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)

Dithiocarbamates and iron chelators were recently considered for the treatment of AIDS and neurodegenerative diseases. In this study, we show that dithiocarbamates and metal chelators can potently block the activation of nuclear factor kappa B (NF-kappa B), a transcription factor involved in human immunodeficiency virus type 1 (HIV-1) expression, signaling, and immediate early gene activation during inflammatory processes. Using cell cultures, the pyrrolidine derivative of dithiocarbamate (PDTC) was investigated in detail. Micromolar amounts of PDTC reversibly suppressed the release of the inhibitory subunit I kappa B from the latent cytoplasmic form of NF-kappa B in cells treated with phorbol ester, interleukin 1, and tumor necrosis factor alpha. Other DNA binding activities and the induction of AP-1 by phorbol ester were not affected. The antioxidant PDTC also blocked the activation of NF-kappa B by bacterial lipopolysaccharide (LPS), suggesting a role of oxygen radicals in the intracellular signaling of LPS. This idea was supported by demonstrating that treatment of pre-B and B cells with LPS induced the production of O2- and H2O2. PDTC prevented specifically the kappa B-dependent transactivation of reporter genes under the control of the HIV-1 long terminal repeat and simian virus 40 enhancer. The results from this study lend further support to the idea that oxygen radicals play an important role in the activation of NF-kappa B and HIV-1.
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PMID:Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. 131 83

Several novel imidotriphosphate analogues of thymidine have been synthesized and have been shown to be effective inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT). When the alpha,beta-bridging oxygens of thymidine triphosphate (TTP) and 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) were replaced by a nitrogen, the resulting analogues were no longer substrates but instead became competitive inhibitors of HIV-1 RT. The most potent of the alpha,beta-imidotriphosphate derivatives tested was thymidine 5'-[alpha,beta-imido]triphosphate (TMPNPP, 1a). This analogue has a Ki value of 2.4 microM, inhibiting HIV-1 RT 400-fold more potently than it inhibits DNA polymerase I large fragment (Klenow). 3'-Azido-3'-deoxythymidine 5'-[alpha,beta-imido]triphosphate (AZTMPNPP, 1b) gave a Ki value about 10-fold greater than that for TMPNPP, indicating that a 3'-azido substituent decreases the affinity of AZTTP to HIV-1 RT relative to the normal 3'-OH substituent. Dideoxythymidine 5'-[alpha,beta-imido]triphosphate (ddTMPNPP, 1c) was intermediate in potency, giving a Ki value of 15 microM. In contrast, substitution at the beta,gamma-bridging oxygen by nitrogen did not block the enzymatic cleavage of the adjacent alpha,beta-phosphate linkage, and 3'-azidothymidine 5'-[beta,gamma-imido]triphosphate (AZTMPPNP, 1e), the 5'-[beta,gamma-imido]triphosphate analogue of AZTTP, is therefore both a substrate for and a potent inhibitor of HIV-1 RT with an observed Ki value of 87 nM. Further nitrogen substitution of the bridging oxygens in the phosphate chain decreases the inhibitory potency by approximately 10-fold, as in the case of thymidine 5'-[alpha,beta:beta,gamma-diimido]triphosphate (TMPNPNP, 1d).
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PMID:New thymidine triphosphate analogue inhibitors of human immunodeficiency virus-1 reverse transcriptase. 137 62

The practice of transfusion medicine has undergone substantial change over the last decade. Much of the impetus for the change has come from the isolation of human immunodeficiency virus (HIV) and the linkage of HIV transmission to blood transfusion. The purpose of this paper is to collate and review the literature relating to the indications for blood transfusion and provide recommendations for the appropriate utilization of blood products. Peer-reviewed and published studies and reviews relating to aspects of clinical blood transfusion were identified through computer searches and searching of the bibliographies of identified articles. Emphasis was placed on the literature published within the last decade and particularly in the years 1985-91. Material was chosen which was of proved clinical importance and in which findings were consistent among different investigators or different centres. Less emphasis was placed on material reporting new findings of uncertain clinical relevance or findings that were not consistent with majority reports. It is concluded that the only indication for red cell transfusion is to increase the oxygen carrying capacity of the blood and that an adjustment downwards in the haemoglobin concentration at which blood is transfused (transfusion trigger) from the traditional level of 100 g.L-1 is supported by the physiological and clinical data. Perioperative haemoglobin concentrations of 80 g.L-1 are acceptable in otherwise healthy young patients. The transfusion trigger should be adjusted upwards from this in medically compromised patients and in the elderly (greater than 60 yr). Fresh frozen plasma (FFP) is only indicated when there are documented deficiencies of coagulation factors. Platelet concentrates (PC) are indicated for the treatment of clinical coagulopathy resulting from thrombocytopaenia or platelet dysfunction. Routine or prophylactic administration of either FFP or PC after cardiopulmonary bypass or during resuscitation from haemorrhage is not indicated.
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PMID:Perioperative haemotherapy: I. Indications for blood component transfusion. 139 59

