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1

Proteasome inhibitors induce peroxisome proliferator-activated receptor transactivation through RXR accumulation and a protein kinase C-dependent pathway  

SciTech Connect

Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a member of nuclear hormone receptors, forms a heterodimeric DNA binding complex with retinoid X receptor (RXR) and serves as a transcriptional regulator of gene expression. In this study, using luciferase assay of a reporter gene containing PPAR response element (PPRE), we found PPRE transactivity was additively induced by PPAR{gamma} activator (15dPGJ{sub 2}) and RXR activator (9-cis retinoic acid, 9-cis RA). Proteasome inhibitors MG132 and MG262 also stimulate PPRE transactivity in a concentration-dependent manner, and this effect is synergistic to 15dPGJ{sub 2} and 9-cis RA. PKC activation by 12-myristate 13-acetate (PMA) and ingenol 3,20-dibenzoate (IDB) also led to an increased PPRE activation, and this action was additive to PPAR{gamma} activators and 9-cis RA, but not to proteasome inhibitors. Results indicate that the PPAR{gamma} enhancing effect of proteasome inhibitors was attributed to redox-sensitive PKC activation. Western blot analysis showed that the protein level of RXR{alpha}, but not PPAR{gamma}, RXR{beta}, or PKC isoforms, was accumulated in the presence of proteasome inhibitors. Taken together, we conclude that proteasome inhibitors can upregulate PPRE activity through RXR{alpha} accumulation and a PKC-dependent pathway. The former is due to inhibition of RXR{alpha} degradation through ubiquitin-dependent proteasome system, while the latter is mediated by reactive oxygen species (ROS) production.

Tsao, W.-C. [Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Wu, H.-M. [Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Chi, K.-H. [Cancer Center, Veterans General Hospital, Taipei, Taiwan (China); Chang, Y.-H. [Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Lin, W.-W. [Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan (China)]. E-mail: wwl@ha.mc.ntu.edu.tw

2005-03-10

2

Inhibitor of DNA Binding 2 Is a Small Molecule-Inducible Modulator of Peroxisome Proliferator-Activated Receptor-? Expression and Adipocyte Differentiation  

PubMed Central

We previously identified the small molecule harmine as a regulator of peroxisome proliferator activated-receptor ? (PPAR?) and adipocyte differentiation. In an effort to identify signaling pathways mediating harmine’s effects, we performed transcriptional profiling of 3T3-F442A preadipocytes. Inhibitor of DNA biding 2 (Id2) was identified as a gene rapidly induced by harmine but not by PPAR? agonists. Id2 is also induced in 3T3-L1 preadipocytes treated with dexamethasone, 3-isobutyl-1-methylxanthine, and insulin, suggesting that Id2 regulation is a common feature of the adipogenic program. Stable overexpression of Id2 in preadipocytes promotes expression of PPAR? and enhances morphological differentiation and lipid accumulation. Conversely, small interfering RNA-mediated knockdown of Id2 antagonizes adipocyte differentiation. Mice lacking Id2 expression display reduced adiposity, and embryonic fibroblasts derived from these mice exhibit reduced PPAR? expression and a diminished capacity for adipocyte differentiation. Finally, Id2 expression is elevated in adipose tissues of obese mice and humans. These results outline a role for Id2 in the modulation of PPAR? expression and adipogenesis and underscore the utility of adipogenic small molecules as tools to dissect adipocyte biology.

Won Park, Kye; Waki, Hironori; Villanueva, Claudio J.; Monticelli, Laurel A.; Hong, Cynthia; Kang, Sona; MacDougald, Ormond A.; Goldrath, Ananda W.; Tontonoz, Peter

2008-01-01

3

Hydrogen peroxide generation in peroxisome proliferator-induced oncogenesis  

Microsoft Academic Search

Peroxisome proliferators are a structurally diverse group of non-genotoxic chemicals that induce predictable pleiotropic responses including the development of liver tumors in rats and mice. These chemicals interact variably with peroxisome proliferator-activated receptors (PPARs), which are members of the nuclear receptor superfamily. Evidence derived from mice with PPAR? gene disruption indicates that of the three PPAR isoforms (?, ?\\/? and

Anjana V Yeldandi; M. Sambasiva Rao; Janardan K Reddy

2000-01-01

4

Dysfunction of peroxisomes in twitcher mice brain: A possible mechanism of psychosine-induced disease  

SciTech Connect

Psychosine (galactosylsphingosine) accumulates in Brain of Krabbe disease (KD) patients as well as twitcher mice, a murine model of KD, resulting in loss of oligodendrocytes and myelin. This study documents progressive loss of peroxisomal proteins/functions and induction of expression of inflammatory cytokine TNF-{alpha} in twitcher brain. The observed decrease in peroxisomal proteins was accompanied by decreased level of peroxisome proliferator-activated receptor-alpha (PPAR-{alpha}), one of the transcription factors required for expression of peroxisomal protein genes. The role of psychosine in down-regulation of PPAR-{alpha} activity was further supported by decreased PPAR-{alpha} mediated PPRE transcriptional activity in cells transfected with PPAR-{alpha} and PPRE reporters. The psychosine-induced down-regulation of PPAR activity and cell death was attenuated by sPLA{sub 2} inhibitor. Therefore, this study provides First evidence of peroxisomal abnormality in a lysosomal disorder, suggesting that such dysfunction of peroxisomes may play a role in the pathogenesis of Krabbe disease.

Haq, Ehtishamul [Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425 (United States); Contreras, Miguel A. [Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425 (United States); Giri, Shailendra [Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425 (United States); Singh, Inderjit [Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425 (United States); Singh, Avtar K. [Department of Pathology and Laboratory Medicine, Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29425 (United States)]. E-mail: singha@musc.edu

2006-04-28

5

Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors.  

PubMed Central

Lipoxygenase (LOX) metabolites from arachidonic acid and linoleic acid have been implicated in atherosclerosis, inflammation, keratinocyte differentiation and tumour progression. We previously showed that peroxisome proliferator-activated receptors (PPARs) play a role in keratinocyte differentiation and that the PPARalpha ligand 8S-hydroxyeicosatetraenoic acid is important in this process. We hypothesized that blocking LOX activity would block PPAR-mediated keratinocyte differentiation. Three LOX inhibitors, nordihydroguaiaretic acid, quercetin and morin, were studied for their effects on primary keratinocyte differentiation and PPAR activity. All three LOX inhibitors blocked calcium-induced expression of the differentiation marker keratin 1. In addition, activity of a PPAR-responsive element was inhibited in the presence of all three inhibitors, and this effect was mediated primarily through PPARalpha and PPARgamma. LOX inhibitors decreased the activity of a chimaeric PPAR-Gal4-ligand-binding domain reporter system and this effect was reversed by addition of PPAR ligands. Ligand-binding studies revealed that the LOX inhibitors bind directly to PPARs and demonstrate a novel mechanism for these inhibitors in altering PPAR-mediated gene expression.

Thuillier, Philippe; Brash, Alan R; Kehrer, James P; Stimmel, Julie B; Leesnitzer, Lisa M; Yang, Peiying; Newman, Robert A; Fischer, Susan M

2002-01-01

6

Activation of Peroxisome Proliferator-Activated Receptor ?/? Induces Lung Cancer Growth via Peroxisome Proliferator-Activated Receptor Coactivator ?-1?  

PubMed Central

We previously demonstrated that a selective agonist of peroxisome proliferator–activated receptor ?/? (PPAR?/?), GW501516, stimulated human non–small cell lung carcinoma (NSCLC) growth, partly through inhibition of phosphatase and tensin homolog deleted on chromosome 10 expression. Here, we show that GW501516 also decreases the phosphorylation of AMP-activated protein kinase ? (AMPK?), a major regulator of energy metabolism. This was mediated through specific activation of PPAR?/?, as a PPAR?/? small interfering RNA inhibited the effect. However, AMPK? did not mediate the growth-promoting effects of GW501516, as silencing of AMPK? did not inhibit GW501516-induced cell proliferation. Instead, we found that GW501516 stimulated peroxisome proliferator–activated receptor coactivator ? (PGC)-1?, which activated the phosphatidylinositol 3 kinase (PI3-K)/Akt mitogenic pathway. An inhibitor of PI3-K, LY294002, had no effect on PGC-1?, consistent with PGC-1? being upstream of PI3-K/Akt. Of note, an activator of AMPK?, 5-amino-4-imidazole carboxamide riboside, inhibited the growth-promoting effects of GW501516, suggesting that although AMPK? is not responsible for the mitogenic effects of GW501516, its activation can oppose these events. This study unveils a novel mechanism by which GW501516 and activation of PPAR?/? stimulate human lung carcinoma cell proliferation, and suggests that activation of AMPK? may oppose this effect.

Han, ShouWei; Ritzenthaler, Jeffrey D.; Sun, XiaoJuan; Zheng, Ying; Roman, Jesse

2009-01-01

7

Hepatic peroxisomal and drug metabolizing activity in CD-1 mice after oral treatment with a novel 5-lipoxygenase inhibitor.  

PubMed

The effects of zileuton, a 5-lipoxygenase inhibitor, on hepatic peroxisomal enzyme activity as well as hepatic drug metabolizing activity in male and female CD-1 mice were assessed after oral administration of the drug (50, 150, or 450 mg/kg/day) for 14 days. The effects were compared to those in mice receiving clofibrate (CLOF;462 mg/kg/day, po) or sodium phenobarbital (PB; 50 mg/kg/day, po). Zileuton pretreatment caused hepatomegaly and elevated liver peroxisomal KCN-insensitive palmitoyl CoA oxidase activity in a dose-dependent manner. However, these changes were marginal (< or = 121% increase), when compared to those elicited by CLOF (approximately 370% increase). In both sexes, zileuton pretreatment also caused a dose-dependent increase in the levels of liver microsomal cytochrome P450 2B and cytochrome P450 4A (CYP4A) proteins, and their associated monoxygenase activity. In the case of CYP4A, the induction of lauric acid 12-hydroxylase activity by zileuton was more pronounced in female (maximal 851% increase) than in male mice (maximal 111% increase). Based on the dose normalized response observed in CD-1 mice, zileuton can be considered a relatively weak inducer of peroxisome enzyme activities (cf.CLOF) and a moderate inducer of cytochromes P450. Moreover, zileuton exhibits characteristics of both a PB- and a CLOF-type hepatic enzyme inducer, especially in the female mice. PMID:8661344

Rodrigues, A D; Machinist, J M

1996-04-01

8

Indole-3-butyric acid induces lateral root formation via peroxisome-derived indole-3-acetic acid and nitric oxide.  

PubMed

Controlled plant growth requires regulation through a variety of signaling molecules, including steroids, peptides, radicals of oxygen and nitrogen, as well as the 'classical' phytohormone groups. Auxin is critical for the control of plant growth and also orchestrates many developmental processes, such as the formation of new roots. It modulates root architecture both slowly, through actions at the transcriptional level and, more rapidly, by mechanisms targeting primarily plasma membrane sensory systems and intracellular signaling pathways. The latter reactions use several second messengers, including Ca(2+) , nitric oxide (NO) and reactive oxygen species (ROS). Here, we investigated the different roles of two auxins, the major auxin indole-3-acetic acid (IAA) and another endogenous auxin indole-3-butyric acid (IBA), in the lateral root formation process of Arabidopsis and maize. This was mainly analyzed by different types of fluorescence microscopy and inhibitors of NO production. This study revealed that peroxisomal IBA to IAA conversion is followed by peroxisomal NO, which is important for IBA-induced lateral root formation. We conclude that peroxisomal NO emerges as a new player in auxin-induced root organogenesis. In particular, the spatially and temporally coordinated release of NO and IAA from peroxisomes is behind the strong promotion of lateral root formation via IBA. PMID:23795714

Schlicht, Markus; Ludwig-Müller, Jutta; Burbach, Christian; Volkmann, Dieter; Baluska, Frantisek

2013-06-25

9

Activation of peroxisome proliferator-activated receptor beta/delta induces lung cancer growth via peroxisome proliferator-activated receptor coactivator gamma-1alpha.  

PubMed

We previously demonstrated that a selective agonist of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta), GW501516, stimulated human non-small cell lung carcinoma (NSCLC) growth, partly through inhibition of phosphatase and tensin homolog deleted on chromosome 10 expression. Here, we show that GW501516 also decreases the phosphorylation of AMP-activated protein kinase alpha (AMPKalpha), a major regulator of energy metabolism. This was mediated through specific activation of PPARbeta/delta, as a PPARbeta/delta small interfering RNA inhibited the effect. However, AMPKalpha did not mediate the growth-promoting effects of GW501516, as silencing of AMPKalpha did not inhibit GW501516-induced cell proliferation. Instead, we found that GW501516 stimulated peroxisome proliferator-activated receptor coactivator gamma (PGC)-1alpha, which activated the phosphatidylinositol 3 kinase (PI3-K)/Akt mitogenic pathway. An inhibitor of PI3-K, LY294002, had no effect on PGC-1alpha, consistent with PGC-1alpha being upstream of PI3-K/Akt. Of note, an activator of AMPKalpha, 5-amino-4-imidazole carboxamide riboside, inhibited the growth-promoting effects of GW501516, suggesting that although AMPKalpha is not responsible for the mitogenic effects of GW501516, its activation can oppose these events. This study unveils a novel mechanism by which GW501516 and activation of PPARbeta/delta stimulate human lung carcinoma cell proliferation, and suggests that activation of AMPKalpha may oppose this effect. PMID:18776129

Han, Shouwei; Ritzenthaler, Jeffrey D; Sun, Xiaojuan; Zheng, Ying; Roman, Jesse

2008-09-05

10

Salt Stress Causes Peroxisome Proliferation, but Inducing Peroxisome Proliferation Does Not Improve NaCl Tolerance in Arabidopsis thaliana  

Microsoft Academic Search

The PEX11 family of peroxisome membrane proteins have been shown to be involved in regulation of peroxisome size and number in plant, animals, and yeast cells. We and others have previously suggested that peroxisome proliferation as a result of abiotic stress may be important in plant stress responses, and recently it was reported that several rice PEX11 genes were up

Shiro Mitsuya; Mahmoud El-Shami; Imogen A. Sparkes; Wayne L. Charlton; Carine de Marcos Lousa; Barbara Johnson; Alison Baker; Michael V. Mickelbart

2010-01-01

11

Peroxisome proliferator-activated receptor ? confers resistance to peroxisome proliferator-activated receptor ?-induced apoptosis in colorectal cancer cells.  

PubMed

Peroxisome proliferator-activated receptor ? (PPAR?) may serve as a useful target for drug development in non-diabetic diseases. However, some colorectal cancer cells are resistant to PPAR? agonists by mechanisms that are poorly understood. Here, we provide the first evidence that elevated PPAR? expression and/or activation of PPAR? antagonize the ability of PPAR? to induce colorectal carcinoma cell death. More importantly, the opposing effects of PPAR? and PPAR? in regulating programmed cell death are mediated by survivin and caspase-3. We found that activation of PPAR? results in decreased survivin expression and increased caspase-3 activity, whereas activation of PPAR? counteracts these effects. Our findings suggest that PPAR? and PPAR? coordinately regulate cancer cell fate by controlling the balance between the cell death and survival and demonstrate that inhibition of PPAR? can reprogram PPAR? ligand-resistant cells to respond to PPAR? agonists. PMID:21765467

Wang, D; Ning, W; Xie, D; Guo, L; DuBois, R N

2011-07-18

12

Morphometric and cytochemical evaluation of clofibrate-induced peroxisomal proliferation in adult rat hepatocytes cultured on floating collagen gels  

Microsoft Academic Search

Summary  The present ultrastructural morphometric and cytochemical studies demonstrate clofibrate induced changes in peroxisomes in\\u000a adult rat hepatocytes maintained for 14 days in primary culture on floating collagen gels. Catalase activity and the number\\u000a and diameter of peroxisomes were reduced in hepatocytes cultured for between 2\\/3 and 7 days. However, hepatocytes cultured\\u000a for 7–14 days had well-developed peroxisomes containing crystalloid nucleoids.

Kazunori Furukawa; Yohichi Mochizuki; Norimasa Sawada; Mikio Gotoh; Hideyuki Tsukada

1988-01-01

13

Hepatic Peroxisomal and Drug Metabolizing Activity in CD1 Mice after Oral Treatment with a Novel 5Lipoxygenase Inhibitor  

Microsoft Academic Search

The effects of zileuton, a 5-lipoxygenase inhibitor, on hepatic peroxisomal enzyme activity as well as hepatic drug metabolizing activity in male and female CD-1 mice were assessed after oral administration of the drug (50, 150, or 450 mg\\/kg\\/day) for 14 days. The effects were compared to those in mice receiving clofibrate (CLOF; 462 mg\\/kg\\/day, po) or sodium phenobarbital (PB; 50

A. David Rodrigues; Joseph M. Machinist

1996-01-01

14

Lipid accumulation in the livers of chlorpromazine-treated rats does not induce peroxisome proliferation.  

