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)

Alveolar macrophages (AMs) exposed to asbestos are well known to produce TNF-alpha, which induces the production of TGF-beta1, leading to lung fibrogenesis. The present study examines the production of TGF-beta1 by AMs exposed to chrysotile B asbestos (CH) in vivo or in vitro and the relationship between TGF-beta1 production and apoptosis in cultures of AMs. Rats instilled with CH via the trachea showed increases in TNF-alpha, IL-1beta and IL-6 in the bronchoalveolar lavage fluid (BALF) 1 day after the instillation, followed by increases in TGF-beta1 and apoptotic cells 5 days after. The AMs from these BALFs produced a significantly increased amount of TGF-beta1 in culture compared to those from the control rats. The addition of 2.5 mug/cm2 of CH augmented the production of TGF-beta1 by the AMs from the control to the same level as produced by the AMs from the CH-treated rats. The apoptosis of AMs was not induced at 2.5 microg/cm2 of CH, but was drastically induced at over 12.5 microg/cm2. In contrast, the production of TGF-beta1 by AMs peaked at around 2.5 microg/cm2 of CH, and it lasted for 11 days. In addition, Bcl-2 and Bcl-xL increased in the AMs surviving under the exposure to CH. Taken together, these results indicate that AMs can autonomously, without other pulmonary cells, acquire the lasting ability to produce TGF-beta1 independently of apoptosis under low exposure to CH. The AMs with the lasting production of TGF-beta1 may contribute not only to lung fibrosis but also to immune suppression.
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PMID:Long-lasting production of TGF-beta1 by alveolar macrophages exposed to low doses of asbestos without apoptosis. 1817 39

Apo2 ligand (Apo2L)/TRAIL induces apoptosis of cancer cells that express the specific receptors while sparing normal cells. Because the tumor microenvironment protects myeloma from chemotherapy, we investigated whether hemopoietic stroma induces resistance to Apo2L/TRAIL apoptosis in this disease. Apo2L/TRAIL-induced death was diminished in myeloma cell lines (RPMI 8226, U266, and MM1s) directly adhered to a human immortalized HS5 stroma cell line but not adhered to fibronectin. In a Transwell assay, with myeloma in the upper well and HS5 cells in the lower well, Apo2L/TRAIL apoptosis was reduced when compared with cells exposed to medium in the lower well. Using HS5 and myeloma patients' stroma-conditioned medium, we determined that soluble factor(s) produced by stroma-myeloma interactions are responsible for a reversible Apo2/TRAIL apoptosis resistance. Soluble factor(s) attenuated procaspase-8, procaspase-3, and poly(ADP-ribose) polymerase cleavage and diminished mitochondrial membrane potential changes without affecting Bcl-2 family proteins and/or Apo2L/TRAIL receptors. Soluble factor(s) increased the baseline levels of the anti-apoptotic protein c-FLIP in all cell lines tested. Inhibition of c-FLIP by means of RNA interference increased Apo2/TRAIL sensitivity in RPMI 8226 cells. Unlike direct adhesion to fibronectin, soluble factor(s) have no impact on c-FLIP redistribution within cellular compartments. Cyclohexamide restored Apo2L/TRAIL sensitivity in association with down-regulation of c-FLIP, suggesting that c-FLIP synthesis, not intracellular traffic, is essential for soluble factor(s) to regulate c-FLIP. Additionally, IL-6 conferred resistance to Apo2L/TRAIL-mediated apoptosis in association with increased c-FLIP levels. In conclusion, the immune cytotoxic effect of Apo2L/TRAIL can be restored at least in part by c-FLIP pathway inhibitors.
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PMID:Bone marrow stroma confers resistance to Apo2 ligand/TRAIL in multiple myeloma in part by regulating c-FLIP. 1820 50

