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 present study was to evaluate the effects of taspine isolated from Radix et Rhizoma Leonticsi on the growth and apoptosis of human umbilical vein endothelial cell (HUVEC) line by MTT and flow cytometer, respectively. At the same time, a series of changes were observed in HUVEC treated by taspine, including microstructure, protein expression of bax, bcl-2 and VEGF. The change of microstructure was observed by transmission electron microscope (TEM). The protein expression of bax and bcl-2 was detected by immunohistochemistry (IHC), and VEGF protein secreted was determined by enzyme-linked immunosorbent assay (ELISA). The results showed taspine could inhibit growth and induce apoptosis of HUVEC in a dose-dependent manner. Cell cycle was significantly stopped at the S phase. Under electronic microscope, the morphology of HUVEC treated with taspine showed nuclear karyopycnosis, chromatin agglutination and typical apoptotic body. Bcl-2 and VEGF expressions were decreased and bax expression was increased. All these results demonstrate that taspine has an inhibitory effect on growth of HUVEC and can induce its apoptosis.
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PMID:Taspine isolated from Radix et Rhizoma Leonticis inhibits growth of human umbilical vein endothelial cell (HUVEC) by inducing its apoptosis. 1797 67

This study was aimed to investigate the inhibitory effect of combined transfection of p53 and angiostatin (AS) genes on K562 cells and to explore its mechanism. pVTRIO2-hp53-hAS was transfected into K562 cells with lipofectamine 2000, RT-PCR was used to determine the expression of gene of interest in transfected cells, MTT growth curve and flow cytometry were used to analyze the cell cycle for observation biological changes of cells, the cellular immunochemistry assay was used to observe the expression differences between VEGF, Bcl-2 and Bax proteins. The results indicated that the genes of interest have been transfected and stably expressed, the increase of K562 with genes of interest was slower than that without genes of interest (p<0.05). And the increase of K562 in double gene group was slower than that in p53 and AS groups (0.264+/-0.011 at last day A290 nm; 0.652+/-0.039 at last day A290 nm; 0.604+/-0.017 at last day A290 nm respectively) (p<0.05). After transfection, the expressions of VEGF and Bcl-2 protein decreased, but the expressions of Bax increased. It is concluded that the combined transfection of p53 and AS genes into K562 cells shows more notable and powerful inhibition on proliferation than those transfected with single one gene. The synergistic mechanism of p53 and AS genes may be commonly influenced the pathway of Bcl-2 and Bax expression.
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PMID:[Inhibitory effect of combined transfection of p53 and AS genes on K562 cell proliferation]. 1808 60

Abnormalities in the STAT3 pathway are involved in the oncogenesis of several cancers. However, the mechanism by which dysregulated STAT3 signaling contributes to the progression of human colorectal cancer (CRC) has not been elucidated, nor has the role of JAK, the physiological activator of STAT3, been evaluated. To investigate the role of both JAK and STAT3 in CRC progression, we inhibited JAK with AG490 and depleted STAT3 with a SiRNA. Our results demonstrate that STAT3 and both JAK1 and 2 are involved in CRC cell growth, survival, invasion, and migration through regulation of gene expression, such as Bcl-2, p1(6ink4a), p21(waf1/cip1), p27(kip1), E-cadherin, VEGF, and MMPs. Importantly, the FAK is not required for STAT3-mediated regulation, but does function downstream of JAK. In addition, our data show that proteasome-mediated proteolysis promotes dephosphorylation of the JAK2, and consequently, negatively regulates STAT3 signaling in CRC. Moreover, immunohistochemical staining reveals that nuclear staining of phospho-STAT3 mostly presents in adenomas and adenocarcinomas, and a positive correlation is found between phospho-JAK2 immunoreactivity and the differentiation of colorectal adenocarcinomas. Therefore, our findings illustrate the biologic significance of JAK1, 2/STAT3 signaling in CRC progression and provide novel evidence that the JAK/STAT3 pathway may be a new potential target for therapy of CRC.
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PMID:Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. 1832 73

