Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methionine sulfoxide reductase (MsrA) catalyzes the reduction of methionine sulfoxide to methionine, which is able to scavenge oxidatively damaged proteins. Oxidative stress has been linked to the pathophysiology of Alzheimer's disease, and a decrease in MsrA activity has also been implicated in Alzheimer's disease. The transactivator of transcription (TAT) protein from human immunodeficiency virus 1 has been used to deliver full-length proteins into mammalian cells. We produced genetic in-frame TAT-MsrA fusion protein and successfully transduced it into PC12 cells, where it showed enzymatic activity. We showed that transduction of TAT-MsrA increased cell viability and reduced DNA fragmentation in PC12 cells treated with amyloid-beta (A beta). We suggest that MsrA transduction could reduce the oxidative damage caused to cellular proteins by A beta and could play a role in the treatment of Alzheimer's disease.
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PMID:Increased viability of PC12 cells exposed to amyloid-beta peptide by transduction with human TAT-methionine sulfoxide reductase. 1466 89

Recent data point to important roles for proteinases and their cognate proteinase-activated receptors (PARs) in the ontogeny and pathophysiology of the nervous system. PARs are a family of G-protein-coupled receptors that can affect neural cell proliferation, morphology and physiology. PARs also have important roles in neuroinflammatory and degenerative diseases such as human immunodeficiency virus-associated dementia, Alzheimer's disease and pain. These receptors might also influence the pathogenesis of stroke and multiple sclerosis, conditions in which the blood-brain barrier is disrupted. The diversity of effects of PARs on neural function and their widespread distribution in the nervous system make them attractive therapeutic targets for neurological disorders. Here, we review the roles of PARs in the central and peripheral nervous systems during health and disease, with a focus on neuroinflammatory and degenerative disorders.
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PMID:Proteinase-activated receptors in the nervous system. 1468 60

The fluid mosaic model of the plasma membrane has evolved considerably since its original formulation 30 years ago. Membrane lipids do not form a homogeneous phase consisting of glycerophospholipids (GPLs) and cholesterol, but a mosaic of domains with unique biochemical compositions. Among these domains, those containing sphingolipids and cholesterol, referred to as membrane or lipid rafts, have received much attention in the past few years. Lipid rafts have unique physicochemical properties that direct their organisation into liquid-ordered phases floating in a liquid-crystalline ocean of GPLs. These domains are resistant to detergent solubilisation at 4 degrees C and are destabilised by cholesterol- and sphingolipid-depleting agents. Lipid rafts have been morphologically characterised as small membrane patches that are tens of nanometres in diameter. Cellular and/or exogenous proteins that interact with lipid rafts can use them as transport shuttles on the cell surface. Thus, rafts act as molecular sorting machines capable of co-ordinating the spatiotemporal organisation of signal transduction pathways within selected areas ('signalosomes') of the plasma membrane. In addition, rafts serve as a portal of entry for various pathogens and toxins, such as human immunodeficiency virus 1 (HIV-1). In the case of HIV-1, raft microdomains mediate the lateral assemblies and the conformational changes required for fusion of HIV-1 with the host cell. Lipid rafts are also preferential sites of formation for pathological forms of the prion protein (PrPSc) and of the [beta]-amyloid peptide associated with Alzheimer's disease. The possibility of modulating raft homeostasis, using statins and synthetic sphingolipid analogues, offers new approaches for therapeutic interventions in raft-associated diseases.
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PMID:Lipid rafts: structure, function and role in HIV, Alzheimer's and prion diseases. 1498 85