Oxygen radical scavengers, such as dithiocarbamates and cysteine derivatives, inhibit activation of the ubiquitous transcription factor nuclear factor kappa B (NF-kappa B) after treatment of cells with tumor necrosis factor, phorbol ester, and interleukin-1. An involvement of oxygen radicals was more directly evident from the induction of NF-kappa B by low concentrations of H2O2 and the demonstration that cells stimulated with various NF-kappa B inducers release H2O2 and superoxide. In this study, we used the antioxidant pyrrolidine dithiocarbamate (PDTC) to investigate whether the activation of NF-kappa B by the viral transactivator Tax from human T-cell leukemia virus type I also depends on the production of reactive oxygen intermediates. The Tax-induced activation of the DNA-binding activity of NF-kappa B in Jurkat T cells was potently suppressed by micromolar concentrations of PDTC. Within the same concentration range, PDTC and two other dithiocarbamates also strongly interfered with transactivation of the long terminal repeat (LTR) of human immunodeficiency virus type 1 by Tax but had no effect on transactivation of the same LTR by Tat. Transactivation of the human T-cell leukemia virus type I LTR by Tax was also barely influenced. Tax seems to activate NF-kappa B by a mechanism shared with all other inducers of NF-kappa B tested so far. It appears that one of the pleiotropic activities of Tax leads to an enhanced production of oxygen radicals that are required for activation of NF-kappa B.
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PMID:Antioxidants selectively suppress activation of NF-kappa B by human T-cell leukemia virus type I Tax protein. 140 92

Activation of the cellular transcription factor nuclear factor-kappa B (NF-kappa B) by cytokines and other immunostimulants has been tightly linked with enhanced replication of human immunodeficiency virus-type 1 (HIV-1) in infected cells. Various immunomodulators are currently being examined in animal and human trials for their suitability as adjuvants in potential vaccines against acquired immunodeficiency syndrome (AIDS). It may prove to be beneficial to select adjuvants that do not induce NF-kappa B activation and particularly if the vaccines are to be aimed at seropositive individuals. We have examined a battery of synthetic immunostimulants of the muramyl peptide family for their ability to activate NF-kappa B in human and mouse cell lines. In this report, we demonstrate selective activation of NF-kappa B in different cell lines and by different muramyl peptides possessing immunostimulatory activities. The mechanism of such activation is apparently via production of reactive oxygen intermediates (ROI) since pretreatment of cells with antioxidants blocked subsequent activation of NF-kappa B. However, among all the molecules tested only one lipophilic, non-pyrogenic adjuvant active muramyl peptide showed a complete lack of NF-kappa B activation in all cell lines tested. This molecule could well become the adjuvant of choice in future AIDS vaccines.
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PMID:Selection of a muramyl peptide based on its lack of activation of nuclear factor-kappa B as a potential adjuvant for AIDS vaccines. 142 73

We assessed qualitative and quantitative differences in surfactant lipid composition of bronchoalveolar lavage (BAL) fluid in patients with acquired immune deficiency syndrome (AIDS) and Pneumocystis carinii (PC) pneumonia. Five normal volunteers and 27 patients with human immunodeficiency virus (HIV) infection underwent BAL for evaluation of possible pulmonary infection. Bronchoalveolar lavage studies in eight patients were negative for PC organisms, and 19 were positive. Pneumocystis carinii pneumonia was graded (mild vs moderate to severe) by initial alveolar-arterial oxygen gradient. Bronchoalveolar lavage fluid was centrifuged, the lipids were extracted from the supernatant, and total lipid profiles of dephosphorylated glycerolipids were analyzed as trimethylsilylether derivatives by high temperature gas-liquid chromatography. Phospholipase A2 levels were determined using a radiolabeled E coli membrane method. Compared to the normal volunteers (109 +/- 13 micrograms/5 ml) and the PC negative group (107 +/- 13 micrograms/5 ml), total BAL lipid was reduced for both the mild PC pneumonia group (73 +/- 10 micrograms/5 ml) and the moderate to severe PC pneumonia group (46 +/- 4 micrograms/5 ml). There was a parallel reduction of diacylglycerol lipids: normal volunteers, 52 +/- 7 micrograms/5 ml; PC negative, 52 +/- 9 micrograms/5 ml; mild PC pneumonia, 35 +/- 7 micrograms/5 ml; and moderate to severe PC pneumonia, 15 +/- 2 micrograms/5 ml. Phospholipase A2 activity in moderate to severe PC pneumonia was twice that of the PC negative patients, and 30 times that for normals. The data demonstrate a marked diminution in surfactant glycerophospholipid in patients with AIDS and PC pneumonia and suggest a potential role for surfactant abnormality in the pathophysiology of this disease.
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PMID:Reduction of pulmonary surfactant in patients with human immunodeficiency virus infection and Pneumocystis carinii pneumonia. 144 80