We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.
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PMID:Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas. 1832 52

beta-Catenin, the downstream target of glycogen synthase kinase-3beta (GSK-3beta), plays a vital role in ischemic preconditioning (IP)-mediated cardioprotection. In the present study, we investigated the mechanism of IP-mediated cardioprotection through suppression of beta-catenin expression by intramyocardial injection of adeno-sh-RNA against beta-catenin (BCT) (4 x 10(8) pfu). Adeno-LacZ (LZ) was used as control. The rats were randomized into (a) LZ + ischemia-reperfusion (IR); (b) LZIPIR; (c) BCTIR; and (d) BCTIPIR. Isolated hearts from each group were subjected to 30 min of I followed by 2 h of R. Both IPIR group hearts were subjected to IP (5 min I + 10 min R; four cycles) before IR. Significant reduction in left ventricular functional recovery (78 vs. 88 mm Hg), dp/dt(max) (1,802 vs. 2,189 mm Hg/sec), and aortic flow (4 vs. 9 ml/min) was observed in BCTIPIR compared with LZIPIR at 120 min of reperfusion. Increased infarct size (42 vs. 24%) and apoptotic cardiomyocytes (122 vs. 58 counts/60 HPF) were observed in BCTIPIR compared with LZIPIR. Realtime PCR and Western blot analysis showed significant downregulation in mRNA and protein expression of VEGF, Bcl-2, and survivin in BCTIPIR compared with LZIPIR. These findings indicated for the first time that silencing beta-catenin abolished IP-mediated cardioprotection, probably through inhibition of VEGF-Bcl-2 and survivin.
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PMID:Adeno-sh-beta-catenin abolishes ischemic preconditioning-mediated cardioprotection by downregulation of its target genes VEGF, Bcl-2, and survivin in ischemic rat myocardium. 1840 48

CNS neurons use robust cytoprotective mechanisms to ensure survival and functioning under conditions of injury. These involve pathways induced by endogenous neuroprotective cytokines such as erythropoietin (EPO). Recently, in contrast to its well known deleterious roles, TNF has also been shown to exhibit neuroprotective properties. In the present study, we investigated the molecular mechanisms by which TNF receptor (TNFR)I mediates neuroprotection by comparing the gene expression profiles of lesioned cortex from WT and TNFRI KO mice after permanent middle cerebral artery occlusion. Several known neuroprotective molecules were identified as TNFRI targets, notably members of the Bcl-2 family, DNA repair machinery and cell cycle, developmental, and differentiation factors, neurotransmitters and growth factors, as well as their receptors, including EPO receptor (EPOR), VEGF, colony-stimulating factor receptor 1, insulin-like growth factor (IGF), and nerve growth factor (NGF). Further analysis showed that induction of EPOR and VEGF expression in primary cortical neurons after glucose deprivation (GD) largely depended on TNFRI and was further up-regulated by TNF. Also, EPO- and VEGF-induced neuroprotection against GD, oxygen-glucose deprivation, and NMDA excitotoxicity depended significantly on TNFRI presence. Finally, EPO prevented neuronal damage induced by kainic acid in WT but not TNFRI KO mice. Our results identify cross-talk between tissue protective cytokines, specifically that TNFRI is necessary for constitutive and GD-induced expression of EPOR and VEGF and for EPO-mediated neuroprotection.
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PMID:TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury. 1841 1

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.
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PMID:Resveratrol: a multitargeted agent for age-associated chronic diseases. 1841 53

Transplantation of Bcl-2-transduced human umbilical vein endothelial cells (ECs) in protein gels into the gastrocnemius muscle improves local reperfusion in immunodeficient mouse hosts with induced hind limb ischemia. We tested the hypothesis that incorporation of local, sustained growth factor delivery could enhance and accelerate this effect. Tissue engineering scaffolds often use synthetic polymers to enable controlled release of proteins, but most synthetic delivery systems have major limitations, most notably hydrophobicity and inefficient protein loading. Here, we report the development of a novel alginate-based delivery system for vascular endothelial growth factor-A(165) (VEGF) that exhibits superior loading efficiency and physical properties to previous systems in vitro. In vivo, VEGF released from alginate microparticles within protein gels was biologically active and, when combined with EC transplantation, led to increased survival of transplanted cells at 28 days. The composite graft described also improved early (14 days) tissue perfusion and late (28 days) muscle myoglobin expression, a sign of recovery from ischemia, compared with EC transplantation and VEGF delivery separately. We conclude that our improved approach to sustained VEGF delivery in tissue engineering is useful in vivo and that the integration of high efficiency protein delivery enhances the therapeutic effect of protein gel-based EC transplantation.
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PMID:Engineering of multifunctional gels integrating highly efficient growth factor delivery with endothelial cell transplantation. 1845 Aug 13