PubMed

Treatment of rats with 25 mg/kg/day of the neuroleptic drug chlorpromazine for periods of 7, 28 or 90 days causes a slow accumulation of lipid in large droplets in centrilobular hepatocytes. There is little or no damage to hepatocytes as assessed by changes in glucose-6-phosphatase activity and by electron microscopy. Furthermore there is no indication of a change in peroxisomal beta-oxidation of fatty acids or in microsomal omega-oxidation of fatty acids. It is, therefore, clear that lipid accumulation in the liver does not automatically induce peroxisomal and microsomal fatty acid oxidising enzymes. PMID:2986319

Price, S C; Hall, D E; Hinton, R H

1985-04-01

15

Peroxisome Proliferator-Activated Receptor ? Induces Pancreatic Cancer Cell Apoptosis  

Microsoft Academic Search

Peroxisome proliferator-activated receptor gamma (PPAR-?) decreases the growth of certain cancer cells. In the present study, we found that six different human pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-2, HPAF-II, MIA PaCa-2, and PANC-1) expressed PPAR-? m-RNA and synthesized the protein. The endogenous and exogenous PPAR-? ligands 15-deoxy-d12,14-prostaglandin J2 (15-PGJ2) and ciglitazone decreased cell number, cell viability, and increased floating\\/attached

Guido Eibl; Moritz N. Wente; Howard A. Reber; Oscar J. Hines

2001-01-01

16

Visfatin is induced by peroxisome proliferator-activated receptor gamma in human macrophages  

PubMed Central

Obesity is a low grade chronic inflammatory disease associated with an increased number of macrophages (ATM) in adipose tissue. Within the adipose tissue, ATM are the major source of visfatin/PBEF/NAMPT. The nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)? exerts anti-inflammatory effects in macrophages by inhibiting cytokine production and enhancing alternative differentiation. In this study, we investigated whether PPAR? modulates visfatin expression in murine (BMDM) and human (RM, M1, M2, ATM) macrophage models and preadipocyte-derived adipocytes. We show that synthetic PPAR? ligands increased visfatin gene expression in a PPAR?-dependent manner in primary human macrophages (RM) and ATM, but not in adipocytes. The increase of visfatin mRNA (3-fold) was paralleled by an increase of protein expression (30%) and secretion (30%). Electrophoretic Mobility Shift Assay (EMSA) experiments and transient transfection assays indicated that PPAR? induces visfatin promoter activity in human macrophages by binding to a DR1-PPAR? response element. Finally, we show that PPAR? ligands increase NAD+ production in primary human macrophages and this regulation is dampened in the presence of visfatin siRNA or by the visfatin-specific inhibitor FK866. Taken together, our results suggest that PPAR? regulates the expression of visfatin in macrophages leading to increased NAD+ levels.

Mayi, Therese Hervee; Duhem, Christian; Copin, Corinne; Bouhlel, Mohamed Amine; Rigamonti, Elena; Pattou, Francois; Staels, Bart; Chinetti-Gbaguidi, Giulia

2010-01-01

17

Rosiglitazone, peroxisome proliferator receptor-gamma agonist, ameliorates gentamicin-induced nephrotoxicity in rats  

Microsoft Academic Search

Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe gram-negative\\u000a infections. Reactive oxygen spaces (ROS) are important mediators of gentamicin-induced nephrotoxicity. Peroxisome proliferator-activated\\u000a receptors (PPARs) have different activities including antioxidant properties. This study was performed to investigate the\\u000a protective role of PPAR-? agonist against GEN-induced nephrotoxicity. Male Wistar Albino rats were randomly

Emin Ozbek; Yusuf Ozlem Ilbey; Abdulmuttalip Simsek; Mustafa Cekmen; Fatih Mete; Adnan Somay

2010-01-01

18

Peroxisome Proliferator-Activated Receptor g-Dependent Repression of the Inducible Nitric Oxide Synthase Gene  

Microsoft Academic Search

The peroxisome proliferator-activated receptor g (PPARg) is a member of the nuclear receptor superfamily that activates target gene transcription in a ligand-dependent manner. In addition, liganded PPARg can inhib- it transcription of genes induced by gamma interferon (IFN-g) and\\/or lipopolysaccharides (LPSs), including the inducible nitric oxide synthase (iNOS) gene. Inhibition of the iNOS promoter is achieved partially through an- tagonizing

MEI LI; GABRIEL PASCUAL; CHRISTOPHER K. GLASS

2000-01-01

19

Peroxisome proliferators induce apoptosis and decrease DNA synthesis in hepatoma cell lines.  

PubMed

We examined the effects of various peroxisome proliferators (PPs) such as the hypolipidaemic agents clofibric acid (CLO), bezafibrate (BEZA), ciprofibrate (CIPRO) and nafenopin (NAFE) and the plasticizer di-(2-ethylhexyl)phthalate (DEHP) on peroxisomal enzyme activities, apoptosis and DNA synthesis in rat FaO and human HepG2 hepatoma cell lines. Both growing and confluent cultures were treated with PPs (250 microM) for 48 or 72 h. In accordance with our previous observations in PP-treated primary hepatocyte cultures of rat and human origin, the various PPs increased peroxisomal enzyme activities in rat FaO cells but not in human HepG2 cells. PPs strongly induced apoptosis in FaO cells. They did not affect TGFbeta-induced apoptosis, with the exception of DEHP and NAFE, respectively blocking and increasing induced apoptosis in confluent cultures. Moreover, PPs produced a minor, but significant, decrease in DNA synthesis in FaO cells. PPs also decreased DNA synthesis in growing HepG2 cells, and CLO, CIPRO and NAFE induced apoptosis in confluent HepG2 cultures. This is in opposition with the effects of PPs on primary hepatocyte cultures, i.e. inhibition of both spontaneous and TGFbeta-induced apoptosis and increases in DNA synthesis in rat hepatocytes, and unchanged mitosis-apoptosis balance in human hepatocytes. PMID:10889518

Goll, V; Viollon-Abadie, C; Nicod, L; Richert, L

2000-03-01

20

Interferon-gamma-induced regulation of peroxisome proliferator-activated receptor gamma and STATs in adipocytes.  

PubMed

Interferon-gamma (IFN-gamma) is known primarily for its roles in immunological responses but also has been shown to affect fat metabolism and adipocyte gene expression. To further investigate the effects of IFN-gamma on fat cells, we examined the effects of this cytokine on the expression of adipocyte transcription factors in 3T3-L1 adipocytes. Although IFN-gamma regulated the expression of several adipocyte transcription factors, IFN-gamma treatment resulted in a rapid reduction of both peroxisome proliferator-activated receptor (PPAR) protein and mRNA. A 48-h exposure to IFN-gamma also resulted in a decrease of both CCAAT/enhancer-binding alpha and sterol regulatory element binding protein (SREBP-1) expression. The short half-life of both the PPARgamma mRNA and protein likely contributed to the rapid decline of both cytosolic and nuclear PPARgamma in the presence of IFN-gamma. Our studies clearly demonstrated that the IFN-gamma-induced loss of PPARgamma protein is partially inhibited in the presence of two distinct proteasome inhibitors. Moreover, IFN-gamma also inhibited the transcription of PPARgamma, which was accompanied by a decrease in PPARgamma mRNA accumulation. In addition, exposure to IFN-gamma resulted in a substantial increase in STAT 1 expression and a small increase in STAT 3 expression. IFN-gamma treatment of 3T3-L1 adipocytes (48-96 h) resulted in a substantial inhibition of insulin-sensitive glucose uptake. These data clearly demonstrate that IFN-gamma treatment results in the development of insulin resistance, which is accompanied by the regulation of various adipocyte transcription factors, in particular the synthesis and degradation of PPARgamma. PMID:11106650

Waite, K J; Floyd, Z E; Arbour-Reily, P; Stephens, J M

2000-12-05

21

Degradation and turnover of peroxisomes in the yeast Hansenula polymorpha induced by selective inactivation of peroxisomal enzymes  

Microsoft Academic Search

Inactivation of peroxisomal enzymes in the yeast Hansenula polymorpha was studied following transfer of cells into cultivation media in which their activity was no longer required for growth. After transfer of methanol-grown cells into media containing glucose — a substrate that fully represses alcohol oxidase synthesis — the rapid inactivation of alcohol oxidase and catalase was paralleled by a disappearance

Marten Veenhuis; Anneke Douma; Wim Harder; Masako Osumi

1983-01-01

22

Expression of bax in lung cancer cell apoptosis induced by peroxisome proliferator-activated receptor-? agonists  

Microsoft Academic Search

Objective  To discuss the relationship between Bax expression level and lung cancer cell apoptosis induced by peroxisome proliferator-activated\\u000a receptor-? (PPAR-?) agonists.\\u000a \\u000a \\u000a \\u000a Methods  RT-PCR and Western blot analysis were used to detect PPAR-? expression in the lung cancer cells, and TUNEL was used to detect\\u000a apoptosis induced by PPAR-? agonists, while in situ hybridization and immunohistochemistry were used to monitor the changes\\u000a of

Zhang Min; Zou Ping; Bai Ming; Jin Yang; Guo Rong; Tao Xiaolan; He Wei

2002-01-01

23

Gene expression for peroxisome-associated enzymes in hepatocellular carcinomas induced by ciprofibrate, a hypolipidemic compound  

SciTech Connect

Administration of hypolipidemic compounds leads to marked proliferation of peroxisomes and peroxisome-associated enzymes (PAE) in the livers of rodents and non-rodent species. The increase peroxisome-associated enzymes such as fatty acid ..beta..-oxidation system and catalase is shown to be due to an increase in the levels of mRNA. In this experiment they have examined hepatocellular carcinomas (HCC), induced in male F-344 rats by ciprofibrate (0.025%, w/w for 60 weeks), for gene expression of PAE. Total RNA was purified from HCC as well as from control and ciprofibrate (0.025% for 2 weeks) fed rat livers. Northern blot analysis was performed using (32/sub p/)cDNA probes for albumin, fatty acetyl-CoA oxidase, enoyl-CoA hydratase 3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme and catalase. mRNA levels in HCC for albumin, fatty acid ..beta..-oxidation enzymes and catalase were comparable with those levels observed in the livers of rats given ciprofibrate for 2 weeks. In control livers the mRNAs for ..beta..-oxidation enzymes were low. Albumin mRNA levels in all the 3 groups were comparable. Additional studies are necessary to determine whether the increased level of mRNAs for the ..beta..-oxidation enzymes in HCC is due to the effect of ciprofibrate or to the gene amplification.

Rao, M.S.; Nemali, M.R.; Reddy, J.K.

1986-03-05

24

Inhibitors of the Arachidonic Acid Pathway and Peroxisome Proliferator-Activated Receptor Ligands Have Superadditive Effects on Lung Cancer Growth Inhibition  

Microsoft Academic Search

Arachidonic acid (AA) metabolizing enzymes and peroxisome proliferator-activated receptors (PPARs) have been shown to regulate the growth of epithelial cells. We have previously reported that exposure to the 5-lipoxygenase activating protein-directed inhibitor MK886 but not the cyclooxygenase inhibitor, indomethacin, reduced growth, increased apoptosis, and up-regulated PPARA and ; expression in breast cancer cell lines. In the present study, we explore

Ingalill Avis; Alfredo Martinez; Jordi Tauler; Enrique Zudaire; Anatoly Mayburd; Raed Abu-Ghazaleh; Frank Ondrey; James L. Mulshine

2005-01-01

25

Dysfunctional lysosomal autophagy leads to peroxisomal oxidative burnout and damage during endotoxin-induced stress.  

PubMed

Mammalian peroxisomes are ubiquitous organelles that possess a comprehensive ensemble of more than 50 enzymes. Cells regulate the number of organelles through dynamic interplay between biogenesis and degradation. Under basal conditions, approximately 30% of the peroxisomal pool is turned over daily. Recycling of peroxisomes is necessary for preservation of their functional competence, and correctly functioning autophagic/lysosomal pathways play a central role. In this study, we investigated (1) how lipopolysaccharide (LPS) influences peroxisomal dynamics and functions; and (2) how a superimposed lysosomal dysfunction affects pexophagy and modifies peroxisomal responses to LPS. We demonstrated that a transiently increased autophagic degradation of peroxisomes, pexophagy, followed by increased proliferation of peroxisomes is a default response to endotoxic stress. Impairment of autophagy due to lysosomal dysfunction, however, abolishes the above peroxisomal dynamics and results in accumulation of functionally compromised peroxisomes. These exhibit an imbalance between preserved hydrogen peroxide (H 2O 2)-generating acyl-CoA oxidase (ACOX) and dysfunctional/inactivated catalase (CAT), which leads to intra-peroxisomal redox disequilibrium. This metabolic-oxidative mismatch causes further worsening of peroxisomal functions, peroxisomal burnout, with the consequence of enhanced oxidative stress and aggravated organ injury. PMID:23328407

Vasko, Radovan; Goligorsky, Michael S

2013-01-17

26

Peroxisome proliferator-activated receptor {alpha} agonist-induced down-regulation of hepatic glucocorticoid receptor expression in SD rats  

SciTech Connect

It was reported that glucocorticoid production was inhibited by fenofibrate through suppression of type-1 11{beta}-hydroxysteroid dehydrogenase gene expression in liver. The inhibition might be a negative-feedback regulation of glucocorticoid receptor (GR) activity by peroxisome proliferator-activated receptor alpha (PPAR{alpha}), which is quickly induced by glucocorticoid in the liver. However, it is not clear if GR expression is changed by fenofibrate-induced PPAR{alpha} activation. In this study, we tested this possibility in the liver of Sprague-Dawley rats. GR expression was reduced by fenofibrate in a time- and does-dependent manner. The inhibition was observed in liver, but not in fat and muscle. The corticosterone level in the blood was increased significantly by fenofibrate. These effects of fenofibrate were abolished by PPAR{alpha} inhibitor MK886, suggesting that fenofibrate activated through PPAR{alpha}. In conclusion, inhibition of GR expression may represent a new molecular mechanism for the negative feedback regulation of GR activity by PPAR{alpha}.

Chen Xiang; Li Ming; Sun Weiping; Bi Yan; Cai Mengyin; Liang Hua; Yu Qiuqiong; He Xiaoying [Department of Endocrinology, Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, Guang Dong 510630 (China); Weng Jianping [Department of Endocrinology, Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, Guang Dong 510630 (China)], E-mail: wjianp@mail.sysu.edu.cn

2008-04-18

27

Activation of Peroxisome Proliferator-activated Receptor ? (PPAR?) Suppresses Hypoxia-inducible Factor-1? (HIF-1?) Signaling in Cancer Cells*  

PubMed Central

Activation of peroxisome proliferator-activated receptor ? (PPAR?) has been demonstrated to inhibit tumor growth and angiogenesis, yet the mechanisms behind these actions remain to be characterized. In this study, we examined the effects of PPAR? activation on the hypoxia-inducible factor-1? (HIF-1?) signaling pathway in human breast (MCF-7) and ovarian (A2780) cancer cells under hypoxia. Incubation of cancer cells under 1% oxygen for 16 h significantly induced HIF-1? expression and activity as assayed by Western blotting and reporter gene analysis. Treatment of the cells with PPAR? agonists, but not a PPAR? agonist, prior to hypoxia diminished hypoxia-induced HIF-1? expression and activity, and addition of a PPAR? antagonist attenuated the suppression of HIF-1? signaling. Activation of PPAR? attenuated hypoxia-induced HA-tagged HIF-1? protein expression without affecting the HA-tagged HIF-1? mutant protein level, indicating that PPAR? activation promotes HIF-1? degradation in these cells. This was further confirmed using proteasome inhibitors, which reversed PPAR?-mediated suppression of HIF-1? expression under hypoxia. Using the co-immunoprecipitation technique, we found that activation of PPAR? enhances the binding of HIF-1? to von Hippel-Lindau tumor suppressor (pVHL), a protein known to mediate HIF-1? degradation through the ubiquitin-proteasome pathway. Following PPAR?-mediated suppression of HIF-1? signaling, VEGF secretion from the cancer cells was significantly reduced, and tube formation by endothelial cells was dramatically impaired. Taken together, these findings demonstrate for the first time that activation of PPAR? suppresses hypoxia-induced HIF-1? signaling in cancer cells, providing novel insight into the anticancer properties of PPAR? agonists.

Zhou, Jundong; Zhang, Shuyu; Xue, Jing; Avery, Jori; Wu, Jinchang; Lind, Stuart E.; Ding, Wei-Qun

2012-01-01

28

Peroxisome proliferator-activated receptor y (PPARy) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis  

Microsoft Academic Search

Objective: Activation of peroxisome proliferator-activated receptor a (PPARa) and PPARg plays beneficial roles in cardiovascular disorders such as atherosclerosis and heart reperfusion. Although PPARa and g have been documented to reduce oxidative stress in the vasculature and the heart, the role of PPARy remains poorly studied. Methods and results: We focused on PPARy function in the regulation of oxidative stress-induced

Matthieu Pesant; Stephanie Sueur; Patrick Dutartre; Mireille Tallandier; Paul A. Grimaldi; Luc Rochette; Jean-Louis Connat

2006-01-01

29

Activation of Peroxisome Proliferator-Activated Receptor-? Reverses Squamous Metaplasia and Induces Transitional Differentiation in Normal Human Urothelial Cells  

PubMed Central

We observed that in urothelium, both cornifying and noncornifying forms of squamous metaplasia are accompanied by changes in the localization of the nuclear hormone receptors, peroxisome proliferator activated receptor ? (PPAR-?) and retinoid X receptor (RXR-?). To obtain objective evidence for a role for PPAR-?-mediated signaling in urothelial differentiation, we examined expression of the cytokeratin isotypes CK13, CK20, and CK14 as indicators of transitional, terminal transitional, and squamous differentiation, respectively, in cultures of normal human urothelial cells. In control culture conditions, normal human urothelial cells showed evidence of squamous differentiation (CK14+, CK13?, CK20?). Treatment with the high-affinity PPAR-? agonist, troglitazone (TZ), resulted in gain of CK13 and loss of CK14 protein expression. The effect of TZ was significantly augmented when the autocrine-stimulated epidermal growth factor receptor pathway was inhibited and this resulted in induction of CK20 expression. The RXR-specific inhibitors PA452, HX531, and HX603 inhibited the TZ-induced CK13 expression, supporting a role for RXR in the induction of CK13 expression. Thus, signaling through PPAR-? can mediate transitional differentiation of urothelial cells and this is modulated by growth regulatory programs.

Varley, Claire Lucy; Stahlschmidt, Jens; Smith, Barbara; Stower, Michael; Southgate, Jennifer

2004-01-01

30

Calcium induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation.  

