Coenzyme Q10 Protect Mice Against Inflammatory Responses During Experimental Cerebral Malaria

Malaria is a life threatening infectious diseases transmitted by the bite of infected female Anopheles mosquito and responsible for high morbidity and mortality rates. Cerebral malaria is a complex neurological syndrome, whose pathology is mediated by inflammatory processes triggered by the immune system of the host following infection with Plasmodium falciparum. Coenzyme Q10 is an obligatory cofactor in the electron transport chain. The reduced form of Coenzyme Q10 serves as a potent antioxidant additionally; Coenzyme Q10 has been identified as a modulator of gene expression, inflammation and apoptosis. However, the modulatory effects of Coenzyme Q10 Plasmodium berghei ANKA infection process and risk occurrence of experimental cerebral malaria (ECM) have not been determined. The aim of this study was to elucidate the putative impact of oral administration of Coenzyme-Q10 on the initiation or regulation of inflammatory immune response in ECM of C57BL/6 mice during Plasmodium berghei ANKA (PbA) infection. We observed that oral administration of Coenzyme-Q10 both before and after PbA infection significantly hampered infiltration of inflammatory monocytes into the brain. Furthermore, pro-inflammatory cytokine TNF-α, which is associated with inflammation during ECM, was down-regulated in Coenzyme-Q10 administered mice. Remarkably, Coenzyme-Q10 was very effective in inhibiting dendritic cell differentiation. These data collectively demonstrated the immuno-modulatory function of Coenzyme-Q10 on host inflammatory responses during ECM. Keywords: Plasmodium berghei ANKA, Coenzyme Q10, experimental cerebral malaria DOI: 10.7176/JNSR/9-2-05

Coenzyme Q10 and endogenous antioxidants neuro-protect mice brain against deleterious effects of melarsoprol and Trypanasoma brucei rhodesiense

Melarsoprol (Mel B) is the only efficacious drug against late stage Human African Trypanosomiasis (HAT), but inadvertently is very toxic and induces Post Treatment Reactive Encephalopathy (PTRE) that is lethal in 5% of the patients. Investigations were conducted to establish the neuro-protective role of Coenzyme Q10 (CoQ10) and other cellular antioxidants ((Manganese Superoxide dismutase (MnSOD), Glutathione Reductase (GR), Copper-Zinc Superoxide dismutase (SOD-1) and glutathione (GSH)) against Mel B toxicity, PTRE and putative resultant brain degeneration in a mouse model. Female Swiss-white mice were infected with Trypanasoma brucei rhodesiense parasite and manipulated to simulate all phases of PTRE and HAT. Expression profiles of the antioxidants in brain tissues were assessed using immunoblots, while GSH was measured spectrophotometrically. Trypanosoma brucei rhodesiense infection resulted in elevation of expression of endogenous antioxidants in the early stage of infection (21dpi), with significant expression (two fold) observed at the terminal stage of the disease (57dpi). CoQ10 assisted in boosting Levels of GSH upon induction of severe late stage of HAT. Similarly CoQ10 administration significantly augmented levels of SOD-1, GR and GSH in infected than in uninfected mice that were treated with Melarsoprol. The time dependent dynamics of antioxidant suppression due to Melarsoprol, and potential ameliorating effects of CoQ10 on the same, indicate putative mechanism underlying and antidote to the toxicity of the drug with potential application in formulation of novel Melarsoprol-based drugs and development of novel markers for staging the disease. Key Words: Trypanasoma brucei rhodesiense, endogenous antioxidants, late stage HAT; Coenzyme Q10; Melarsoprol;   Abbreviations: GSH, glutathione; CoQ10, Coenzyme Q10; MnSOD, Manganese Superoxide dismutase; GR, Glutathione Reductase; SOD-1, Copper-Zinc Superoxide dismutase; Mel B, melarsoprol; PTRE, Post treatment reactive encephalopathy; HAT, Human African Trypanoomiasis; HEPES, N-2 hydroxyethylpiperazine-N`-2 ethane sulfonic acid; ICDH, isocitrate dehydrogenase; LDH, lactate dehydrogenase; MnSOD, manganese superoxide dismutase; NADP+, nicotinamide adenine dinucleotide phosphate, NO, nitric oxide; ONOO-, peroxynitrite; ROS, reactive oxygen species; SDS, sodium dodecyl sulfate; TCA, tricarboxylic acid; DAB, diaminobenzidine;  PBS, Phosphate buffered saline; dpi, days post infection

