HPD Research Day | February 16, 2018

61 Objective. Define the roles of Nrf2 and mTORC1 in regulating cobalamin content downstream of neurotrophic factors in SH-SY5Y neuroblastoma cells. Background. Vitamin B12 (cobalamin) serves as a cofactor for methionine synthase, which catalyzes the regeneration of methionine from homocysteine. Cellular cobalamin processing requires proper lysosomal acidification and the availability of cytoplasmic glutathione. Mechanistic target of rapamycin complex 1 (mTORC1) abrogates lysosomal acidification and Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) promotes glutathione production. Both mTORC1 and Nrf2 are activated downstream of neurotrophic factor-induced receptor tyrosine kinase signaling. We seek to understand the individual roles of Nrf2 and mTORC1 in regulating cobalamin content in this setting. Methods. SH-SY5Y cells were pre-treated with temsirolimus (TEMS) or treated with either neuregulin-1 (NRG-1) or brain-derived neurotrophic factor (BDNF). RT-qPCR was performed to measure gene expression. Cobalamin analysis was done via HPLC. Results. Both 1 nM and 100 nM NRG-1 decreases LMBRD1 (probable lysosomal cobalamin transporter) expression, but only 1 nM NRG-1 decreased ATP6V1H (V-type proton ATPase subunit H) mRNA. 10 nM BDNF decreased both LMBRD1 and ATP6V1H mRNA levels. 10 nM BDNF may selectively increase adenosylcobalamin. Furthermore, pre- treatment of cells with 100 nM TEMS and treatment with 100 nM NRG-1 increased cobalamin content over either agent alone. Conclusion. Our research suggests that different neurotrophic factors play unique roles in regulating cobalamin processing, NRG-1 may have opposing effects at various concentrations, and that mTORC1 activation can limit cobalamin content in SH-SY5Y cells. Grants. This research was partially funded by the A2 Milk Company. Atrium – Poster 65 12:15-1:15 p.m. The Impact of Pre-Combination Antiretroviral Therapy Versus Combination Antiretroviral Therapy Era on HIV-Associated Neurocognitive Disorders: A Systematic Review Farzana Shaik, Ph.D., Ph.D. in Pharmacy, College of Pharmacy, Nova Southeastern University Barry Bleidt, PharmD, Ph.D., Professor, College of Pharmacy, Nova Southeastern University Objectives. The objective of this presentation is a systematic literature review to consider HIV-associated neurocognitive disorder (HAND) rates before and during the cART era. Background. This paper is a combination of literature reviews, observational studies, prospective studies and retrospective studies. A second objective of this systematic review is to identify and summarize recent studies that examine asymptomatic neurocognitive impairment in HAND during the pre-combination Antiretroviral Therapy (pre-cART) and combination Antiretroviral Therapy (cART) era. Methods. A systematic literature review was conducted to include English- language articles published from 2006 to 2016 on January 19th, 2017. A total of four electronic databases were used including MEDLINE, PUBMED, EMBASE, and PsycINFO and were searched to identify potentially relevant articles. Conference abstracts and dissertation defenses were not included in this review. The search combined free text and medical subject headings (MeSH) disease terms with HIV-associated neurocognitive AND combination antiretroviral therapy with asymptotic neurocognitive impairment OR mild cognitive disorder OR HIV-associated dementia. Results. Despite enhanced research efforts and effective cART, there still is a high prevalence of HAND within the HIV-infected population. Although the most severe form of HAND, HIV-associated dementia (HAD) is much less common in cART era, researchers still pose questions about any long-term benefit of cART with respect to milder forms of HAND. Preliminary findings have shown that patients with ANI will progress more quickly to more severe forms of HAND than those without ANI. Given this, the relevance of the correct diagnosis of ANI is crucial where well over 50% of all HIV-infected patients suffer from some stage of HAND mentioned above. Conclusions. There are various social, economic, and public health implications surrounding HIV & neurocognitive disorders. The burden of disease for this population is increasing at an exponential rate but are still unaware of the long-term survival with chronic immune activation. Future studies should assess the will this impact the aging population, the role of medication adherence, the impact of comorbidities affect HIV-associated neurocognitive disorders and the role of poly-pharmacy. Overall there is a continued need for biomarkers of HAND predisposition, detection, and monitoring.