PubMed

Previous studies have shown that raising cytosolic calcium in myotubes induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha expression and mitochondrial biogenesis. This finding suggests that the increases in cytosolic calcium in skeletal muscle during exercise may mediate the exercise-induced increase in mitochondria. The initial aim of this study was to determine whether raising calcium in skeletal muscle induces the same adaptations as in myotubes. We found that treatment of rat epitrochlearis muscles with a concentration of caffeine that raises cytosolic calcium to a concentration too low to cause contraction induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha expression and mitochondrial biogenesis. Our second aim was to elucidate the pathway by which calcium induces these adaptations. Raising cytosolic calcium has been shown to activate calcium/calmodulin-dependent protein kinase in muscle. In the present study raising cytosolic calcium resulted in increases in phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor-2, which were blocked by the calcium/calmodulin-dependent protein kinase inhibitor KN93 and by the p38 mitogen-activated protein kinase inhibitor SB202190. The increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha expression and mitochondrial biogenesis were also prevented by inhibiting p38 activation. We interpret these findings as evidence that p38 mitogen-activated protein kinase is downstream of calcium/calmodulin-dependent protein kinase in a signaling pathway by which increases in cytosolic calcium lead to increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha expression and mitochondrial biogenesis in muscle. PMID:17488713

Wright, David C; Geiger, Paige C; Han, Dong-Ho; Jones, Terry E; Holloszy, John O

2007-05-07

31

Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells.  

PubMed

In X-ALD, mutation/deletion of ALD gene (ABCD1) and the resultant very long chain fatty acid (VLCFA) derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD). The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal ?-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs) (1 and 3) in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL) and cell survival (phospho-Erk1/2) proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid) leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD. PMID:23923017

Singh, Jaspreet; Khan, Mushfiquddin; Pujol, Aurora; Baarine, Mauhamad; Singh, Inderjit

2013-07-26

32

Histone Deacetylase Inhibitor Upregulates Peroxisomal Fatty Acid Oxidation and Inhibits Apoptotic Cell Death in Abcd1-Deficient Glial Cells  

PubMed Central

In X-ALD, mutation/deletion of ALD gene (ABCD1) and the resultant very long chain fatty acid (VLCFA) derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD). The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal ?-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs) (1 and 3) in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL) and cell survival (phospho-Erk1/2) proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid) leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD.

Singh, Jaspreet; Khan, Mushfiquddin; Pujol, Aurora; Baarine, Mauhamad; Singh, Inderjit

2013-01-01

33

Conjugated linoleic acid activates peroxisome proliferator-activated receptor ? and ? subtypes but does not induce hepatic peroxisome proliferation in Sprague–Dawley rats  

Microsoft Academic Search

Since conjugated linoleic acid (CLA) has structural and physiological characteristics similar to peroxisome proliferators, we hypothesized that CLA would activate peroxisome proliferator-activated receptor (PPAR). We compared the effects of dietary CLA (0.0, 0.5, 1.0 and 1.5% by weight) with a peroxisome proliferator (0.01% Wy-14,643) in female and male Sprague–Dawley (SD) rats. Dietary CLA had little effect on body weight, liver

Silvia Y Moya-Camarena; John P Vanden Heuvel; Martha A Belury

1999-01-01

34

Ligand activation of peroxisome proliferator-activated receptor ?/? (PPAR?/?) inhibits chemically induced skin tumorigenesis  

PubMed Central

Peroxisome proliferator-activated receptor (PPAR)?/?-null mice exhibit enhanced tumorigenesis in a two-stage chemical carcinogenesis model as compared with wild-type mice. Previous work showed that ligand activation of PPAR?/? induces terminal differentiation and inhibits proliferation of primary keratinocytes, and this effect does not occur in the absence of PPAR?/? expression. In the present studies, the effect of ligand activation of PPAR?/? on skin tumorigenesis was examined using both in vivo and ex vivo skin carcinogenesis models. Inhibition of chemically induced skin tumorigenesis was observed in wild-type mice administered GW0742, and this effect was likely the result of ligand-induced terminal differentiation and inhibition of replicative DNA synthesis. These effects were not found in similarly treated PPAR?/?-null mice. Ligand activation of PPAR?/? also inhibited cell proliferation and induced terminal differentiation in initiated/neoplastic keratinocyte cell lines representing different stages of skin carcinogenesis. These studies suggest that topical administration of PPAR?/? ligands may be useful as both a chemopreventive and/or a chemotherapeutic approach to inhibit skin cancer.

Bility, Moses T.; Devlin-Durante, Meghann K.; Blazanin, Nicholas; Glick, Adam B.; Ward, Jerrold M.; Kang, Boo Hyon; Kennett, Mary J.; Gonzalez, Frank J.; Peters, Jeffrey M.

2008-01-01

35

Pyruvate inhibits clofibrate-induced hepatic peroxisomal proliferation and free radical production in rats  

Microsoft Academic Search

In an effort to identify the effects of the 3-carbon compound pyruvate on free radical production, we measured hepatic total peroxisomal ?-oxidation and catalase activity and the production of lipofuscin-like products in male Sprague-Dawley rats consuming an adequate diet supplemented with pyruvate, vitamin E, or the peroxisome proliferator and free radical enhancer clofibrate for 22 days (n = 5 in

Ronald T. Stanko; Gail Sekas; Israel A. Isaacson; Martha R. Clarke; Timothy R. Billiar; Harbhaian S. Paul

1995-01-01

36

Anthocyanins induce cholesterol efflux from mouse peritoneal macrophages: the role of the peroxisome proliferator-activated receptor {gamma}-liver X receptor {alpha}-ABCA1 pathway.  

PubMed

It is widely accepted that stimulation of reverse cholesterol transport, the efflux of excess cholesterol from peripheral tissues and transferring it to the liver for biliary excretion, is becoming an important component in reducing excess cholesterol deposition in atherosclerotic plaques. The ATP-binding cassette transporter has been identified as a key regulator of macrophage cholesterol efflux and apoAI-mediated reverse cholesterol transport. In vivo studies have documented anthocyanins, a large group of naturally phenolic compounds rich in plants, possess substantial capacities in improving plasma cholesterol levels. In this study, we investigated the potential role of anthocyanins in modulating cholesterol efflux from mouse peritoneal macrophages and macrophage-derived foam cells and the possible molecular mechanism linking ABCA1 to cholesterol efflux. Incubation of the mouse peritoneal macrophages and macrophage-derived foam cells with cyanidin-3-O-beta-glucoside and peonidin-3-O-beta-glucoside led to dose-dependent (1-100 microM) induction in cholesterol efflux and ABCA1 mRNA expression, and this effect could be blocked by the ABCA1 inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, disodium salt, and a general inhibitor of gene transcription actinomycin D. Treatment of the macrophages with anthocyanins also activated peroxisome proliferator-activated receptor gamma, liver X receptor alpha mRNA expression, and their mediated gene expression. Addition of geranylgeranyl pyrophosphate ammonium salt or GW9662 markedly inhibited the anthocyanin-induced increase of ABCA1 gene expression and apoAI-mediated cholesterol efflux. These data demonstrated that anthocyanin induces cholesterol efflux from mouse peritoneal macrophages and macrophage-derived foam cells and that stimulation of cholesterol efflux by anthocyanin is mediated, at least in part, by peroxisome proliferator-activated receptor gamma-liver X receptor alpha-ABCA1 signaling pathway activation. PMID:16107338

Xia, Min; Hou, Mengjun; Zhu, Huilian; Ma, Jing; Tang, Zhihong; Wang, Qing; Li, Yan; Chi, Dongsheng; Yu, Xiaoping; Zhao, Ting; Han, Pinghua; Xia, Xiaodong; Ling, Wenhua

2005-08-17

37

Ginsenoside Rb? induces type I collagen expression through peroxisome proliferator-activated receptor-delta.  

PubMed

Wrinkle formation is one of the primary characteristics of skin aging, the major cause of wrinkle is the loss of structural protein type I collagen in dermal layer of skin. Topical application of natural substances to reduce wrinkle is gaining attention in recent years. Although a number of polyphenoic compounds are suggested to prevent ultraviolet-induced wrinkle, very few of them are able to increase type I collagen synthesis directly. Ginseng has been known in folk medicine of its beneficial effect to skin. The present study investigate the effect of ginsenoside on type I collagen induction in human dermal fibroblasts. Ginsenoside Rb? was shown to induce type I collagen expression in dermal fibroblasts in a dose- and time-dependent manner. Recent studies suggest the important post-transcriptional regulatory role of microRNAs; here we demonstrated that miR-25 can directly inhibit type I collagen protein expression, and treatment of fibroblasts with Rb? can reduce the inhibition by decreasing miR-25 level. Furthermore, we identified that the nuclear receptor, peroxisome proliferator-activated receptor-delta (PPAR?) is the key mediator of Rb?-induced type I collagen expression. Knockdown of PPAR? by small-interference RNA abolished the Rb?-induced type I collagen production and reversed the Rb?-suppressed miR-25 expression. These results demonstrated that ginsenoside Rb? can increase target gene expression through transcriptional pathway, at the same time, inhibit the corresponding miRNA expression to minimize the translation repression. Furthermore, this study provide solid support of ginsenoside Rb?-induced type I collagen expression, which warrant further study in the dermatological application of ginsenosides in skin disorders. PMID:22692056

Kwok, Hoi-Hin; Yue, Patrick Ying-Kit; Mak, Nai-Ki; Wong, Ricky Ngok-Shun

2012-06-09

38

Peroxisomal disorders.  

PubMed

The peroxisomal disorders represent a group of genetic diseases in man in which there is an impairment in one or more peroxisomal functions. The peroxisomal disorders are subdivided into three subgroups comprising: (1) the peroxisome biogenesis disorders (PBDs); (2) the single peroxisomal (enzyme-) protein deficiencies; and (3) the single peroxisomal substrate transport deficiencies. The PBD group comprises four different disorders that include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). ZS, NALD, and IRD are clearly distinct from RCDP and are usually referred to as the Zellweger spectrum with ZS being the most severe, and IRD the less severe disorder, with sometimes onset in adulthood. The single peroxisomal enzyme deficiency group comprises seven different disorders, of which D-bifunctional protein and phytanoyl-CoA hydroxylase (adult Refsum disease) deficiencies are the most frequent. The single peroxisomal substrate transport deficiency group consists of only one disease, X-linked adrenoleukodystrophy. It is the purpose of this chapter to describe the current state of knowledge about the clinical, biochemical, cellular, and molecular aspects of peroxisomal diseases, and to provide guidelines for their post- and prenatal diagnosis. Therapeutic interventions are mostly limited to X-linked adrenoleukodystrophy. PMID:23622381

Aubourg, Patrick; Wanders, Ronald

2013-01-01

39

Changes in expression of cellular oncogenes and endogenous retrovirus-like sequences during hepatocarcinogenesis induced by a peroxisome proliferator  

Microsoft Academic Search

Previous studies have demonstrated that BR-931, a hepatic peroxisome proliferator, can induce liver tumours in mice and rats. Since alterations in gene expression may play a critical role in multistage hepatocarcinogenesis, the present studies examined the expression of the c-myc, c-H-ras, epidermal growth factor (EGF) receptor and ODC (ornithine decarboxylase) genes, as well as endogenous retrovirus-like sequences, in F344 rat

LL Hsieh; H Shinozuka; IB Weinstein

1991-01-01

40

Rosiglitazone, peroxisome proliferator receptor-gamma agonist, ameliorates gentamicin-induced nephrotoxicity in rats.  

PubMed

Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe gram-negative infections. Reactive oxygen spaces (ROS) are important mediators of gentamicin-induced nephrotoxicity. Peroxisome proliferator-activated receptors (PPARs) have different activities including antioxidant properties. This study was performed to investigate the protective role of PPAR-? agonist against GEN-induced nephrotoxicity. Male Wistar Albino rats were randomly divided into the following four groups, each of which consisted of six animals: (1) control; (2) intraperitoneally injected with GEN for 14 consecutive days (100 mg/kg/day); (3) treatment with rosiglitazone (RSG) via nasogastric gavage (10 mg/kg/daily for 14 days); (4) treatment with GEN + RSG combination for 14 day. Rats were decapitated on the 15th day and kidneys were removed. Urine was collected for every 24 h for the determination of daily urine volume. Urea, creatinine, Na(+) and K(+) levels were measured in blood. Malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) levels along with glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activities were determined in the renal tissue. Changes in body weight were recorded. GEN treatment was found to cause nephrotoxicity as evidenced by elevation of serum urea and creatinine levels. Renal impairment was also assessed by the renal histology. The significant decrease in GSH and increases in MDA and NO levels as well as a decrease in GSH-Px, CAT, and SOD activities indicated that GEN-induced renal damage was mediated through oxidative reactions. On the other hand, RSG administration protected kidney tissue against GEN-induced and free radical-mediated oxidative renal damage in rats. PMID:19779845

Ozbek, Emin; Ilbey, Yusuf Ozlem; Simsek, Abdulmuttalip; Cekmen, Mustafa; Mete, Fatih; Somay, Adnan

2009-09-25

41

Identification of transcriptional networks involved in peroxisome proliferator chemical-induced hepatocyte proliferation  

EPA Science Inventory

Peroxisome proliferator chemical (PPC) exposure leads to increases in rodent liver tumors through a non-genotoxic mode of action (MOA). The PPC MOA includes increased oxidative stress, hepatocyte proliferation and decreased apoptosis. We investigated the putative genetic regulato...

42

The peroxisome proliferator-activated receptor gamma is an inhibitor of ErbBs activity in human breast cancer cells.  

PubMed

One of the most interesting recent developments in the nuclear receptor field has been the identification of natural and synthetic agonists of the peroxisome proliferator-activated receptor (PPAR) family, coupled with a growing recognition that the gamma isoform (PPARgamma) affects pathways important in a variety of human diseases. Here we show that the activation of PPARgamma through the 15-deoxy-Delta-12,14-prostaglandin J(2) (PG-J(2)) ligand causes a dramatic inhibition of ErbB-2 and ErbB-3 tyrosine phosphorylation caused by neuregulin 1 (NRG1) and neuregulin 2 (NRG2) in MCF-7 cells. This effect is accompanied by a very efficient blocking of ErbBs effects upon proliferation, differentiation and cell death in these cells. Preincubation of MCF-7 cells with PG-J(2) before addition of NRG1 and NRG2 had a dramatic growth-suppressive effect accompanied by accumulation of cells in the G0/G1 compartment of the cell cycle, and a marked increase in apoptosis. NRG1 and NRG2 induce G1 progression, which was associated with stimulation of the phosphatidylinositol-3 kinase (PI 3-K) pathway, whereas survival was dependent on ERK1/ERK2 activation. Both pathways were inhibited by PG-J(2). Furthermore, PG-J(2) can abolish the NRG1 and NRG2-induced increase in anchorage-independent growth of these cells. PG-J(2) also blocks phosphorylation of other receptor tyrosine kinases, such as IGF-IR, in MCF-7 cells, and suppress proliferation of other breast cancer cell lines. In summary, our data show a specific inhibitory action of PG-J(2) on the activity of the ErbB receptors in breast cancer cells. PMID:11739643

Pignatelli, M; Cortés-Canteli, M; Lai, C; Santos, A; Perez-Castillo, A

2001-11-01

43

Pioglitazone inhibits homocysteine-induced migration of vascular smooth muscle cells through a peroxisome proliferator-activated receptor gamma-independent mechanism.  

PubMed

1. Peroxisome proliferator-activated receptor (PPAR)-gamma agonists have been demonstrated to exert protective effects against homocysteine (Hcy)-induced pathogenesis. However, the effects of PPAR-gamma agonists on Hcy-induced migration are unknown. In the present study, we examined the effect of pioglitazone on the migration of vascular smooth muscle cells (VSMC) induced by Hcy and the possible mechanism involved. 2. Vascular smooth muscle cells were isolated from the thoracic aortas of male Sprague-Dawley rats. The migration of VSMC was examined using a transwell technique. The generation of intracellular reactive oxygen species (ROS) was measured using the ROS-sensitive fluoroprobe 2',7'-dichlorodihydrofluorescein diacetate. The activity of NAD(P)H oxidase was assessed by lucigenin enhanced chemiluminescence. Activation of p38 mitogen-activated protein kinase (MAPK) was determined by western blotting. 3. The results showed that pioglitazone dose-dependently inhibited the migration of VSMC induced by Hcy. This was not reversed by the PPAR-gamma antagonist GW9662. In addition, pretreatment with the NAD(P)H oxidase inhibitor diphenylene iodonium (DPI), the free radical scavenger N-acetylcysteine and the p38 MAPK inhibitor SB202190 blocked Hcy-induced VSMC migration. Furthermore, we observed that pioglitazone suppressed Hcy-induced intracellular ROS production; similar effects were observed with DPI and NAC. Pioglitazone attenuated Hcy-induced activation of NAD(P)H oxidase. Moreover, pioglitazone blocked Hcy-induced p38 MAPK phosphorylation; similar effects were observed for DPI, NAC and SB202190. 4. The data demonstrate that pioglitazone inhibits Hcy-induced VSMC migration that is independent of PPAR-gamma. Furthermore, part of the biological effect of pioglitazone involves a decrease in the levels of NAD(P)H oxidase derived-ROS and p38 MAPK activation. PMID:18759864

Li, Li; Gao, Ping-Jin; Xi, Rui; Wu, Chun-Fang; Zhu, Ding-Liang; Yan, Jing; Lu, Guo-Ping

2008-08-26

44

Peroxisome Proliferator-activated Receptor ? Activation by Ligands and Dephosphorylation Induces Proprotein Convertase Subtilisin Kexin Type 9 and Low Density Lipoprotein Receptor Expression*  

PubMed Central

Proprotein convertase subtilisin kexin type 9 (PCSK9) plays an important role in cholesterol homeostasis by enhancing the degradation of LDL receptor (LDLR) protein. Peroxisome proliferator-activated receptor ? (PPAR?) has been shown to be atheroprotective. PPAR? can be activated by ligands and/or dephosphorylation with ERK1/2 inhibitors. The effect of PPAR? on PCSK9 and LDLR expression remains unknown. In this study, we investigated the effects of PPAR? on PCSK9 and LDLR expression. At the cellular levels, PPAR? ligands induced PCSK9 mRNA and protein expression in HepG2 cells. PCSK9 expression was induced by inhibition of ERK1/2 activity but inhibited by ERK1/2 activation. The mutagenic study and promoter activity assay suggested that the induction of PCSK9 expression by ERK1/2 inhibitors was tightly linked to PPAR? dephosphorylation. However, PPAR? activation by ligands or ERK1/2 inhibitors induced hepatic LDLR expression. The promoter assay indicated that the induction of LDLR expression by PPAR? was sterol regulatory element-dependent because PPAR? enhanced sterol regulatory element-binding protein 2 (SREBP2) processing. In vivo, administration of pioglitazone or U0126 alone increased PCSK9 expression in mouse liver but had little effect on PCSK9 secretion. However, the co-treatment of pioglitazone and U0126 enhanced both PCSK9 expression and secretion. Similar to in vitro, the increased PCSK9 expression by pioglitazone and/or U0126 did not result in decreased LDLR expression and function. In contrast, pioglitazone and/or U0126 increased LDLR protein expression and membrane translocation, SREBP2 processing, and CYP7A1 expression in the liver, which led to decreased total and LDL cholesterol levels in serum. Our results indicate that although PPAR? activation increased PCSK9 expression, PPAR? activation induced LDLR and CYP7A1 expression that enhanced LDL cholesterol metabolism.

