Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well established that the two major glial cells in the central nervous system (CNS), astrocytes and microglia, are key participants in mediating the neurologic dysfunction associated with HIV infection of the CNS. In this study, we investigated the ability of the major envelope glycoprotein of HIV, glycoprotein 120 (gp120), to regulate intercellular adhesion molecule-1 (ICAM-1) expression in glial cells, because ICAM-1 is important in mediating immune responsiveness in the CNS, facilitating entry of HIV-infected cells into the CNS, and promoting syncytia formation. Our results indicate that gp120 enhances ICAM-1 gene expression in primary rat astrocytes, primary human astrocytes, a human astroglioma cell line CRT, and primary rat microglia. The signal transduction events involved in gp120-mediated enhancement of ICAM-1 appear to involve activation of both protein kinase C and tyrosine kinase, because inhibitors of protein kinase C and tyrosine kinase abrogate gp120-mediated ICAM-1 expression in both astrocytes and microglia. Moreover, gp120 induces tyrosine phosphorylation of signal transducer and activator of transcription (STAT-1 alpha) as well as the Janus kinase (JAK2) in glial cells. We also demonstrate that gp120-mediated ICAM-1 expression has functional significance, as it enhances the ability of monocytic cells to bind to gp120-stimulated human astrocytes in an ICAM-1/beta 2 integrin-dependent fashion. These results provide new insights into how gp120 can influence the involvement of glial cells in the pathogenesis of AIDS dementia complex.
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PMID:HIV glycoprotein 120 enhances intercellular adhesion molecule-1 gene expression in glial cells. Involvement of Janus kinase/signal transducer and activator of transcription and protein kinase C signaling pathways. 855 11

Our objective was to characterize the effect of zidovudine therapy on AIDS dementia complex (dementia) free survival among HIV-infected men and women in a population-based cohort with free access to antiretroviral therapy in the province of British Columbia. Time to diagnosis of dementia among individuals was examined on the basis of zidovudine duration, CD4+ cell count at first treatment, gender, and transmission group [men having sex with men (MSM), intravenous drug users (IDU), heterosexuals]. We restricted the analysis to subjects with CD4+ cells counts within 12 months prior to treatment start date. Among 641 participants eligible for analysis, median duration of follow-up was 3.6 years, under which 86 (9.3%) events of dementia occurred. Participants were less likely to develop dementia with: increased zidovudine exposure (OR=0.26, 95% CI: 0.14-0.49), at least 260 CD4+ cells/mm3 (median) (OR=0.52, 95% CI: 0.34-0.78), and MSM risk group (OR=0.57, 95% CI: 0.35-0.94). Those infected through heterosexual contact had an increased risk (RR=2.04, 95% CI: 1.02-4.07). Using Cox's proportional hazards model, controlling for CD4+ cell count at treatment start date, independent predictors of dementia-free survival were: duration of zidovudine (OR=0.28, 95% CI: 0.15-0.52) and MSM transmission group (OR=0.61, 95% CI: 0.37-1.00). In this observational treatment cohort, factors associated with dementia-free survival include duration of zidovudine (AZT) therapy and MSM transmission group. It is not clear from these data whether the AZT protective effect is exclusive to this agent or whether other therapies might offer a similar protective effect.
Int J STD AIDS 2000 Jan
PMID:The impact of zidovudine on dementia-free survival in a population of HIV-positive men and women on antiretroviral therapy. 1066 2

Microglia, the resident macrophage of the brain, mediates immune and inflammatory responses in the central nervous system (CNS). Activation of microglia and secretion of inflammatory cytokines associate with the pathogenesis of CNS diseases, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease, prion disease, and AIDS dementia. Microbial pathogens, cytokines, chemokines, and costimulatory molecules are potent inducers of microglial activation in the CNS. Signaling through its receptor, IL-3 induces the activation of JAK-STAT and MAP kinase pathways in microglial cells. In this study, we found that in vitro treatment of EOC-20 microglial cells with tyrphostin AG490 blocked IL-3-induced tyrosine phosphorylation of JAK2, STAT5A, and STAT5B signaling proteins. Stable transfection of EOC-20 cells with a dominant negative JAK2 mutant also blocked IL-3-induced tyrosine phosphorylation of JAK2, STAT5A, and STAT5B in microglia. The blockade of JAK2-STAT5 pathway resulted in a decrease in IL-3-induced proliferation and expression of CD40 and major histocompatibility complex class II molecules in microglia. These findings highlight the fact that JAK2-STAT5 signaling pathway plays a critical role in mediating IL-3-induced activation of microglia.
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PMID:Signaling through JAK2-STAT5 pathway is essential for IL-3-induced activation of microglia. 1473 Jul 12

