Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The DNA sequence for Kaposi's sarcoma-associated herpesvirus was originally detected in Kaposi's sarcoma biopsy specimens. Since its discovery, it has been possible to detect virus in cell lines established from AIDS-associated body cavity-based B-cell lymphoma and to propagate virus from primary Kaposi's sarcoma lesions in a human renal embryonic cell line, 293. In this study, we analyzed the infectivity of Kaposi's sarcoma-associated herpesvirus produced from these two sources. Viral isolates from cultured cutaneous primary KS cells was transmitted to an Epstein-Barr virus-negative Burkitt's B-lymphoma cell line, Louckes, and compared to virus induced from a body cavity-based B-cell lymphoma cell line. While propagation of body cavity-based B-cell lymphoma-derived virus was not observed in 293 cell cultures, infection with viral isolates obtained from primary Kaposi's sarcoma lesions induced injury in 293 cells typical of herpesvirus infection and was associated with apoptotic cell death. Interestingly, transient overexpression of the Kaposi's sarcoma-associated herpesvirus v-Bcl-2 homolog delayed the process of apoptosis and prolonged the survival of infected 293 cells. In contrast, the broad-spectrum caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk failed to protect infected cell cultures, suggesting that Kaposi's sarcoma-associated herpesvirus-induced apoptosis occurs through a Bcl-2-dependent pathway. Kaposi's sarcoma-associated herpesvirus isolates from primary Kaposi's sarcoma lesions and body cavity-based lymphomas therefore may differ and are likely to have distinct contributions to the pathophysiology of Kaposi's sarcoma.
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PMID:Distinct biology of Kaposi's sarcoma-associated herpesvirus from primary lesions and body cavity lymphomas. 981 47

Apoptosis is the main cause of CD4+ T-lymphocyte depletion in acquired immune deficiency syndrome (AIDS). Various agents appear to be able to trigger apoptosis in CD4+ T cells, including viral proteins (i.e. gp120, Tat), inappropriate secretion of inflammatory cytokines by activated macrophages (i.e. tumor necrosis factor alpha) and toxins produced by opportunistic micro-organisms. Since oxidative stress can also induce apoptosis, it can be hypothesized that such a mechanism could participate in CD4+ T-cell apoptosis observed in AIDS. This correlates strongly with the observation that AIDS patients present low levels of antioxidants (i.e. superoxide dismutase-Mn, vitamin E, selenium and glutathion) most likely due to inappropriate nutrition (i.e. diets poor in antioxidants), alcohol and drug consumption, and digestive problems associated with the disease. Furthermore, the coadministration of the antiviral drug zidovudine with antioxidants increases its therapeutic potential. Finally, the following additional observations support the hypothesis that oxidative stress is involved in cell apoptosis in AIDS: (1) The depletion of the anti-apoptotic/antioxidant protein Bcl-2 in human immunodeficiency virus (HIV)-infected CD4+ cells; (2) a decrease of apoptosis in HIV-infected cells treated with antioxidants and; (3) the presence of the pro-apoptotic/pro-oxidant cytokines secreted by activated macrophages in AIDS patients. Therefore, anti-apoptotic/antioxidant strategies should be considered, alongside antiviral strategies, in order to design a more efficient therapy for AIDS in the near future.
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PMID:The keys of oxidative stress in acquired immune deficiency syndrome apoptosis. 988 26