Duan, Yajun; Chen, Yuanli; Hu, Wenquan; Li, Xiaoju; Yang, Xiaoxiao; Zhou, Xin; Yin, Zhinan; Kong, Deling; Yao, Zhi; Hajjar, David P.; Liu, Lin; Liu, Qiang; Han, Jihong

2012-01-01

45

A peroxisomal ABC transporter promotes seed germination by inducing pectin degradation under the control of ABI5.  

PubMed

Seed dormancy is essential for most plants to control the timing of germination. In Arabidopsis thaliana, PED3 is a single-copy gene encoding an ATP-binding cassette transporter that is required for peroxisomal fatty acid beta-oxidation. PED3 is involved in the import of several biologically important molecules into the peroxisome, including very-long-chain fatty acids associated with the breakdown of seed-reserve lipids, and precursors of auxin and jasmonic acid. The germination of ped3 mutants is significantly impaired, suggesting that PED3 regulates dormancy and germination. A transcriptome analysis revealed that many genes containing the core motif of the ABA responsive element (ABRE) in their promoter regions, and the ABA insensitive 5 (ABI5) transcription factor that binds to ABRE, are abnormally up-regulated in imbibed ped3 seeds. Expression of polygalacturonase inhibiting proteins (PGIPs) is also up-regulated specifically in ped3 after imbibition. By contrast, the ped3 abi5 double mutant does not show any of these expression patterns. The results indicate that the abi5 mutation normalizes PGIP expression and rescues the impaired germination phenotype of the ped3 mutant. PGIPs are known to act as inhibitors of polygalacturonases that degrade pectin. The amount of PGIP1 transcript regulates the timing of radicle protrusion. The impaired germination of ped3 could also be rescued by removal of pectin from the seed coat using exogenous polygalacturonase or acidic conditions. Overall, our results suggest that PED3, a peroxisomal ABC transporter, promotes seed germination by suppressing PGIPs under the control of ABI5. PMID:20345608

Kanai, Masatake; Nishimura, Mikio; Hayashi, Makoto

2010-03-11

46

MECHANISMS OF PEROXISOME PROLIFERATOR-INDUCED CARCINOGENESIS: HISTORICAL PERSPECTIVES AND CURRENT STATUS  

EPA Science Inventory

This report is a comprehensive review of past and current thinking, as reflected in the scientific literature, on the mechanisms by which peroxisome proliferating agents are thought to act as carcinogens. he report is divided into four main sections: (1) background information on...

47

Cucurbitane Triterpenoid from Momordica charantia Induces Apoptosis and Autophagy in Breast Cancer Cells, in Part, through Peroxisome Proliferator-Activated Receptor ? Activation  

PubMed Central

Although the antitumor activity of the crude extract of wild bitter gourd (Momordica charantia L.) has been reported, its bioactive constituents and the underlying mechanism remain undefined. Here, we report that 3?,7?-dihydroxy-25-methoxycucurbita-5,23-diene-19-al (DMC), a cucurbitane-type triterpene isolated from wild bitter gourd, induced apoptotic death in breast cancer cells through peroxisome proliferator-activated receptor (PPAR) ? activation. Luciferase reporter assays indicated the ability of DMC to activate PPAR?, and pharmacological inhibition of PPAR? protected cells from DMC's antiproliferative effect. Western blot analysis indicated that DMC suppressed the expression of many PPAR?-targeted signaling effectors, including cyclin D1, CDK6, Bcl-2, XIAP, cyclooxygenase-2, NF-?B, and estrogen receptor ?, and induced endoplasmic reticulum stress, as manifested by the induction of GADD153 and GRP78 expression. Moreover, DMC inhibited mTOR-p70S6K signaling through Akt downregulation and AMPK activation. The ability of DMC to activate AMPK in liver kinase (LK) B1-deficient MDA-MB-231 cells suggests that this activation was independent of LKB1-regulated cellular metabolic status. However, DMC induced a cytoprotective autophagy presumably through mTOR inhibition, which could be overcome by the cotreatment with the autophagy inhibitor chloroquine. Together, the ability of DMC to modulate multiple PPAR?-targeted signaling pathways provides a mechanistic basis to account for the antitumor activity of wild bitter gourd.

Weng, Jing-Ru; Bai, Li-Yuan; Chiu, Chang-Fang; Hu, Jing-Lan; Chiu, Shih-Jiuan; Wu, Chia-Yung

2013-01-01

48

Cucurbitane Triterpenoid from Momordica charantia Induces Apoptosis and Autophagy in Breast Cancer Cells, in Part, through Peroxisome Proliferator-Activated Receptor ? Activation.  

PubMed

Although the antitumor activity of the crude extract of wild bitter gourd (Momordica charantia L.) has been reported, its bioactive constituents and the underlying mechanism remain undefined. Here, we report that 3 ? ,7 ? -dihydroxy-25-methoxycucurbita-5,23-diene-19-al (DMC), a cucurbitane-type triterpene isolated from wild bitter gourd, induced apoptotic death in breast cancer cells through peroxisome proliferator-activated receptor (PPAR) ? activation. Luciferase reporter assays indicated the ability of DMC to activate PPAR ? , and pharmacological inhibition of PPAR ? protected cells from DMC's antiproliferative effect. Western blot analysis indicated that DMC suppressed the expression of many PPAR ? -targeted signaling effectors, including cyclin D1, CDK6, Bcl-2, XIAP, cyclooxygenase-2, NF- ? B, and estrogen receptor ? , and induced endoplasmic reticulum stress, as manifested by the induction of GADD153 and GRP78 expression. Moreover, DMC inhibited mTOR-p70S6K signaling through Akt downregulation and AMPK activation. The ability of DMC to activate AMPK in liver kinase (LK) B1-deficient MDA-MB-231 cells suggests that this activation was independent of LKB1-regulated cellular metabolic status. However, DMC induced a cytoprotective autophagy presumably through mTOR inhibition, which could be overcome by the cotreatment with the autophagy inhibitor chloroquine. Together, the ability of DMC to modulate multiple PPAR ? -targeted signaling pathways provides a mechanistic basis to account for the antitumor activity of wild bitter gourd. PMID:23843889

Weng, Jing-Ru; Bai, Li-Yuan; Chiu, Chang-Fang; Hu, Jing-Lan; Chiu, Shih-Jiuan; Wu, Chia-Yung

2013-06-13

49

Overexpression of peroxisomal testis-specific 1 protein induces germ cell apoptosis and leads to infertility in male mice.  

PubMed

Peroxisomal testis-specific 1 gene (Pxt1) is the only male germ cell-specific gene that encodes a peroxisomal protein known to date. To elucidate the role of Pxt1 in spermatogenesis, we generated transgenic mice expressing a c-MYC-PXT1 fusion protein under the control of the PGK2 promoter. Overexpression of Pxt1 resulted in induction of male germ cells' apoptosis mainly in primary spermatocytes, finally leading to male infertility. This prompted us to analyze the proapoptotic character of mouse PXT1, which harbors a BH3-like domain in the N-terminal part. In different cell lines, the overexpression of PXT1 also resulted in a dramatic increase of apoptosis, whereas the deletion of the BH3-like domain significantly reduced cell death events, thereby confirming that the domain is functional and essential for the proapoptotic activity of PXT1. Moreover, we demonstrated that PXT1 interacts with apoptosis regulator BAT3, which, if overexpressed, can protect cells from the PXT1-induced apoptosis. The PXT1-BAT3 association leads to PXT1 relocation from the cytoplasm to the nucleus. In summary, we demonstrated that PXT1 induces apoptosis via the BH3-like domain and that this process is inhibited by BAT3. PMID:21460186

Kaczmarek, Karina; Studencka, Maja; Meinhardt, Andreas; Wieczerzak, Krzysztof; Thoms, Sven; Engel, Wolfgang; Grzmil, Pawel

2011-04-01

50

Overexpression of peroxisomal testis-specific 1 protein induces germ cell apoptosis and leads to infertility in male mice  

PubMed Central

?Peroxisomal testis-specific 1 gene (Pxt1) is the only male germ cell–specific gene that encodes a peroxisomal protein known to date. To elucidate the role of Pxt1 in spermatogenesis, we generated transgenic mice expressing a c-MYC-PXT1 fusion protein under the control of the PGK2 promoter. Overexpression of Pxt1 resulted in induction of male germ cells’ apoptosis mainly in primary spermatocytes, finally leading to male infertility. This prompted us to analyze the proapoptotic character of mouse PXT1, which harbors a BH3-like domain in the N-terminal part. In different cell lines, the overexpression of PXT1 also resulted in a dramatic increase of apoptosis, whereas the deletion of the BH3-like domain significantly reduced cell death events, thereby confirming that the domain is functional and essential for the proapoptotic activity of PXT1. Moreover, we demonstrated that PXT1 interacts with apoptosis regulator BAT3, which, if overexpressed, can protect cells from the PXT1-induced apoptosis. The PXT1-BAT3 association leads to PXT1 relocation from the cytoplasm to the nucleus. In summary, we demonstrated that PXT1 induces apoptosis via the BH3-like domain and that this process is inhibited by BAT3.

Kaczmarek, Karina; Studencka, Maja; Meinhardt, Andreas; Wieczerzak, Krzysztof; Thoms, Sven; Engel, Wolfgang; Grzmil, Pawel

2011-01-01

51

The Ras Inhibitors Caveolin-1 and Docking Protein 1 Activate Peroxisome Proliferator-Activated Receptor ? through Spatial Relocalization at Helix 7 of Its Ligand-Binding Domain ?  

PubMed Central

Peroxisome proliferator-activated receptor ? (PPAR?) is a transcription factor that promotes differentiation and cell survival in the stomach. PPAR? upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPAR? is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPAR? signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPAR? and enhanced nuclear translocation and ligand-independent transcription of PPAR? target genes. In contrast, Cav1 overexpression sequestered PPAR? in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPAR?'s ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPAR? and to inhibit cell proliferation. Ligand-activated PPAR? also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPAR? regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPAR? to ligands, limiting proliferation of gastric epithelial cells.

Burgermeister, Elke; Friedrich, Teresa; Hitkova, Ivana; Regel, Ivonne; Einwachter, Henrik; Zimmermann, Wolfgang; Rocken, Christoph; Perren, Aurel; Wright, Matthew B.; Schmid, Roland M.; Seger, Rony; Ebert, Matthias P. A.

2011-01-01

52

The role of peroxisome proliferator-activated receptor-{beta}/{delta} in epidermal growth factor-induced HaCaT cell proliferation  

SciTech Connect

Epidermal growth factor (EGF) has been shown to be a potent mitogen for epidermal cells both in vitro and in vivo, thus contributing to the development of an organism. It has recently become clear that peroxisome proliferator-activated receptor-{beta}/{delta} (PPAR{beta}/{delta}) expression and activation is involved in the cell proliferation. However, little is known about the role of PPAR{beta}/{delta} in EGF-induced proliferation of HaCaT keratinocytes. In this study, HaCaT cells were cultured in the presence and absence of EGF and we identified that EGF induced an increase of PPAR{beta}/{delta} mRNA and protein level expression in time-dependent and dose-dependent manner, and AG1487, an EGF receptor (EGFR) special inhibitor, caused attenuation of PPAR{beta}/{delta} protein expression. Electrophoretic mobility shift assay (EMSA) revealed that EGF significantly increased PPAR{beta}/{delta} binding activity in HaCaT keratinocytes. Antisense phosphorothioate oligonucleotides (asODNs) against PPAR{beta}/{delta} caused selectively inhibition of PPAR{beta}/{delta} protein content induced by EGF and significantly attenuated EGF-mediated cell proliferation. Treatment of the cells with L165041, a specific synthetic ligand for PPAR{beta}/{delta}, significantly enhanced EGF-mediated cell proliferation. Finally, c-Jun ablation inhibited PPAR{beta}/{delta} up-regulation induced by EGF, and chromatin immunoprecipitation (ChIP) showed that c-Jun bound to the PPAR{beta}/{delta} promoter and the binding increased in EGF-stimulated cells. These results demonstrate that EGF induces PPAR{beta}/{delta} expression in a c-Jun-dependent manner and PPAR{beta}/{delta} plays a vital role in EGF-stimulated proliferation of HaCaT cells.

Liang Pengfei [Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 (China); Jiang Bimei [Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078 (China); Yang Xinghua [Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 (China); Xiao Xianzhong [Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078 (China)], E-mail: XianzhongXiao@xysm.net; Huang Xu [Department of Hyperbaric Oxygen, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 (China); Long Jianhong; Zhang Pihong; Zhang Minghua; Xiao Muzhang; Xie Tinghong [Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 (China); Huang Xiaoyuan [Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 (China)], E-mail: huxzhong@yahoo.com.cn

2008-10-15

53

The peroxisome proliferator-activated receptor , an integrator of transcriptional repression and nuclear receptor signaling  

Microsoft Academic Search

The three PPAR (peroxisome proliferator-activated receptor) isoforms are critical regulators of lipid homeostasis by controlling the balance between the burning and storage of long chain fatty acids. Whereas PPAR and PPAR have been studied extensively, the function of PPAR remains the most elusive. Intriguingly, in cotransfection experiments, PPAR is a potent inhibitor of ligand-induced transcriptional activity of PPAR and PPAR.

Yanhong Shi; Michelle Hon; Ronald M. Evans

2002-01-01

54

Peroxisome biogenesis in Saccharomyces cerevisiae  

Microsoft Academic Search

The observation that peroxisomes ofSaccharomyces cerevisiae can be induced by oleic acid has opened the possibility to investigate the biogenesis of these organelles in a biochemically and genetically well characterized organism. Only few enzymes have been identified as peroxisomal proteins inSaccharomyces cerevisiae so far; the three enzymes involved in ß-oxidation of fatty acids, enzymes of the glyoxylate cycle, catalase A

Wolf-H. Kunau; Andreas Hartig

1992-01-01

55

Peroxisome deficiency-induced ER stress and SREBP-2 pathway activation in the liver of newborn PEX2 knock-out mice  

PubMed Central

Disruption of the Pex2 gene leads to peroxisome deficiency and widespread metabolic dysfunction. We previously demonstrated that peroxisomes are critical for maintaining cholesterol homeostasis, using peroxisome-deficient Pex2?/? mice on a hybrid Swiss Webster×129S6/SvEv (SW/129) genetic background. Peroxisome deficiency activates hepatic endoplasmic reticulum (ER) stress pathways, leading to dysregulation of the endogenous sterol response mechanism. Herein, we demonstrate a more profound dysregulation of cholesterol homeostasis in newborn Pex2?/? mice congenic on a 129S6/SvEv (129) genetic background, and substantial differences between newborn versus postnatal Pex2?/? mice in factors that activate ER stress. These differences extend to relationships between activation of genes regulated by SREBP-2 versus PPAR?. The SREBP-2 pathway is induced in neonatal Pex2?/? livers from 129 and SW/129 strains, despite normal hepatic cholesterol levels. ER stress markers are increased in newborn 129 Pex2?/? livers, which occurs in the absence of hepatic steatosis or accumulation of peroxins in the ER. Moreover, the induction of SREBP-2 and ER stress pathways is independent of PPAR? activation in livers of newborn 129 and SW/129 Pex2?/? mice. Two-week-old wild-type mice treated with the peroxisome proliferator WY-14,643 show strong induction of PPAR?-regulated genes and decreased expression of SREBP-2 and its target genes, further demonstrating that SREBP-2 pathway induction is not dependent on PPAR? activation. Lastly, there is no activation of either SREBP-2 or ER stress pathways in kidney and lung of newborn Pex2?/? mice, suggesting a parallel induction of these pathways in peroxisome-deficient mice. These findings establish novel associations between SREBP-2, ER stress and PPAR? pathway inductions.

Kovacs, Werner J.; Charles, Khanichi N.; Walter, Katharina M.; Shackelford, Janis E.; Wikander, Thomas M.; Richards, Michael J.; Fliesler, Steven J.; Krisans, Skaidrite K.; Faust, Phyllis L.

