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 aim of the present study was to examine the role of endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligand on the permeability and structure of small intestine tight junctions (TJs) in an animal model of experimental colitis, induced by dinitrobenzene sulfuric acid (DNBS). Four days after colitis induction with DNBS, the ileal TJs were studied by means of transmission electron microscopy using lanthanum nitrate and immunohistochemistry of occludin, zonula occludens 1, and claudin 2. Administration of DNBS to wild-type mice induced colon injury associated with a significant increase of plasma and colon tumor necrosis factor-alpha levels and with a significant increase of ileal permeability. Distal colitis in mice induced an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. Small intestinal permeability was associated with the presence of apoptosis (evaluated by FAS ligand expression and terminal deoxynucleotidyltransferase-mediated UTP nick end labeling coloration), which was associated with a significantly increased expression of proapoptotic Bax and decreased ileum content of antiapoptotic Bcl-2. Absence of a functional PPAR-alpha gene in PPAR-alpha knockout mice resulted in a significant augmentation of all the above-described parameters. Taken together, our results clearly demonstrate that endogenous PPAR-alpha ligands reduced small intestinal permeability in experimental colitis through the regulation of apoptosis and TJ protein.
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PMID:Absence of functional peroxisome proliferator-activated receptor-alpha enhanced ileum permeability during experimental colitis. 1751 53

Mitochondrial myopathy patients (MMPs) have impaired oxidative phosphorylation and exercise intolerance. Endurance training of MMPs improves exercise tolerance, but also increases mutational load. To assess the regulation of mitochondrial content in MMPs, we measured proteins involved in 1) biogenesis, 2) oxidative stress, and 3) apoptosis in MMPs and healthy controls (HCs) both before and after endurance training. Before training, MMPs had a greater mitochondrial content, along with a 1.4-fold (P < 0.05) higher expression of the biogenesis regulator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). The DNA repair enzyme 8-oxoguanine DNA glycolase-1 (OGG-1), the antioxidant manganese superoxide dismutase (MnSOD), and the apoptotic proteins AIF and Bcl-2 were higher in MMPs compared with HCs. Aconitase, an enzyme sensitive to oxidative stress, was 52% lower (P < 0.05) in MMPs when calculated based on an estimate of mitochondrial volume and oxidative stress-induced protein modifications tended to be higher in MMPs compared with HCs. Endurance training (ET) induced increases in mitochondrial content in both HC subjects and MMPs, but there was no effect of training on the regulatory proteins Tfam or PGC-1alpha. In MMPs, training induced a selective reduction of OGG-1, an increase in MnSOD, and a reduction in aconitase activity. Thus, before training, MMPs exhibited an adaptive response of nuclear proteins indicative of a compensatory increase in mitochondrial content. Following training, several parallel adaptations occurred in MMPs and HCs, which may contribute to previously observed functional improvements of exercise in MMPs. However, our results indicate that muscle from MMPs may be exposed to greater levels of oxidative stress during the course of training. Further investigation is required to evaluate the long-term benefits of endurance training as a therapeutic intervention for mitochondrial myopathy patients.
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PMID:The effect of training on the expression of mitochondrial biogenesis- and apoptosis-related proteins in skeletal muscle of patients with mtDNA defects. 1755 Oct 3

Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in 80% of non Hodgkin's lymphoma cells and are thought to play an important role in the resistance of lymphoma cells to current chemotherapeutic agents. Gossypol, an orally-active polyphenolic aldehyde derived from the cotton plant, has been known to have potential anti-neoplastic activity. Recently, gossypol was found to bind to the BH3 binding groove of Bcl-xL and with lesser affinity to Bcl-2. The present study was conducted to determine whether gossypol increases the sensitivity of non-Hodgkin's lymphoma cells to the actions of chemotherapeutic agents by potentiating treatment-induced apoptosis. The interactions observed between gossypol and chemotherapeutic drugs were analyzed using the median effect principle (CalcuSyn analysis). Our data showed that treatment of Ramos cells with gossypol not only induced cell arrest on the G(0)/G(1) phase, but also augmented apoptosis and growth inhibition induced by etoposide (VP-16), doxorubicin hydrochloride (ADM), vincristine (VCR), and paclitaxel (taxol). However, when gossypol was combined with cisplatin (DDP) an antagonistic effect was observed. Gossypol-induced cell cycle arrest was accompanied by decreased expression of cyclin D1 in Ramos cells. In addition, the peroxisome proliferator-activated receptor (PARP) pathway is, at least in part, involved in the gossypol-induced apoptosis when combined with VP-16. These data indicate that single-agent gossypol is effective in inhibiting growth of non-Hodgkin's lymphoma cells in vitro and combination studies with certain secondary chemotherapeutic agents further demonstrate it's synergistic cytotoxicity. These findings support future preclinical and clinical studies of gossypol in the treatment of non-Hodgkin's lymphoma.
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PMID:Synergistic cytotoxicity of Bcl-xL inhibitor, gossypol and chemotherapeutic agents in non-Hodgkin's lymphoma cells. 1834 25