Since the onset of the acquired immune deficiency syndrome (AIDS) epidemic fifteen years ago, much has been learned about the effects of the human immunodeficiency virus (HIV) in the nervous system. This review summarizes the pathology findings in the central nervous system (CNS). There is now abundant evidence that HIV can infect the CNS directly, leading to a characteristic HIV encephalitis (HIVE) which occurs in 10-50 p. 100 of AIDS autopsy series. Multinucleated giant cells are the pathognomonic feature of HIVE and are found predominantly in the central white matter and deep grey matter. Evidence of productive HIV infection in the CNS is confined to cells of the microglial/macrophage lineage, from which the giant cells are almost certainly derived. These cells are known to express both CD4 and beta-chemokine receptors, which act in conjunction to permit HIV entry. Restricted infection of astrocytes has also been identified by a variety of methods. HIVE is frequently associated with white matter damage ranging from inflammatory (microglia, macrophages and sparse lymphocytes) to degenerative (myelin loss and axonal damage) pathology. Although giant cells are seen less frequently in neocortical grey matter, significant neuronal loss has been established in a number of studies. Recent investigations using markers of apoptosis, (including TUNEL, Bcl-2 and BAX), have established the presence of DNA damage in some neurons and in other cell types. Axonal damage has also been confirmed by evidence of amyloid precursor protein expression. The CNS is also vulnerable to opportunistic infections and high grade B-cell lymphomas as a result of the immune suppression of advanced HIV infection. Cytomegalovirus (CMV) infection is reported in 10-30 p. 100 of AIDS cases at autopsy, toxoplasma in 10-25 p. 100, progressive multifocal leucoencephalopathy in about 5 p. 100 and lymphomas, usually primary, in up to 10 p. 100. A wide variety of other infections has also been reported. These may coexist with HIVE and may be difficult to diagnose in life. CMV gives rise to microglial nodular encephalitis, ventriculitis, necrotising encephalitis and myelo-radiculitis. Presymptomatic HIV positive patients do not show HIVE or opportunistic infections or lymphomas in the CNS. They frequently display a low-grade T-cell infiltrate in the leptomeninges and parenchyma, particularly around vessels. This lymphocytic infiltrate has been attributed to presumed early invasion of the CNS by HIV although the exact timing of entry is uncertain. It is possible that reported abnormalities in presymptomatic cases such as gliosis, microglial activation and rising proviral load may anticipate the onset of HIVE but most studies show that significant CNS damage and HIV-related pathology is confined to patients with AIDS. HIV-related pathology in the spinal cord includes not only HIV myelitis, opportunistic infections and lymphomas, but also vacuolar myelopathy (VM) which affects predominantly the dorsolateral white matter tracts. The cause of VM is not understood and has not been unequivocally linked with HIV infection. It is noted that none of these neuropathological features (including HIVE) correlates exactly with the clinical expression of AIDS-related dementia (ARD). The exact contribution of macrophage activation and cytokine release, astrocytic infection, neuronal loss and axonal damage to the neuropsychiatric syndromes of advanced HIV infection remain to be determined. While the current understanding of the pathogenesis of HIVE and ARD is beyond the scope of this review it is axiomatic that accurate documentation of neuropathology findings will help to resolve the outstanding dilemmas relating to HIV infection of the CNS. There is considerable optimism that progress in therapeutic regimes for HIV-infected patients will succeed in eliminating the virus from the blood and from lymphoid tissue. (ABSTRACT TRUNCATED)
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PMID:The neuropathology of adult HIV infection. 993 3

Lymphomas in 10 cynomolgus monkeys infected with a simian immunodeficiency virus (SIVsm) were studied with regard to proliferative activity and apoptosis-related gene expression. All were diffuse large-cell lymphomas, showed mono or oligoclonality and a 9/10 diploid cellular DNA content. Expression of a simian homologue to Epstein-Barr virus (HVMF-1) was shown in nine cases. The lymphomas showed moderate to high proliferative activity by Ki67 immunostaining and DNA flow cytometry, and a low number of apoptotic cells detected by TdT-mediated dUTP nick-end labeling (TUNEL). Immunohistochemistry showed abundant tumor infiltrating TIA-1(+) cytotoxic lymphocytes (CTL) and macrophages. Bcl-2, Mcl-1, and also Bax and Bak, but not p53 were demonstrable in the tumor cells by immunostaining. Our findings suggest a causal relationship between HVMF-1 infection and a low apoptotic index of the lymphomas due to the expression of Bcl-2. The apparent inefficient function of tumor-infiltrating CTL could be due to inactivation of CTL and/or resistance of the lymphoma cells to CTL effects. The tumors showed immunoreactivity for CD18, CD29, and CD49d, but not for CD11a, mimicking the phenotype of human Epstein-Barr virus (EBV)-related lymphomas. In summary, our observations indicate a high similarity between this simian model of acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARL) and human ARL and other immunosuppression-related lymphomas.
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PMID:Proliferation and apoptosis-related gene expression in experimental acquired immunodeficiency syndrome-related simian lymphoma. 994 80

