Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase CK2 is a ubiquitous and pleiotropic seryl/threonyl protein kinase which is highly conserved in evolution indicating a vital cellular role for this kinase. The holoenzyme is generally composed of two catalytic (alpha and/or alpha') and two regulatory (beta) subunits, but the free alpha/alpha' subunits are catalytically active by themselves and can be present in cells under some circumstances. Special attention has been devoted to phosphorylation status and structure of these enzymic molecules, however, their regulation and roles remain intriguing. Until recently, CK2 was believed to represent a kinase especially required for cell cycle progression in non-neural cells. At present, with respect to recent findings, four essential features suggest potentially important roles for this enzyme in specific neural functions: (1) CK2 is much more abundant in brain than in any other tissue; (2) there appear to be a myriad of substrates for CK2 in both synaptic and nuclear compartments that have clear implications in development, neuritogenesis, synaptic transmission, synaptic plasticity, information storage and survival; (3) CK2 seems to be associated with mechanisms underlying long-term potentiation in hippocampus; and (4) neurotrophins stimulate activity of CK2 in hippocampus. In addition, some data are suggestive that CK2 might play a role in processes underlying progressive disorders due to Alzheimer's disease, ischemia, chronic alcohol exposure or immunodeficiency virus HIV. The present review focuses mainly on the latest data concerning the regulatory mechanisms and the possible neurophysiological functions of this enzyme.
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PMID:Casein kinase 2 as a potentially important enzyme in the nervous system. 1065 42

Glutathione deficiency has been associated with a number of neurodegenerative diseases including Lou Gehrig's disease, Parkinson's disease, and HIV. A crucial role for glutathione is as a free radical scavenger. Alzheimer's disease (AD) brain is characterized by oxidative stress, manifested by protein oxidation, lipid oxidation, oxidized glutathione, and decreased activity of glutathione S-transferase, among others. Reasoning that elevated levels of endogenous glutathione would offer protection against free radical-induced oxidative stress, rodents were given in vivo injections of N-acetylcysteine (NAC), a known precursor of glutathione, to study the vulnerability of isolated synaptosomal membranes treated with Fe2+/H2O2, a known hydroxyl free radical producer. Protein carbonyls, a marker of protein oxidation, were measured. NAC significantly increased endogenous glutathione levels in cortical synaptosome cytosol (P < 0.01). As reported previously, protein carbonyl levels of the Fe2+/H2O2-treated synaptosomes were significantly higher compared to that of non-treated controls (P < 0.01), consistent with increased oxidative stress. In contrast, protein carbonyl levels in Fe2+/H2O2-treated synaptosomes isolated from NAC-injected animals were not significantly different from saline-injected non-treated controls, demonstrating protection against hydroxyl radical induced oxidative stress. These results are consistent with the notion that methods to increase endogenous glutathione levels in neurodegenerative diseases associated with oxidative stress, including AD, may be promising.
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PMID:In-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain. 1067 51

A stress-activated serine/threonine protein kinase, p38 mitogen-activated protein kinase (p38 MAPK), belongs to the MAP kinase superfamily. Diverse extracellular stimuli, including ultraviolet light, irradiation, heat shock, high osmotic stress, proinflammatory cytokines and certain mitogens, trigger a stress-regulated protein kinase cascade culminating in activation of p38 MAPK through phosphorylation on a TGY motif within the kinase activation loop. p38 MAPK appears to play a major role in apoptosis, cytokine production, transcriptional regulation, and cytoskeletal reorganization, and has been causally implicated in sepsis, ischemic heart disease, arthritis, human immunodeficiency virus infection, and Alzheimer's disease. The availability of specific inhibitors helps to clarify the role that p38 MAPK plays in these processes, and may ultimately offer therapeutic benefit for certain critically ill patients.
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PMID:MAP kinase pathways activated by stress: the p38 MAPK pathway. 1080 18

The structure and function of neurons are changed not only during development of the central nervous system but also in certain neurological disorders, such as Alzheimer's disease and human immunodeficiency virus type 1 (HIV-1) -associated dementia. Immunological activation and altered production of neurotoxins and neurotrophins by brain macrophages are thought to play an important role in neuronal structure and function. This review describes the clinical and pathological features of both Alzheimer's disease and HIV-1-associated dementia and tries to interpret the role of the macrophage and astrocytes therein. The consequences of activation of macrophages by amyloid-beta in Alzheimer's disease and HIV infection of macrophages in HIV-1-associated dementia and the similarities between these diseases will be discussed. Although the neuropathology of Alzheimer's disease and HIV-1-associated dementia differs, Alzheimer's disease is a cortical dementia and HIV-1-associated dementia is a subcortical dementia, the process of macrophage activation and the resulting pathways leading to neurotoxicity seem very similar. In both Alzheimer's disease and HIV-1-associated dementia, interaction of macrophages and astrocytes appear to play an important role.
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PMID:Role of macrophage activation in the pathogenesis of Alzheimer's disease and human immunodeficiency virus type 1-associated dementia. 1084 12

Chemokines constitute a large and still growing family of structurally-related small (8-10 kDa) cytokines that have chemotactic activity for leukocytes. Recently, some receptors for chemokines were reported to be used as a co-receptor by HIV at infection. In addition to their well-established role in inflammatory response and recently-reported role as a co-receptor for HIV, recent data suggest that chemokines and their receptors physiologically and pathologically play crucial roles as the mediators for intercellular communication among the cells intrinsic to and recruited into the brain; i.e., neurons, astrocytes, microglia, endothelial cells and leukocytes. Some chemokines such as SDF-1 and fractalkine are constitutively produced in the brain, implicating that they have an important role in maintenance of CNS homeostasis or determination of the patterning of neurons and/or glial cells in developing brain and normal adult brain. Chemokines such as MCP-1, MIP-1 alpha and CINC were shown to be induced by various neuroinflammatory stimuli, suggesting that they are involved in various neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, stroke and AIDS dementia syndrome. Chemokines and their receptors are potential targets for therapeutic intervention in neurodegenerative diseases.
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PMID:[Chemokines as mediators for intercellular communication in the brain]. 1087 3