There is no question that chronic alcohol (ethanol) abuse, a leading worldwide problem, causes neuronal dysfunction and brain damage. However, various epidemiologic studies in recent years have indicated that in comparisons with abstainers or never-drinkers, light/moderate alcohol consumers have lower risks of age-dependent cognitive decline and/or dementia, including Alzheimer's disease (AD). Such reduced risks have been variously attributed to favorable circulatory and/or cerebrovascular effects of moderate ethanol intake, but they could also involve ethanol "preconditioning" phenomena in brain glia and neurons. Here we summarize our experimental studies showing that moderate ethanol preconditioning (MEP; 20-30 mM ethanol) of rat brain cultures prevents neurodegeneration due to beta-amyloid, an important protein implicated in AD, and to other neuroinflammatory proteins such as gp120, the human immunodeficiency virus 1 envelope protein linked to AIDS dementia. The MEP neuroprotection is associated with suppression of neurotoxic protein-evoked initial increases in [Ca(+2)](i) and proinflammatory mediators--e.g., superoxide anion, arachidonic acid, and glutamate. Applying a sensor --> transducer --> effector model to MEP, we find that onset of neuroprotection correlates temporally with elevations in "effector" heat shock proteins (HSP70, HSP27, and phospho-HSP27). The effector status of HSPs is supported by the fact that inhibiting HSP elevations due to MEP largely restores gp120-induced superoxide potentiation and subsequent neurotoxicity. As upstream mediators, synaptic N-methyl-d-aspartate receptors may be initial prosurvival sensors of ethanol, and protein kinase C epsilon and focal adhesion kinase are likely transducers during MEP that are essential for protective HSP elevations. Regarding human consumption, we speculate that moderate ethanol intake might counter incipient cognitive deterioration during advanced aging or AD by exerting preconditioning-like suppression of ongoing neuroinflammation related to amyloidogenic protein accumulation.
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PMID:Moderate ethanol preconditioning of rat brain cultures engenders neuroprotection against dementia-inducing neuroinflammatory proteins: possible signaling mechanisms. 2042 15

HIV-associated dementia (HAD) has received little attention in sub-Saharan Africa, and there are no data available from Malawi. We used the International HIV Dementia Scale (IHDS), a cross-cultural, simple and validated screening tool to study the prevalence of suspected HAD, defined as an IHDS score <or=10, in adult patients of a large urban antiretroviral (ART) clinic in Blantyre, Malawi. Use of the IHDS was feasible in our setting. The overall prevalence of suspected HAD was 14.0% (95% confidence interval 8.9-19.1%); there was no significant difference in prevalence between 134 patients on ART for at least six months and 45 patients not on ART (13.4% versus 15.6%; P = 0.722). Male gender and low education level were independent risk factors of suspected HAD. More knowledge of the value of the IHDS to predict ART outcomes is required.
Int J STD AIDS 2010 May
PMID:High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients. 2049 7

This study aimed to determine the prevalence of HIV neurocognitive impairment in HIV-infected men who have sex with men aged 18-50 years, using a simple battery of screening tests in routine clinical appointments. Those with suspected abnormalities were referred on for further assessment. The cohort was also followed up over time to look at evolving changes. HIV-infected participants were recruited at three clinical sites in London during from routine clinical visits. They could be clinician or self-referred and did not need to be symptomatic. They completed questionnaires on anxiety, depression, and memory. They were then screened using the Brief Neurocognitive Screen (BNCS) and International HIV Dementia Scale (IHDS). Two hundred and five HIV-infected subjects were recruited. Of these, 59 patients were excluded as having a mood disorder and two patients were excluded due to insufficient data, leaving 144 patients for analysis. One hundred and twenty-four (86.1%) had a normal composite z score (within 1 SD of mean) calculated for their scores on the three component tests of the BNCS. Twenty (13.9%) had an abnormal z score, of which seven (35%) were symptomatic and 13 (65%) asymptomatic. Current employment and previous educational level were significantly associated with BNCS scores. Of those referred onwards for diagnostic testing, only one participant was found to have impairment likely related to HIV infection. We were able to easily screen for mood disorders and cognitive impairment in routine clinical practice. We identified a high level of depression and anxiety in our cohort. Using simple screening tests in clinic and an onward referral process for further testing, we were not able to identify neurocognitive impairment in this cohort at levels consistent with published data.
Int J STD AIDS 2017 06
PMID:Low levels of neurocognitive impairment detected in screening HIV-infected men who have sex with men: The MSM Neurocog Study. 2751 Jun 45