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)

Oxidative stress is defined as a disturbance in the prooxidant-antioxidant balance, leading to potential cell damage. Reactive oxygen species such as superoxide radicals, hydroxyl radicals and hydrogen peroxide may act also as secondary intermediaries in intracellular signaling leading to cell death. The neuroprotective effect of melatonin has been observed both in vivo and in vitro. The objective of this research, therefore, was to better understand the cellular mechanisms of neuronal cell degeneration induced via oxidative stress and the protective roles of melatonin on this cell death. In the present study, the effects of melatonin on H(2)O(2)-induced neuronal cell degeneration in human dopaminergic neuroblastoma SH-SY5Y cultured cells were investigated. The results showed that H(2)O(2) significantly decreased cell viability and melatonin reversed the toxic effects of H(2)O(2). An inhibition of caspase enzyme activity by Ac-DEVD-CHO, a caspase-3 inhibitor, significantly increased cell viability in H(2)O(2)-treated cells. The phosphorylation of transcription factors, nuclear factor kappa B (NF-kappaB) was increased in H(2)O(2)-treated cells and this effect was abolished by melatonin. Translocation of phosphorylated NF-kappaB to perinuclear and nuclear sites, estimated using immunofluorescence, occurred to a greater extent in H(2)O(2)-treated cells than in untreated control cells and again this effect was abolished by melatonin. In addition, induction of Bcl-2 and Bax proteins was demonstrated in SH-SY5Y cultured cells treated with H(2)O(2), whereas the induction of Bax but not Bcl-2 was diminished by melatonin. In light of these finding, it is possible that the antioxidative stress effect of melatonin associated with inhibition of Bax expression, may offer a means of treating neuronal degeneration and disease.
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PMID:Melatonin protects against hydrogen peroxide-induced cell death signaling in SH-SY5Y cultured cells: involvement of nuclear factor kappa B, Bax and Bcl-2. 1687 16

Human B lymphocytes and derived lines from a spectrum of B cell malignancy were studied for expression of dopaminergic pathway components and for their cytostatic response to the catecholamine and related, potentially therapeutic compounds. Proliferating normal lymphocytes and dividing malignant clones rapidly arrested on exposure to dopamine in the low (</=10 muM) micromolar range. The antiparkinsonian drugs l-DOPA and apomorphine (particularly) were similarly antiproliferative. With the exception of D4, dopamine receptors D1-D5 were variably expressed among normal and neoplastic B cell populations, as was the dopamine transporter. Transcripts for D1 and D2 were frequently found, whereas D3 and D5 revealed restricted expression; dopamine transporter was detected in most cases. Nevertheless, pharmacological analysis disclosed that dopamine targeted cycling B cells independent of these structures. Rather, oxidative stress constituted the primary mechanism: the catecholamine's actions being mimicked by hydrogen peroxide and reversed by exogenous catalase, and evidence for the intracellular redox protein thioredoxin contributing protection. Among proliferating clones, growth arrest was accompanied by cell death in populations deplete in antiapoptotic Bcl-2: resting lymphocytes escaping low micromolar dopamine toxicity. Dysregulated bcl-2 expression, although preventing oxidative-induced caspase-dependent apoptosis, by itself conferred only minor protection against dopamine cytostasis. The selective impact of dopamine on lymphocytes that are in active cycle indicates an axis for therapeutic intervention not only in B cell neoplasia but also in lymphoproliferative disturbances generally. Rational tailoring of drug delivery systems already in development for Parkinson's disease could provide ideal vehicles for carrying the oxidative hit directly to the target populations.
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PMID:Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma. 1693 64

One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of Bcl-2 family proteins, we found a unique folded conformation adopted by tethered aromatic groups in the ligand that significantly enhanced binding affinity to Bcl-XL. This finding led us to design compounds that were biased by nonbonding interactions present in a urea tether to adopt this bioactive, folded motif. To characterize the key interactions that induce the desired conformational bias, a series of substituted N,N'-diarylureas were prepared and analyzed using X-ray crystallography and quantum mechanical calculations. Stabilizing pi-stacking interactions and destabilizing steric interactions were predicted to work in concert in two of the substitution patterns to promote the bioactive conformation as a global energy minimum and result in a high target binding affinity. Conversely, intramolecular hydrogen bonding present in the third substitution motif promotes a less active, extended conformer as the energetically favored geometry. These findings were corroborated when the inhibition constant of binding to Bcl-XL was determined for fully elaborated analogues bearing these structural motifs. Finally, we obtained the NMR solution structure of the disubstituted N,N'-diarylurea bound to Bcl-XL demonstrating the folded conformation of the urea motif engaged in extensive pi-interactions with the protein.
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PMID:Design, synthesis, and computational studies of inhibitors of Bcl-XL. 1716 73

