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)

Treatment of pancreatic cancer remains a major challenge and new anticancer drugs are urgently required. Our study presents the marine natural compound spongistatin 1 as a promising experimental drug. Spongistatin 1 was applied in an orthotopic in vivo model of human pancreatic cancer. Spongistatin 1 significantly reduced tumor growth, which correlates with a strong apoptosis induction (DNA-fragmentation) and long-term effects on clonogenic survival of pancreatic tumor cells (L3.6pl) in vitro. In addition, the formation of metastasis was reduced in spongistatin 1-treated mice, which is in line with a diminished MMP-9 activity in tumor tissue determined by zymography. Based on the pronounced efficacy of spongistatin 1, the underlying mechanisms were studied in more detail. In vitro adhesion, as well as migration, and invasion assays showed spongistatin 1 to influence these critical steps in the metastatic cascade. Furthermore, spongistatin 1 induced anoikis in L3.6pl cells. Exposure to spongistatin 1 leads to phosphorylation, and thus inactivation of the antiapoptotic protein Bcl-2 in pancreatic tumor cells. siRNA experiments silencing Bcl-2 suggest a role of Bcl-2 in anoikis and cell migration. Taken together, spongistatin 1 not only proved to be a potent experimental drug but also served as a chemical tool to examine the role of the antiapoptotic protein Bcl-2 in pancreas carcinoma, thereby supporting the hypothesis of a link between apoptosis signaling and metastasis.
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PMID:The marine compound spongistatin 1 targets pancreatic tumor progression and metastasis. 2014 89

The objective of this study was to evaluate molecular markers involved in mammary tumorigenesis in a canine model that mimics many essential elements of human breast cancer. Thirty mammary gland tumors and control tissues obtained from female dogs were included in the study. We analyzed changes in the expression of markers of hormone and receptor status (estradiol, estrogen receptor; ER and HER-2/neu), hormone metabolism (CYP1A1 and CYP1B1), cell proliferation and survival [proliferating cell nuclear antigen (PCNA), glutathione S-transferase-P (GST-P), nuclear factor-kappaB (NF-kappaB-p50, NF-kappaB-p65), phosphorylated-inhibitor of kappaB-alpha (p-IkappaB-alpha) and IkappaB], apoptosis (Bcl-2, Bax, caspases, Apaf-1, cytochrome-C, and PARP), invasion [matrix metalloproteinases-2 and -9 (MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and reversion-inducing cysteine-rich protein with Kazal motifs (RECK)], angiogenesis [vascular endothelial growth factor (VEGF)], and epigenetics [DNA methyltransferase (Dnmt-1), histone deacetylase (HDAC-1)] by immunohistochemical localization and Western blot analysis and correlated these with histological grade. The present study provides evidence that increased expression of ER, HER-2/neu, estradiol, and its metabolizing enzymes, as well as proteins involved in cell proliferation, apoptosis evasion, invasion, and angiogenesis may confer a selective growth advantage to canine mammary tumors. To our knowledge this is the first report on the hallmark capabilities of canine mammary tumors, which lends credence to the view that the dog is a valuable model for human breast cancer studies.
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PMID:Evaluation of molecular markers in canine mammary tumors: correlation with histological grading. 2022 57

