.3 U/mL), which are comparable with E. coli l-asparaginase type-II cytotoxicity in vitro. Administration of PAL (200-400 U/kg) to L5178y-bearing mice for five times (a total dose of 1000-2000 U/kg) was well tolerated and showed the increase of life span (ILS) = 12-16%, P < 0.05. Data obtained suggest that PAL from R. toruloides has a potential for cancer treatment.