Monocytes are precursors of tissue macrophages, which are major targets of human immunodeficiency virus type 1 (HIV-1) infection. Although few blood monocytes are infected, their resulting activation could play a key role in the pathogenesis of HIV disease by modulating their transendothelial migration and inducing the production of reactive oxygen species (ROS). ROS participate in chronic inflammation, HIV replication, and the apoptosis of immune system cells seen in HIV-infected subjects. Published data on monocyte activation are controversial, possibly because most studies have involved monocytes isolated from their blood environment by various procedures that may alter cell responses. We therefore used flow cytometry to study, in whole blood, the activation and redox status of monocytes from HIV-infected patients at different stages of the disease. We studied the expression of adhesion molecules, actin polymerization, and cellular levels of H2O2, Bcl-2, and thioredoxin. Basal H2O2 production correlated with viral load and was further enhanced by bacterial N-formyl peptides and endotoxin. The enhanced H2O2 production by monocytes from asymptomatic untreated patients with CD4(+) cell counts above 500/microliter was associated with a decrease in the levels of Bcl-2 and thioredoxin. In contrast, in patients with AIDS, Bcl-2 levels returned to normal and thioredoxin levels were higher than in healthy controls. Restoration of these antioxidant and antiapoptotic molecules might explain, at least in part, why monocyte numbers remain relatively stable throughout the disease. Alterations of adhesion molecule expression and increased actin polymerization could play a role in transendothelial migration of these activated monocytes.
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PMID:Redox and activation status of monocytes from human immunodeficiency virus-infected patients: relationship with viral load. 1023 14

The role of Bcl-2, Bax, and Bcl-x in the apoptosis of T lymphocytes in HIV-infected individuals was investigated. A strong correlation between Bcl-2 downregulation and spontaneous apoptosis has been reported by various groups in short-term cultures of CD8+ but not of CD4+ T lymphocytes. We describe a similar correlation in CD4+ T cells and provide an explanation why Bcl-2 downregulation in these cells has not been detected so far. In apoptotic cells not only Bcl-2, but also the CD4 surface receptors, are downregulated, preventing the detection of these cells in flow cytometric analysis. In contrast to Bcl-2, no correlation is detectable between Bax or Bcl-x expression and apoptosis. T lymphocytes of HIV-infected, but not of control, individuals display ex vivo a heterogeneous Bcl-2 expression pattern with a low and a high Bcl-2-expressing lymphocyte fraction. The proportion of low Bcl-2-expressing T cells correlates with a higher viral load in these individuals. Antiretroviral therapy significantly reduces the proportion of low Bcl-2-expressing lymphocytes, which is associated with a decrease in apoptosis. Bcl-2 downregulation and spontaneous apoptosis of T lymphocytes from HIV-infected individuals can be partially prevented by the exogeneous addition of IL-2, but not of IL-12, IL-4, or antibodies that prevent the CD95/CD95 ligand pathway of apoptosis.
AIDS Res Hum Retroviruses 1999 Jun 10
PMID:Downregulation of Bcl-2, but not of Bax or Bcl-x, is associated with T lymphocyte apoptosis in HIV infection and restored by antiretroviral therapy or by interleukin 2. 1038 Nov 68