Endothelial progenitor cells (EPC) play a fundamental role in tissue regeneration and vascular repair. Current research suggests that EPC are more resistant to oxidative stress as compared to differentiated endothelial cells. Here we hypothesized that EPC not only possess the ability to protect themselves against oxidative stress but also confer this protection upon differentiated endothelial cells by release of paracrine factors. To test this hypothesis, HUVEC incubated with conditioned medium obtained from early EPC cultures (EPC-CM) were exposed to H2O2 to assess the accumulation of intracellular ROS, extent of apoptosis and endothelial cell functionality. Under oxidative stress conditions HUVEC treated with EPC-CM exhibited substantially lower levels of intracellular oxidative stress (0.2+/-0.02 vs. 0.4+/-0.03 relative fluorescence units, p<0.05) compared to control medium. Moreover, the incubation with EPC-CM elevated the expression level of antioxidant enzymes in HUVEC (catalase: 2.6+/-0.4; copper/zinc superoxide dismutase (Cu/ZnSOD): 1.6+/-0.1; manganese superoxide dismutase (MnSOD): 1.4+/-0.1-fold increase compared to control, all p<0.05). Furthermore, EPC-CM had the distinct potential to reverse the functional impairment of HUVEC as measured by their capability to form tubular structures in vitro. Finally, incubation of HUVEC with EPC-CM resulted in a significant reduction of apoptosis (0.34+/-0.01 vs. 1.52+/-0.12 relative fluorescence units, p<0.01) accompanied by an increased expression ratio of the anti/pro-apoptotic factors Bcl-2/Bax to 2.9+/-0.7-fold (compared to control, p<0.05). Most importantly, neutralization of selected cytokines such as VEGF, HGF, IL-8 and MMP-9 did not significantly reverse the cyto-protective effect of EPC-CM (p>0.05), suggesting that soluble factors secreted by EPC, possibly via broad synergistic actions, exert strong cyto-protective properties on differentiated endothelium through modulation of intracellular antioxidant defensive mechanisms and pro-survival signals.
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PMID:Paracrine factors secreted by endothelial progenitor cells prevent oxidative stress-induced apoptosis of mature endothelial cells. 2022 93

Medulloblastoma (MB) is the most common malignant brain tumor in children. Bcl-2 and MMP-9 promote the pathogenesis and progression of MB. The expression of both bcl-2 and MMP-9 is regulated by the transcription factor NF-kappaB. Curcumin, a natural food additive, has a potent anti-proliferative effect, presumably mediated through NF-kappaB suppression. The tumor-suppressing effects of curcumin are well documented, however, its effect on MB is unknown. Our objectives were to: a) examine the effect of curcumin on MB cell proliferation and apoptosis; b) characterize the mechanism that mediates the effect of curcumin; c) examine the effects of curcumin on MB cell migration. We report that curcumin inhibited cell proliferation and blocked clonogenicity of MB cells. Furthermore, curcumin down-regulated bcl-2 and bcl(x)l, leading to caspase-mediated cell death. Finally, curcumin blocked migration of MB cells. Thus, we propose developing curcumin as a novel therapeutic agent for MB.
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PMID:Curcumin (diferuloylmethane) induces apoptosis and blocks migration of human medulloblastoma cells. 2033 61

As flavonoids, chalcones possess a wide variety of biological activities including anticancer properties. In the present study we have investigated the in vitro antiproliferative and antiangiogenic effects of four synthetic chalcones. E-2-(4'-methoxybenzylidene)-1-benzosuberone (3) was the most active compound with IC(50)=10(-7)mol l(-1) in Jurkat cells. In both Jurkat and HeLa chalcone 3-treated cells we found a significant increase in the proportion of cancer cells in the G(2)/M phase of the cell cycle as well as an increase in cells having sub-G(0)/G(1) DNA content which is considered to be a marker of apoptotic cell death. Apoptosis was also confirmed by annexin V staining and DNA fragmentation. These effects were associated with reduced expression of the anti-apoptotic gene, Bcl-2, and increased expression of the pro-apoptotic gene, Bax. Furthermore, chalcone 3 was selected to evaluate its effect on some angiogenic events. In non-toxic concentrations, chalcone 3 inhibited VEGF-induced migration of human umbilical vein endothelial cells. Moreover, it also decreased secretion of matrix metalloproteinase (mainly MMP-9) and vascular endothelial growth factor (VEGF). In conclusion, the present study has assessed the in vitro antiproliferative/antiangiogenic potential of chalcone 3. This results generate a rationale for in vivo efficacy studies with this compound in preclinical cancer models.
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PMID:In vitro antiproliferative and antiangiogenic effects of synthetic chalcone analogues. 2045 Sep 69