OTK18 was isolated by mRNA differential display of human monocyte-derived macrophages (MDM) infected with human immunodeficiency virus type one (HIV-1). Northern blot and real-time reverse transcription polymerase chain reaction showed low levels of OTK18 expression in human tissue, which markedly increased during advanced HIV-1 encephalitis (HIVE). Immunocytochemistry, using rabbit polyclonal antisera, showed OTK18 localized to brain mononuclear phagocytes (MP) in moderate to severe HIV-1 encephalitis. OTK18 expression was selective and not found in HIV-1-infected brain tissue with limited neuropathological abnormalities, nor in cytomegalovirus encephalitis, multiple sclerosis, Alzheimer's disease, or uninfected control brains. Thus, OTK18 expression in brain mononuclear phagocytes is a signature for advanced HIV-1 encephalitis.
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PMID:OTK18 expression in brain mononuclear phagocytes parallels the severity of HIV-1 encephalitis. 1508 Dec 64

chlamdAs with other organ systems, the vulnerability of the nervous system to infectious agents increases with aging. Several different infectious agents can cause neurodegenerative conditions, with prominent examples being human immunodeficiency virus (HIV-1) dementia and prion disorders. Such infections of the central nervous system (CNS) typically have a relatively long incubation period and a chronic progressive course, and are therefore increasing in frequency as more people live longer. Infectious agents may enter the central nervous system in infected migratory macrophages, by transcytosis across blood-brain barrier cells or by intraneuronal transfer from peripheral nerves. Synapses and lipid rafts are important sites at which infectious agents may enter neurons and/or exert their cytotoxic effects. Recent findings suggest the possibility that infectious agents may increase the risk of common age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and stroke. While scenarios can be envisioned whereby viruses such as Chlamydia pneumoniae, herpes simplex and influenza promote damage to neurons during aging, there is no conclusive evidence for a major role of these pathogens in neurodegenerative disorders. In the case of stroke, blood vessels may be adversely affected by bacteria or viruses resulting in atherosclerosis.
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PMID:Infectious agents and age-related neurodegenerative disorders. 1516 5

Memantine, a low-to-moderate-affinity NMDA receptor antagonist, can be used to treat cognitive impairment associated with Alzheimer's disease. However, its potential neuroprotective effects for human immunodeficiency virus type 1-associated (HIV-1-associated) dementia are less well appreciated. To this end we studied hippocampal synaptic function in a severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE). Human monocyte-derived macrophages (MDMs) infected with HIV-1(ADA) were injected stereotactically into the caudate and putamen of SCID mice, generating HIVE. These brain subregions are among those most affected in humans. Impaired synaptic transmission and long-term potentiation (LTP) were detected in the CA1 region of hippocampal brain slices of HIVE mice. Memantine-treated HIVE mice showed significant improvements in synaptic function during frequency facilitation tests and LTP induced by high-frequency stimulation when compared with untreated animals. Immunocytochemical measures of neuronal antigens mirrored the neuronal physiological tests. These results demonstrate that memantine attenuates hippocampal synaptic impairment in murine HIVE and provide a rationale for its use in infected humans who experience cognitive decline.
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PMID:Memantine protects hippocampal neuronal function in murine human immunodeficiency virus type 1 encephalitis. 1530 53

The chemistry of organic polycyclic cage compounds has intrigued medicinal chemists for over 50 years, yet little is published about their pharmacological profiles. Polycyclic cage compounds have important pharmaceutical applications, ranging from the symptomatic and proposed curative treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease (e.g., amantadine and memantine), to use as anti-viral agents against influenza and the immunodeficiency virus (HIV). The polycyclic cage appears to be a useful scaffold to yield drugs with a wide scope of applications, and can be used also to modify and improve the pharmacokinetic and pharmacodynamic properties of drugs in current use. This review attempts to summarize the pharmacological profiles of polycyclic cage compounds with an emphasis on the lesser known pentacycloundecanes, homocubanes, and trishomocubanes.
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PMID:Pharmacology and structure-activity relationships of bioactive polycyclic cage compounds: a focus on pentacycloundecane derivatives. 1538 31