Due to long-term toxicity of current Hodgkin's lymphoma (HL) treatment, the present challenge is to find new therapies that specifically target deregulated signaling cascades, including NF-kappaB, which are involved in Hodgkin (H) and Reed-Sternberg (RS) cell proliferation and resistance to apoptosis. We previously presented evidence that dimeric procyanidin B2 (B2) can interact with NF-kappaB proteins inhibiting the binding of NF-kappaB to DNA. Herein, we investigated if B2, acting at a late event in NF-kappaB signaling cascade, could be effective in inhibiting NF-kappaB in H-RS cells with different mechanisms of constitutive NF-kappaB activation. B2 caused a concentration-dependent inhibition of NF-kappaB-DNA binding to a similar extent (41-48% inhibition at 25 microM B2) in all the tested H-RS cell lines (L-428, KM-H2, L-540, L-1236 and HDML-2). This was associated with the inhibition of NF-kappaB-driven gene expression, including cytokines (IL-6, TNFalpha and RANTES) and anti-apoptotic proteins (Bcl-xL, Bcl-2, XIAP and cFLIP). The finding of similar amounts of RelA and p50 proteins in the nucleus, but decreased NF-kappaB-DNA binding, even in those H-RS cells characterized by mutations in the inhibitory IkappaB proteins, supports that B2 acts by preventing the binding of NF-kappaB to DNA. B2 did not inhibit AP-1 and STAT3 constitutive activation in H-RS cells, indicating that the moderate effects of B2 on cell viability are due to the complex signaling aberrations in HL. Thus, several signaling pathways should be targeted when designing therapeutics for HL. In this regard, the capacity of B2 to inhibit NF-kappaB could be valuable in a multi-drug approach.
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PMID:Dimeric procyanidin B2 inhibits constitutively active NF-kappaB in Hodgkin's lymphoma cells independently of the presence of IkappaB mutations. 1827 36

The regeneration and remodeling of the transplanted liver is the result of hepatocyte proliferation and apoptosis (programmed cell death). The purpose of this study was to verify the influence of immunosuppressants on the expression levels of genes: IL-6 (regulator of hepatocyte proliferation), pro-apoptotic (Bak and Bax) and anti-apoptotic (Bcl-Xl and Bcl-2). 36 newborn suckling rats (age 5-7 days, weight 6-10 g) were divided into four groups: hepatectomy, hepatectomy plus methylprednisolone, hepatectomy plus CsA and hepatectomy plus Tac. The same experiments were performed in 24 weaning rats (age 21-23 days, weight 30-50 g). The animals were killed one day after the hepatectomy and the remnant livers were analyzed. The livers of all animals exhibited histological changes of liver regeneration. The immunosuppressants did not promote any alteration on IL-6 gene expression levels. Methylprednisolone and CsA increased the expression levels of Bak gene in newborn rats. However, methylprednisolone and Tac promoted increased expression levels of Bcl-2 in all groups. We hypothesize that these effects explain the efficacy of these drugs on the treatment of acute and chronic liver rejection as the expression of Bcl-2 in cholangiocytes is decreased as a consequence of bile duct lesions
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PMID:Effect of the immunosuppressants on hepatocyte cells proliferation and apoptosis during liver regeneration after hepatectomy - molecular studies. 1832 Jun 11

Keeping in view the fact that a single acquired genetic abnormality "Bcr-Abl chimeric gene" accompanied by elevated telomerase activity has been widely recognized to be responsible for the leukemic myelopoiesis observed in chronic myeloid leukemia (CML), the present study was addressed to understand as to how selective and specific knock-down of human telomerase reverse transcriptase (hTERT) gene within mononuclear cells derived from untreated CML subjects could influence the apoptotic, genotypic (such as Bcr-Abl; C-myc; Bcl-2; IL-6; GMCSF; IL-3; and acetylated H(3) and H(4)), and phenotypic (such as CD34 and CD89) characteristics of these cells. Based upon these results, we propose that hTERT gene-based drug design may be useful in the treatment of leukemic myelopoiesis.
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PMID:Functional genomics of hTERT gene in leukemic myelopoiesis. 1840 31