Transforming growth factor (TGF)-beta1 has been reported to cause endothelial cell apoptosis. However, conflicting data have also demonstrated that TGF-beta1 promotes endothelial cell survival. In this study, the effect of TGF-beta1 on apoptosis of cultured bovine pulmonary artery endothelial cells (PAEC) induced by multiple stimuli was investigated. TGF-beta1 protected against apoptosis of bovine PAEC induced by serum deprivation or the VEGF receptor inhibitor SU-5416, but not by UV light exposure or TNFalpha. Neither caspase-8 nor caspase-12 was activated by serum deprivation or the VEGF receptor blocker. However, blockade of VEGF receptors activated caspase-9, an effect that was abolished by TGF-beta1. Furthermore, serum deprivation and inhibition of VEGF receptors significantly decreased the protein level of Bcl-2, an effect that was also abrogated by TGF-beta1. In addition, the baseline level of Bcl-2 was enhanced by TGF-beta1 and reduced by inhibition of activin receptor-like kinase 5 (ALK5), a TGF-beta1 type I receptor. Furthermore, inhibition of ALK5 caused apoptosis of bovine PAEC. These results suggest that TGF-beta1 signaling is critical for maintenance of bovine PAEC survival. Finally, the protective effects of TGF-beta1 on bovine PAEC apoptosis and Bcl-2 reduction were abolished by ALK5 inhibition, but not by inhibition of non-SMAD signaling pathways. Also, TGF-beta1 activated SMAD2 and SMAD1/5, an effect that was abolished by ALK5 inhibition. The results of this study suggest that TGF-beta1 protects against bovine PAEC apoptosis, possibly through ALK5-mediated Bcl-2 induction and subsequent inhibition of the mitochondria-mediated intrinsic pathway of apoptosis. Understanding the mechanism by which TGF-beta1 promotes endothelial cell survival may provide a better treatment for apoptosis-dependent vascular diseases, such as emphysema.
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PMID:Transforming growth factor-beta1 protects against pulmonary artery endothelial cell apoptosis via ALK5. 1845 97

Chemoprevention represents a promising strategy to reducing the incidence of prostate cancer which afflicts more than 240,000 males annually in the U.S. 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CCDO-Me) and C-28 imidazole (CDDO-Im) derivatives are synthetic oleanane triterpenoids that exhibit several-fold more potent antiinflammatory activity than naturally occurring oleanolic acid, but have not been investigated for prevention of the prostate. In order to evaluate the anticancer activity of CDDOs for prostate cancer, we have investigated the effect of synthetic oleanane triterpenoids on molecular targets relevant to the chemoprevention and treatment of prostate cancer in vitro in TRAMPC-1 cells derived from the primary tumor in the prostate of a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse. Data demonstrate that CDDOs strongly inhibit the proliferation of TRAMPC-1 cells with a potency order of CDDO-Me>CDDO-Im>CDDO. Because CDDO-Me showed the most growth inhibitory activity it was further analyzed for the anticancer activity. CDDO-Me induced apoptosis in TRAMPC-1 cells as shown by the increased binding of annexin V-FITC and cleavage of procaspases 3, -8, and -9. It effectively inhibited the molecular targets such as p-Akt, NF-kappaB, and p-mTOR and downstream effectors of mTOR (p-S6K1, cyclin-D1, and cdk4). Further, CDDO-Me inhibited NF-kappaB-regulated antiapoptotic Bcl-2, Bcl-xL, and XIAP and proangiogenic VEGF. Taken together, these data demonstrate that CDDO-Me is potentially a potent chemopreventive agent that inhibits several molecular targets that are known to play critical roles in the development and progression of prostate cancer.
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PMID:CDDO-Me inhibits proliferation, induces apoptosis, down-regulates Akt, mTOR, NF-kappaB and NF-kappaB-regulated antiapoptotic and proangiogenic proteins in TRAMP prostate cancer cells. 1847 40


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