2012-01-01

56

Eicosapentaenoic acid (EPA) induces peroxisome proliferator-activated receptors and ameliorates experimental autoimmune encephalomyelitis.  

PubMed

Eicosapentaenoic acid (EPA), one of the n-3 polyunsaturated fatty acids, is a neuroprotective lipid with anti-inflammatory properties. We investigated the possible therapeutic effect of EPA on experimental autoimmune encephalomyelitis (EAE). EAE mice were fed a diet with or without EPA. The clinical EAE scores of the EPA-fed mice were significantly lower than those of the non-EPA mice. In the EPA-treated mice, IFN-? and IL-17 productions were remarkably inhibited and the expression levels of peroxisome proliferator-activated receptors were significantly enhanced in the CNS-infiltrating CD4T cells. Thus EPA shows promise as a potential new therapeutic agent against multiple sclerosis. PMID:23276800

Unoda, Kiichi; Doi, Yoshimitsu; Nakajima, Hideto; Yamane, Kazushi; Hosokawa, Takafumi; Ishida, Shimon; Kimura, Fumiharu; Hanafusa, Toshiaki

2012-12-28

57

Immunohistochemical distribution of activated nuclear factor ?B and peroxisome proliferator-activated receptors in carbon tetrachloride-induced chronic liver injury in rats  

Microsoft Academic Search

We investigated the immunohistochemical distribution of active NF-?B p65 and peroxisome proliferator-activated receptor (PPAR) subtypes alpha and gamma in the different phases of liver steatonecrosis and cirrhosis induced in rats after 3 and 9 weeks of carbon tetrachloride (CCl4) intoxication. CCl4 treatment can induce changes in the expression of NF-?B and PPARs. Immunohistochemical analysis of liver tissue sections from rats with

Claudine Orfila; Jean-Claude Lepert; Laurent Alric; Georges Carrera; Maryse Béraud; Bernard Pipy

2005-01-01

58

Catalepsy induced by nitric oxide synthase inhibitors  

Microsoft Academic Search

1.1. Previous study showed that NG-nitro-l-arginine (l-NOARG), an inhibitor of nitric oxide synthase, induces catalepsy in a dose-dependent manner in male albino-Swiss mice.2.2. The objective of the present work was to further investigate this effect, extending it to other NOS inhibitors.3.3. Results showed that l-NOARG (40–80 mg\\/kg IP), NG-nitro-l-arginine methylester (l-NAME, 40–160 mg\\/kg IP) or NG-monomethyl-l-arginine (l-NMMA, 80 mg\\/kg IP)

E. A. Del Bel; C. A. da Silva; F. S. Guimarães

1998-01-01

59

Dietary conjugated linoleic acid induces peroxisome-specific enzyme accumulation and ornithine decarboxylase activity in mouse liver  

Microsoft Academic Search

Previous studies have shown that the dietary fatty acids, conjugated linoleic acids (CLA), inhibit carcinogenesis in the colon, mammary gland, forestomach, and skin. Several properties of this chemoprotective polyunsaturated fatty acid suggest it will act as an hepatic peroxisome proliferator. This study evaluated the effect of dietary CLA on the accumulation of enzymes associated with peroxisome proliferation in rodent liver.

Martha A. Belury; Silvia Y. Moya-Camarena; Kai-Li Liu; John P. Vanden Heuvel

1997-01-01

60

Chemoprevention of chemically-induced skin tumorigenesis by ligand activation of peroxisome proliferator-activated receptor-?/? (PPAR?/?) and inhibition of cyclooxygenase 2 (COX2)  

PubMed Central

Ligand activation of peroxisome proliferator-activated receptor-?/? (PPAR?/?) and inhibition of cyclooxygenase-2 (COX2) activity by non-steroidal anti-inflammatory drugs (NSAID) can both attenuate skin tumorigenesis. The present study examined the hypothesis that combining ligand activation of PPAR?/? with inhibition of COX2 activity will increase the efficacy of chemoprevention of chemically-induced skin tumorigenesis over that observed with either approach alone. To test this hypothesis, wild-type and Ppar?/?-null mice were initiated with 7, 12-dimethylbenz[a]anthracene (DMBA), topically treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) to promote tumorigenesis, and then immediately treated with topical application of the PPAR?/? ligand GW0742, dietary administration of the COX2 inhibitor nimesulide, or both GW0742 and nimesulide. Ligand activation of PPAR?/? with GW0742 caused a PPAR?/?-dependent delay in the onset of tumor formation. Nimesulide also delayed the onset of tumor formation and caused inhibition of tumor multiplicity (46%) in wild-type mice but not in Ppar?/?-null mice. Combining ligand activation of PPAR?/? with dietary nimesulide resulted in a further decrease of tumor multiplicity (58%) in wild-type mice but not in Ppar?/?-null mice. Biochemical and molecular analysis of skin and tumor samples demonstrate that these effects were due to modulation of terminal differentiation, attenuation of inflammatory signaling and induction of apoptosis, through both PPAR?/?-dependent and PPAR?/?-independent mechanisms. Increased levels and activity of PPAR?/? by nimesulide was also observed. These studies support the hypothesis that combining ligand activation of PPAR?/? with inhibition of COX2 activity increases the efficacy of preventing chemically-induced skin tumorigenesis as compared to either approach alone.

Zhu, Bokai; Bai, Robert; Kennett, Mary J.; Kang, Boo-Hyon; Gonzalez, Frank J.; Peters, Jeffrey M.

2010-01-01

61

The peroxisome proliferator-activated receptor-? agonist pioglitazone protects against cisplatin-induced renal damage in mice.  

PubMed

Peroxisome proliferator-activated receptor-? (PPAR-?) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-? agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10?mg?kg(-1) ). Pioglitazone was administered for six consecutive days in doses of 15 or 30?mg?kg(-1) ?day(-1) , per os (p.o.), starting 3?days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-? agonists in human application for protecting against drugs-induced nephrotoxicity. Copyright © 2012 John Wiley & Sons, Ltd. PMID:22987311

Jesse, Cristiano R; Bortolatto, Cristiani F; Wilhelm, Ethel A; Roman, Silvane Souza; Prigol, Marina; Nogueira, Cristina W

2012-09-14

62

Peroxisome Proliferator-Activated Receptor-? Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells  

PubMed Central

Background Ligands activating the transcription factor peroxisome proliferator–activated receptor-? (PPAR?) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPAR? agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPAR? in human transplantation are unknown. Methods and Results We tested the effects of PPAR? agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-?–dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPAR? agonists 15-deoxy-prostaglandin-J2, ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO+ memory T cells, and plasma levels of inflammatory cytokines. The PPAR? antagonist GW9662 reversed the protective effects of PPAR? agonists, confirming the involvement of PPAR?-mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPAR? effects. Conclusion Our results suggest that PPAR? agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.

Tobiasova, Zuzana; Zhang, Lufeng; Yi, Tai; Qin, Linfeng; Manes, Thomas D.; Kulkarni, Sanjay; Lorber, Marc I.; Rodriguez, Frederick C.; Choi, Je-Min; Tellides, George; Pober, Jordan S.; Kawikova, Ivana; Bothwell, Alfred L.M.

2012-01-01

63

Activation of peroxisome proliferator-activated receptor ? induces fatty acid ?-oxidation in skeletal muscle and attenuates metabolic syndrome  

PubMed Central

In this study, we defined the role of peroxisome proliferator-activated receptor ?/? (PPAR?) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPAR? subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPAR? controls fatty acid oxidation by regulating genes involved in fatty acid transport, ?-oxidation, and mitochondrial respiration. Similar PPAR?-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid ?-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid ?-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPAR? is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.

Tanaka, Toshiya; Yamamoto, Joji; Iwasaki, Satoshi; Asaba, Hiroshi; Hamura, Hiroki; Ikeda, Yukio; Watanabe, Mitsuhiro; Magoori, Kenta; Ioka, Ryoichi X.; Tachibana, Keisuke; Watanabe, Yuichiro; Uchiyama, Yasutoshi; Sumi, Koichi; Iguchi, Haruhisa; Ito, Sadayoshi; Doi, Takefumi; Hamakubo, Takao; Naito, Makoto; Auwerx, Johan; Yanagisawa, Masashi; Kodama, Tatsuhiko; Sakai, Juro

2003-01-01

64

Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?  

Microsoft Academic Search

The purpose of the workshop “Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?” was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur

Russell C. Cattley; John DeLuca; Cliff Elcombe; Penelope Fenner-Crisp; Brian G. Lake; Daniel S. Marsman; Timothy A. Pastoor; James A. Popp; Denise E. Robinson; Bernard Schwetz; Jonathan Tugwood; Walter Wahli

1998-01-01

65

Activators of Peroxisome Proliferator-Activated Receptors Protect Human Skin from Ultraviolet-B-Light-Induced Inflammation  

Microsoft Academic Search

Peroxisome proliferator-activated receptors (PPAR) are members of a nuclear receptor superfamily, which were initially described in the context of fatty acid degradation and adipocyte differentiation. In this study we tested the hypothesis that peroxisome proliferator-activated receptor activation also controls inflammation. In an in vitro model with human keratinocytes inflammation was mimicked by irradiation with ultraviolet B light (150 mJ per

Stefan Kippenberger; Stefan Marcel Loitsch; Marcella Grundmann-Kollmann; Stephanie Simon; Tu-Anh Dang; Katja Hardt-Weinelt; Roland Kaufmann; August Bernd

2001-01-01

66

Peroxisome proliferator-activated receptor ? activation induces 11?-hydroxysteroid dehydrogenase type 1 activity in human alternative macrophages  

PubMed Central

Objectives 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) catalyses the intracellular reduction of inactive cortisone to active cortisol, the natural ligand activating the glucocorticoid receptor (GR). Peroxisome Proliferator-Activated Receptor gamma (PPAR?) is a nuclear receptor controlling inflammation, lipid metabolism and the macrophage polarization state. In this study, we investigated the impact of macrophage polarization on the expression and activity of 11?-HSD1 and the role of PPAR therein. Methods and Results 11?-HSD1 gene expression is higher in pro-inflammatory M1 and anti-inflammatory M2 macrophages than in resting macrophages (RM), whereas its activity is highest in M2 macrophages. Interestingly, PPAR? activation induces 11?-HSD1 enzyme activity in M2 macrophages, but not in RM or M1 macrophages. Consequently, human M2 macrophages displayed enhanced responsiveness to the 11?-HSD1 substrate cortisone, an effect amplified by PPAR -induction of 11?-HSD1 activity, as illustrated by an increased expression of GR target genes. Conclusions Our data identify a positive cross-talk between PPAR? and GR in human M2 macrophages via the induction of 11?-HSD1 expression and activity.

Chinetti-Gbaguidi, Giulia; Bouhlel, Mohamed Amine; Copin, Corinne; Duhem, Christian; Derudas, Bruno; Neve, Bernardette; Noel, Benoit; Eeckhoute, Jerome; Lefebvre, Philippe; Seckl, Jonathan R.; Staels, Bart

2012-01-01

67

The Hansenula polymorpha PEX14 gene encodes a novel peroxisomal membrane protein essential for peroxisome biogenesis.  

PubMed Central

We have cloned the Hansenula polymorpha PEX14 gene by functional complementation of the chemically induced pex14-1 mutant, which lacked normal peroxisomes. The sequence of the PEX14 gene predicts a novel protein product (Pex14p) of 39 kDa which showed no similarity to any known protein and lacked either of the two known peroxisomal targeting signals. Biochemical and electron microscopical analysis indicated that Pex14p is a component of the peroxisomal membrane. The synthesis of Pex14p is induced by peroxisome-inducing growth conditions. In cells of both pex14-1 and a PEX14 disruption mutant, peroxisomal membrane remnants were evident; these contained the H.polymorpha peroxisomal membrane protein Pex3p together with a small amount of the major peroxisomal matrix proteins alcohol oxidase, catalase and dihydroxyacetone synthase, the bulk of which resided in the cytosol. Unexpectedly, overproduction of Pex14p in wild-type H. polymorpha cells resulted in a peroxisome-deficient phenotype typified by the presence of numerous small vesicles which lacked matrix proteins; these were localized in the cytosol. Apparently, the stoichiometry of Pex14p relative to one or more other components of the peroxisome biogenesis machinery appears to be critical for protein import.

Komori, M; Rasmussen, S W; Kiel, J A; Baerends, R J; Cregg, J M; van der Klei, I J; Veenhuis, M

1997-01-01

68

Inhibition of c-Jun-N-terminal Kinase Increases Cardiac Peroxisome Proliferator-activated Receptor ? Expression and Fatty Acid Oxidation and Prevents Lipopolysaccharide-induced Heart Dysfunction*  

PubMed Central

Septic shock results from bacterial infection and is associated with multi-organ failure, high mortality, and cardiac dysfunction. Sepsis causes both myocardial inflammation and energy depletion. We hypothesized that reduced cardiac energy production is a primary cause of ventricular dysfunction in sepsis. The JNK pathway is activated in sepsis and has also been implicated in impaired fatty acid oxidation in several tissues. Therefore, we tested whether JNK activation inhibits cardiac fatty acid oxidation and whether blocking JNK would restore fatty acid oxidation during LPS treatment. LPS treatment of C57BL/6 mice and adenovirus-mediated activation of the JNK pathway in cardiomyocytes inhibited peroxisome proliferator-activated receptor ? expression and fatty acid oxidation. Surprisingly, none of the adaptive responses that have been described in other types of heart failure, such as increased glucose utilization, reduced ?MHC:?MHC ratio or induction of certain microRNAs, occurred in LPS-treated mice. Treatment of C57BL/6 mice with a general JNK inhibitor (SP600125) increased fatty acid oxidation in mice and a cardiomyocyte-derived cell line. JNK inhibition also prevented LPS-mediated reduction in fatty acid oxidation and cardiac dysfunction. Inflammation was not alleviated in LPS-treated mice that received the JNK inhibitor. We conclude that activation of JNK signaling reduces fatty acid oxidation and prevents the peroxisome proliferator-activated receptor ? down-regulation that occurs with LPS.

Drosatos, Konstantinos; Drosatos-Tampakaki, Zoi; Khan, Raffay; Homma, Shunichi; Schulze, P. Christian; Zannis, Vassilis I.; Goldberg, Ira J.

2011-01-01

69

NAFENOPIN-INDUCED HEPATIC MICROBODY (PEROXISOME) PROLIFERATION AND CATALASE SYNTHESIS IN RATS AND MICE  

Microsoft Academic Search

Nafenopin (2-methyl-2(p-(1,2,3,4-tetrahydro-l-naphthyl)phenoxy)-propionic acid ; Su- 13437), a potent hypolipidemic compound, was administered in varying concentrations in ground Purina Chow to male and female rats, wild type (Csa strain) mice and acatalasemic (Csb strain) mice to determine the hepatic microbody proliferative and catalase-inducing effects . In all groups of animals, administration of nafenopin at dietary levels of 0 .125% and 0.25%

JARNARDAN K. REDDY; DANIEL L. AZARNOFF; DONALD J. SVOBODA; JADA D. PRASAD

70

Peroxisome Proliferator-Activated Receptor ; as a Molecular Target of Resveratrol-Induced Modulation of Polyamine Metabolism  

Microsoft Academic Search

Previous results indicate that the polyphenol resveratrol inhibits cell growth of colon carcinoma cells via modulation of polyamine metabolic key enzymes. The aim of this work was to specify the underlying molecular mechanisms and to identify a possible role of transcription factor peroxisome proliferator-activated receptor ; (PPAR;). Cell growth was determined by bromodeoxyuridine incorporation and crystal violet staining. Protein levels

Sandra Ulrich; Stefan M. Loitsch; Oliver Rau; Andreas von Knethen; Bernhard Brune; Manfred Schubert-Zsilavecz; Jurgen M. Stein

71

Peroxisomal Proliferator-Activated Receptor  Agonists Induce Partial Reversion of Epithelial-Mesenchymal Transition in Anaplastic Thyroid Cancer Cells  

Microsoft Academic Search

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor characterized by marked epithelial mesenchymal tran- sition, which leads, almost invariably, to death. Peroxisomal proliferator-activated receptor (PPAR)- agonists have re- centlyemergedaspotentialantineoplasticdrugs.Toestablish whether ATC could be a target of PPAR agonists, we first examined PPAR protein expression in a panel of six ATC cell lines and then studied the biologic effects of

Aurora Aiello; Giuseppe Pandini; Francesco Frasca; Enrico Conte; Antonella Murabito; Antonella Sacco; Marco Genua; Riccardo Vigneri; Antonino Belfiore

2006-01-01

72

Statins enhance peroxisome proliferator-activated receptor ? coactivator-1? activity to regulate energy metabolism  

Microsoft Academic Search

Peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) serves as an inducible coactivator for a number of transcription\\u000a factors to control energy metabolism. Insulin signaling through Akt kinase has been demonstrated to phosphorylate PGC-1? at\\u000a serine 571 and downregulate its activity in the liver. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors\\u000a that reduce cholesterol synthesis in the liver. In this study, we

Wenxian Wang; Chi-Wai Wong

2010-01-01

73

Peroxisome proliferator-induced acyl-CoA thioesterase from rat liver cytosol: molecular cloning and functional expression in Chinese hamster ovary cells.  