Ethereum Crypto-Games : Mechanics, Prevalence and Gambling Similarities

Ethereum crypto-games are a booming and relatively unexplored area of the games industry. While there is no consensus definition yet, ‘crypto-games’ commonly denotes games that store tokens, e.g. in-game items, on a distributed ledger atop a cryptocurrency network. This enables the trading of game items for cryptocurrency, which can then be exchanged for regular currency. Together with their chance-based mechanics, this makes crypto-games part of the recent convergence of digital gaming and gambling. In a first effort to scope the field, this paper surveys popular crypto-games, which use the Ethereum cryptocurrency, to tease out characteristic technical properties and gameplay. It then compares the games’ features with criteria found in current legal and psychological definitions of gambling. We find that the popular crypto-games selected meet a combined legal and psychological definition of gambling, and conclude with ramifications for future research

The Medical Education Partnership Initiative (MEPI): Innovations and Lessons for Health Professions Training and Research in Africa

MEPI was a $130 million competitively awarded grant by President's Emergency Plan for AIDS Relief (PEPFAR) and National Institutes of Health (NIH) to 13 Medical Schools in 12 Sub-Saharan African countries and a Coordinating Centre (CC). Implementation was led by Principal investigators (PIs) from the grantee institutions supported by Health Resources and Services Administration (HRSA), NIH and the CC from September, 2010 to August, 2015. The goals were to increase the capacity of the awardees to produce more and better doctors, strengthen locally relevant research, promote retention of the graduates within their countries and ensure sustainability. MEPI ignited excitement and stimulated a broad range of improvements in the grantee schools and countries. Through in-country consortium arrangements African PIs expanded the programme from the 13 grantees to over 60 medical schools in Africa, creating vibrant South–South and South–North partnerships in medical education, and research. Grantees revised curricular to competency based models, created medical education units to upgrade the quality of education and established research support centres to promote institutional and collaborative research. MEPI stimulated the establishment of ten new schools, doubling of the students’ intake, in some schools, a three-fold increase in post graduate student numbers, and faculty expansion and retention. Sustainability of the MEPI innovations was assured by enlisting the support of universities and ministries of education and health in the countries thus enabling integration of the new programs into the regular national budgets. The vibrant MEPI annual symposia are now the largest medical education events in Africa attracting global participation. These symposia and innovations will be carried forward by the successor of MEPI, the African Forum for Research and Education in Health (AFREhealth). AFREhealth promises to be more inclusive and transformative bringing together other health professionals including nurses, pharmacists, and dentists.<p

Conception et synthèse de catalyseurs de cuivre bio-inspirés pour l'activation de liaisons C-H

