Despite the remarkable success of combination antiretroviral therapy at curtailing HIV progression, emergence of drug-resistant viruses, chronic low-grade inflammation, and adverse effects of combination antiretroviral therapy treatments, including metabolic disorders collectively present the impetus for development of newer and safer antiretroviral drugs. Curcumin, a phytochemical compound, was previously reported to have some in vitro anti-HIV and anti-inflammatory activities, but poor bioavailability has limited its clinical utility. To circumvent the bioavailability problem, we derivatized curcumin to sustain retro-aldol decomposition at physiological pH. The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours. Both curcumin and curcumin A showed similar inhibition of one round of HIV-1 infection in cultured lymphoblastoid (also called CEM) T cells (IC50=0.7 μM). But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM). Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription. Finally, we showed curcumin A induced expression of HO-1 and decreased cell cycle progression of T cells. Our findings thus indicate that altering the core structure of curcumin could yield more stable compounds with potent antiretroviral and anti-inflammatory activities.
Therefore, CD4+ count could be a clinical marker of untreated depression in HIV+. Also, mental health care may be relevant to primary care of HIV+ patients.
Heptamethine cyanine dyes are a class of near infrared (NIR) dyes that have captured the interest of the scientific community. Although applications that utilize NIR fluorescence technology are rapidly expanding, progress is limited by the lack of availability and cost of suitable compounds that can be utilized as labels and/or probes. Herein, we report the use of microwave assisted organic synthesis of five NIR cyanine dyes in yields ranging from 64-83% with a significant reduction in solvent use. Spectra characteristics including absorbance and emission spectra, molar absorptivity, quantum yield, fluorescence lifetime, and redox potentials were determined for each synthesized NIR cyanine dye.
Bipolar disorder (BD) is a severe neuropsychiatric disorder with poorly understood pathophysiology and typically treated with the mood stabilizer, lithium carbonate. Animal studies as well as human genetic studies indicate that lithium affects molecular targets that are involved in neuronal growth, survival and maturation, and notably molecules involved in Wnt signaling. Given the ethical challenge to obtaining brain biopsies for investigating dynamic molecular changes associated with lithium-response in the central nervous system (CNS), one may consider the use of neurons obtained from olfactory tissues to achieve this goal.The olfactory epithelium contains olfactory receptor neurons at different stages of development and glial-like supporting cells. This provides a unique opportunity to study dynamic changes in the CNS of patients with neuropsychiatric diseases, using olfactory tissue safely obtained from nasal biopsies. To overcome the drawback posed by substantial contamination of biopsied olfactory tissue with non-neuronal cells, a novel approach to obtain enriched neuronal cell populations was developed by combining nasal biopsies with laser-capture microdissection. In this study, a system for investigating treatment-associated dynamic molecular changes in neuronal tissue was developed and validated, using a small pilot sample of BD patients recruited for the study of the molecular mechanisms of lithium treatment response.
Background Major depressive disorder (MDD) is highly prevalent among HIV-infected (HIV+) individuals, and is associated with non-adherence to antiretroviral therapy (ART), and accelerated disease progression. MDD is underdiagnosed and undertreated among low-income African Americans, who are disproportionately impacted by the HIV epidemic. To improve detection and treatment of depression among African Americans living with HIV/AIDS, it is important to understand culturally and contextually relevant aspects of MDD and attitudes about mental health treatment. Methods A focus group session was conducted with seven providers and staff at a primary care center that serves a largely African-American community heavily impacted by the HIV epidemic in Washington, DC. Data were analyzed using an inductive approach to distill prominent themes, perspectives, and experiences among participating providers. Results Five themes emerged to characterize the lived experiences of HIV+ African-American patients: (a) Changes in perceptions of HIV over time; (b) HIV is comorbid with mental illness, particularly depression and substance abuse; (c) Stigma is associated with both HIV and depression; (d) Existing mental health services vary and are insufficient and (e) Suggestions for optimal treatment for comorbid HIV and depression. Limitation This study reflects the views of providers from one clinic in this community. Conclusion Substantial economic disadvantage, pervasive childhood adversity, limited education and limited resources jointly put members of this community at risk for acquisition of HIV and for development of depression and addictions. These contextual factors provide an important reminder that any patient-level depression identification or intervention in this community will have to be mindful of such circumstances.
There is growing evidence that lithium used in the treatment of bipolar disorder (BD) affects molecular targets that are involved in neuronal growth, survival, and maturation, but it remains unclear if neuronal alterations in any of these molecules predict specific symptom changes in BD patients undergoing lithium monotherapy. The goals of this study were to (a) determine which molecular changes in the olfactory neurons of symptomatic patients receiving lithium are associated with antimanic or antidepressant response, and (b) uncover novel intraneuronal regulatory mechanisms of lithium therapy. Twenty-two treatment-naïve non-smoking patients, with symptomatic BD underwent nasal biopsies for collection of olfactory tissues, prior to their treatment and following a 6-week course of lithium monotherapy. Sixteen healthy controls were also biopsied. Combining laser capture microdissection with real-time polymerase chain reaction, we investigated baseline and treatment-associated transcriptional changes in candidate molecular targets of lithium action in the olfactory neuroepithelium. Baseline mRNA levels of glycogen synthase kinase 3 beta (GSK3β) and collapsin response mediator protein 1 (CRMP1) genes were significantly associated with BD status and with severity of mood symptoms. Among BD subjects, treatment-associated downregulation of CRMP1 expression was most predictive of decreases in both manic and depressive symptoms. This study provides a novel insight into the relevance of CRMP1, a key molecule in semaphorin-3A signaling during neurodevelopment, in the molecular mechanism of action of lithium, and in the pathophysiology of BD. It supports the use of human-derived olfactory neuronal tissues in the evaluation of treatment response of psychiatric disorders.
Objective Given neuroimaging evidences of overlap in the circuitries for decision-making and olfactory processing, we examined the hypothesis that impairment in psychophysical tasks of olfaction would independently predict poor performances on Iowa Gambling Task (IGT), a laboratory task that closely mimics real-life decision-making, in a US cohort of HIV-infected (HIV+) individuals. Method IGT and psychophysical tasks of olfaction were administered to a Washington DC-based cohort of largely African American HIV+ subjects (N=100), and to a small number of demographically-matched non-HIV healthy controls (N=43) from a different study. Constructs of olfactory ability and decision-making were examined through confirmatory factor analysis (CFA). Structural equation models (SEMs) were used to evaluate the validity of the path relationship between these two constructs Result The 100 HIV+ participants (56% female; 96% African Americans; median age = 48 years) had median CD4 count of 576 cells/μl and median HIV RNA viral load <48 copies per milliliter. Majority of HIV+ participants performed randomly throughout the course of IGT tasks, and failed to demonstrate a learning curve. Confirmatory factor analysis provided support for a unidimensional factor underlying poor performances on IGT. Nomological validity for correlations between olfactory ability and IGT performance was confirmed through SEM. Finally, factor scores of olfactory ability and IGT performance strongly predicted 6 months history of drug use, while olfaction additionally predicted hallucinogen use. Conclusion This study suggests that combination of simple, office-based tasks of olfaction and decision-making may identify those HIV+ individuals who are more prone to risky decision-making. This finding may have significant clinical, public health value if joint impairments in olfaction and IGT task correlates with more decreased activity in brain regions relevant to decision-making.
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