Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. We have previously shown that acute exposure to the HIV coat protein gp120 interferes with the beta-adrenergic regulation of astroglial and microglial cells (Levi et al., 1993). In particular, exposure to 100 pM gp120 for 30 min depressed the phosphorylation of vimentin and glial fibrillary acidic protein (GFAP) induced by isoproterenol in rat cortical astrocyte cultures. In the present study we have extended our analysis on the effects of gp120 on astroglial protein phosphorylation. 2. We found that chronic (3-day) treatment of the cells with 100 pM gp120 before exposure to isoproterenol was substantially more effective than acute treatment in depressing the stimulatory effect of the beta-adrenergic agonist on vimentin and GFAP phosphorylation. 3. Even after chronic treatment with gp120, no differences were found in the levels and solubility of these proteins. 4. Besides stimulating the phosphorylation of intermediate filament proteins, isoproterenol inhibited the incorporation of 32P into a soluble acidic protein of 80,000 M(r), which was only minimally present in Triton X-100-insoluble extracts. 5. Treatment of astrocytes with a phorbol ester or exposure to 3H-myristic acid indicated that the acidic 80,000 M(r) protein is a substrate for protein kinase C (PKC) and is myristoylated, thus suggesting that it is related to the MARCKS family of PKC substrates. 6. Acute (30-min) treatment with 100 pM gp120 totally prevented the inhibitory effect of isoproterenol on the phosphorylation of the 80,000 M(r) MARCKS-like protein. 7. Our studies corroborate the hypothesis that viral components may contribute to the neuropathological changes observed in AIDS through the alteration of signal transduction systems in glial cells.
Cell Mol Neurobiol 1994 Apr
PMID:Human immunodeficiency virus protein gp120 interferes with beta-adrenergic receptor-mediated protein phosphorylation in cultured rat cortical astrocytes. 784 74

In previous work, it was found that the heavy chain variable gene (VH) repertoire of human antibodies to HIV is markedly skewed and that the gp120 molecule is a ligand for VH3 gene products. Here, we have analysed the light chain (L-chain) variable region genes (VL) expressed by a panel of human monoclonal antibodies derived from an immunized volunteer, an AIDS patient and seropositive asymptomatic donors, and specific for HIV-1 p25, gp41 and gp120 proteins. We found that, in contrast to VH gene-family use, the VL repertoire does not exhibit a family-bias. We noticed however, a tendency to the use of VL genes that map to the downstream portion of the kappa locus. The VL genes expressed have mutated at lower rates than the corresponding VH genes and show no clustering of the replacement mutations in the hypervariable regions. We also found that the third hypervariable regions (CDR3) of the L-chains have undergone a marked diversification, with addition of untemplated nucleotides, frequent truncation at the 3' end of the VLs and somatic mutation. These molecular events result in a length heterogeneity of the CDR3s and an apparently positive selection of specific highly reactive amino acids. We conclude that the specificity of, at least some of the anti-HIV antibodies, is dictated by the L-chain CDR3 regions which bear the imprints of antigenic selection.
Mol Immunol 1995 Jan
PMID:Variable region light chain genes encoding human antibodies to HIV-1. 787 59

Bronchoalveolar lavage (BAL) macrophages from patients with symptomatic or asymptomatic HIV-1 infections were obtained, and their ability to restrict in vitro the growth of an AIDS-associated strain of Mycobacterium avium was compared with cells obtained from normal volunteers. BAL macrophage populations from HIV-1-infected subjects (symptomatic or asymptomatic) spontaneously released significant amounts of IL-6, IL-1 beta, and TNF-alpha, whereas BAL macrophages from normal volunteers released very low amounts of these cytokines. Phagocytosis of M. avium was shown to be similar in both HIV-1-infected subjects and in control subjects. BAL macrophages from HIV-1-infected subjects released significantly greater quantities of IL-6, IL-1 beta, and TNF-alpha than did cells from normal volunteers upon M. avium ingestion. Growth of M. avium was similar in BAL macrophages from all three subject groups. Finally, BAL macrophages from normal volunteers were obtained, and these cells were doubly infected with a macrophage tropic isolate of HIV-1 at a low multiplicity of infection and with an AIDS-associated strain of M. avium. There were no significant differences in cytokine release by cells co-infected with M. avium and HIV-1 and cells infected with M. avium alone. The growth of mycobacteria and the viral replication in doubly infected cells were compared with those in cells infected with only one of the pathogens, and it was shown that HIV-1 infection had no significant effect on M. avium growth.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Oct
PMID:Interaction between Mycobacterium avium and human immunodeficiency virus type 1 (HIV-1) in bronchoalveolar macrophages of normal and HIV-1-infected subjects. 791 17