Copper-oxygen adducts in enzymes have been proposed to be responsible for the activation of C-H bonds, a process that has industrial applications. The first part of this thesis is therefore dedicated to a discussion on various copper oxygenases and their model complexes. Recently, key reactive intermediates have emerged and among them mixed valent CuIICuIII species have been proposed to be responsible for strong C-H bond activation.In this work the stabilisation and spectroscopic characterisation of high valent intermediates using dinucleating ligands based on a 1,8-naphthyridine spacer are explored. The generation of Cu2:O2 species from the activation of O2 by CuI2 complexes is discussed. Two µ-ɳ2:ɳ2-peroxo-CuII2 complexes have been prepared at -80°C and characterised by spectroscopy and density functional theory (DFT). Our attempts at generating dinuclear systems using new dissymmetric ligands with an amide function are also discussed. Finally the successful characterisation of mixed valent CuIICuIII species by mono-electronic oxidation of CuII2 complexes is described (cyclic voltammetry, electron paramagnetic resonance, UV-visible, near infrared and DFT).The last part focusses on probing the reactivity of CuIICuIII species, for which the literature is almost inexistent. When sterically congested ligands are used to support the mixed valent system, intramolecular aliphatic C-H oxidation was observed, whether as the CuIICuIII species supported by a less bulky ligand was able to oxidise toluene. Interestingly the addition of a base made the system catalytic.Les adduits cuivre-oxygène dans les métallo-enzymes ont été proposés comme étant responsables de l'activation de liaisons C-H, processus qui ont un intérêt pour des applications industrielles potentielles. La première partie de ce travail est consacrée à une présentation de différentes mono-oxygénases à cuivre et de leurs complexes modèles. Récemment, des intermédiaires réactionnels ont émergé et parmi ceux-ci, des espèces de valence mixte CuIICuIII ont été proposées comme étant des espèces réactives clés pour l'activation de liaisons C-H fortes.Dans ce travail, à partir de ligands binucléants basés sur un espaceur 1,8-naphtyridine, la stabilisation et les caractérisations spectroscopiques de ce type d’intermédiaires à haut degré d’oxydation sont explorées. La préparation d’espèces Cu2:O2 à partir de l'activation du dioxygène par les complexes CuI2 est discutée. Deux complexes µ-ɳ2:ɳ2-peroxo-CuII2 ont été préparés à -80°C et caractérisés par différentes méthodes spectroscopiques associées à des calculs par la théorie de la fonctionnelle de la densité (DFT). A partir de nouveaux ligands dissymétriques possédant une fonction amide, nos tentatives pour contrôler la préparation des complexes binucléaires associés sont également présentées. Puis, les caractérisations des espèces à valence mixte CuIICuIII obtenues par mono-oxydation électronique des complexes CuII2 sont décrites (voltammétrie cyclique, résonance paramagnétique électronique, UV-visible, proche infrarouge et DFT).Enfin, ce travail est complété par l’étude de la réactivité des espèces CuIICuIII, pour lesquelles la littérature est presque inexistante. Lorsque des ligands stériquement encombrés sont utilisés dans les espèces à valence mixte, des oxydations intramoléculaires sont observées, alors que l’espèce CuIICuIII possédant un ligand moins encombré oxyde le toluène. Il est à noter que l'ajout d'une base rend le système catalytique

Conception et synthèse de catalyseurs de cuivre bio-inspirés pour l'activation de liaisons C-H

Copper-oxygen adducts in enzymes have been proposed to be responsible for the activation of C-H bonds, a process that has industrial applications. The first part of this thesis is therefore dedicated to a discussion on various copper oxygenases and their model complexes. Recently, key reactive intermediates have emerged and among them mixed valent CuIICuIII species have been proposed to be responsible for strong C-H bond activation.In this work the stabilisation and spectroscopic characterisation of high valent intermediates using dinucleating ligands based on a 1,8-naphthyridine spacer are explored. The generation of Cu2:O2 species from the activation of O2 by CuI2 complexes is discussed. Two µ-ɳ2:ɳ2-peroxo-CuII2 complexes have been prepared at -80°C and characterised by spectroscopy and density functional theory (DFT). Our attempts at generating dinuclear systems using new dissymmetric ligands with an amide function are also discussed. Finally the successful characterisation of mixed valent CuIICuIII species by mono-electronic oxidation of CuII2 complexes is described (cyclic voltammetry, electron paramagnetic resonance, UV-visible, near infrared and DFT).The last part focusses on probing the reactivity of CuIICuIII species, for which the literature is almost inexistent. When sterically congested ligands are used to support the mixed valent system, intramolecular aliphatic C-H oxidation was observed, whether as the CuIICuIII species supported by a less bulky ligand was able to oxidise toluene. Interestingly the addition of a base made the system catalytic.Les adduits cuivre-oxygène dans les métallo-enzymes ont été proposés comme étant responsables de l'activation de liaisons C-H, processus qui ont un intérêt pour des applications industrielles potentielles. La première partie de ce travail est consacrée à une présentation de différentes mono-oxygénases à cuivre et de leurs complexes modèles. Récemment, des intermédiaires réactionnels ont émergé et parmi ceux-ci, des espèces de valence mixte CuIICuIII ont été proposées comme étant des espèces réactives clés pour l'activation de liaisons C-H fortes.Dans ce travail, à partir de ligands binucléants basés sur un espaceur 1,8-naphtyridine, la stabilisation et les caractérisations spectroscopiques de ce type d’intermédiaires à haut degré d’oxydation sont explorées. La préparation d’espèces Cu2:O2 à partir de l'activation du dioxygène par les complexes CuI2 est discutée. Deux complexes µ-ɳ2:ɳ2-peroxo-CuII2 ont été préparés à -80°C et caractérisés par différentes méthodes spectroscopiques associées à des calculs par la théorie de la fonctionnelle de la densité (DFT). A partir de nouveaux ligands dissymétriques possédant une fonction amide, nos tentatives pour contrôler la préparation des complexes binucléaires associés sont également présentées. Puis, les caractérisations des espèces à valence mixte CuIICuIII obtenues par mono-oxydation électronique des complexes CuII2 sont décrites (voltammétrie cyclique, résonance paramagnétique électronique, UV-visible, proche infrarouge et DFT).Enfin, ce travail est complété par l’étude de la réactivité des espèces CuIICuIII, pour lesquelles la littérature est presque inexistante. Lorsque des ligands stériquement encombrés sont utilisés dans les espèces à valence mixte, des oxydations intramoléculaires sont observées, alors que l’espèce CuIICuIII possédant un ligand moins encombré oxyde le toluène. Il est à noter que l'ajout d'une base rend le système catalytique

