Role of Divalent Cations in HIV-1 Replication and Pathogenicity.

Divalent cations are essential for life and are fundamentally important coordinators of cellular metabolism, cell growth, host-pathogen interactions, and cell death. Specifically, for human immunodeficiency virus type-1 (HIV-1), divalent cations are required for interactions between viral and host factors that govern HIV-1 replication and pathogenicity. Homeostatic regulation of divalent cations' levels and actions appear to change as HIV-1 infection progresses and as changes occur between HIV-1 and the host. In people living with HIV-1, dietary supplementation with divalent cations may increase HIV-1 replication, whereas cation chelation may suppress HIV-1 replication and decrease disease progression. Here, we review literature on the roles of zinc (Zn2+), iron (Fe2+), manganese (Mn2+), magnesium (Mg2+), selenium (Se2+), and copper (Cu2+) in HIV-1 replication and pathogenicity, as well as evidence that divalent cation levels and actions may be targeted therapeutically in people living with HIV-1.

Bioenergetic adaptations to HIV infection. Could modulation of energy substrate utilization improve brain health in people living with HIV-1?

The human brain consumes more energy than any other organ in the body and it relies on an uninterrupted supply of energy in the form of adenosine triphosphate (ATP) to maintain normal cognitive function. This constant supply of energy is made available through an interdependent system of metabolic pathways in neurons, glia and endothelial cells that each have specialized roles in the delivery and metabolism of multiple energetic substrates. Perturbations in brain energy metabolism is associated with a number of different neurodegenerative conditions including impairments in cognition associated with infection by the Human Immunodeficiency Type 1 Virus (HIV-1). Adaptive changes in brain energy metabolism are apparent early following infection, do not fully normalize with the initiation of antiretroviral therapy (ART), and often worsen with length of infection and duration of anti-retroviral therapeutic use. There is now a considerable amount of cumulative evidence that suggests mild forms of cognitive impairments in people living with HIV-1 (PLWH) may be reversible and are associated with specific modifications in brain energy metabolism. In this review we discuss brain energy metabolism with an emphasis on adaptations that occur in response to HIV-1 infection. The potential for interventions that target brain energy metabolism to preserve or restore cognition in PLWH are also discussed.

Homeostatic bioenergetic network regulation - a novel concept to avoid pharmacoresistance in epilepsy.

INTRODUCTION: Despite epilepsy being one of the most prevalent neurological disorders, one third of all patients with epilepsy cannot adequately be treated with available antiepileptic drugs. One of the significant causes for the failure of conventional pharmacotherapeutic treatment is the development of pharmacoresistance in many forms of epilepsy. The problem of pharmacoresistance has called for the development of new conceptual strategies that improve future drug development efforts. AREAS COVERED: A thorough review of the recent literature on pharmacoresistance in epilepsy was completed and select examples were chosen to highlight the mechanisms of pharmacoresistance in epilepsy and to demonstrate how those mechanistic findings might lead to improved treatment of pharmacoresistant epilepsy. The reader will gain a thorough understanding of pharmacoresistance in epilepsy and an appreciation of the limitations of conventional drug development strategies. EXPERT OPINION: Conventional drug development efforts aim to achieve specificity of symptom control by enhancing the selectivity of drugs acting on specific downstream targets; this conceptual strategy bears the undue risk of development of pharmacoresistance. Modulation of homeostatic bioenergetic network regulation is a novel conceptual strategy to affect whole neuronal networks synergistically by mobilizing multiple endogenous biochemical and receptor-dependent molecular pathways. In our expert opinion we conclude that homeostatic bioenergetic network regulation might thus be used as an innovative strategy for the control of pharmacoresistant seizures. Recent focal adenosine augmentation strategies support the feasibility of this strategy.

Doping-control urinalysis of a ginseng extract, Cold-FX, in athletes.

Nutraceuticals may induce doping infractions through contamination of the product itself or their ingestion might be metabolized within the body to create a positive doping control test. We tested this possibility using a commercially available, proprietary ginseng root extract (Cold-FX, CV Technologies Inc., Edmonton, AB). After athletes ingested Cold-FX for 28 d at 400 mg/d, urine samples were collected and processed under strict IOC doping control guidelines and then analyzed for a full screen of IOC banned/restricted substances by an IOC-approved laboratory. There were no positive tests for any banned substances in any of the subjects. Our study demonstrates that ingestion of Cold-FX for 28 d at 400 mg/d does not represent a doping concern for athletes. Carefully controlled clinical studies like this one are necessary to provide the athlete, the nutraceutical industry and IOC regulatory bodies with information to avoid inadvertent exposure to banned/restricted or potentially unhealthy substances.