PubMed Central

We have isolated and cloned a cDNA that codes for one of the peroxisome proliferator-induced acyl-CoA thioesterases of rat liver. The deduced amino acid sequence corresponds to the major induced isoform in cytosol. Analysis and comparison of the deduced amino acid sequence with the established consensus sequences suggested that this enzyme represents a novel kind of esterase with an incomplete lipase serine active site motif. Analyses of mRNA and its expression indicated that the enzyme is significantly expressed in liver only after peroxisome proliferator treatment, but isoenzymes are constitutively expressed at high levels in testis and brain. The reported cDNA sequence is highly homologous to the recently cloned brain acyl-CoA thioesterase [Broustas, Larkins, Uhler and Hajra (1996) J. Biol. Chem. 271, 10470-10476], but subtle differences throughout the sequence, and distinct differences close to the resulting C-termini, suggest that they are different enzymes, regulated in different manners. A full-length cDNA clone was expressed in Chinese hamster ovary cells and the expressed enzyme was characterized. The palmitoyl-CoA hydrolysing activity (Vmax) was induced approx. 9-fold to 1 micromol/min per mg of cell protein, which was estimated to correspond to a specific activity of 250 micromol/min per mg of cDNA-expressed enzyme. Both the specific activity and the acyl-CoA chain length specificity were very similar to those of the purified rat liver enzyme.

Engberg, S T; Aoyama, T; Alexson, S E; Hashimoto, T; Svensson, L T

1997-01-01

74

Role of the p50 subunit of NF-?B in vitamin E-induced changes in mice treated with the peroxisome proliferator, ciprofibrate  

PubMed Central

Peroxisome proliferators (PPs) are a diverse class of chemicals, which cause a dramatic increase in the size and number of hepatic peroxisomes in rodents and eventually lead to the development of hepatic tumors. Nuclear factor-?B (NF-?B) is a transcription factor activated by reactive oxygen and is involved in cell proliferation and apoptosis. Previously we found that the peroxisome proliferator ciprofibrate (CIP) activates NF-?B and that dietary vitamin E decreases CIP-induced NF-?B DNA binding. We therefore hypothesized that inhibition of NF-?B by vitamin E is necessary for effects of vitamin E on CIP-induced cell proliferation and the inhibition of apoptosis by CIP. Sixteen B6129 female mice (p50+/+) and twenty mice deficient in the p50 subunit of NF-?B (p50?/?) were fed a purified diet containing 10 or 250 mg/kg vitamin E (?-tocopherol acetate) for 28 days. At that time, half of the mice were placed on the same diet with 0.01% CIP for 10 days. CIP treatment increased the DNA binding activity of NF-?B and cell proliferation, but had no significant effect on apoptosis. Compared to wild-type mice, the p50?/? mice had lower NF-?B activation, higher basal levels of cell proliferation and apoptosis, and a lower ratio of reduced glutathione to oxidized glutathione (GSH/GSSG). There was approximately a 60% reduction in cell proliferation in the CIP-treated p50?/? mice fed higher vitamin E in comparison to the p50?/? mice fed lower vitamin E. Dietary vitamin E also inhibited the DNA binding activity of NF-?B, increased apoptosis, and increased the GSH/GSSG ratio. This study shows the effects of vitamin E on cell growth parameters do not appear to be solely through decreased NF-?B activation, suggesting that vitamin E is acting by other molecular mechanisms.

Calfee-Mason, Karen G.; Lee, Eun Y.; Spear, Brett T.; Glauert, Howard P.

2008-01-01

75

Proteolytic cleavage of plant proteins by peroxisomal endoproteases from senescent pea leaves  

Microsoft Academic Search

.   The degradation of peroxisomal and nonperoxisomal proteins by endoproteases of purified peroxisomes from senescent pea (Pisum sativum L.) leaves has been investigated. In our experimental conditions, most peroxisomal proteins were endoproteolytically degraded.\\u000a This cleavage was prevented, to some extent, by incubation with 2?mM phenylmethylsulfonylfluoride, an inhibitor of serine\\u000a proteinases. The peroxisomal enzymes glycolate oxidase (EC 1.1.3.1), catalase (EC 1.11.1.6)

Stefania Distefano; José M. Palma; Iva McCarthy; Luis A. del Río

1999-01-01

76

Peroxisome proliferator-activated receptor ? ligands induce cell cycle arrest and apoptosis in human renal carcinoma cell lines  

Microsoft Academic Search

Aim:To study the effect of peroxisome proliferator-actived receptor ? (PPAR?) ligands on cell proliferation and apoptosis in human renal carcinoma cell lines.Methods:The expression of PPAR? was investigated by reverse transcriptase polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry. The effect of thiazolidinedione (TZD) PPAR? ligands on growth of renal cell carcinoma (RCC) cells was measured by MTT assay and flow

Feng-guang Yang; Zhi-wen Zhang; Dian-qi Xin; Chang-jin Shi; Jie-ping Wu; Ying-lu Guo; You-fei Guan

2005-01-01

77

Transient complex peroxisomal interactions  

PubMed Central

Mitochondria and peroxisomes are ubiquitous subcellular organelles that fulfill essential metabolic functions, rendering them indispensable for human development and health. Both are highly dynamic organelles that can undergo remarkable changes in morphology and number to accomplish cellular needs. While mitochondrial dynamics are also regulated by frequent fusion events, the fusion of mature peroxisomes in mammalian cells remained a matter of debate. In our recent study, we clarified systematically that there is no complete fusion of mature peroxisomes analogous to mitochondria. Moreover, in contrast to key division components such as DLP1, Fis1 or Mff, mitochondrial fusion proteins were not localized to peroxisomes. However, we discovered and characterized novel transient, complex interactions between individual peroxisomes which may contribute to the homogenization of the often heterogeneous peroxisomal compartment, e.g., by distribution of metabolites, signals or other “molecular information” via interperoxisomal contact sites.

Bonekamp, Nina A.; Schrader, Michael

2012-01-01

78

Peroxisome diversity and evolution  

PubMed Central

Peroxisomes are organelles bounded by a single membrane that can be found in all major groups of eukaryotes. A single evolutionary origin of this cellular compartment is supported by the presence, in diverse organisms, of a common set of proteins implicated in peroxisome biogenesis and maintenance. Their enzymatic content, however, can vary substantially across species, indicating a high level of evolutionary plasticity. Proteomic analyses have greatly expanded our knowledge on peroxisomes in some model organisms, including plants, mammals and yeasts. However, we still have a limited knowledge about the distribution and functionalities of peroxisomes in the vast majority of groups of microbial eukaryotes. Here, I review recent advances in our understanding of peroxisome diversity and evolution, with a special emphasis on peroxisomes in microbial eukaryotes.

Gabaldon, Toni

2010-01-01

79

Peroxisome Biogenesis and Function  

PubMed Central

Peroxisomes are small and single membrane-delimited organelles that execute numerous metabolic reactions and have pivotal roles in plant growth and development. In recent years, forward and reverse genetic studies along with biochemical and cell biological analyses in Arabidopsis have enabled researchers to identify many peroxisome proteins and elucidate their functions. This review focuses on the advances in our understanding of peroxisome biogenesis and metabolism, and further explores the contribution of large-scale analysis, such as in sillco predictions and proteomics, in augmenting our knowledge of peroxisome function In Arabidopsis.

Kaur, Navneet; Reumann, Sigrun; Hu, Jianping

2009-01-01

80

The peroxisome proliferator-activated receptor ?/? (PPAR?/?) agonist GW501516 prevents TNF-?-induced NF-?B activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1.  

PubMed

Nuclear factor (NF)-?B is a ubiquitously expressed transcription factor controlling the expression of numerous genes involved in inflammation. The aim of this study was to evaluate whether activation of the peroxisome proliferator-activated receptor (PPAR) ?/? prevented TNF-?-induced NF-?B activation in human HaCaT keratinocytes and, if so, to determine the mechanism involved. The PPAR?/? agonist GW501516 inhibited the increase caused by TNF-? in the mRNA levels of the NF-?B target genes interleukin 8 (IL-8), TNF-? and thymic stromal lymphopoietin (TSLP). Likewise, GW501516 prevented the increase in NF-?B DNA-binding activity observed in cells exposed to TNF-?. The reduction in NF-?B activity following GW501516 treatment in cells stimulated with TNF-? did not involve either increased I?B? protein levels or a reduction in the translocation of the p65 subunit of NF-?B. In contrast, GW501516 treatment decreased TNF-?-induced p65 acetylation. Acetylation of p65 is mainly regulated by p300, a transcriptional co-activator that binds to and acetylates p65. Of note, AMP kinase (AMPK) activation phosphorylates p300 and reduces its binding to p65. GW501516 increased AMPK phosphorylation and the subsequent p300 phosphorylation, leading to a marked reduction in the association between p65 and this transcriptional co-activator. In addition, treatment with the PPAR?/? agonist increased SIRT1 protein levels. Finally, the reduction in IL-8 mRNA levels following GW501516 treatment in TNF-?-stimulated cells was abolished in the presence of the PPAR?/? antagonist GSK0660, the AMPK inhibitor compound C and the SIRT1 inhibitor sirtinol, indicating that the effects of GW501516 on NF-?B activity were dependent on PPAR?/?, AMPK and SIRT1, respectively. PMID:21146504

Barroso, Emma; Eyre, Elena; Palomer, Xavier; Vázquez-Carrera, Manuel

2010-12-10

81

Treatment of Bacterial Induced Diseases Using DNA Methyl Transferase Inhibitors.  

National Technical Information Service (NTIS)

Methods for treating and/or preventing disease conditions caused or induced or aggravated by microbes, especially bacteria, by inhibiting DNA methyltransferase activity, such as by administering to an animal a DNA methyltransferase inhibitor, are disclose...

C. Stephens L. Shapiro L. S. Kahng R. Wright S. J. Benkovic

2003-01-01

82

Mitochondrial division/mitophagy inhibitor (Mdivi) Ameliorates Pressure Overload Induced Heart Failure  

PubMed Central

Background We have previously reported the role of anti-angiogenic factors in inducing the transition from compensatory cardiac hypertrophy to heart failure and the significance of MMP-9 and TIMP-3 in promoting this process during pressure overload hemodynamic stress. Several studies reported the evidence of cardiac autophagy, involving removal of cellular organelles like mitochondria (mitophagy), peroxisomes etc., in the pathogenesis of heart failure. However, little is known regarding the therapeutic role of mitochondrial division inhibitor (Mdivi) in the pressure overload induced heart failure. We hypothesize that treatment with mitochondrial division inhibitor (Mdivi) inhibits abnormal mitophagy in a pressure overload heart and thus ameliorates heart failure condition. Materials and Methods To verify this, ascending aortic banding was done in wild type mice to create pressure overload induced heart failure and then treated with Mdivi and compared with vehicle treated controls. Results Expression of MMP-2, vascular endothelial growth factor, CD31, was increased, while expression of anti angiogenic factors like endostatin and angiostatin along with MMP-9, TIMP-3 was reduced in Mdivi treated AB 8 weeks mice compared to vehicle treated controls. Expression of mitophagy markers like LC3 and p62 was decreased in Mdivi treated mice compared to controls. Cardiac functional status assessed by echocardiography showed improvement and there is also a decrease in the deposition of fibrosis in Mdivi treated mice compared to controls. Conclusion Above results suggest that Mdivi inhibits the abnormal cardiac mitophagy response during sustained pressure overload stress and propose the novel therapeutic role of Mdivi in ameliorating heart failure.

Givvimani, Srikanth; Munjal, Charu; Tyagi, Neetu; Sen, Utpal; Metreveli, Naira; Tyagi, Suresh C.

2012-01-01

83

Peroxisomal disorders in neurology  

Microsoft Academic Search

Although peroxisomes were initially believed to play only a minor role in mammalian metabolism, it is now clear that they catalyse essential reactions in a number of different metabolic pathways and thus play an indispensable role in intermediary metabolism. The metabolic pathways in which peroxisomes are involved include the biosynthesis of ether phospholipids and bile acids, the oxidation of very

R. J. A. Wanders; H. S. A. Heymans; R. B. H. Schutgens; P. G. Barth; H. van den Bosch; J. M. Tager

1988-01-01

84

CD36 signaling inhibits the translation of heat shock protein 70 induced by oxidized low density lipoprotein through activation of peroxisome proliferators-activated receptor ?  

PubMed Central

Oxidized LDL (OxLDL), a causal factor in atherosclerosis, induces the expression of heat shock proteins (Hsp) in a variety of cells. In this study, we investigated the role of CD36, an OxLDL receptor, and peroxisome proliferator-activated receptor ? (PPAR?) in OxLDL-induced Hsp70 expression. Overexpression of dominant-negative forms of CD36 or knockdown of CD36 by siRNA transfection increased OxLDL-induced Hsp70 protein expression in human monocytic U937 cells, suggesting that CD36 signaling inhibits Hsp70 expression. Similar results were obtained by the inhibition of PPAR? activity or knockdown of PPAR? expression. In contrast, overexpression of CD36, which is induced by treatment of MCF-7 cells with troglitazone, decreased Hsp70 protein expression induced by OxLDL. Interestingly, activation of PPAR? through a synthetic ligand, ciglitazone or troglitazone, decreased the expression levels of Hsp70 protein in OxLDL-treated U937 cells. However, major changes in Hsp70 mRNA levels were not observed. Cycloheximide studies demonstrate that troglitazone attenuates Hsp70 translation but not Hsp70 protein stability. PPAR? siRNA transfection reversed the inhibitory effects of troglitazone on Hsp70 translation. These results suggest that CD36 signaling may inhibit stress-induced gene expression by suppressing translation via activation of PPAR? in monocytes. These findings reveal a new molecular basis for the anti-inflammatory effects of PPAR?.

Lee, Kyoung-Jin; Ha, Eun-Soo; Kim, Min-Kyoung; Lee, Sang-Hoon; Suh, Jae Sung; Lee, Sun-Hee; Park, Kyeong Han; Park, Jeong Hyun; Kim, Dae Joong; Kang, Dongmin; Kim, Byung-Chul; Jeoung, Dooil; Kim, Young-Kyoun; Kim, Ho-Dirk

2008-01-01

85

Bisphenol A diglycidyl ether induces apoptosis in tumour cells independently of peroxisome proliferator-activated receptor-gamma, in caspase-dependent and -independent manners.  

PubMed

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors which are involved in many biological processes, such as regulation of cell differentiation, lipid metabolism, inflammation and cell death. PPARs consist of three families, PPAR-alpha, PPAR-delta and PPAR-gamma. Bisphenol A diglycidyl ether (BADGE) has been described as a pure antagonist of PPAR-gamma. However, recent data also revealed PPAR-gamma-agonistic activities of BADGE. Here we show that BADGE kills transformed cells by apoptosis and promotes the cytotoxic effects of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and indomethacin. The cytotoxic effect of BADGE does not require PPAR-gamma expression and is mediated in caspase-dependent and caspase-independent manners. PMID:11879183

Fehlberg, Sebastian; Trautwein, Stefan; Göke, Alexandra; Göke, Rüdiger

2002-03-15

86

Activation of peroxisome proliferator-activated receptor-{delta} by GW501516 prevents fatty acid-induced nuclear factor-{kappa}B activation and insulin resistance in skeletal muscle cells.  

PubMed

Elevated plasma free fatty acids cause insulin resistance in skeletal muscle through the activation of a chronic inflammatory process. This process involves nuclear factor (NF)-kappaB activation as a result of diacylglycerol (DAG) accumulation and subsequent protein kinase Ctheta (PKCtheta) phosphorylation. At present, it is unknown whether peroxisome proliferator-activated receptor-delta (PPARdelta) activation prevents fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. In C2C12 skeletal muscle cells, the PPARdelta agonist GW501516 prevented phosphorylation of insulin receptor substrate-1 at Ser(307) and the inhibition of insulin-stimulated Akt phosphorylation caused by exposure to the saturated fatty acid palmitate. This latter effect was reversed by the PPARdelta antagonist GSK0660. Treatment with the PPARdelta agonist enhanced the expression of two well known PPARdelta target genes involved in fatty acid oxidation, carnitine palmitoyltransferase-1 and pyruvate dehydrogenase kinase 4 and increased the phosphorylation of AMP-activated protein kinase, preventing the reduction in fatty acid oxidation caused by palmitate exposure. In agreement with these changes, GW501516 treatment reversed the increase in DAG and PKCtheta activation caused by palmitate. These effects were abolished in the presence of the carnitine palmitoyltransferase-1 inhibitor etomoxir, thereby indicating that increased fatty acid oxidation was involved in the changes observed. Consistent with these findings, PPARdelta activation by GW501516 blocked palmitate-induced NF-kappaB DNA-binding activity. Likewise, drug treatment inhibited the increase in IL-6 expression caused by palmitate in C2C12 and human skeletal muscle cells as well as the protein secretion of this cytokine. These findings indicate that PPARdelta attenuates fatty acid-induced NF-kappaB activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Our results point to PPARdelta activation as a pharmacological target to prevent insulin resistance. PMID:20185762

Coll, Teresa; Alvarez-Guardia, David; Barroso, Emma; Gómez-Foix, Anna Maria; Palomer, Xavier; Laguna, Juan C; Vázquez-Carrera, Manuel

2010-02-25

87

Neuronal apoptosis induced by histone deacetylase inhibitors  

Microsoft Academic Search

Histone acetylation has a key role in transcriptional activation, whereas deacetylation of histones correlates with the transcriptional repression and silencing of genes. Genetic repression may have an important role in neuronal aging, atrophy and degenerative diseases. Our aim was to study how histone deacetylase inhibitors, trichostatin A (TSA) and sodium butyrate, affect the metabolism of cultured rat cerebellar granule neurons

Antero Salminen; Tero Tapiola; Pauliina Korhonen; Tiina Suuronen

1998-01-01

88

The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation.  