This study investigated radioresistance mechanisms in the doxorubicin-resistant acute myelogenous leukemia (AML)-2/DX100. AML-2/DX100 also showed resistance to radiation. AML-2/DX100 characterized by down-regulated catalase expression was supersensitive to exogenous hydrogen peroxide whereas they increased defense mechanisms against endogenous reactive oxygen species (ROS) as compared with AML-2/WT. In AML-2/WT, radiation increased Bax expression and its translocation to mitochondria but had little effect on translocation of Bcl-2 and consequently induced the release of cytochrome c from the mitochondria with the subsequent caspase-3 activation. On the contrary, in AML-2/DX100, radiation neither increased Bax expression nor its translocation to mitochondria while it increased Bcl-2 translocation to mitochondria. A specific p38 MAPK inhibitor SB203580 increased radioresistance in AML-2/WT but little in AML-2/DX100. It inhibited radiation-induced Bax translocation in AML-2/WT but not in AML-2/DX100, indicating that p38 MAPK is working after irradiation in AML-2/WT but not in AML-2/DX100. Electrophoretic mobility shift assay and Western blot analysis revealed that NF-kappaB in AML-2/DX100 was more activated with degradation of cytosolic IkappaBalpha than was that of AML-2/WT. cDNA microarray showed that Bfl-1/A1 and granzyme H in AML-2/DX100 were highly up-regulated (6.21-fold) and down-regulated (6.49-fold), respectively, as compared with each of AML-2/WT, which were confirmed by RT-PCR assay. Taken together, these results indicate that radioresistance mechanisms of AML-2/DX100 could be related to alterations in ROS-scavenging activity, in mitochondrial translocation of Bax and Bcl-2, and in expression of pro-apoptotic (granzyme H) and anti-apoptotic (Bfl-1/A1) genes. It has been shown that balance of p38 MAPK and NF-kappaB signals is a determinant in radiosensitivity of AML-2/WT and AML-2/DX100.
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PMID:Balance of NF-kappaB and p38 MAPK is a determinant of radiosensitivity of the AML-2 and its doxorubicin-resistant cell lines. 1721 10

In the present study, we investigated the effects of tetramethylpyrazine (TMP) on hydrogen peroxide (H2O2)-induced apoptosis in PC12 cells. The apoptosis in H2O2-induced PC12 cells was accompanied by a decrease in Bcl-2/Bax protein ratio, release of cytochrome c to cytosol and the activation of caspase-3. TMP not only suppressed the down-regulation of Bcl-2, up-regulation of Bax and the release of mitochondrial cytochrome c to cytosol, but also attenuated caspase-3 activation and eventually protected against H2O2-induced apoptosis. These results indicated that TMP blocked H2O2-induced apoptosis by the regulation of Bcl-2 family members, suppression of cytochrome c release, and caspase cascade activation in PC12 cells.
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PMID:Neuroprotective effects of tetramethylpyrazine on hydrogen peroxide-induced apoptosis in PC12 cells. 1732 Nov 70

Oxidative stress plays an important role in Alzheimer's disease and other neurodegenerative disorders. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L, shows potent antioxidant property. In this paper, the neuroprotective effects of salidroside on hydrogen peroxide (H2O2)-induced apoptosis in SH-SY5Y cells were investigated. Pretreatment with salidroside markedly attenuated H2O2-induced cell viability loss and apoptotic cell death in a dose-dependent manner. The mechanisms by which salidroside protected neuron cells from oxidative stress included the induction of several antioxidant enzymes, thioredoxin, heme oxygenase-1, and peroxiredoxin-I; the downregulation of pro-apoptotic gene Bax and the upregulation of anti-apoptotic genes Bcl-2 and Bcl-X(L). Furthermore, salidroside dose-dependently restored H2O2-induced loss of mitochondrial membrane potential as well as the elevation of intracellular calcium level. These results suggest that salidroside has protective effects against oxidative stress-induced cell apoptosis, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases implicated with oxidative stress.
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PMID:Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. 1734 19

BNip3 is a prominent representative of apoptotic Bcl-2 proteins with rather unique properties initiating an atypical programmed cell death pathway resembling both necrosis and apoptosis. Many Bcl-2 family proteins modulate the permeability state of the outer mitochondrial membrane by forming homo- and hetero-oligomers. The structure and dynamics of the homodimeric transmembrane domain of BNip3 were investigated with the aid of solution NMR in lipid bicelles and molecular dynamics energy relaxation in an explicit lipid bilayer. The right-handed parallel helix-helix structure of the domain with a hydrogen bond-rich His-Ser node in the middle of the membrane, accessibility of the node for water, and continuous hydrophilic track across the membrane suggest that the domain can provide an ion-conducting pathway through the membrane. Incorporation of the BNip3 transmembrane domain into an artificial lipid bilayer resulted in pH-dependent conductivity increase. A possible biological implication of the findings in relation to triggering necrosis-like cell death by BNip3 is discussed.
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PMID:Unique dimeric structure of BNip3 transmembrane domain suggests membrane permeabilization as a cell death trigger. 1741 96