Few studies have evaluated the over or the underexpression of genes directly in samples of aneurysmal wall and extracranial pericranial vascular tissue to investigate the genetic influence in formation and rupture of intracranial aneurysms. We present the results obtained using the DNA microarray technique analysis on sample tissues collected during surgery. We collected and analyzed 12 aneurismal and 9 peripheral arteries (superficial temporal (STA) and middle meningeal artery (MMA) specimens from ruptured aneurysm group patients (13 cases), 10 aneurismal and 12 STA and MMA samples from unruptured aneurysm group patients (14 cases) and 5 STA and MMA artery specimens from control group patients (4 cases). Total RNA was isolated from samples and subjected to cDNA microarray analysis with the use of the human genome U133A GeneChip oligonucleotide microarray (Affymetrix, Santa Clara, CA), which allows to analyze a total number of 14,500 genes in the same time. For genes of interest, real-time RT-PCR was performed to confirm their expression level. Total RNA was isolated from samples and subjected to DNA microarray analysis with the use of the human genome U133A GeneChip oligonucleotide microarray, which allows to analyze a total number of 14,500 genes at the same time. For genes of interest, real-time RT-PCR was performed to confirm their expression level. Regarding ruptured aneurysms, genes were identified showing differential expressions (overexpressed or downregulated) pertaining to specific pathways, particularly those for the structural proteins of the extracellular matrix, members of matrix metalloproteinase (MMP) family (which resulted as being overexpressed) and genes involved in apoptotic phenomena. Particularly, real-time RT-PCR analysis confirmed the upregulation of MMP-2, MMP-9 and pro-apoptotic genes, such as Fas, Bax and Bid, and the downregulation of anti-apoptotic genes, such as Bcl-X(L) and Bcl-2. In a compared analyses of ruptured vs unruptured aneurysms, a different expression was also detected regarding gene coding the tissue inhibitor of matrix metalloproteinases 3 (TIMP-3), which appeared markedly downregulated in unruptured aneurysms, where its expression in unruptured aneurysms was similar to that observed in controls. Another gene differently expressed is nitric oxide synthase (iNOS), which appeared overexpressed in ruptured aneurysms when compared to unruptured aneurysms. Our study is the first, to our knowledge, that compares gene expression profiles (genoma-wide) in intracranial aneurysms. The results of our study suggest that the inhibitor of the metalloproteinase, the pathway of nitric oxide and the apoptotic process play a key-role in reducing the resistance of the arterial wall, that can result in formation and rupture of the intracranial aneurysms.
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PMID:Comparative evaluation of genome-wide gene expression profiles in ruptured and unruptured human intracranial aneurysms. 2048 32

Dauricine, a bioactive component of Asiatic Moonseed Rhizome, has been widely used to treat a large number of inflammatory diseases in traditional Chinese medicine. In our study, we demonstrated that dauricine inhibited colon cancer cell proliferation and invasion, and induced apoptosis by suppressing nuclear factor-kappaB (NF-kappaB) activation in a dose- and time-dependent manner. Addition of dauricine inhibited the phosphorylation and degradation of IkappaBalpha, and the phosphorylation and translocation of p65. Moreover, dauricine down-regulated the expression of various NF-kappaB-regulated genes, including genes involved cell proliferation (cyclinD1, COX2, and c-Myc), anti-apoptosis (survivin, Bcl-2, XIAP, and IAP1), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). In athymic nu/nu mouse model, we further demonstrated that dauricine significantly suppressed colonic tumor growth. Taken together, our results demonstrated that dauricine inhibited colon cancer cell proliferation, invasion, and induced cell apoptosis by suppressing NF-kappaB activity and the expression profile of its downstream genes. These findings provide evidence for a novel role of dauricine in preventing or treating colon cancer through modulation of NF-kappaB singling pathway.
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PMID:Dauricine induces apoptosis, inhibits proliferation and invasion through inhibiting NF-kappaB signaling pathway in colon cancer cells. 2050 40

