HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling

HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF. Results showed that cocaine exposure during HIV infection significantly increased the level of p24, reactive oxygen species (ROS), ATP-utilization and upregulated energy sensor AMPKs, CDC25B/C, MAP/Tau and Wee1 protein expression. Increased ROS production subsequently inhibits OCR/ECAR ratio and OXPHOS, and eventually upregulate epigenetics remodeling complex SWI/SNF in CHME-5 cells. These results suggest that HIV infection induced energy deficit and metabolic dysfunction is accelerated by cocaine inducing energy sensor AMPKs, mitochondrial biogenesis and chromatin remodeling complex SWI/SNF activation, which may lead to neuroAIDS disease progression

Effect of histamine and histamine antagonists on natural and antibody-dependent cellular cytotoxicity of human lymphocytes in vitro

The in vitro effect of histamine and its antagonists, cimetidine and clemastine fumarate, on natural killer (NK) and antibody-dependent cellular Cytotoxicity (ADCC) activities of human lymphocytes was investigated. The histamine 1 (H1) antagonist, clemastine fumarate, and the histamine 2 (H2) antagonist, cimetidine, but not histamine alone, inhibited the NK and ADCC activities of lymphocytes when added directly to the mixture of effector and target cells in a 51Cr-release assay. This inhibition was proportional to the concentration of drugs added and was observed at various effector to target ratios against several targets. H1 and H2 antagonists also inhibited NK activities of T cells as well as Percoll-separated, NK-enriched effector cells. The inhibition was significantly reversed by histamine. In target binding assays, clemastine fumarate and cimetidine also decreased the target binding capacity of effector lymphocytes. Further, PBL precultured with histamine (10-3-10-4 M) for 24 hr showed a significant decrease in their NK and ADCC activities. In coculture experiments, PBL precultured with histamine suppressed the NK activity of normal autologous effector lymphocytes. PBL precultured with histamine showed an increased number of OKT8+ cells, as estimated using monoclonal antibodies. The suppression of Cytotoxicity was not due to either direct toxicity, steric hindrance, crowding, or cell death, but by functionally viable suppressor cells. An immunoregulatory role for histamine in NK and ADCC reactions is proposed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25092/1/0000524.pd

Immunoregulation of natural and lymphokine-activated killer cells by selenium

The effect of selenium (Se) on natural killer (NK) and lymphokine-activated killer (LAK) cell activities and proliferative responses of human lymphocytes was studied in vitro. Direct addition of Se at 1.0 [mu]g/ml final concentration to the mixture of target and effector cells during a 4 h cytotoxicity assay significantly suppressed the NK activity of normal lymphocytes. When lymphocytes were preincubated with Se at concentrations as low as 0.2 [mu]g/ml for a period of 48 h, a significant inhibitory effect on NK activity was observed. In the LAK cell assay, direct addition of Se at concentrations of 0.2-1.0 [mu]g/ml to a mixture of target and effector cells did not show any effects on LAK cell activity, whereas LAK cells generated in the presence of Se at 0.8 [mu]g/ml showed significant inhibition of their functions. Lymphocyte proliferative responses to T cell mitogens such as phytohemagglutinin (PHA) and concanavalin A (Con A) were also significantly suppressed by direct addition of Se at 0.5-1.0 [mu]g/ml. The inhibitory effect of Se was not due to nonspecific toxicity of effector cells as demonstrated by viability nor was the effect directed against target cells. These studies suggest that although Se is an essential micronutrient for various immune mechanisms, an excess of Se may have a deleterious effect on certain immunological functions. As these activities are considered to be important defense mechanisms against tumors and virus infections, a nutritional imbalance of Se could result in an increased risk of these disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28589/1/0000397.pd

Electroconvulsive Therapy Increases Plasma Levels of Interleukin-6 a

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74956/1/j.1749-6632.1990.tb40529.x.pd

Association of decreased T-cell-mediated natural cytotoxicity and interferon production in Down's Syndrome

Total peripheral blood lymphocytes (PBL) and isolated subpopulations from children with Down's Syndrome (DS) and age-matched healthy controls were investigated for their (1) natural killer (NK) and antibody-dependent cellular cytotoxic activities, (2) interleukin 2 (IL-2)-induced augmentation of NK activity, (3) lectin-dependent cellular cytotoxicity (LDCC), (4) ability of serum- and culture-derived soluble suppressor factor(s) to inhibit NK activity of normal lymphocytes, and (5) capacity to produce interferon (IFN) against tumor targets in vitro. T lymphocytes from DS patients demonstrated significantly decreased NK activity against K562 target cells compared to controls. DS lymphocytes also demonstrated a significant reduction in LDCC activity and IL-2-induced enhancement of NK activity. Furthermore, the ability of DS lymphocytes to produce IFN in vitro against K562 target cells was also significantly lower than that for normal PBL. Although sera from DS patients showed a significantly greater inhibitory effect on the NK activity of allogeneic normal PBL than normal sera, culture supernates from DS lymphocytes demonstrated suppressive effects comparable to culture supernates from normal PBL. These studies suggest an association between the decreased NK activity of T-cell subpopulations and lower IFN production by PBL from patients with DS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24622/1/0000032.pd