PubMed

Increased NADP reduced (NADPH) oxidase 4 (Nox4) and reduced expression of the nuclear hormone receptor peroxisome proliferator-activated receptor ? (PPAR?) contribute to hypoxia-induced pulmonary hypertension (PH). To examine the role of Nox4 activity in pulmonary vascular cell proliferation and PH, the current study used a novel Nox4 inhibitor, GKT137831, in hypoxia-exposed human pulmonary artery endothelial or smooth muscle cells (HPAECs or HPASMCs) in vitro and in hypoxia-treated mice in vivo. HPAECs or HPASMCs were exposed to normoxia or hypoxia (1% O(2)) for 72 hours with or without GKT137831. Cell proliferation and Nox4, PPAR?, and transforming growth factor (TGF)?1 expression were measured. C57Bl/6 mice were exposed to normoxia or hypoxia (10% O(2)) for 3 weeks with or without GKT137831 treatment during the final 10 days of exposure. Lung PPAR? and TGF-?1 expression, right ventricular hypertrophy (RVH), right ventricular systolic pressure (RVSP), and pulmonary vascular remodeling were measured. GKT137831 attenuated hypoxia-induced H(2)O(2) release, proliferation, and TGF-?1 expression and blunted reductions in PPAR? in HPAECs and HPASMCs in vitro. In vivo GKT137831 inhibited hypoxia-induced increases in TGF-?1 and reductions in PPAR? expression and attenuated RVH and pulmonary artery wall thickness but not increases in RVSP or muscularization of small arterioles. This study shows that Nox4 plays a critical role in modulating proliferative responses of pulmonary vascular wall cells. Targeting Nox4 with GKT137831 provides a novel strategy to attenuate hypoxia-induced alterations in pulmonary vascular wall cells that contribute to vascular remodeling and RVH, key features involved in PH pathogenesis. PMID:22904198

Green, David E; Murphy, Tamara C; Kang, Bum-Yong; Kleinhenz, Jennifer M; Szyndralewiez, Cédric; Page, Patrick; Sutliff, Roy L; Hart, C Michael

2012-08-16

89

Bisphenol A Diglycidyl Ether Induces Adipogenic Differentiation of Multipotent Stromal Stem Cells through a Peroxisome Proliferator-Activated Receptor Gamma-Independent Mechanism  

PubMed Central

Background: Bisphenol A (BPA) and bisphenol A diglycidyl ether (BADGE), used in manufacturing coatings and resins, leach from packaging materials into food. Numerous studies suggested that BPA and BADGE may have adverse effects on human health, including the possibility that exposure to such chemicals can be superimposed on traditional risk factors to initiate or exacerbate the development of obesity. BPA is a suspected obesogen, whereas BADGE, described as a peroxisome proliferator–activated receptor gamma (PPAR?) antagonist, could reduce weight gain. Objectives: We sought to test the adipogenic effects of BADGE in a biologically relevant cell culture model. Methods: We used multipotent mesenchymal stromal stem cells (MSCs) to study the adipogenic capacity of BADGE and BPA and evaluated their effects on adipogenesis, osteogenesis, gene expression, and nuclear receptor activation. Discussion: BADGE induced adipogenesis in human and mouse MSCs, as well as in mouse 3T3-L1 preadipocytes. In contrast, BPA failed to promote adipogenesis in MSCs, but induced adipogenesis in 3T3-L1 cells. BADGE exposure elicited an adipogenic gene expression profile, and its ability to induce adipogenesis and the expression of adipogenic genes was not blocked by known PPAR? antagonists. Neither BADGE nor BPA activated or antagonized retinoid “X” receptor (RXR) or PPAR? in transient transfection assays. Conclusions: BADGE can induce adipogenic differentiation in both MSCs and in preadipocytes at low nanomolar concentrations comparable to those that have been observed in limited human biomonitoring. BADGE probably acts through a mechanism that is downstream of, or parallel to, PPAR?.

Chamorro-Garcia, Raquel; Kirchner, Severine; Li, Xia; Janesick, Amanda; Casey, Stephanie C.; Chow, Connie

2012-01-01

90

Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathways  

Microsoft Academic Search

ZM447439 (ZM) is a potent and selective inhibitor of aurora-A and -B kinase with putative anti-tumoral activity. Inhibitors of aurora kinases were shown to induce apoptosis in vitro and in vivo. To investigate the underlying mechanisms, cell death pathways triggered by ZM was analysed in HCT-116 colorectal cancer cells. Through correlation of polyploidization and apoptosis in different knockout cells, the

Minglun Li; Anke Jung; Ute Ganswindt; Patrizia Marini; Anna Friedl; Peter T. Daniel; Kirsten Lauber; Verena Jendrossek; Claus Belka

2010-01-01

91

Transformation of Epithelial Cells Stably Transfected with H202-generating Peroxisomal Urate Oxidase1  

Microsoft Academic Search

Peroxisome proliferators, a group of structurally diverse nongenotoxic agents, induce predictable pleiotropic responses in liver, including the developmentofliver tumorsin rats and mice. These agentstranscription ally activate the three genes ofthe peroxisomal fi oxidation enzymesystem by interacting with the peroxisome proliferator-activated receptor(s). It has been proposedthat H202 generatedby the peroxisomal(I oxidation system leads to DNA damage and neoplastictransformation.Consistent with this hypothesis

Ruiyrn Chu; Yulian Lin; Kirthi C. Reddy; Jie Pan; M. Sambasiva Rao; Janardan K. Reddy; Anjana V. Yeldandi

92

Vinegar-Baked Radix Bupleuri Regulates Lipid Disorders via a Pathway Dependent on Peroxisome-Proliferator-Activated Receptor-? in High-Fat-Diet-Induced Obese Rats  

PubMed Central

The aim of this study was to investigate the antiobesity and antihyperlipidemic effects of vinegar-baked Radix Bupleuri (VBRB) on high-fat diet- (HFD-) induced obese rats. After being fed HFD for two weeks, rats were dosed orally with VBRB or fenofibrate, once daily for further twelve weeks. VBRB (1.0?g?kg?1 per day) produced effects similar to fenofibrate (100?mg?kg?1) in reducing body weight (BW) gain, visceral fat-pad weights, plasma lipid levels, as well as hepatic TG and cholesterol content of HFD-fed rats. VBRB also lowered hepatic lipid droplet accumulation and the size of epididymal adipocytes in HFD-fed rats. VBRB and fenofibrate reversed the HFD-induced downregulation of hepatic peroxisome proliferator-activated receptor (PPAR)?. HFD-induced reductions in the hepatic levels of acyl-CoA oxidase (ACO) and cytochrome P450 isoform 4A1 (CYP4A1) proteins were reversed by VBRB and fenofibrate. The elevated expression of hepatic sterol regulatory element binding proteins (SREBPs) in HFD-fed rats was lowered by VBRB and fenofibrate. The results of this study show that VBRB suppresses BW gain and body fat accumulation by increasing fatty acid oxidation, an effect which is likely mediated via upregulation of PPAR? and downregulation of SREBP expression in the liver of HFD-fed rats.

Tzeng, Thing-Fong; Lu, Hung-Jen; Liou, Shorong-Shii; Chang, Chia Ju; Liu, I-Min

2012-01-01

93

Characterization of Aspergillus nidulans peroxisomes by immunoelectron microscopy.  

PubMed

In previous work, we have demonstrated that oleate induces a massive proliferation of microbodies (peroxisomes) in Aspergillus nidulans. Although at a lower level, proliferation of peroxisomes also occurs in cells growing under conditions that induce penicillin biosynthesis. Here, microbodies in oleate-grown A. nidulans cells were characterized by using several antibodies that recognize peroxisomal enzymes and peroxins in a broad spectrum of eukaryotic organisms such as yeast, and plant, and mammalian cells. Peroxisomes were immunolabeled by anti-SKL and anti-thiolase antibodies, which suggests that A. nidulans conserves both PTS1 and PTS2 import mechanisms. Isocitrate lyase and malate synthase, the two key enzymes of the glyoxylate cycle, were also localized in these organelles. In contrast to reports of Neurospora crassa, our results demonstrate that A. nidulans contains only one type of microbody (peroxisomes) that carry out the glyoxylate cycle and contain 3-ketoacyl-CoA thiolase and proteins with the C-terminal SKL tripeptide. PMID:9818356

Valenciano, S; De Lucas, J R; Van der Klei, I; Veenhuis, M; Laborda, F

1998-10-01

94

The peroxisomal catalase gene in the methylotrophic yeast Pichia methanolica.  

PubMed

In this paper, we describe the CTA1 gene, which encodes a peroxisomal catalase in the methylotrophic yeast Pichia methanolica. The P. methanolica CTA1 gene (PmCTA1) comprises a 1,530-bp open reading frame corresponding to a protein of 510 amino acid residues, and its deduced amino acid sequence shows high similarity to those of Cta1ps from other methylotrophic yeasts (about 79%). Expression of PmCTA1 in a peroxisomal catalase-depleted (Cbcta1Delta) Candida boidinii strain restored the methylotrophic growth of the host strain, while the expression of PmCTA1-DeltaSRL, which lacks peroxisome targeting signal type 1, did not. In P. methanolica, expression of PmCTA1 was induced when cells were grown on peroxisome-inducing carbon sources, viz., methanol, oleate, and D-alanine. Taken together, these results indicate that PmCTA1 encodes a functional peroxisomal catalase in P. methanolica. PMID:20699560

Nakagawa, Tomoyuki; Yoshida, Kyoko; Takeuchi, Akihito; Ito, Takashi; Fujimura, Shuki; Matsufuji, Yoshimi; Tomizuka, Noboru; Yurimoto, Hiroya; Sakai, Yasuyoshi; Hayakawa, Takashi

2010-08-07

95

Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis through the Modulation of Peroxisome Proliferator-activated Receptor ? Activation Pathway in Gastric Cancer*  

PubMed Central

Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3?-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor ? (PPAR-?) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-? inhibitor. We found that IH increased PPAR-? activity and modulated the expression of PPAR-? regulated genes in GC cells. Also, the increase in PPAR-? activity was reversed in the presence of PPAR-?-specific inhibitor and a mutated PPAR-? dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-?. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-? that are reported to be critical for its activity and could competitively bind to PPAR-?. IH significantly increased the expression of PPAR-? in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-? activation pathway in GC.

Ramachandran, Lalitha; Manu, Kanjoormana Aryan; Shanmugam, Muthu K.; Li, Feng; Siveen, Kodappully Sivaraman; Vali, Shireen; Kapoor, Shweta; Abbasi, Taher; Surana, Rohit; Smoot, Duane T.; Ashktorab, Hassan; Tan, Patrick; Ahn, Kwang Seok; Yap, Chun Wei; Kumar, Alan Prem; Sethi, Gautam

2012-01-01

96

Activation of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) induces cell death through MAPK-dependent mechanism in osteoblastic cells  

SciTech Connect

The present study was undertaken to determine the role of the mitogen-activated protein kinase (MAPK) subfamilies in cell death induced by PPAR{gamma} agonists in osteoblastic cells. Ciglitazone and troglitazone, PPAR{gamma} agonists, resulted in a concentration- and time-dependent cell death, which was largely attributed to apoptosis. But a PPAR{alpha} agonist ciprofibrate did not affect the cell death. Ciglitazone caused reactive oxygen species (ROS) generation and ciglitazone-induced cell death was prevented by antioxidants, suggesting an important role of ROS generation in the ciglitazone-induced cell death. ROS generation and cell death induced by ciglitazone were inhibited by the PPAR{gamma} antagonist GW9662. Ciglitazone treatment caused activation of extracellular signal-regulated kinase (ERK) and p38. Activation of ERK was dependent on epidermal growth factor receptor (EGFR) and that of p38 was independent. Ciglitazone-induced cell death was significantly prevented by PD98059, an inhibitor of ERK upstream kinase MEK1/2, and SB203580, a p38 inhibitor. Ciglitazone treatment increased Bax expression and caused a loss of mitochondrial membrane potential, and its effect was prevented by N-acetylcysteine, PD98059, and SB203580. Ciglitazone induced caspase activation, which was prevented by PD98059 and SB203580. The general caspase inhibitor z-DEVD-FMK and the specific inhibitor of caspases-3 DEVD-CHO exerted the protective effect against the ciglitazone-induced cell death. The EGFR inhibitors AG1478 and suramin protected against the ciglitazone-induced cell death. Taken together, these findings suggest that the MAPK signaling pathways play an active role in mediating the ciglitazone-induced cell death of osteoblasts and function upstream of a mitochondria-dependent mechanism. These data may provide a novel insight into potential therapeutic strategies for treatment of osteoporosis.

Kim, Sung Hun [Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of); Yoo, Chong Il [Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of); Medical Research Institute, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of); Kim, Hui Taek [Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of); Medical Research Institute, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of); Park, Ji Yeon [Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of); Kwon, Chae Hwa [Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of); Keun Kim, Yong [Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of) and Medical Research Institute, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of) and MRC for Ischemic Tissue Regeneration, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of)]. E-mail: kim430@pusan.ac.kr

2006-09-01

97

Ketogenic diet-induced peroxisome proliferator-activated receptor-? activation decreases neuroinflammation in the mouse hippocampus after kainic acid-induced seizures  

Microsoft Academic Search

Similar to fasting, the ketogenic diet (KD) has anti-inflammatory effects and protects against excitotoxicity-mediated neuronal cell death. Recent studies have shown that peroxisome proliferator-activated receptor (PPAR)? has anti-inflammatory effects in seizure animal models. However, the exact mechanisms underlying the anti-inflammatory effects of the KD have not been determined for seizures. Here we investigated the effect of the KD and acetoacetate

Eun Ae Jeong; Byeong Tak Jeon; Hyun Joo Shin; Nayoung Kim; Dong Hoon Lee; Hyun Joon Kim; Sang Soo Kang; Gyeong Jae Cho; Wan Sung Choi; Gu Seob Roh

2011-01-01

98

Peroxisome proliferator-activated receptor {alpha}-independent peroxisome proliferation  

SciTech Connect

Hepatic peroxisome proliferation, increases in the numerical and volume density of peroxisomes, is believed to be closely related to peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) activation; however, it remains unknown whether peroxisome proliferation depends absolutely on this activation. To verify occurrence of PPAR{alpha}-independent peroxisome proliferation, fenofibrate treatment was used, which was expected to significantly enhance PPAR{alpha} dependence in the assay system. Surprisingly, a novel type of PPAR{alpha}-independent peroxisome proliferation and enlargement was uncovered in PPAR{alpha}-null mice. The increased expression of dynamin-like protein 1, but not peroxisome biogenesis factor 11{alpha}, might be associated with the PPAR{alpha}-independent peroxisome proliferation at least in part.

Zhang Xiuguo [Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621 (Japan); Tanaka, Naoki [Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621 (Japan) and Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621 (Japan)]. E-mail: naopi@hsp.md.shinshu-u.ac.jp; Nakajima, Takero [Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621 (Japan); Kamijo, Yuji [Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621 (Japan); Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621 (Japan); Gonzalez, Frank J. [Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892 (United States); Aoyama, Toshifumi [Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621 (Japan)

2006-08-11

99

Neuronal Inactivation of Peroxisome Proliferator-activated Receptor ? Coactivator 1? (PGC-1?) Protects Mice from Diet-induced Obesity and Leads to Degenerative Lesions*  

PubMed Central

Peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?) is a transcriptional coactivator that regulates diverse aspects of energy metabolism in peripheral tissues. Mice deficient in PGC-1? have elevated metabolic rate and are resistant to diet-induced obesity. However, it remains unknown whether this alteration in energy balance is due to the action of PGC-1? in peripheral tissues or the central nervous system. In this study, we generated neuronal PGC-1? knock-out mice (B?KO) using calcium/calmodulin-dependent protein kinase II? (CaMKII?)-Cre to address its role in the regulation of energy balance and neuronal function. Unlike whole body PGC-1? null mice, B?KO mice have normal adaptive metabolic response to starvation and cold exposure in peripheral tissues. In contrast, B?KO mice are hypermetabolic, and similar to whole body PGC-1? null mice, are also resistant to diet-induced obesity, resulting in significantly improved metabolic profiles. Neuronal inactivation of PGC-1? leads to striatal lesions that are reminiscent of neurodegeneration in whole body PGC-1? null brain and impairs nutritional regulation of hypothalamic expression of genes that regulate systemic energy balance. Together, these studies have demonstrated a physiological role for neuronal PGC-1? in the control of energy balance. Our results also implicate CaMKII?-positive neurons as an important part of the neural circuitry that governs energy expenditure in vivo.

Ma, Di; Li, Siming; Lucas, Elizabeth K.; Cowell, Rita M.; Lin, Jiandie D.

2010-01-01

100

Perfluorooctanoic Acid Induced-Developmental Cardiotoxicity: Are Peroxisome Proliferator Activated Receptor ? (PPAR?) and Bone Morphorgenic Protein 2 (BMP2) Pathways Involved?  

PubMed

Perfluorooctanoic acid (PFOA) is an environmental contaminant known to induce developmental toxicity in animal models through activation of the peroxisome proliferator-activated receptor ? (PPAR?). Previously, it was demonstrated that in ovo exposure to PFOA induced cardiotoxicity in chicken embryos and hatchlings. To investigate potential PPAR?-mediated mechanisms, fertile chicken eggs were injected prior to incubation with WY 14,643, a PPAR? agonist. Cardiac morphology and function were evaluated in late-stage embryos and hatchlings. Histologically, unlike PFOA, WY 14,643 did not induce thinning of the right ventricular wall. Via echocardiography, however, WY 14,643 induced effects similar to those of PFOA, including increased left ventricular wall thickness and mass, elevated heart rate, ejection fraction, fractional shortening, and decreased stroke volume. Additionally, to investigate mechanisms associated with early heart development, a separate group of fertile chicken eggs was injected prior to incubation with PFOA or WY 14,643 and in early-stage embryos, gene expression and protein concentration associated with the bone morphogenic protein (BMP2) pathway were determined. Although changes were not statistically consistent among doses, expression of BMP2, Nkx2.5, and GATA4 mRNA in early embryos was altered by PFOA exposure; however, protein concentrations of these targets were not markedly altered by either PFOA or WY 14,643. Protein levels of pSMAD1/5, a transcriptional regulator stimulated by BMPs, were altered by both PFOA and WY 14,643, but in different directions; PFOA reduced cytoplasmic pSMAD1/5, whereas WY 14,643 decreased nuclear pSMAD1/5. Taken together, these data suggest that developmental cardiotoxicity induced by PFOA likely involves both PPAR? and BMP2 pathways. PMID:23941634

Jiang, Qixiao; Lust, Robert M; Dewitt, Jamie C

2013-04-01

101

Corrosion inhibitors for chlorides induced corrosion in reinforced concrete structures  

Microsoft Academic Search

Reinforcements corrosion is the most important cause of premature failure on reinforced concrete structures. Phenomena promoting corrosion are the ingress of chlorides and the reaction of atmospheric CO2 with cement paste. Aim of this paper is the investigation on the effectiveness of three organic commercial inhibitors in preventing carbon steel chlorides induced corrosion in concrete, since there is not yet

M. Ormellese; M. Berra; F. Bolzoni; T. Pastore

2006-01-01

102

Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors.  