Osteopontin (OPN) is widely overexpressed in various cancers, including gliomas, and plays an important role in tumorigenesis. However, the expression pattern and functions of OPN splice variants expressed in gliomas remain unclear. The aims of our current study were to examine the expression pattern and functions of OPN splice variants in gliomas. In present study, the mRNA levels of OPN splice variants are markedly increased in gliomas tissues, and all OPN splice variants were also found in U251 and U87 cells. Furthermore, knock-down and regain of function experiments were designed to explore the functions of OPN splice variants in U251 and U87 cells. Lentiviral vectors of OPN small interference RNA (siRNA) targeting all three endogenous mRNAs of OPN and OPN splice variants synonymous mutant that were not silenced by OPN siRNA were constructed. Our results showed that all OPN splice variants synonymous mutant-protected glioma cells from apoptosis induced by OPN siRNA through alteration of the levels of Bcl-2 family proteins and OPN-b Mu elicted a significant effect. Both OPN-a Mu and -c Mu promoted glioma cell invasion through alteration of the levels of uPA, MMP-2, and MMP-9 expressions and the activities of MMP-2 and MMP-9 via activation PI-3K/AKT/NF-kappaB signaling pathway. Moreover, OPN-c Mu showed the strongest effect on glioma cell invasion, while OPN-b Mu showed no effect on the invasion of U251 and U87 cells. Thus, different splice variants of OPN have divergent functions in regulating apoptosis and invasion of glioma cells, which broadens their importance in glioma biotherapy.
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PMID:Expression pattern of osteopontin splice variants and its functions on cell apoptosis and invasion in glioma cells. 2051 Nov 84

Crotepoxide (a substituted cyclohexane diepoxide), isolated from Kaempferia pulchra (peacock ginger), although linked to antitumor and anti-inflammatory activities, the mechanism by which it exhibits these activities, is not yet understood. Because nuclear factor kappaB (NF-kappaB) plays a critical role in these signaling pathways, we investigated the effects of crotepoxide on NF-kappaB-mediated cellular responses in human cancer cells. We found that crotepoxide potentiated tumor necrosis factor (TNF), and chemotherapeutic agents induced apoptosis and inhibited the expression of NF-kappaB-regulated gene products involved in anti-apoptosis (Bcl-2, Bcl-xL, IAP1,(2) MCl-1, survivin, and TRAF1), apoptosis (Bax, Bid), inflammation (COX-2), proliferation (cyclin D1 and c-myc), invasion (ICAM-1 and MMP-9), and angiogenesis (VEGF). We also found that crotepoxide inhibited both inducible and constitutive NF-kappaB activation. Crotepoxide inhibition of NF-kappaB was not inducer-specific; it inhibited NF-kappaB activation induced by TNF, phorbol 12-myristate 13-acetate, lipopolysaccharide, and cigarette smoke. Crotepoxide suppression of NF-kappaB was not cell type-specific because NF-kappaB activation was inhibited in myeloid, leukemia, and epithelial cells. Furthermore, we found that crotepoxide inhibited TAK1 activation, which led to suppression of IkappaBalpha kinase, abrogation of IkappaBalpha phosphorylation and degradation, nuclear translocation of p65, and suppression of NF-kappaB-dependent reporter gene expression. Overall, our results indicate that crotepoxide sensitizes tumor cells to cytokines and chemotherapeutic agents through inhibition of NF-kappaB and NF-kappaB-regulated gene products, and this may provide the molecular basis for crotepoxide ability to suppress inflammation and carcinogenesis.
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PMID:Crotepoxide chemosensitizes tumor cells through inhibition of expression of proliferation, invasion, and angiogenic proteins linked to proinflammatory pathway. 2749 62

Matrix metalloproteinases (MMPs) constitute a large family of enzymes that degrade extracellular matrix proteins (ECM). MMPs are implicated in different pathological conditions such as cancer. Bcl-2 and P53 are key controllers of programmed cell death (PCD) or apoptosis. The aim of the present study was to determine the MMP-9, P53 and Bcl-2 levels in Egyptian patients with Mycobacterium tuberculosis (MTB) (Group I) compared with healthy control individuals (Group II). The concentrations of serum MMP-9 were determined quantitatively using enzyme immunoassay (EIA). P53 and Bcl-2 levels were assayed by flow cytometric analysis using specific monoclones. MMP-9 level was significantly higher in MTB patients compared with healthy control. Similarly, P53 and Bcl-2 levels were increased in MTB patients compared with healthy ones. These data reflect the alteration of MMP-9 level during the course of MTB infection, accompanied with apparent dysregulation of cellular apoptosis as indicated by P53 and Bcl-2 over-expression.
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PMID:Pattern of matrix metalloproteinases-9, P53 and BCL-2 proteins in Egyptian patients with pulmonary Mycobacterium tuberculosis. 2058 85


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