Marek's disease (MD) is a lymphoproliferative disease of chickens that is caused by a highly cell-associated oncogenic alpha-herpesvirus, Marek's disease virus (MDV). The role of cytokines and other related proteins in MD pathogenesis and immunity is poorly understood. The aim of this study was to examine the transcriptional profiling of a panel of cytokines and other immune-related genes in the splenic tissues of chickens infected with a highly oncogenic strain of MDV during cytolytic infection and latency. Real-time polymerase chain reaction analysis revealed significant upregulation in the expression levels of interleukins (IL)-1beta, IL-4, IL-6, IL-10, IL-12p35, and IL-13, interferons (IFN)-1alpha, IFN-1beta, and IFN-gamma, chicken myelomonocytic growth factor (cMGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and inducible nitric oxide synthase (iNOS) in the infected chickens at 5 d post-inoculation (lytic infection). The changes in the mRNA levels of IL-18 and MHC I were minimal in comparison to those of the control birds. There was no significant difference in the expression levels of IL-2, IL-8, MHC II, Bcl-2, Bcl-x, and Nr-13 between the two groups. With the exception of IL-10, which showed high transcriptional activity beyond the lytic phase, the expression patterns of all the tested genes were similar between the infected and age-matched control birds at 15 d post-inoculation (latency infection). Of the genes examined, in addition to the high transcriptional activities of IL-1beta, IL-6, IL-12, iNOS, and type 1 and 2 IFNs, the relative expression levels of IL-4, IL-10, and IL-13 were significantly upregulated in the infected chickens during the lytic phase of infection compared to uninfected controls (a 9- to 50-fold difference). This observation suggests that (1) an immune response with a Th-2 characteristic is induced by a very virulent plus MDV strain during the lytic phase of infection; and (2) there is no significant MDV-specific immune response in the latent phase of infection.
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PMID:Marek's disease virus induces Th-2 activity during cytolytic infection. 1843 33

Domoic acid is a marine biotoxin associated with harmful algal blooms and is the causative agent of amnesic shellfish poisoning in marine animals and humans. It is also an excitatory amino acid analog to glutamate and kainic acid which acts through glutamate receptors eliciting a very rapid and potent neurotoxic response. The hippocampus, among other brain regions, has been identified as a specific target site having high sensitivity to DOM toxicity. Histopathology evidence indicates that in addition to neurons, the astrocytes were also injured. Electron microscopy data reported in this study further supports the light microscopy findings. Furthermore, the effect of DOM was confirmed by culturing primary astrocytes from the hippocampus and the brain stem and subsequently exposing them to domoic acid. The RNA was extracted and used for biomarker analysis. The biomarker analysis was done for the early response genes including c-fos, c-jun, c-myc, Hsp-72; specific marker for the astrocytes- GFAP and the glutamate receptors including GluR 2, NMDAR 1, NMDAR 2A and B. Although, the astrocyte-GFAP and c-fos were not affected, c-jun and GluR 2 were down-regulated. The microarray analysis revealed that the chemokines / cytokines, tyrosine kinases (Trk), and apoptotic genes were altered. The chemokines that were up-regulated included - IL1-alpha, IL-Beta, IL-6, the small inducible cytokine, interferon protein 10P-10, CXC chemokine LIX, and IGF binding proteins. The Bax, Bcl-2, Trk A and Trk B were all down-regulated. Interestingly, only the hippocampal astrocytes were affected. Our findings suggest that astrocytes may present a possible target for pharmacological interventions for the prevention and treatment of amnesic shellfish poisoning and for other brain pathologies involving excitotoxicity.
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PMID:Regional susceptibility to domoic acid in primary astrocyte cells cultured from the brain stem and hippocampus. 1864 70