In this study, we investigated the effects of continentalic acid (CA, (-)-pimara-8(14), 15-diene-19-oic acid), a diterpenic acid, isolated from Aralia continentalis, on the proliferation and apoptosis induction of HepG2 cells. In 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, the inhibitory effect became gradually stronger with the passage of time, 24, 48 and 72 h after treatment with CA, and the most significant effect was observed at 72 h. CA treatment for 72 h induced DNA fragmentation in a dose-dependent manner. Furthermore, flow cytometric analysis of HepG2 cells exposed to CA showed that apoptotic cells increased in a dose-dependent manner. The induction of apoptosis in HepG2 cells by CA was mediated through the activation of caspase-3, Bak, and Bax, and then through the cleavage of peroxisome proliferator-activated receptor (PARP) and the down-regulation of Bcl-2. These results demonstrate that CA efficiently induces apoptosis and is a good candidate for further evaluation as an effective chemotherapeutic agent.
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PMID:Continentalic acid from Aralia continentalis induces growth inhibition and apoptosis in HepG2 cells. 1880 61

To determine the involvement of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in cytoprotection, we subjected N2-A cells to oxygen-glucose deprivation followed by reoxygenation (H-R). Following H-R insults, H(2)O(2) production was increased while cell viability declined, which was accompanied by loss of mitochondrial membrane potential (MMP), cytochrome c release, caspases 9 and 3 activation, poly(ADP-ribose)polymerase (PARP) cleavage and apoptosis. Rosiglitazone up to 5 microM protected cell viability, normalized MMP, and prevented apoptotic signals. The protective effect of rosiglitazone was abrogated by GW9662, a PPAR-gamma antagonist, or a specific PPAR-gamma small interference RNA (siRNA) but not a control scRNA. PPAR-gamma overexpression alone was effective in maintaining MMP and preventing apoptosis and its protective effect was also abrogated by PPAR-gamma siRNA or GW9662. To elucidate the mechanism by which PPAR-gamma protects MMP and prevents apoptosis, we analyzed Bcl-2, Bcl-xl, and phosphorylated Bad (p-Bad). H-R suppressed them. Rosiglitazone or PPAR-gamma overexpression restored them via PPAR-gamma. Rosiglitazone or PPAR-gamma overexpression preserved phosphorylated Akt and 3-phosphoinositide-dependent kinase-1 (PDK-1) in a PPAR-gamma dependent manner. These results indicate that ligand-activated PPAR-gamma protects N2-A cells against H-R damage by enhancing Bcl-2/Bcl-xl and maintaining p-Bad via preservation of p-Akt.
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PMID:Rosiglitazone and PPAR-gamma overexpression protect mitochondrial membrane potential and prevent apoptosis by upregulating anti-apoptotic Bcl-2 family proteins. 1922 77

Among the carcinogenic chemicals of cigarette smoking, 4-(methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is the most potent. The activation of peroxisome proliferator-activated receptor (PPAR)gamma can arrest the growth of lung cancer. We hypothesized that PPARgamma activation inhibits NNK-mediated proliferation of lung cancer cells. PPARgamma expression was increased in 94.7% human lung cancer tumor tissues, compared with their paired corresponding nontumor tissues. PPARgamma was also found to be abundant in all the lung cancer cell lines tested. Troglitazone dose-dependently inhibited the NNK-mediated proliferation of lung cancer cells that expressed PPARgamma. Troglitazone blocked NNK-induced up-regulation of HO-1, Bcl-2, and c-IAP2, and recovered Bad activity that was suppressed by NNK. NNK promoted the nuclear p21, whereas troglitazone increased cytosolic p21. Troglitazone increased PPARgamma transcriptional activity in NNK-treated cells and a PPARgamma dominant-negative inhibitor completely suppressed the action of troglitazone, indicating that troglitazone against NNK was PPARgamma-dependent. The findings reveal a novel molecular pathway of PPARgamma activation against cigarette smoking-related lung cancer.
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PMID:PPARgamma activation extinguishes smoking carcinogen by inhibiting NNK-mediated proliferation. 1934 18