We have come to understand apoptosis as not merely a single form of cell death, but as a fundamental theme in cell biology that has far-reaching implications in the fields of physiology and pathology. At the present time, however, the mechanism of apoptosis is not clearly understood, as research into apoptosis is still at the initial stages. Nevertheless, the links between apoptosis and a variety of pathological conditions are gradually becoming clearer. In this article, we will provide a simple explanation of apoptosis and its mechanism as a novel concept of cell death and discuss the way in which apoptosis has been linked to a variety of pathological conditions. WHAT IS APOPTOSIS?: In normal tissue, cells that are no longer needed are rapidly eliminated without affecting the overall function of the tissue. In this process cells undergo an active and spontaneous suicide called programmed cell death. In fact, the majority of physiological cell deaths take the form of apoptosis. The word apoptosis is used, in contrast to necrosis, to describe the situation in which a cell actively pursues a course toward death upon receiving certain stimuli [1]. The morphological changes of apoptosis found in most cell types first involve contraction in cell volume and condensation of the nucleus. When this happens the intracellular organelles such as the mitochondria retain their normal morphology. As apoptosis proceeds, blebbing of the plasma membrane occurs, and the nucleus becomes fragmented. Finally, the cell itself fragments to form apoptotic bodies that are engulfed by nearby phagocytes. With respect to biochemical changes, it is known that the chromosomes become fragmented into nucleosome units, and DNA forms characteristic ladder patterns when subjected to agarose gel electrophoresis. MECHANISM OF APOPTOSIS: It has been reported that apoptosis is induced in various cells by many kinds of irritations, but the precise mechanism is still unclear. Cell injuries that induce apoptosis include those that cause DNA damage such as radiation and anticancer drugs, those that are mediated by the TNF receptor and Fas receptor (the so-called "death signal receptors"), and the deprivation of cytokines that supply survival signals such as IL-3 and erythropoietin. The tumor suppressor gene p53 plays a very important role in apoptosis induced by damage to DNA. This has been demonstrated by studying resistance to apoptosis of cells derived from p53 knockout mice [2]. Other than the irritations that induce apoptosis, molecules that have been strongly implicated as major players in the drama of apoptosis include the Bcl-2 family proteins and the IL-1 converting enzyme (ICE) and its homolog proteases (caspase family). Both groups of proteins show homology with proteins that affect cell death in nematodes. It is believed that molecules that contribute to cell death have been well conserved in multicellular organisms all the way from the relatively primitive nematodes to mammals including humans. It was discovered that Bcl-2 suppressed apoptosis induced in IL-3 dependent cells by deprivation of IL-3 [3]. It has since become the gene around which apoptosis research revolves. Recently, it has become clear that cell death involving the Bcl-2 protein is under the control of similar proteins from the same family [4]. It is interesting that the phenomenon of cell death may be regulated by the balance of the molecules involved in it. APOPTOSIS ABNORMALITIES AND DISEASE: Physiological cell death plays a major role in the growth and permanent maintenance of the human body [5]. In the process of forming the nervous system, neurons that do not form proper connections die. Physiological cell death also accompanies the removal of virus-infected cells by cytotoxic T cells, the elimination of autoreactive immune cells, the formation of the gut, the reconstitution of cartilage and bone, etc. When physiological cell death that normally should occur is inhibited, inappropriate physiological cell death may occur that is harmful to the body and forms the basis of disease. For example, in patients with neural degenerative disorders such as Alzheimer's disease and Parkinson's disease, we can find premature cell death in a particular subset of neurons. The death of T cells in AIDS patients is also a form of physiological cell death. Inhibition of cell death in the immune system enables the survival of autoreactive B cells and T cells, and is therefore a cause of autoimmune disorders. Apoptosis has been particularly linked to cancer. Normal cells are programmed for death if they are subjected to many types of non-physiological stress such as anticancer drugs or radiation, if they become isolated from surrounding cells and are unable to receive their tissue-specific survival signals [6], or if oncogenes are expressed haphazardly [7]. On the other hand, it is believed that the ability to survive is enhanced in transformed cancer cells because they are more resistant to apoptosis, they exhibit resistance to anticancer drugs, they are no longer dependent on survival signals, and they can metastasize. Therefore, the cancer progresses as the cancer cells maintain the proliferative superiority they acquire from their oncogenes. In other words, when cancer cells become resistant to apoptosis, they become resistant to treatment, metastasize, and proliferate destructively. The concept that the malignancy of cancer is due to its resistance to apoptosis is a relatively new one and is worthy of further study.
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PMID:Physician Education: Apoptosis. 1038 21