Association of decreased natural and antibody-dependent cellular cytotoxicity and production of natural killer cytotoxic factor and interferon in neonates

Cord blood lymphocytes (CBL) were compared with adult peripheral blood lymphocytes (a-PBL) for their: (i) natural killer (NK) and antibody-dependent cellular cytotoxic (ADCC) activities, (ii) target-binding capacity, (iii) ability to induce soluble natural killer cytotoxic factor (NKCF), (iv) interferon (IFN)-, interleukin 2 (IL-2)-, and lectin-induced augmentation of NK activity, and (v) ability to produce IFN against tumor targets in vitro. CBL depleted of adherent cells and Percoll-separated, NK-enriched subpopulations demonstrated significantly lower NK, ADCC, and target-binding activities compared to a-PBL. CBL produced significantly lower levels of NKCF directed against K562 tumor targets in comparison with a-PBL. Although the NK activity of CBL was not stimulated by either IFN or IL-2 to the same levels shown by a-PBL, the percentage enhancement of cytotoxicity of CBL by IFN and IL-2 was greater than that of a-PBL. Lectin-induced enhancement of cytotoxicity was significantly greater for CBL in comparison with a-PBL. Further, the ability of CBL lymphocytes to produce IFN-[gamma] in vitro against K562 target cells was significantly lower than that of adult PBL. These studies suggest an association between decreased NK, ADCC, and target-binding activities, induction of NKCF and IFN production by CBL, and increased susceptibility of neonates to infection.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25603/1/0000150.pd

Interactive Effects of Morphine on HIV Infection: Role in HIV-Associated Neurocognitive Disorder

HIV epidemic continues to be a severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV. The frequency of drug abuse among HIV infected patients is rapidly increasing and is another major issue since injection drug users are at a greater risk of developing HIV associated neurocognitive dysfunctions compared to non-drug users infected with HIV. Brain is a major target for many of the recreational drugs and HIV. Evidences suggest that opiate drug abuse is a risk factor in HIV infection, neural dysfunction and progression to AIDS. The information available on the role of morphine as a cofactor in the neuropathogenesis of HIV is scanty. This review summarizes the results that help in understanding the role of morphine use in HIV infection and neural dysfunction. Studies show that morphine enhances HIV-1 infection by suppressing IL-8, downregulating chemokines with reciprocal upregulation of HIV coreceptors. Morphine also activates MAPK signaling and downregulates cAMP response element-binding protein (CREB). Better understanding on the role of morphine in HIV infection and mechanisms through which morphine mediates its effects may help in devising novel therapeutic strategies against HIV-1 infection in opiate using HIV-infected population

Decreased natural and antibody-dependent cellular cytotoxic activities in intravenous drug abusers

Peripheral blood lymphocytes from 14 adult male patients admitted to the hospital with complications of intravenous drug abuse (IDA) were examined for natural killer (NK) and antibody-dependent cellular cytotoxic (ADCC) activities, lectin-dependent cellular cytotoxicity, and interferon (IFN)- and interleukin 2 (IL-2)-induced NK activity. Serum was also assayed for circulating interferon levels and soluble factor(s) capable of suppressing the cytotoxic potential of allogeneic lymphocytes from healthy donors. IDA patients demonstrated significantly decreased levels of NK and ADCC activities compared to age- and sex-matched healthy controls. The lectin, phytohemagglutinin, could significantly enhance the cytotoxicity of IDA lymphocytes: however, activity was not completely restored to normal levels. IDA sera demonstrated a significant inhibitory effect on the NK and ADCC activities of normal allogeneic lymphocytes, and these sera contained negligible levels of circulating IFN. Although the NK activity of IDA lymphocytes could not be restored completely to normal levels by either IFN-[alpha] or IL-2 the percentage enhancement of cytotoxicity was remarkably higher in IDA patients with significantly reduced NK activity than that observed using PBL from patients with near normal NK activity. The ability of IFN or IL-2 to enhance the decreased cytotoxicity of PBL from drug abusers suggests a novel therapeutic approach to the management of the complications of IDA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26335/1/0000422.pd

Reactive oxygen species (ROS) mediated enhanced anti-candidal activity of ZnS-ZnO nanocomposites with low inhibitory concentrations

Enhanced antifungal activity against the yeast species Candida albicans, Candida tropicalis and Saccharomyces cerevisiae was displayed by ZnS-ZnO nanocomposites prepared by a simple precipitation technique. The antifungal activity was significantly more in the presence of indoor light than under dark conditions and was a clear confirmation of the inhibitory role of reactive oxygen species (ROS) generated in situ by the photocatalytic nanocomposites. The generation of ROS was further evidenced by flow cytometry results and membrane permeabilisation studies. Time kill assay and growth curve analysis indicated diminished antifungal activity under dark conditions due primarily to Zn2+ efflux in solution. © 2015 The Royal Society of Chemistry