The multifaceted role of vitamin b6 in cancer: drosophila as a model system to investigate dna damage

A perturbed uptake of micronutrients, such as minerals and vitamins, impacts on different human diseases, including cancer and neurological disorders. Several data converge towards a crucial role played by many micronutrients in genome integrity maintenance and in the establishment of a correct DNA methylation pattern. Failure in the proper accomplishment of these processes accelerates senescence and increases the risk of developing cancer, by promoting the formation of chromosome aberrations and deregulating the expression of oncogenes. Here, the main recent evidence regarding the impact of some B vitamins on DNA damage and cancer is summarized, providing an integrated and updated analysis, mainly centred on vitamin B6. In many cases, it is difficult to finely predict the optimal vitamin rate that is able to protect against DNA damage, as this can be influenced by a given individual's genotype. For this purpose, a precious resort is represented by model organisms which allow limitations imposed by more complex systems to be overcome. In this review, we show that Drosophila can be a useful model to deeply understand mechanisms underlying the relationship between vitamin B6 and genome integrity

Molecular characterization of pyridoxine 5′-phosphate oxidase and its pathogenic forms associated with neonatal epileptic encephalopathy

Defects of vitamin B6 metabolism are responsible for severe neurological disorders, such as pyridoxamine 5′-phosphate oxidase deficiency (PNPOD; OMIM: 610090), an autosomal recessive inborn error of metabolism that usually manifests with neonatal-onset severe seizures and subsequent encephalopathy. At present, 27 pathogenic mutations of the gene encoding human PNPO are known, 13 of which are homozygous missense mutations; however, only 3 of them have been characterised with respect to the molecular and functional properties of the variant enzyme forms. Moreover, studies on wild type and variant human PNPOs have so far largely ignored the regulation properties of this enzyme. Here, we present a detailed characterisation of the inhibition mechanism of PNPO by pyridoxal 5′-phosphate (PLP), the reaction product of the enzyme. Our study reveals that human PNPO has an allosteric PLP binding site that plays a crucial role in the enzyme regulation and therefore in the regulation of vitamin B6 metabolism in humans. Furthermore, we have produced, recombinantly expressed and characterised several PNPO pathogenic variants responsible for PNPOD (G118R, R141C, R225H, R116Q/R225H, and X262Q). Such replacements mainly affect the catalytic activity of PNPO and binding of the enzyme substrate and FMN cofactor, leaving the allosteric properties unaltered

Behavioral Impact of the Regulation of the Brain 2-Oxoglutarate Dehydrogenase Complex by Synthetic Phosphonate Analog of 2-Oxoglutarate: Implications into the Role of the Complex in Neurodegenerative Diseases

Decreased activity of the mitochondrial 2-oxoglutarate dehydrogenase complex (OGDHC) in brain accompanies neurodegenerative diseases. To reveal molecular mechanisms of this association, we treated rats with a specific inhibitor of OGDHC, succinyl phosphonate, or exposed them to hypoxic stress. In males treated with succinyl phosphonate and in pregnancy-sensitized females experiencing acute hypobaric hypoxia, we revealed upregulation of brain OGDHC (within 24 hours), with the activity increase presumably representing the compensatory response of brain to the OGDHC inhibition. This up-regulation of brain OGDHC was accompanied by an increase in exploratory activity and a decrease in anxiety of the experimental animals. Remarkably, the hypoxia-induced elevation of brain OGDHC and most of the associated behavioral changes were abrogated by succinyl phosphonate. The antagonistic action of hypoxia and succinyl phosphonate demonstrates potential therapeutic significance of the OGDHC regulation by the phosphonate analogs of 2-oxoglutarate

US–Canada Beaufort Sea Maritime Boundary Dispute in the Perspective of International Law

Introduction. Maritime boundary disputes and exercising sovereignty in the Arctic are of great current interest in the International Law since there is no uniform understanding of the limits of applicability of the United Nations Convention on the Law of the Sea 1982 to the Arctic Ocean taking into account the international customary law and historic rights of the coastal states. One of such disputes is the US-Canada Beaufort Sea maritime boundary dispute which is of vast importance due to the hydrocarbon exploration of these states in the outlined area as well as due to the conclusion and entry into force of the Treaty between the Kingdom of Norway and the Russian Federation concerning Maritime Delimitation and Cooperation in the Barents Sea and the Arctic Ocean 2010.Materials and methods. The theoretical background of this research consists of works of distinguished Russian and foreign scholars and specialists in International Law. The analytical framework includes the treaties between Arctic coastal states concerning maritime delimitation (the Convention Concerning the Limits of Their Respective Possessions on the Northwest Coast of America and the Navigation of the Pacific Ocean 1825, Treaty concerning the Cession of the Russian Possessions in North America by his Majesty the Emperor of all the Russia to the United States of America 1867, Agreement between the United States of America and the Union of Soviet Socialist Republics on the maritime boundary 1990), national legislation of the US and Canada, diplomatic notes. The research is based on methods such as formal logic, including analysis, synthesis, analogy and modeling historical research, as well as systematic, historical and comparative methods.Research results. Based on the results of the study, the author notes that there are considerable differences in the US and Canada’s legal stances concerning the disputed area of the Beaufort Sea, including in particular the opposing views of these states on the applicability of the Convention 1825 to their relations (according to Canada, it applies to maritime areas, whereas the US favours its literal construction which limits its scope to land areas).  The US and Canada also base their claims on the rules on special circumstances and the doctrine of estoppel which are reflected in their national legislation. The legal analysis of the different approaches to the resolution of the dispute in question allows making the conclusion on the perspective and necessity of its settlement, particularly, in the context of the Russian Arctic claims.Discussion and conclusions. Based on the legal analysis of the international treaties on the Arctic delimitation, US and Canada national legislation and doctrinal views, the author comes to the conclusion that sustaining the status-quo is beneficial for both parties since it does not affect the legal positions of other states in similar disputes, nor does it hinder the international cooperation in the Arctic