Perhaps as many as 25-50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? This article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. In addition, interferon-gamma (IFN-gamma) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-alpha and IL1-beta, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
Mol Neurobiol
PMID:HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. 799 15

Therapeutic agents which target NF-kappa B transcription factor may be useful in the management of AIDS, cancer and inflammation. Since oxidative stress has been implicated in the signaling pathway, the use of antioxidants to inhibit NF-kappa B activation has gained attention. In the present study, we examined the effects of catechol derivatives, nitecapone and OR-1246, which have been identified to possess potent antioxidant properties, on NF-kappa B activation by monitoring its DNA binding activity. Both nitecapone and OR-1246 (10-300 microM) inhibited NF-kappa B activation induced by tumor necrosis factor-alpha in Jurkat T (acute human leukemia) cells. Nitecapone was a better inhibitor than OR-1246. The observed effects may, at least in part, be due to the ability of the two compounds to directly inhibit DNA binding activity of activated NF-kappa B. The inhibitory capability of OR-1246 on NF-kappa B DNA binding does not appear to be a sole mechanism, as it did not inhibit NF-kappa B activation induced by okadaic acid. Hence, catechol derivatives inhibit NF-kappa B transcription factor through multiple mechanisms, and nitecapone and OR-1246 may be useful as therapeutic agents targeting NF-kappa B.
Biochem Mol Biol Int 1994 Feb
PMID:Inhibition of NF-kappa B transcription factor by catechol derivatives. 801 35

A replication-defective virus (BM5d) of approximately 4.9 kb, is responsible for a retrovirus induced immunodeficiency syndrome in mice (MAIDS) that shares many features with AIDS. BM5d is characterized by deletions in env and pol genes, furthermore its gag gene differs markedly from gag of other BM5 ecotropic viruses, particularly in its p12 sequence. The p12 region of the gag gene has been shown to account for the pathogenicity of the BM5d retrovirus. During our studies of BM5d integration in mice we found that p12-like sequences are present in the mouse genome of uninfected healthy C57BL/6 mice. Cloning and sequencing of this p12 gag homologue has revealed a high (63% to 89%) amino acid derived sequence identity with other retroviruses and shown that the major differences among p12 of pathogenic viral strains compared to non-pathogenic ones consist of a four amino acids deletion and a high abundance of proline and basic amino acids in their p12 region.
Biochem Mol Biol Int 1994 Mar
PMID:A p12 gag gene homologue is present in the mouse genome. 803 19

Footprinting experiments using both DNase I and methidium propyl-EDTA.Fe(II) have been used to investigate the sequence selectivity in binding to DNA of pentamidine and four butamidine analogues active against the Pneumocystis carinii pathogen, which afflicts patients with acquired immunodeficiency syndrome. In common with pentamidine, the butamidine drugs, which contain cis- or trans-1,4-but-2-ene linkers and either bis(amidine) or bis(imidazolidine) terminal groups, bind selectively to DNA sequences composed of at least 4 consecutive A.T base pairs. None of the drugs tolerates the presence of a G.C base pair within the binding site. Consistently in the DNase I and methidium propyl-EDTA.Fe(II) footprinting experiments, the cis-isomers produce stronger footprints than do the trans-isomers, despite their similar hydrogen-bonding potentialities. The present experimental data support the view that the conformation of the drug plays a determining role in the binding reaction. Starting from the known structure of a pentamidine-oligonucleotide complex, it is possible to rationalize the different capacities of the cis- and trans-butamidine analogues to recognize defined DNA sequences in terms of the radius of curvature of the molecule and the distance between the positively charged terminal groups. Together, these features constitute critical factors favoring (cis-conformation) or hampering (trans-conformation) the fitting of the drugs into the minor groove of DNA. In terms of structure-activity relationships, the AT-specific recognition of DNA by this series of butamidine derivatives cannot be directly correlated with their potencies against Pneumocystis carinii pneumonia.
Mol Pharmacol 1994 Aug
PMID:Sequence-selective binding to DNA of cis- and trans- butamidine analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine. 807 93