Progressive cerebral amyloid beta-protein (A beta) deposition is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Elevated levels of A beta(42) peptide formation have been linked to early-onset familial AD-causing gene mutations in the amyloid beta-protein precursor (A beta PP) and the presenilins. Sequential cleavage of A beta PP by the beta- and gamma-secretases generates the N- and C-termini of the A beta peptide, making both the beta- and gamma-secretase enzymes potential therapeutic targets for AD. The identity of the A beta PP gamma-secretase and the mechanism by which the C-termini of A beta are formed remain uncertain, although it has been suggested that the presenilins themselves are novel intramembrane-cleaving gamma-secretases of the aspartyl protease class [Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., and Selkoe, D. J. (1999) Nature 398, 513-517]. In this study we report the identification of L-685,458 as a structurally novel inhibitor of A beta PP gamma-secretase activity, with a similar potency for inhibition of A beta(42) and A beta(40) peptides. This compound contains an hydroxyethylene dipeptide isostere which suggests that it could function as a transition state analogue mimic of an aspartyl protease. The preferred stereochemistry of the hydroxyethylene dipeptide isostere was found to be the opposite to that required for inhibition of the HIV-1 aspartyl protease, a factor which may contribute to the observed specificity of this compound. Specific and potent inhibitors of A beta PP gamma-secretase activity such as L-685,458 will enable important advances toward the identification and elucidation of the mechanism of action of this enigmatic protease.
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PMID:L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. 1091 80

Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer's disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer's disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales.
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PMID:Evaluation of memantine for neuroprotection in dementia. 1106 Jul 51

Lipoprotein(a) [Lp(a)] is an enigmatic lipoprotein particle present in the plasma from humans, great apes and hedgehogs. Plasma levels of Lp(a) vary widely between individuals and are largely determined by specific sequences within the gene encoding apo(a), the unique highly polymorphic glycoprotein attached to apoB of low density lipoprotein (LDL) to form Lp(a). Elevated plasma concentrations of LP(a) are associated with the premature development of atherosclerosis. A major goal of our laboratory is to better understand the metabolism of Lp(a) and its function in humans. We have identified unexpected and large variations in plasma Lp(a) levels during renal disease, HIV-infection and in sepsis. Moreover, we have observed an association between Lp(a) and Alzheimer disease. Taken together, our observations suggest that Lp(a) may constitute a novel target in our fight against cardiovascular and neurodegenerative disorders.
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PMID:[Lipoprotein (a) in Alzheimer's atherosclerosis]. 1114 Mar 10

It has been suggested that up to 15% of patients with AIDS may develop HIV-associated dementia. The syndrome may be either abrupt or insidious and is characterized by poor prognosis. Increasing cognitive impairment will necessitate the patient receiving a substantial amount of care and support in the community in addition to medical treatment and periods of hospitalization. The impact of caregiver burden is reasonably well documented in Alzheimer's disease, but there is a dearth of literature relating to caregiving and HIV-associated dementia. The current investigation is an observational study based on a small group of individuals which evaluates the experiences of these particular individuals as they care for their partner, friend, or son with HIV-associated dementia. The caregivers experience the stresses described in the non-HIV dementia literature; however, the nature of HIV disease means that there are issues involved in caring for this patient group that distinguish it from other types of dementia care; these include difficulties relating to specific HIV medical problems and problems with service shortfalls. The caregiver is more likely to be a parent or partner than a child of the patient due to the early age onset seen in this disease compared with Alzheimer's disease. Caregivers express their need for information about dealing with the everyday physical, behavioral, and emotional challenges and about services and benefits available. The interviewees expressed concerns over a perceived lack of communication and information from professionals involved in the patient's care and in the provision of services. The study offers an insight into the relevant issues affecting such caregivers and suggests areas of unmet needs that might be addressed in future service provisions.
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PMID:The burden of care: the impact of HIV-associated dementia on caregivers. 1136 87

A case study of a 34-year-old HIV-positive woman, who is on drug therapy and who has the genetic defect for Huntington's disease, raises questions regarding her long-term prognosis. Huntington's disease is a neurologic disorder marked by dementia and involuntary movement. Some of the personality changes that result from Huntington's disease, such as impulsive behavior and substance abuse, could put a patient at greater risk for being exposed to HIV. Patients with Huntington's disease are expected to eventually need institutionalization and death is usually expected within 15 to 20 years after diagnosis. Unlike HIV, Huntington's disease can only be transmitted vertically, and offspring are encouraged to get tested for the genetic disorder when they are of childbearing age. The success of antiretroviral treatments to prolong lives of HIV positive people gives rise to a host of ethical and logistical questions surrounding an aging HIV-positive population who have the potential to develop other chronic illnesses, such as Alzheimer's or Huntington's. Several questions need to be addressed, such as deciding who will have access to diverse genetic tests that are currently being developed, or will there be adequate facilities to care for HIV positive patients who develop multiple chronic illnesses. The patient in this case study decided to continue her therapy, but has difficulty keeping up with her medication as she progresses into dementia.
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PMID:Looking forward, looking back. 1136 98


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