We have previously demonstrated that cells of murine T-cell lymphoma, when grown in vivo or in vitro in an environment of high cell density, undergo phenotypic alterations, providing them with survival benefits. However, it is unclear whether the acquisition of such growth-related phenotypic alterations is inheritable in successive cell generations and if these alterations are associated with an irreversible alteration in their tumorigenic ability and evolution of multidrug resistance. To investigate this, tumor cells of a murine model of a T-cell lymphoma, designated as Dalton's lymphoma, and obtained from high and low cell density environment in vitro and in vivo, were transplanted in mice with or without the administration of anticancer drugs followed by analysis of their phenotypic properties and tumorigenic potential as measured by kinetics of tumor growth and survival of the tumor-bearing host. Kinetics of tumor progression was comparatively rapid in tumor-bearing mice transplanted with tumor cells from a high cell density environment, causing an early death of the host. Moreover, under these conditions the antitumor response of anticancer drugs, cisplatin, doxorubicin, and methotrexate, was found to be less effective compared with mice transplanted with tumor cells from a low cell density environment. The tumor cells from a high cell density source showed a long-term alteration in their survival properties both in vitro and in vivo, indicating that such alterations were sustainable over successive cell cycles. The study also discusses the possible mechanisms indicating the role of MDR1, Hsp70 and 90, Bcl-2, IL-1, IL-6, IL-10, IFNgamma, and TGFbeta in the evolution of multidrug resistance in tumor cells obtained from a high cell density environment.
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PMID:Cell density-dependent alterations in tumorigenic potential of a murine T-cell lymphoma: implication in the evolution of multidrug resistance in tumor cells. 1869 91

Hypothermia is a standard method for organ protection during cardiac surgery in children. However, the mechanisms of hypothermia-induced cell protection have not yet been clearly established. Therefore, the aim of our studies was to elucidate molecular effects of clinically relevant mild and deep hypothermia on endothelial cells. The endothelium plays a pivotal role in the interaction between blood cells and actively participates in complex inflammatory events. We isolated primary human umbilical vein endothelial cells (HUVEC) and investigated cell viability, proliferation and inflammatory characteristics after TNF-alpha stimulation under mild (32 degrees C) and deep (17 degrees C) hypothermia in comparison to normothermia (37 degrees C). As a protective mechanism of endothelial cells kept under hypothermic conditions we found a significant upregulation of the antiapoptotic protein Bcl-2, resulting in the same cell viability under hypothermic conditions. Unexpectedly we demonstrated significantly higher IL-6 release after 6h of mild hypothermia. In contrast, hypothermia diminished inflammatory chemokines such as IL-8, MCP-1 and COX-2 protein expression which could lead to reduced leukocyte recruitment under hypothermia. Underlying mechanisms of this downregulation were found to be reduced ERK 1/2 phosphorylation and incomplete IkappaB-alpha degradation resulting in reduced NFkappaB-dependent proinflammatory gene expression. The upregulation of Bcl-2 protein and the higher IL-6 release after 6h of mild hypothermia are new and interesting cellular mechanisms of hypothermia in endothelial cell biology. Both factors may play a major role as cell protective mechanisms in hypothermia.
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PMID:Hypothermia downregulates inflammation but enhances IL-6 secretion by stimulated endothelial cells. 1879 Jun 95

Recent studies have shown that increased lymphocyte apoptosis contributes to sepsis-induced mortality. Furthermore, studies have demonstrated that IL-10 can suppress lymphocyte apoptosis, in part, by upregulating Bcl-2 expression and interfering with activation induced cell death. We have previously shown that intrathymic delivery of IL-10 with an adenoviral vector in wild-type mice significantly improves outcome to sepsis. Presently, we investigated the role of endogenous IL-10 expression on thymocyte apoptosis and outcome in IL-10 null mice subject to induction of generalized polymicrobial peritonitis via cecal ligation and puncture. Compared to wild-type C57BL/6 mice, IL-10 null mice demonstrated increased mortality and enhanced lymphocyte apoptosis. Intrathymic injection with an adenoviral vector expressing human IL-10 prior to cecal ligation and puncture in IL-10 null mice significantly improved outcome and decreased thymic caspase-3 activity. Furthermore, plasma concentrations of IL-6 were also significantly reduced in IL-10 null mice treated with the IL-10 expressing adenovirus. In contrast, injection of a control adenovirus did not improve outcome in IL-10 null mice, nor was caspase-3 activity reduced. Thus, local thymic expression of IL-10 not only improves outcome but also reduces local tissue apoptosis and caspase-3 activity, and appears to attenuate the systemic proinflammatory cytokine response.
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PMID:Endogenous IL-10 regulates sepsis-induced thymic apoptosis and improves survival in septic IL-10 null mice. 1895 26


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