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

It has been thought that there is a particular balance between interferon and humoral immunity in the specific antiviral activity exerted by these systems. A possible relationship has been observed between some interferon-related proteins and the interferon serum level and a predictive significance can be assigned to MxA protein regarding the progression of some haematological malignancies. Both natural and recombinant interferon have been shown to be effective in the treatment of T-cell cutaneous lymphoma and the myeloma cell expression of Bcl-2 oncoprotein correlates to the response to interferon therapy in multiple myeloma patients. It has been thought that the combined therapy including interferon and cis-retinoic acid might be effective in the therapy of metastatic melanoma and breast cancer, whereas the combination of interferon with other chemotherapeutic agents appears to be effective in the treatment of hepatocellular cancer. It has been confirmed that interferon-alpha is useful in the therapy of chronic hepatitis C and a better knowledge regarding the mechanism of action of beta interferon in the therapy of multiple sclerosis has been acquired. Finally, a remarkable report regards the effectiveness of interferon in the therapy of idiopatic dilated cardiomiopathy.
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PMID:[Clinical use of interferon]. 911 15

The Fas and FasL apoptotic pathway was investigated by protein immunohistochemistry, flow cytometry, and reverse transcriptase-PCR analysis to assess whether it is involved in the elimination of target and/or effector cells from the central nervous system (CNS) during adoptively transferred chronic relapsing experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In addition to Fas and FasL, we studied Bax, an intracellular protein of the apoptotic cascade, the Bax antagonist and anti-apoptotic molecule Bcl-2, and DNA fragmentation, the final step in the apoptotic pathway. Infiltrating CD4+ T cells and parenchymal microglia expressed Fas, FasL, and Bax, and about half of these cells showed DNA fragmentation, a combination indicative of ongoing apoptosis. Using flow cytometry and reverse transcriptase-PCR, a positive correlation was seen between disease activity and up-regulation of the Fas system; in fact, Fas and FasL were expressed at low levels at the onset of EAE and increased at the height of disease to involve about one-third of all infiltrating lymphocytes. In the normal CNS, Fas immunoreactivity was constitutively present at low levels on oligodendrocytes and was up-regulated in the CNS during the course of EAE. However, oligodendrocytes showed no Bax reactivity or DNA fragmentation and expressed high levels of Bcl-2, as did the majority of infiltrating CD3+ cells, a pattern inconsistent with apoptosis. Thus, while molecules of the apoptotic cascade are well represented in the CNS during EAE, their expression correlates with elimination of infiltrating cells and microglia, not the myelinating cell, the oligodendrocyte.
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PMID:Cell death during autoimmune demyelination: effector but not target cells are eliminated by apoptosis. 954 18

Multiple sclerosis (MS) is a chromatic inflammatory disease of the central nervous system. T lymphocytes play a major role in the pathogenesis of the disease. The exact mechanisms by which the inflammation is regulated in MS have not yet been defined. Studies in animal models of MS suggest that apoptosis of T cells is the main factor terminating inflammation. The process of apoptosis itself is regulated by a range of pro- and anti-apoptotic proteins. The bcl-2 gene family is an important member of these proteins. The present study investigated the expression of the anti-apoptotic protein bcl-2 in 11 chronic MS cases including five relapsing-remitting and six chronic progressive MS patients. A total of 35 lesions containing all stages of demyelinating activity were studied. The number of CD 3-positive T cells and the absolute and relative numbers of T cells expressing bcl-2 were determined by double immunocytochemistry. Bcl-2 is expressed by T lymphocytes in MS plaques. Patients with chronic progressive MS have a higher proportion of bcl-2 expressing T cells than patients with relapsing remitting disease. Highest numbers of bcl-2-positive T lymphocytes were found in remyelinating and demyelinated lesions, whereas active demyelinating lesions revealed lower numbers. These data indicate that cell-death-related proteins such as the anti-apoptotic protein bcl-2 are expressed in MS lesions and that they might have important effects on the regulation of elimination or persistence of inflammatory cells in the central nervous system.
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PMID:Bcl-2 expressing T lymphocytes in multiple sclerosis lesions. 971 85