HIV infection affects various parts of the immune system, including the CD4+ lymphocytes and mononuclear phagocytes, and causes a progressive immunodeficiency. This renders the patient susceptible to various opportunistic infections and neoplasms. Reactive oxygen intermediates (ROI) are important for the intracellular killing of microorganisms by mononuclear phagocytes and neutrophils. Although data are discrepant, several studies suggest that the generation of ROI is impaired in mononuclear phagocytes, and possibly also in neutrophils, from HIV-infected individuals. This may lead to deficient killing of intracellular microorganisms predisposing the HIV-infected patient to certain opportunistic infections. Recently, in vitro studies have shown that ROI activate the intracellular transcription factor nuclear factor kappa B (NF-kappa B) which stimulates HIV replication. Intracellular antioxidant systems, such as the glutathione system, seem to be of importance for the regulation of ROI levels and thus probably for HIV replication in vitro. However, the role of ROI in regulation of HIV replication in vivo is unknown at present. The role of ROI in HIV infection is thus difficult to assess, both at the cellular and clinical level. Reduced intracellular concentrations of ROI may lead to impaired phagocyte microbicidal functions, thus predisposing HIV-infected patients to various opportunistic infections. On the other hand, increased ROI levels may be associated with a stimulation of HIV replication leading to clinical deterioration.
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PMID:Reactive oxygen intermediates and human immunodeficiency virus (HIV) infection. 145 84

Acquired immunodeficiency syndrome (AIDS) results from infection with a human immunodeficiency virus (HIV). The long terminal repeat (LTR) region of HIV proviral DNA contains binding sites for nuclear factor kappa B (NF-kappa B), and this transcriptional activator appears to regulate HIV activation. Recent findings suggest an involvement of reactive oxygen species (ROS) in signal transduction pathways leading to NF-kappa B activation. The present study was based on reports that antioxidants which eliminate ROS should block the activation of NF-kappa B and subsequently HIV transcription, and thus antioxidants can be used as therapeutic agents for AIDS. Incubation of Jurkat T cells (1 x 10(6) cells/ml) with a natural thiol antioxidant, alpha-lipoic acid, prior to the stimulation of cells was found to inhibit NF-kappa B activation induced by tumor necrosis factor-alpha (25 ng/ml) or by phorbol 12-myristate 13-acetate (50 ng/ml). The inhibitory action of alpha-lipoic acid was found to be very potent as only 4 mM was needed for a complete inhibition, whereas 20 mM was required for N-acetylcysteine. These results indicate that alpha-lipoic acid may be effective in AIDS therapeutics.
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PMID:Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells. 148 76

For the past several years immunologists have been fascinated by a series of experiments showing that transforming growth factor beta (TGF beta) suppresses T- and B-lymphocyte growth as well as IgM and IgG production by B cells. Moreover, while exerting chemotactic activity on monocytes and inducing expression of interleukin-1 and interleukin-6 by these cells, TGF beta interferes with bacterially induced tumor necrosis factor alpha production, oxygen radical formation and the adhesiveness of granulocytes to endothelial cells. These mechanisms may provide the basis for the effect of TGF beta to prevent the microvascular changes associated with brain edema formation in bacterial meningitis. Given the potential of lymphocytes as well as macrophages to produce TGF beta 1, this cytokine may exert negative feedback signals on the immune response, provided the cytokine is processed from its latent form to the bioactive homodimer. Potent effects of TGF beta have been observed in experimental animals including the inhibition of the generation of virus-specific cytotoxic T cells and antiviral antibodies as well as the diminution of cellular infiltrates with decreased major histocompatibility complex class-II expression and CD8+ T cells in the tissue of virally infected animals. TGF beta may also be of importance in tumor immunology. By the production of bioactive TGF beta as detected in glioblastoma and acute T-cell leukemia, tumor cells may induce an immunodeficiency state and escape immune surveillance. In inflammation, monitoring of TGF beta in the tissue will bring light on the immune regulation in acute and chronic inflammatory diseases.
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PMID:Modulation of the immune response by transforming growth factor beta. 148 57

Dideoxyinosine (DDI, Videx) is a recently developed nucleoside analog with activity against the human immunodeficiency virus. A significant number of patients with AIDS or AIDS-related complex treated with DDI have developed acute pancreatitis. This study was performed to investigate the acute effects of DDI on the pancreas utilizing an isolated ex vivo perfused canine pancreas preparation. Control preparations remained normal throughout a 4-hr perfusion period. The addition of 12.5 mg of DDI to the perfusate (ca. 100 mumol/liter) did not induce any changes in the preparation. The addition of 62.5 mg of DDI to the perfusate (ca. 500 mumol/liter) did not induce changes in the gross appearance, weight gain, or amylase activity. However, the arterial pressure and the oxygen consumption of the preparation decreased significantly after the administration of DDI. The amount of zymogen in the acinar cells also decreased, as evaluated by electron microscopy. Protein secretion increased temporarily, probably as a result of acinar cell emptying (increased secretion without new synthesis). Water and bicarbonate secretion were also increased during the fourth perfusion hour.
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PMID:Acute effects of a nucleoside analog dideoxyinosine (DDI) on the pancreas. 149 95


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