Aldosterone induces extracellular signal-regulated kinase (ERK)-dependent cardiac remodeling. Fenofibrate improves cardiac remodeling in adult rat ventricular myocytes (ARVM) partly via inhibition of aldosterone-induced ERK1/2 phosphorylation and inhibition of matrix metalloproteinases. We sought to determine whether aldosterone caused apoptosis in cultured ARVM and whether fenofibrate ameliorated the apoptosis. Aldosterone (1 microM) induced apoptosis by increasing terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei in ARVM. Spironolactone (100 nM), an aldosterone receptor antagonist, but not RU-486, a glucocorticoid receptor, inhibited aldosterone-mediated apoptosis, indicating that the mineralocorticoid receptor (MR) plays a role. SP-600125 (3 microM)-a selective inhibitor of c-Jun NH(2)-terminal kinase (JNK)-inhibited aldosterone-induced apoptosis in ARVM. Although aldosterone increased the expression of both stress-activated protein kinases, pretreatment with fenofibrate (10 microM) decreased aldosterone-mediated apoptosis by inhibiting only JNK phosphorylation and the aldosterone-induced increases in Bax, p53, and cleaved caspase-3 and decreases in Bcl-2 protein expression in ARVM. In vivo studies demonstrated that chronic fenofibrate (100 mg*kg body wt(-1)*day(-1)) inhibited myocardial Bax and increased Bcl-2 expression in aldosterone-induced cardiac hypertrophy. Similarly, eplerenone, a selective MR inhibitor, used in chronic pressure-overload ascending aortic constriction inhibited myocardial Bax expression but had no effect on Bcl-2 expression. Therefore, involvement of JNK MAPK-dependent mitochondrial death pathway mediates ARVM aldosterone-induced apoptosis and is inhibited by fenofibrate, a peroxisome proliferator-activated receptor (PPAR)alpha ligand. Fenofibrate mediates beneficial effects in cardiac remodeling by inhibiting programmed cell death and the stress-activated kinases.
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PMID:Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms. 1939 58

Borreria hispida (BHE), a weed of Rubiaceae family, is being used from time immemorial as an alternative therapy for diabetes. To evaluate the scientific background of using BHE as therapy to reduce cardiovascular risk, a group of rats were given BHE for a period of 30 days, whereas control animals were given the vehicle only. The animals were sacrificed, the hearts were isolated, and perfused with buffer. All the hearts were subjected to 30-minute ischemia followed by 2-hour reperfusion. Compared with vehicle-treated rats, BHE-treated rat hearts showed improved post-ischemic ventricular function and exhibited reduced myocardial infarct size and cardiomyocyte apoptosis. The level of cytochrome c expression and caspase 3 activation was also reduced. BHE elevated antiapoptotic proteins Bcl-2 and heme oxygenase-1 and stimulated the phosphorylation of survival protein Akt simultaneously decreasing the apoptotic proteins Bax and Src. In addition, BHE enhanced the protein expression of peroxisome proliferator-activated receptor-gamma, peroxisome proliferator-activated receptor-delta, and Glut-4, probably revealing the antiobese and antidiabetic potential of BHE. These results indicate that treatment with BHE improves cardiac function and ameliorates various risk factors associated with cardiac disease, suggesting that BHE can be considered as a potential plant-based nutraceutical and pharmaceutical agent for the management of cardiovascular diseases.
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PMID:Potential role of Borreria hispida in ameliorating cardiovascular risk factors. 1945 54

Restraint stress induces permeability changes in the small intestine, but little is known about the role of endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligand in the defects of the tight junction function. In the present study, we used PPAR-alpha knockout mice to understand the roles of endogenous PPAR-alpha on ileum altered permeability function in models of immobilization stress. The absence of a functional PPAR-alpha gene in PPAR-alpha knockout mice resulted in a significant augmentation of the degree of 1) TNF-alpha production in ileum tissues; 2) the alteration of zonula occludens-1, occludin, and beta-catenin (immunohistochemistry); and 3) apoptosis (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling staining, Bax, Bcl-2 expression). Taken together, our results demonstrate that endogenous PPAR-alpha ligands reduce the degree of tight junction permeability in the ileum tissues associated with immobilization stress, suggesting a possible role of endogenous PPAR-alpha ligands on ileum barrier dysfunction.
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PMID:Role of peroxisome proliferator-activated receptor-alpha in ileum tight junction alteration in mouse model of restraint stress. 1955 62

Helicobacter pylori deregulates the genes that control homeostasis between apoptosis and cell proliferation of gastric epithelial cells. Nuclear factor-kappaB (NF-kappaB) has an important role in H. pylori-induced apoptosis in gastric epithelial cells. The peroxisome proliferator-activated receptor-gamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) regulates growth and the signaling cascade in H. pylori-infected gastric epithelial cells. In the present study, we determined whether 15d-PGJ(2) inhibits apoptosis by regulating apoptotic gene expression and NF-kappaB activation in gastric epithelial cells infected with CagA+, VacA+H. pylori in a Korean isolate (HP99). 15d-PGJ(2) was found to inhibit H. pylori-induced DNA fragmentation and cell death. 15d-PGJ(2) induced downregulation of proapoptotic Bax and upregulation of antiapoptotic Bcl-2 as well as suppression of NF-kappaB activation caused by H. pylori in gastric epithelial cells. The results suggest that 15d-PGJ(2) inhibits apoptotic cell death by inhibiting NF-kappaB activation and apoptotic gene expression in gastric epithelial cells.
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PMID:15-Deoxy-delta 12, 14,-prostaglandin J2 suppresses nuclear factor-kappaB-mediated apoptosis of Helicobacter pylori-infected gastric epithelial cells. 1972 89


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