Infection of susceptible mouse strains with BeAn, a less virulent strain of Theiler's murine encephalomyelitis virus (TMEV), results in immune system-mediated demyelinating lesions in the central nervous system (CNS) similar to those in multiple sclerosis. Since macrophages appear to carry the major detectable antigen burden in vivo, and purification of sufficient cell numbers from the CNS for detailed analysis is difficult, macrophage-like cell lines provide an accessible system with which to study virus-macrophage interactions. The myeloid precursor cell line M1 differentiates in response to cytokines and expresses many characteristics of tissue macrophages. Incubation of TMEV with undifferentiated M1 cells produced neither infection nor apoptosis, whereas differentiated M1 (M1-D) cells developed a restricted virus infection and changes indicative of apoptosis. Virus binding and RNA replication as well as cellular production of alpha/beta interferons increased with differentiation. Although the amount of infectious virus was highly restricted, BeAn-infected M1-D cells synthesized and appropriately processed virus capsid proteins at levels comparable to those for permissive BHK-21 cells. Analysis of Bcl-2 protein family expression in undifferentiated and differentiated cells suggests that susceptibility of M1-D cells to apoptosis may be controlled, in part, by expression of the proapoptotic alpha isoform of Bax and Bak. These data suggest that macrophage differentiation plays a role in susceptibility to TMEV infection and apoptosis.
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PMID:Differentiation of M1 myeloid precursor cells into macrophages results in binding and infection by Theiler's murine encephalomyelitis virus and apoptosis. 1007 76

We investigated the sensitivity to cell death of peripheral blood mononuclear cells (PBMCs) from patients with multiple sclerosis (MS). PBMCs from MS patients, following PHA stimulation, were less sensitive to cell death than those from healthy donors (mean +/- s.e.m., 22.5 +/- 1.9 in MS patients vs 36.5 +/- 2.8 in healthy controls; p = 0.0003). However, when Fas-agonist antibody was added, the increase in respect to apoptosis induced by mitogen alone was even higher in MS patients than in controls. In addition, PHA-activated PBMCs from MS patients showed higher surface expression of Fas than controls, while Bcl-2 expression was decreased. This finding raised the question of whether an impaired generation of apoptotic signals may be contributing to the immune component of MS.
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PMID:Impaired apoptosis in mitogen-stimulated lymphocytes of patients with multiple sclerosis. 1020 42

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system leading to selective destruction of myelin sheaths and/or oligodendrocytes. The immunological mechanisms responsible for myelin destruction and the primary target of the immune response have not yet been identified. Prior studies have reported a variable degree of oligodendrocyte preservation in actively demyelinating lesions. We have previously demonstrated that oligodendrocyte survival is heterogenous and varies between individual MS patients. Bcl-2 belongs to the group of apoptosis-associated proteins that protects cells from cell death. The purpose of the present study was to determine whether bcl-2 expression is associated with oligodendrocyte preservation observed in some early MS lesions. Double immunocytochemistry was performed with antibodies against bcl-2 and myelin oligodendrocyte glycoprotein (MOG) to identify bcl-2-expressing oligodendrocytes within MS lesions from 43 patients. The number of bcl-2-positive oligodendrocytes was determined depending on the lesion demyelinating activity and the disease course of the patients. The number of bcl-2-expressing oligodendrocytes increased within demyelinating lesions compared to the periplaque white matter, with highest numbers in remyelinating lesions. There was a significant association between the presence of bcl-2-positive oligodendrocytes and the presence of remyelination. The highest proportion of bcl-2-positive oligodendrocytes was observed in a subgroup of patients with relapsing-remitting disease course. The expression of apoptosis-associated proteins may contribute to oligodendrocyte preservation or loss in MS lesions.
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PMID:Bcl-2-expressing oligodendrocytes in multiple sclerosis lesions. 1049 20

We evaluated the presence of soluble Fas (sFas), Fas ligand (sFasL), and Bcl-2 in the sera of patients with multiple sclerosis (MS) or human T-lymphotropic virus type I (HTLV-1)-associated myelopathy (HAM) using an enzyme-linked immunosorbent assay (ELISA). Patients with MS in the active phase had higher sFas and Bcl-2 levels than had controls (sFas, p < 0.005; Bcl-2, p < 0.05) or patients in the inactive phase (p < 0.05). In addition, significantly increased serum levels of sFas were found in patients with HAM (p < 0.005). Interestingly, levels of sFasL in sera from patients with HAM and MS in the active stage were higher than those from controls or from patients with MS in the inactive stage or from other inflammatory neurologic diseases (OIND), although this was not statistically significant. These results suggest that serum sFas, sFasL, and Bcl-2 may play an important role in the pathogenesis of MS and HAM.
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PMID:Serum levels of apoptosis-related molecules in patients with multiple sclerosis and human T-lymphotropic virus Type I-associated myelopathy. 1050 41