Design and synthesis of bio-inspired copper catalysts for C-H activation

Les adduits cuivre-oxygène dans les métallo-enzymes ont été proposés comme étant responsables de l'activation de liaisons C-H, processus qui ont un intérêt pour des applications industrielles potentielles. La première partie de ce travail est consacrée à une présentation de différentes mono-oxygénases à cuivre et de leurs complexes modèles. Récemment, des intermédiaires réactionnels ont émergé et parmi ceux-ci, des espèces de valence mixte CuIICuIII ont été proposées comme étant des espèces réactives clés pour l'activation de liaisons C-H fortes.Dans ce travail, à partir de ligands binucléants basés sur un espaceur 1,8-naphtyridine, la stabilisation et les caractérisations spectroscopiques de ce type d’intermédiaires à haut degré d’oxydation sont explorées. La préparation d’espèces Cu2:O2 à partir de l'activation du dioxygène par les complexes CuI2 est discutée. Deux complexes µ-ɳ2:ɳ2-peroxo-CuII2 ont été préparés à -80°C et caractérisés par différentes méthodes spectroscopiques associées à des calculs par la théorie de la fonctionnelle de la densité (DFT). A partir de nouveaux ligands dissymétriques possédant une fonction amide, nos tentatives pour contrôler la préparation des complexes binucléaires associés sont également présentées. Puis, les caractérisations des espèces à valence mixte CuIICuIII obtenues par mono-oxydation électronique des complexes CuII2 sont décrites (voltammétrie cyclique, résonance paramagnétique électronique, UV-visible, proche infrarouge et DFT).Enfin, ce travail est complété par l’étude de la réactivité des espèces CuIICuIII, pour lesquelles la littérature est presque inexistante. Lorsque des ligands stériquement encombrés sont utilisés dans les espèces à valence mixte, des oxydations intramoléculaires sont observées, alors que l’espèce CuIICuIII possédant un ligand moins encombré oxyde le toluène. Il est à noter que l'ajout d'une base rend le système catalytique.Copper-oxygen adducts in enzymes have been proposed to be responsible for the activation of C-H bonds, a process that has industrial applications. The first part of this thesis is therefore dedicated to a discussion on various copper oxygenases and their model complexes. Recently, key reactive intermediates have emerged and among them mixed valent CuIICuIII species have been proposed to be responsible for strong C-H bond activation.In this work the stabilisation and spectroscopic characterisation of high valent intermediates using dinucleating ligands based on a 1,8-naphthyridine spacer are explored. The generation of Cu2:O2 species from the activation of O2 by CuI2 complexes is discussed. Two µ-ɳ2:ɳ2-peroxo-CuII2 complexes have been prepared at -80°C and characterised by spectroscopy and density functional theory (DFT). Our attempts at generating dinuclear systems using new dissymmetric ligands with an amide function are also discussed. Finally the successful characterisation of mixed valent CuIICuIII species by mono-electronic oxidation of CuII2 complexes is described (cyclic voltammetry, electron paramagnetic resonance, UV-visible, near infrared and DFT).The last part focusses on probing the reactivity of CuIICuIII species, for which the literature is almost inexistent. When sterically congested ligands are used to support the mixed valent system, intramolecular aliphatic C-H oxidation was observed, whether as the CuIICuIII species supported by a less bulky ligand was able to oxidise toluene. Interestingly the addition of a base made the system catalytic