The anti-apoptotic oncogene bcl-2 is hypothesized to increase the antioxidant status of cells, thereby protecting them from oxidative stress. In this study, we examined hydrogen peroxide (H2O2)-mediated oxidative stress in Jurkat T lymphoma cells. Over-expression of Bcl-2 did not inhibit cytotoxicity at doses of H2O2 that caused necrosis (>200 microM), but it did block cell death at apoptotic doses (<200 microM). However, these cells exhibited the same initial level of protein and lipid oxidation following exposure to H2O2 as the parental cells, indicating that the anti-apoptotic activity is not associated with general antioxidant properties. Bcl-2 expression was able to protect against secondary protein carbonyl formation, which was linked to lysosome stabilization. Assessment of micronuclei formation in cells over-expressing Bcl-2 showed evidence of increased genomic instability, consistent with the impairment of apoptosis in damaged cells. We conclude that while Bcl-2 can block cytotoxicity associated with apoptosis-inducing levels of oxidative stress, it does not protect the cells from the stress itself. Bcl-2 may promote tumourigenesis by preventing the removal of oxidatively damaged cells.
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PMID:Bcl-2 over-expression promotes genomic instability by inhibiting apoptosis of cells exposed to hydrogen peroxide. 1743 28

The combined effects of hyperthermia (44 degrees C, 20 min) or X-rays (10 Gy) and a new class of furan-fused tetracyclic synthesized compounds (DFs), on apoptosis in human lymphoma U937 cells were investigated. Among the tested compounds (DF1 approximately 6), the combined treatment of 10 microM DF with TIPS (triisopropylsilyloxy) (Designated #3 DF3) and hyperthermia showed the largest potency to induce DNA fragmentation at 6 h after hyperthermia but no enhancement was observed if it was combined with X-rays. Enhancement of hyperthermia-induced apoptosis by DF3 in a dose-dependent manner was observed. When the cells were treated first with DF3 at a nontoxic concentration of 20 microM, and exposed to hyperthermia afterwards, a significant enhancement of heat-induced apoptosis was evidenced by DNA fragmentation, morphological changes and phosphatidylserine externalization. The activation of Bid, but no change of Bax and Bcl-2 were observed after the combined treatment. The release of cytochrome c from mitochondria to cytosol, which was induced by hyperthermia, was enhanced by DF3. Mitochondrial transmembrane potential was decreased and the activation of caspase-3 and caspase-8 was enhanced in the cells treated with the combination. Externalization of Fas was observed following the combined treatment. Flow cytometry revealed rapid and sustained increase of intracellular superoxide due to DF3, and showed subsequent and transient increase in the formation of intracellular hydrogen peroxide (H(2)O(2)), which was further increased when hyperthermia was combined. These results indicate that the intracellular superoxide and H(2)O(2) generated by DF3 enhance the hyperthermia-induced apoptosis via the Fas-mediated mitochondrial caspase-dependent pathway.
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PMID:Enhancement of hyperthermia-induced apoptosis by a new synthesized class of furan-fused tetracyclic compounds. 1745 12

The cytotoxicity of andrographolide to HepG2 human hepatoma cells was investigated in the present study. Growth of HepG2 cells was affected in the presence of andrographolide with an IC(50) of 40.2 microM after 48 h treatment. Flow cytometric analysis and DNA fragmentation assay revealed that andrographolide induced cell cycle arrest at G2/M phase and a late apoptosis of the cells. The occurrence of cell cycle arrest was accompanied by the collapse of mitochondrial membrane potential (MMP) and an intracellular increase of hydrogen peroxide (H(2)O(2)) but a decrease of superoxide radicals (O(2)(-)) and reduced glutathione. In the treated cells, expression of Bax as well as the transcriptional controller of this pro-apoptotic gene, p53, was upregulated but not other apoptotic proteins such as Bad, Bcl-2 and Bcl-X(L). Although the activity of caspase-3, which has direct effect on apoptosis, was also enhanced by the presence of andrographolide, cell death of HepG2 could neither be prevented by a specific inhibitor of capsase-3 nor the pan-caspase inhibitor-zVAD (Val-Ala-Asp), indicating that it was a caspase-independent cell death. Since the overall percentage of apoptotic cells was relatively small throughout the experimental studies, we conclude that the cytotoxic effect of andrographolide on HepG2 cells is primary attributed to the induction of cell cycle arrest via the alteration of cellular redox status.
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PMID:Andrographolide induces cell cycle arrest at G2/M phase and cell death in HepG2 cells via alteration of reactive oxygen species. 1751 26


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