Tau2 antibody recognizes a phosphorylation-independent epitope that is pathologically modified as tau protein is phosphorylated to form neurofibrillary tangles of Alzheimer's disease (AD). Similar modification of tau2 epitope can be induced even in the absence phosphorylation of tau, as we first demonstrated in ischemic foci and in glial cytoplasmic inclusions (GCIs) of multiple system atrophy. This modification of tau2 epitope is distinguishable from those observed in degenerative tauopathies because (1) it is a conformational change, which is reversible upon exposure to a detergent; (2) it shows an absence of fibrils composed of phosphorylated tau protein; and (3) it is characterized by the lack of immunohistochemical labeling by anti-tau antibodies other than tau2. In this study, we expanded this observation to inflammatory foci of different pathologies (human immunodeficiency virus encephalopathy, progressive multifocal leukoencephalopathy or multiple sclerosis) by examining formalin-fixed, paraffin-embedded sections immunostained with a panel of anti-tau antibodies. It was found that tau2 was the only anti-tau antibody that immunolabeled microglia/macrophages in these lesions, and this immunoreactivity was reversibly diminished upon exposure to a detergent. Exclusive apparition of tau2 immunoreactivity in these cells without neurofibrillary pathology may be a secondary event shared with ischemic foci and GCIs. It is, however, related to a unique conformational state of tau, possibly grouped under the name of "tautwopathy", that may represent an initial stage of tau deposition distinct from degenerative tauopathies characterized by fibrils composed of phosphorylated tau protein.
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PMID:Exclusive induction of tau2 epitope in microglia/macrophages in inflammatory lesions-tautwopathy distinct from degenerative tauopathies. 1554 33

Transcriptional regulation in mammalian cells is driven by a complex interplay of multiple transcription factors that respond to signals from either external or internal stimuli. A single transcription factor can control expression of distinct sets of target genes, dependent on its state of post-translational modifications, interacting partner proteins, and the chromatin environment of the cellular genome. Furthermore, many transcription factors can act as either transcriptional repressors or activators, depending on promoter and cellular contexts [Alvarez, M., Rhodes, S.J., Bidwell, J.P., 2003. Context-dependent transcription: all politics is local. Gene 313, 43-57]. Even in this light, the versatility of LSF (Late SV40 Factor) is remarkable. A hallmark of LSF is its unusual DNA binding domain, as evidenced both by lack of homology to any other established DNA-binding domains and by its DNA recognition sequence. Although a dimer in solution, LSF requires additional multimerization with itself or partner proteins in order to interact with DNA. Transcriptionally, LSF can function as an activator or a repressor. It is a direct target of an increasing number of signal transduction pathways. Biologically, LSF plays roles in cell cycle progression and cell survival, as well as in cell lineage-specific functions, shown most strikingly to date in hematopoietic lineages. This review discusses how the unique aspects of LSF DNA-binding activity may make it particularly susceptible to regulation by signal transduction pathways and may relate to its distinct biological roles. We present current progress in elucidation of both tissue-specific and more universal cellular roles of LSF. Finally, we discuss suggestive data linking LSF to signaling by the amyloid precursor protein and to Alzheimer's disease, as well as to the regulation of latency of the human immunodeficiency virus (HIV).
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PMID:Lineage-specific and ubiquitous biological roles of the mammalian transcription factor LSF. 1556 29

Recent evidence supports the notion that the endocannabinoid system may play a crucial role in neuroinflammation. We explored the changes that some elements of this system exhibit in a macaque model of encephalitis induced by simian immunodeficiency virus. Our results show that profound alterations in the distribution of specific components of the endocannabinoid system occur as a consequence of the viral infection of the brain. Specifically, expression of cannabinoid receptors of the CB2 subtype was induced in the brains of infected animals, mainly in perivascular macrophages, microglial nodules, and T-lymphocytes, most likely of the CD8 subtype. In addition, the endogenous cannabinoid-degrading enzyme fatty acid amide hydrolase was overexpressed in perivascular astrocytes as well as in astrocytic processes reaching cellular infiltrates. Finally, the pattern of CB1 receptor expression was not modified in the brains of infected animals compared with that in control animals. These results resemble previous data obtained in Alzheimer's disease human tissue samples and suggest that the endocannabinoid system may participate in the development of human immunodeficiency virus-induced encephalitis, because activation of CB2 receptors expressed by immune cells is likely to reduce their antiviral response and thus could favor the CNS entry of infected monocytes.
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PMID:A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis. 1575 62


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