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

Abnormal Brain Iron Homeostasis in Human and Animal Prion Disorders

Neurotoxicity in all prion disorders is believed to result from the accumulation of PrP-scrapie (PrPSc), a β-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrPC). Limited reports suggest imbalance of brain iron homeostasis as a significant associated cause of neurotoxicity in prion-infected cell and mouse models. However, systematic studies on the generality of this phenomenon and the underlying mechanism(s) leading to iron dyshomeostasis in diseased brains are lacking. In this report, we demonstrate that prion disease–affected human, hamster, and mouse brains show increased total and redox-active Fe (II) iron, and a paradoxical increase in major iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) at the end stage of disease. Furthermore, examination of scrapie-inoculated hamster brains at different timepoints following infection shows increased levels of Tf with time, suggesting increasing iron deficiency with disease progression. Sporadic Creutzfeldt-Jakob disease (sCJD)–affected human brains show a similar increase in total iron and a direct correlation between PrP and Tf levels, implicating PrPSc as the underlying cause of iron deficiency. Increased binding of Tf to the cerebellar Purkinje cell neurons of sCJD brains further indicates upregulation of TfR and a phenotype of neuronal iron deficiency in diseased brains despite increased iron levels. The likely cause of this phenotype is sequestration of iron in brain ferritin that becomes detergent-insoluble in PrPSc-infected cell lines and sCJD brain homogenates. These results suggest that sequestration of iron in PrPSc–ferritin complexes induces a state of iron bio-insufficiency in prion disease–affected brains, resulting in increased uptake and a state of iron dyshomeostasis. An additional unexpected observation is the resistance of Tf to digestion by proteinase-K, providing a reliable marker for iron levels in postmortem human brains. These data implicate redox-iron in prion disease–associated neurotoxicity, a novel observation with significant implications for prion disease pathogenesis

Prion Protein Modulates Cellular Iron Uptake: A Novel Function with Implications for Prion Disease Pathogenesis

Converging evidence leaves little doubt that a change in the conformation of prion protein (PrPC) from a mainly α-helical to a β-sheet rich PrP-scrapie (PrPSc) form is the main event responsible for prion disease associated neurotoxicity. However, neither the mechanism of toxicity by PrPSc, nor the normal function of PrPC is entirely clear. Recent reports suggest that imbalance of iron homeostasis is a common feature of prion infected cells and mouse models, implicating redox-iron in prion disease pathogenesis. In this report, we provide evidence that PrPC mediates cellular iron uptake and transport, and mutant PrP forms alter cellular iron levels differentially. Using human neuroblastoma cells as models, we demonstrate that over-expression of PrPC increases intra-cellular iron relative to non-transfected controls as indicated by an increase in total cellular iron, the cellular labile iron pool (LIP), and iron content of ferritin. As a result, the levels of iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) are decreased, and expression of iron storage protein ferritin is increased. The positive effect of PrPC on ferritin iron content is enhanced by stimulating PrPC endocytosis, and reversed by cross-linking PrPC on the plasma membrane. Expression of mutant PrP forms lacking the octapeptide-repeats, the membrane anchor, or carrying the pathogenic mutation PrP102L decreases ferritin iron content significantly relative to PrPC expressing cells, but the effect on cellular LIP and levels of Tf, TfR, and ferritin is complex, varying with the mutation. Neither PrPC nor the mutant PrP forms influence the rate or amount of iron released into the medium, suggesting a functional role for PrPC in cellular iron uptake and transport to ferritin, and dysfunction of PrPC as a significant contributing factor of brain iron imbalance in prion disorders

Isolation and biochemical characterization of transferrin from the tsetse fly, Glossina morsitan centralis

No Abstract. The Egyptian Journal of Biochemistry and Molecular Biology Vol. 23(2) 2005: 169-18

Technology Transfer Assistance to Enhance Knowledge Exchange and Technology Transfer between Small and Medium Enterprises and Higher Education Institutions in Nairobi Innovation Ecosystem in Kenya

The program and survey was funded by the UK Foreign, Commonwealth and Development Office (FCDO) and Technical University of Kenya RISA Award No. 2023-015 and conducted under NACOSTI Permit No. NACOSTI/P/23/23979 of 23/February/2023. Abstract This survey was conducted as part of a project that seeks to develop a technology transfer assistance model that can effectively bridge the gap existing between technology sources like Higher Education Institutions (HEIs) and technology users like Small and Medium Enterprises (SMEs) and other firms operating in the Nairobi innovation ecosystem. The project team at the Technical University of Kenya (TUK) was one of the grantees in the Research and Innovation Systems for Africa (RISA) program for the year 2023 that was implemented between January, 2023 and December, 2023. The RISA program was funded by the UK Foreign, Commonwealth and Development Office (FCDO) that aims to strengthen research and innovation ecosystems in Africa. The study was anchored on the Theory of Change. The project commenced with a research phase which took place between January and March 2023, with a survey of 1200 SMEs operating within the targeted geographical region. This was followed by in-depth interviews with a cross section of stakeholders from higher education institutions, research institutes, and managers from funding organizations, Non-Governmental Organizations (NGOs), and advocacy groups to obtain insights on technology development and transfer within the Nairobi innovation ecosystem. The findings of the study indicate a gap in the access and assimilation of new technologies by SMEs, driven by factors that have organizational, regulatory and institutional perspectives. The project team held three stakeholder engagement workshops to disseminate the findings of the survey, deliberated on challenges encountered on technology transfer and knowledge exchange between SMEs and HEIs. As part of capacity building at the Technical University of Kenya, the project team in the month of June 2023 conducted a four day Training of Trainers (TOTs) for forty faculty members on Research to Commercialization (R2C). The TUK faculty trained as TOTs facilitated in training three hundred SMEs who were invited to a six day capacity building training. The SME training covered introduction to innovation and entrepreneurship, business planning and strategy, communication and marketing, digitalization and new product development, business finance, and human resource management. The project team prepared a policy brief, and is championing the creation of a model regional technology hub at TUK, to host incubators, accelerators, crosscutting partnerships and collaborations using a quadruple approach strategy that involves four components of a functional innovation ecosystem; people, technology, capital, and infrastructure. Keywords: Knowledge exchange and technology transfer, higher education institutions, small and medium enterprises, Nairobi innovation ecosystem. DOI: 10.7176/EJBM/16-1-07 Publication date: January 31st 202

Scrapie-infected cells show co-localization of PrP and ferritin.

<p>ScN2a and SMB cells cultured in the absence or presence of 0.1 mM FAC were immunostained with 8H4-anti-mouse-FITC followed by anti-ferritin–anti-rabbit-TRITC. Untreated ScN2a cells show minimal PrP reactivity and reaction for ferritin in the cytosol (panels 1–3). Following exposure to FAC, both PrP and ferritin form intracellular aggregates that co-localize for the most part (panels 4–6, arrowheads). Untreated SMB cells show intracellular aggregates of PrP and reaction for ferritin in the cytosol (panels 7–9). However, exposure to FAC increases the reactivity for PrP and ferritin significantly, and, notably, PrP and ferritin form intracellular aggregates that co-localize in vesicular structures (panels 10–12, arrowheads).</p