We have used cationic liposomes to facilitate adeno-associated virus (AAV) plasmid transfections of primary and cultured cell types. AAV plasmid DNA complexed with liposomes showed levels of expression several fold higher than those of complexes with standard plasmids. In addition, long-term expression (> 30 days) of the gene, unlike the transient expression demonstrated by typical liposome-mediated transfection with standard plasmids, was observed. Southern analysis of chromosomal DNA further substantiated the hypothesis that the long-term expression was due to the presence of the transgene in the AAV plasmid-transfected group and not in the standard plasmid-transfected group. AAV plasmid-liposome complexes induced levels of transgene expression comparable to those obtained by recombinant AAV transduction. Primary breast, ovarian, and lung tumor cells were transfectable with the AAV plasmid DNA-liposome complexes. Transfected primary and cultured tumor cells were able to express transgene product even after lethal irradiation. High-level gene expression was also observed in freshly isolated CD3+, CD4+, and CD8+ T cells from normal human peripheral blood. Transfection efficiency ranged from 10 to 50% as assessed by intracellular interleukin-2 levels in interleukin-2-transfected cells. The ability to express transgenes in primary tumor and lymphoid cells may be applied toward tumor vaccine studies and protocols which may eventually permit highly specific modulation of the cellular immune response in cancer and AIDS.
Mol Cell Biol 1994 Apr
PMID:Efficient and sustained gene expression in primary T lymphocytes and primary and cultured tumor cells mediated by adeno-associated virus plasmid DNA complexed to cationic liposomes. 813 45

A strategy for preventing or delaying the peripheral neuropathy induced by 2',3'-dideoxycytidine (ddC) therapy in patients with acquired immunodeficiency syndrome was suggested by findings, in two laboratories, that cultured avian and mammalian cells devoid of mitochondrial DNA continue to replicate at virtually normal rates, provided that the medium is supplemented with uridine and pyruvate. Inasmuch as it is likely that a depletion of mitochondrial DNA also takes place in neuronal cells exposed to ddC, we used PC12 cells, the neuronal model we have reported on previously, in an attempt to rescue these cells from the deleterious effects of ddC. We first show, using undifferentiated PC12 cells, that DNA replication is impaired in mitochondria isolated from cells grown in the presence of ddC. Then, using growth rate as a criterion of the well-being of the cells, we show that the addition of uridine and pyruvate to uninduced cells growing in the presence of ddC results in an average rescue efficiency of 51%, based on the uridine/pyruvate-treated control. This value increases considerably at substantially higher concentrations of uridine alone. Rescue efficiencies of differentiated cells, which do not proliferate, were assessed using neurite outgrowth and neurite survival as criteria. Here the rescue efficiency is 56%, based on the uridine/pyruvate-treated control. In addition, uridine and pyruvate prolong the viability of ddC-treated cells and maintain their healthy appearance; without these compounds, the ddC-treated cells have an abnormal morphology and die off quite rapidly.
Mol Pharmacol 1993 Oct
PMID:Anti-human immunodeficiency virus type 1 therapy and peripheral neuropathy: prevention of 2',3'-dideoxycytidine toxicity in PC12 cells, a neuronal model, by uridine and pyruvate. 823 19

Nuclear factor kappa B (NF-kappa B) is believed to play an important role in the activation of human immunodeficiency virus (HIV) which causes acquired immunodeficiency syndrome (AIDS). Recent findings suggesting an involvement of reactive oxygen species in signal transduction pathways leading to NF-kappa B activation have encouraged the possible clinical use of antioxidants in blocking HIV activation. We have examined the effects of vitamin E and alpha-lipoate derivatives on NF-kappa B activation, and have observed that each of these antioxidants behave differently. Here we propose mechanisms of antioxidant actions in influencing cell signalling for NF-kappa B activation.
Mol Aspects Med 1993
PMID:Vitamin E and alpha-lipoate: role in antioxidant recycling and activation of the NF-kappa B transcription factor. 826 37


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