The human population is exposed to both the ultraviolet A (UVA) and B (UVB) regions of the solar spectrum. UVB induces mainly dipyrimidine photoproducts in DNA by a direct photochemical mechanism, whereas UVA is absorbed by other cellular constituents and induces mainly oxidative damage indirectly. The proportions of the different dipyrimidine photoproducts, and the ratio of dipyrimidine to oxidative damage depend on the exact spectral output of a UV source. Irradiation of human epidermal keratinocytes induces release of cytokines, with cyclobutane pyrimidine dimers playing a significant role in the process. These cytokines may then modulate the activity of cells of the immune system. Freshly isolated human lymphocytes are exquisitely sensitive to UVB irradiation, because of their low deoxyribonucleotide pools. They also have a separate defect in removal of cyclobutane pyrimidine dimers from their DNA. We have observed that frequencies of mutations at the hprt locus in human T-lymphocytes and translocations involving the bcl2 locus in B-lymphocytes appear to be associated with sunlight levels over the period before the blood sample was taken. This may be an indirect cytokine-mediated effect, and may be relevant to the possible link between non-Hodgkin's lymphoma and sunlight. On the other hand, sunlight can have beneficial effects, and may protect against autoimmune diseases including type I diabetes and multiple sclerosis.
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PMID:Possible effects of sunlight on human lymphocytes. 1070 50

Apoptosis is a prerequisite to model the developing nervous system. However, an increased rate of cell death in the adult nervous system underlies neurodegenerative disease and is a hallmark of multiple sclerosis (MS) Alzheimer's- (AD), Parkinson- (PD), or Huntington's disease (HD). Cell surface receptors (e.g., CD95/APO-1/Fas; TNF receptor) and their ligands (CD95-L; TNF) as well as evolutionarily conserved mechanisms involving proteases, mitochondrial factors (e.g. , Bcl-2-related proteins, reactive oxygen species, mitochondrial membrane potential, opening of the permeability transition pore) or p53 participate in the modulation and execution of cell death. Effectors comprise oxidative stress, inflammatory processes, calcium toxicity and survival factor deficiency. Therapeutic agents are being developed to interfere with these events, thus conferring the potential to be neuroprotective. In this context, drugs with anti-oxidative properties, e.g., flupirtine, N-acetylcysteine, idebenone, melatonin, but also novel dopamine agonists (ropinirole and pramipexole) have been shown to protect neuronal cells from apoptosis and thus have been suggested for treating neurodegenerative disorders like AD or PD. Other agents like non-steroidal anti-inflammatory drugs (NSAIDs) partly inhibit cyclooxygenase (COX) expression, as well as having a positive influence on the clinical expression of AD. Distinct cytokines, growth factors and related drug candidates, e.g., nerve growth factor (NGF), or members of the transforming growth factor-beta (TGF-beta ) superfamily, like growth and differentiation factor 5 (GDF-5), are shown to protect tyrosine hydroxylase or dopaminergic neurones from apoptosis. Furthermore, peptidergic cerebrolysin has been found to support the survival of neurones in vitro and in vivo. Treatment with protease inhibitors are suggested as potential targets to prevent DNA fragmentation in dopaminergic neurones of PD patients. Finally, CRIB (cellular replacement by immunoisolatory biocapsule) is an auspicious gene therapeutical approach for human NGF secretion, which has been shown to protect cholinergic neurones from cell death when implanted in the brain. This review summarises and evaluates novel aspects of anti-apoptotic concepts and pharmacological intervention including gene therapeutical approaches currently being proposed or utilised to treat neurodegenerative diseases.
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PMID:Apoptosis modulators in the therapy of neurodegenerative diseases. 1106 Jul 7

Failure of Fas-mediated apoptosis of potentially pathogenic, autoreactive T lymphocytes may be involved in the pathogenesis of multiple sclerosis. The intracellular protein FLIP, a naturally occurring caspase-antagonist, is a potent inhibitor of the Fas signalling pathway that may block Fas-mediated apoptosis of activated lymphocytes. This study reports specific overexpression of both long and short forms of FLIP in intrathecal lymphocytes from patients with multiple sclerosis. The overexpression of FLIP is independent of cellular expressions of Fas receptor or the anti-apoptotic protein Bcl-2. These results provide a better understanding of some of the intrinsic immunoregulatory mechanisms that are involved in multiple sclerosis.
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PMID:Increased cellular expression of the caspase inhibitor FLIP in intrathecal lymphocytes from patients with multiple sclerosis. 1106 39


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