The effects of HIV-1 Tat protein on mitochondria membrane permeability and apoptosis were analysed in lymphoid cells. In this report we show that stable-transfected HIV-Tat cells are primed to undergo apoptosis upon serum withdrawal. This effect was observed in both the Jhan T cell line and the K562 cells, the latter expressing the bcr-abl chimeric gene, which confers resistance to apoptosis induced by different stimuli. Using a cytofluorimetric approach we have determined that serum withdrawal induces a disruption of the transmembrane mitochondrial potential (Deltapsim) followed by an increase of reactive oxygen species (ROS) and the subsequent DNA nuclear loss in K562-Tat cells but not in the K562-pcDNA cell line. These pre-apoptotic events were associated with the cleavage of the caspase-3, while the expression of Bcl-2, Bcl-XL and Bax proteins was not affected by the presence of Tat. Regardless of the steady state of the Bax protein, we found that in both K562 and K562-Tat cells, this protein is located in the nucleus, but after serum withdrawal its localization was mainly in the cytoplasm. The activity of caspase-3 detected in K562-Tat cells after serum withdrawal paralleled with the mitochondria permeability transition. Nevertheless, in Jhan-Tat cells the inhibition of this caspase with the specific inhibitor, z-DEVD-cmk, did not affect the disruption of the mitochondria potential induced by serum withdrawal. Interestingly, we found that HIV-Tat protein accumulates at the mitochondria in the K562-Tat cells cultured under low serum conditions, and this mitochondrial localization correlated with the Deltapsim disruption detected in these cells. In addition, HIV-1 Tat protein synergies with protoporphyrin IX (PPIX), a ligand of the mitochondrial benzodiazepine receptor, in the induction of apoptosis in both Jhan and K562 cells. Thus, HIV-1 Tat protein may induce apoptosis by a mechanism that involves mitochondrial PT and may contribute to the lymphocyte depletion seen in AIDS patients.
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PMID:Susceptibility of HIV-1-TAT transfected cells to undergo apoptosis. Biochemical mechanisms. 1060 13

Expression of Bcl-2, Bcl-x, and Mcl-1 was immunohistochemically evaluated in 33 cases of Kaposi's sarcoma (KS) of the skin. Of these, classic KS (C-KS) accounted for 17 cases (10 in plaque stage and 7 in tumor stage) and acquired immunodeficiency syndrome-associated KS (AIDS-KS) accounted for 16 cases (8 in plaque stage and 8 in tumor stage). In both C-KS and AIDS-KS, Bcl-2 immunoreaction correlated with progression stage, its average score intensity being more than 2-fold in tumors than in plaques. In contrast, Bcl-x and Mcl-1 staining intensity was unrelated to progression stage but was dependent on human immunodeficiency virus infection status. Thus, whereas Bcl-x expression was stronger in C-KS cases, Mcl-1 immunostaining was more intense in AIDS-KS instances. These findings indicate that in cutaneous KS, some Bcl-2 family proteins exhibit differential expressions that are dependent on either progression stage or human immunodeficiency virus infection status.
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PMID:Immunohistochemical detection of Bcl-2 in Kaposi's sarcoma lesions varies according to histopathologic stage, whereas expression of Bcl-x and Mcl-1 differs according to human immunodeficiency virus serologic status of patients. 1078 12

The mechanisms leading to a relative dominance of T cells producing type 2 cytokines in certain human immune disorders are still unclear. We investigated the relative susceptibility to apoptosis induced by primary in vitro activation of human type 1 (producing interferon-gamma (IFN-gamma)) or type 2 (producing IL-4) T cells. Peripheral blood lymphocytes were isolated from patients with immune disorders characterized by expansion of type 2 cells (four with AIDS and hyper-IgE/hypereosinophilia, one with Churg-Strauss syndrome, and one with idiopathic hypereosinophilic syndrome) or from individuals with normal cytokine balances. Cells were stimulated for 16 h with ionomycin and phorbol ester, and apoptosis of cytokine-producing cells was assessed by flow cytometry. T cells with a type-2 cytokine profile, i.e. producing IL-4 alone, were significantly more resistant to activation-induced apoptosis than those producing IFN-gamma alone. This was observed in AIDS patients, whose type 2 cells were mostly CD8+, as well as in the patients with Churg-Strauss and with hypereosinophilic syndrome. CD4+ and CD8+ IL-4-producing cells were equally resistant to apoptosis. Lower susceptibility to apoptosis of type-2 T cells was also observed in subjects with normal cytokine balances. Bcl-2 expression was high in type-2 cells and in viable type-1 cells, whereas it was low in apoptotic type-1 cells. Resistance to activation-induced apoptosis may explain the expansion of cells producing type-2 cytokines in certain immune disorders.
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PMID:Human T cells with a type-2 cytokine profile are resistant to apoptosis induced by primary activation: consequences for immunopathogenesis. 1084 23


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