PubMed

Ketones have previously shown beneficial effects in models of neurodegenerative disorders, particularly against associated mitochondrial dysfunction and cognitive impairment. However, evidence of a synaptic protective effect of ketones remains lacking. We tested the effects of ketones on synaptic impairment induced by mitochondrial respiratory complex (MRC) inhibitors using electrophysiological, reactive oxygen species (ROS) imaging and biochemical techniques. MRC inhibitors dose-dependently suppressed both population spike (PS) and field potential amplitudes in the CA1 hippocampus. Pre-treatment with ketones strongly prevented changes in the PS, whereas partial protection was seen in the field potential. Rotenone (Rot; 100 nmol/L), a MRC I inhibitor, suppressed synaptic function without altering ROS levels and PS depression by Rot was unaffected by antioxidants. In contrast, antioxidant-induced PS recovery against the MRC II inhibitor 3-nitropropionic acid (3-NP; 1 mmol/L) was similar to the synaptic protective effects of ketones. Ketones also suppressed ROS generation induced by 3-NP. Finally, ketones reversed the decreases in ATP levels caused by Rot and 3-NP. In summary, our data demonstrate that ketones can preserve synaptic function in CA1 hippocampus induced by MRC dysfunction, likely through an antioxidant action and enhanced ATP generation. PMID:20374433

Kim, Do Young; Vallejo, Johana; Rho, Jong M

2010-04-02

103

Serotonin reuptake inhibitor-induced perinatal complications.  

PubMed

There are a growing number of concerns about the utilization of serotonin reuptake inhibitors (SRIs) in late pregnancy and the onset of perinatal complications. This review aimed to analyze and summarize the studies evaluating the risk of perinatal complications (such as low birth weight, preterm delivery, withdrawal or toxic phenomena, and other detrimental events/poor neonatal outcomes) related to maternal SRI use in late pregnancy. A computerized search of MEDLINE (1966-January 2007) and PsycINFO (1974-January 2007) databases was performed. Articles describing perinatal complications after late in utero exposure to SRIs were selected and also reviewed for additional references. Fifty studies met the inclusion criteria. Exposure to SRIs late in pregnancy is clearly associated with an increased risk of infants developing a constellation of symptoms, including CNS and respiratory effects, often requiring close infant observation and supportive or specific treatment in intensive care units. Such symptoms are not always due to toxic or withdrawal reactions. Indeed, some evidence suggests that SRIs may interfere with the physiology of the respiratory system and parasympathetic activity in neonates. Of the most methodologically relevant studies reviewed, 50% have been published in the last 3 years. Hence, it is possible that further concerning data will become available in the future. For these reasons, the opportunity of tapering and discontinuing SRIs in late pregnancy should be taken into consideration, although to date the evidence to support such a clinical decision is preliminary. PMID:17407365

Gentile, Salvatore

2007-01-01

104

New isolates of carnation Italian ringspot virus differ from the original one by having replication-associated proteins with a typical tombusvirus-like N-terminus and by inducing peroxisome rather than mitochondrion-derived multivesicular bodies  

Microsoft Academic Search

Five new isolates of carnation Italian ringspot virus (CIRV) from cherry trees, Gypsophila and surface water differ from the original carnation isolate (CIRV-car) and also from Pelargonium necrotic spot virus (PelNSV)\\u000a by having an ORF 1\\/ORF1-RT with a typical tombusvirus-like 5?end and by inducing the formation of peroxisome- rather than\\u000a mitochondrion-derived multivesicular bodies (MVBs). This supports with natural isolates earlier

Renate Koenig; Dietrich-Eckhardt Lesemann; Ernst Pfeilstetter

2009-01-01

105

The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF\\/PGAR\\/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment  

Microsoft Academic Search

The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA was up-regulated

S. J. Mandard; F. J. Zandbergen; N. S. Tan; P. Escher; D. A. Patsouris; M. R. Müller; A. H. Kersten

2004-01-01

106

Peroxisome proliferator-activated receptor gamma (PPAR?) regulates thrombospondin-1 and Nox4 expression in hypoxia-induced human pulmonary artery smooth muscle cell proliferation.  

PubMed

Transforming growth factor-?1 (TGF- ?1) and thrombospondin-1 (TSP-1) are hypoxia-responsive mitogens that promote vascular smooth muscle cell (SMC) proliferation, a critical event in the pathogenesis of pulmonary hypertension (PH). We previously demonstrated that hypoxia-induced human pulmonary artery smooth muscle (HPASMC) cell proliferation and expression of the NADPH oxidase subunit, Nox4, were attenuated by the peroxisome proliferator-activated receptor ? (PPAR?) agonist, rosiglitazone. The current study examines the hypothesis that rosiglitazone regulates Nox4 expression and HPASMC proliferation by attenuating TSP-1 signaling. Selected HPASMC were exposed to normoxic or hypoxic (1% O(2)) environments or TSP-1 (0-1 ?g/ ml) for 72 hours ± administration of rosiglitazone (10 ?M). Cellular proliferation, Nox4, TSP-1, and TGF-?1 expression and reactive oxygen species generation were measured. Mice exposed to hypoxia (10% O(2)) for three weeks were treated with rosiglitazone (10 mg/kg/day) for the final 10 days, and lung TSP-1 expression was examined. Hypoxia increased TSP-1 and TGF-?1 expression and HPASMC proliferation, and neutralizing antibodies to TSP-1 or TGF-?1 attenuated proliferation. Rosiglitazone attenuated hypoxia-induced HPASMC proliferation and increases in mouse lung and HPASMC TSP-1 expression, but failed to reduce increases in TGF-?1 expression or Nox4 expression and activity caused by direct TSP-1 stimulation. Transfecting HPASMC with siRNA to Nox4 attenuated hypoxia- or TSP-1-stimulated HPASMC proliferation. These findings provide novel evidence that TSP-1-mediated Nox4 expression plays a critical role in hypoxia-induced HPASMC proliferation. PPAR? activation with exogenous ligands attenuates TSP-1 expression to reduce Nox4 expression. These results clarify mechanisms of hypoxia-induced SMC proliferation and suggest additional pathways by which PPAR? agonists may regulate critical steps in the pathobiology of PH. PMID:23372933

Green, David E; Kang, Bum-Yong; Murphy, Tamara C; Hart, C Micheal

2012-10-01

107

Effects of peroxisomal catalase inhibition on mitochondrial function.  

PubMed

Peroxisomes produce hydrogen peroxide as a metabolic by-product of their many oxidase enzymes, but contain catalase that breaks down hydrogen peroxide in order to maintain the organelle's oxidative balance. It has been previously demonstrated that, as cells age, catalase is increasingly absent from the peroxisome, and resides instead as an unimported tetrameric molecule in the cell cytosol; an alteration that is coincident with increased cellular hydrogen peroxide levels. As this process begins in middle-passage cells, we sought to determine whether peroxisomal hydrogen peroxide could contribute to the oxidative damage observed in mitochondria in late-passage cells. Early-passage human fibroblasts (Hs27) treated with aminotriazole (3-AT), an irreversible catalase inhibitor, demonstrated decreased catalase activity, increased levels of cellular hydrogen peroxide, protein carbonyls, and peroxisomal numbers. This treatment increased mitochondrial reactive oxygen species levels, and decreased the mitochondrial aconitase activity by ?85% within 24?h. In addition, mitochondria from 3-AT treated cells show a decrease in inner membrane potential. These results demonstrate that peroxisome-derived oxidative imbalance may rapidly impair mitochondrial function, and considering that peroxisomal oxidative imbalance begins to occur in middle-passage cells, supports the hypothesis that peroxisomal oxidant release occurs upstream of, and contributes to, the mitochondrial damage observed in aging cells. PMID:22536190

Walton, Paul A; Pizzitelli, Michael

2012-04-23

108

Effects of Peroxisomal Catalase Inhibition on Mitochondrial Function  

PubMed Central

Peroxisomes produce hydrogen peroxide as a metabolic by-product of their many oxidase enzymes, but contain catalase that breaks down hydrogen peroxide in order to maintain the organelle’s oxidative balance. It has been previously demonstrated that, as cells age, catalase is increasingly absent from the peroxisome, and resides instead as an unimported tetrameric molecule in the cell cytosol; an alteration that is coincident with increased cellular hydrogen peroxide levels. As this process begins in middle-passage cells, we sought to determine whether peroxisomal hydrogen peroxide could contribute to the oxidative damage observed in mitochondria in late-passage cells. Early-passage human fibroblasts (Hs27) treated with aminotriazole (3-AT), an irreversible catalase inhibitor, demonstrated decreased catalase activity, increased levels of cellular hydrogen peroxide, protein carbonyls, and peroxisomal numbers. This treatment increased mitochondrial reactive oxygen species levels, and decreased the mitochondrial aconitase activity by ?85% within 24?h. In addition, mitochondria from 3-AT treated cells show a decrease in inner membrane potential. These results demonstrate that peroxisome-derived oxidative imbalance may rapidly impair mitochondrial function, and considering that peroxisomal oxidative imbalance begins to occur in middle-passage cells, supports the hypothesis that peroxisomal oxidant release occurs upstream of, and contributes to, the mitochondrial damage observed in aging cells.

Walton, Paul A.; Pizzitelli, Michael

2012-01-01

109

Proteomics of the Peroxisome  

PubMed Central

Genomes provide us with a blue print for the potential of a cell. However, the activity of a cell is expressed in its proteome. Full understanding of the complexity of cells demands a comprehensive view of the proteome; its interactions, activity states and organization. Comprehensive proteomic approaches applied to peroxisomes have yielded new insights into the organelle and its dynamic interplay with other cellular structures. As technologies and methodologies improve proteomics hold the promise for new discoveries of peroxisome function and a full description of this dynamic organelle.

Saleem, RA; Smith, JJ; Aitchison, JD

2007-01-01

110

FoxO1 Haploinsufficiency Protects Against High-Fat Diet-Induced Insulin Resistance With Enhanced Peroxisome Proliferator-Activated Receptor ? Activation in Adipose Tissue  

PubMed Central

OBJECTIVE Forkhead box O (FoxO) transcription factors represent evolutionarily conserved targets of insulin signaling, regulating metabolism and cellular differentiation in response to changes in nutrient availability. Although the FoxO1 isoform is known to play a key role in adipogenesis, its physiological role in differentiated adipose tissue remains unclear. RESEARCH DESIGN AND METHODS In this study, we analyzed the phenotype of FoxO1 haploinsufficient mice to investigate the role of FoxO1 in high-fat diet–induced obesity and adipose tissue metabolism. RESULTS We showed that reduced FoxO1 expression protects mice against obesity-related insulin resistance with marked improvement not only in hepatic insulin sensitivity but also in skeletal muscle insulin action. FoxO1 haploinsufficiency also resulted in increased peroxisome proliferator–activated receptor (PPAR)? gene expression in adipose tissue, with enhanced expression of PPAR? target genes known to influence metabolism. Moreover, treatment of mice with the PPAR? agonist rosiglitazone caused a greater improvement in in vivo insulin sensitivity in FoxO1 haploinsufficient animals, including reductions in circulating proinflammatory cytokines. CONCLUSIONS These findings indicate that FoxO1 proteins negatively regulate insulin action and that their effect may be explained, at least in part, by inhibition of PPAR? function.

Kim, Jane J.; Li, Pingping; Huntley, Jessica; Chang, Jeffrey P.; Arden, Karen C.; Olefsky, Jerrold M.

2009-01-01

111

Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice.  

PubMed

Liver X receptor (LXR) activation improves glucose homeostasis in obesity. This improvement, however, is associated with several side effects including hyperlipidemia and hepatic steatosis. Activation of peroxisome proliferator-activated receptor alpha (PPAR?), on the other hand, increases fatty acid oxidation, leading to a reduction of hyperlipidemia. The objective of this study was to investigate whether concurrent activation of LXR/PPAR? can produce synergistic benefits in treating obesity-associated metabolic disorders. Treatment of high fat diet-induced obese mice with T0901317, an LXR activator, or fenofibrate, the PPAR? agonist, or in combination alleviated insulin resistance and improved glucose tolerance. The combined treatment dramatically exacerbated hepatic steatosis. Gene expression analysis in the liver showed that combined treatment increased the expression of genes involved in lipogenesis and fatty acid transport, including srebp-1c, chrebp, acc1, fas, scd1 and cd36. Histochemistry and ex vivo glycerol releasing assay showed that combined treatment accelerated lipid mobilization in adipose tissue. Combined treatment also increased the transcription of glut4, hsl, atgl and adiponectin, and decreased that of plin1, cd11c, ifn? and leptin. Combined treatment markedly elevated the transcription of fgf21 in liver but not in adipose tissue. These results suggest that concurrent activation of LXR and PPAR? as a strategy to control glucose and lipid metabolism in obesity is beneficial but could lead to elevation of lipid accumulation in the liver. PMID:23762402

Gao, Mingming; Bu, Le; Ma, Yongjie; Liu, Dexi

2013-06-07

112

Concurrent Activation of Liver X Receptor and Peroxisome Proliferator-Activated Receptor Alpha Exacerbates Hepatic Steatosis in High Fat Diet-Induced Obese Mice  

PubMed Central

Liver X receptor (LXR) activation improves glucose homeostasis in obesity. This improvement, however, is associated with several side effects including hyperlipidemia and hepatic steatosis. Activation of peroxisome proliferator-activated receptor alpha (PPAR?), on the other hand, increases fatty acid oxidation, leading to a reduction of hyperlipidemia. The objective of this study was to investigate whether concurrent activation of LXR/PPAR? can produce synergistic benefits in treating obesity-associated metabolic disorders. Treatment of high fat diet-induced obese mice with T0901317, an LXR activator, or fenofibrate, the PPAR? agonist, or in combination alleviated insulin resistance and improved glucose tolerance. The combined treatment dramatically exacerbated hepatic steatosis. Gene expression analysis in the liver showed that combined treatment increased the expression of genes involved in lipogenesis and fatty acid transport, including srebp-1c, chrebp, acc1, fas, scd1 and cd36. Histochemistry and ex vivo glycerol releasing assay showed that combined treatment accelerated lipid mobilization in adipose tissue. Combined treatment also increased the transcription of glut4, hsl, atgl and adiponectin, and decreased that of plin1, cd11c, ifn? and leptin. Combined treatment markedly elevated the transcription of fgf21 in liver but not in adipose tissue. These results suggest that concurrent activation of LXR and PPAR? as a strategy to control glucose and lipid metabolism in obesity is beneficial but could lead to elevation of lipid accumulation in the liver.

Gao, Mingming; Bu, Le; Ma, Yongjie; Liu, Dexi

2013-01-01

113

Calmodulin Inhibitor-induced Apoptosis was Prevented by Glycogen Synthase Kinase3 Inhibitors in PC12 Cells  

Microsoft Academic Search

Calmodulin is known to transduce Ca2+ signals by interacting with specific target proteins. In order to determine the role of calmodulin in regulating neuronal\\u000a survival and death, we examined, whether calmodulin inhibitors induce caspase-dependent apoptotic cell death, and whether\\u000a glycogen synthase kinase-3 is involved in calmodulin inhibitor-induced cell death in PC12 cells. W13, a calmodulin specific\\u000a inhibitor increased apoptotic cell

Tsuneo Takadera; Takao Ohyashiki

2007-01-01

114

Peroxisome proliferator-activated receptor-delta induces cell proliferation by a cyclin E1-dependent mechanism and is up-regulated in thyroid tumors.  

PubMed

Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPARdelta induces cell proliferation through a novel cyclin E1-dependent mechanism and is up-regulated in many human thyroid tumors. The expression of PPARdelta was induced coordinately with proliferation in primary human thyroid cells by the activation of serum, thyroid-stimulating hormone/cyclic AMP, or epidermal growth factor/mitogen-activated protein kinase mitogenic signaling pathways. Engineered overexpression of PPARdelta increased thyroid cell number, the incorporation of bromodeoxyuridine, and the phosphorylation of retinoblastoma protein by 40% to 45% in just 2 days, one usual cell population doubling. The synthetic PPARdelta agonist GW501516 augmented these PPARdelta proliferation effects in a dose-dependent manner. Overexpression of PPARdelta increased cyclin E1 protein by 9-fold, whereas knockdown of PPARdelta by small inhibitory RNA reduced both cyclin E1 protein and cell proliferation by 2-fold. Induction of proliferation by PPARdelta was abrogated by knockdown of cyclin E1 by small inhibitory RNA in primary thyroid cells and by knockout of cyclin E1 in mouse embryo fibroblasts, confirming a cyclin E1 dependence for this PPARdelta pathway. In addition, the mean expression of native PPARdelta was increased by 2-fold to 5-fold (P < 0.0001) and correlated with that of the in situ proliferation marker Ki67 (R = 0.8571; P = 0.02381) in six different classes of benign and malignant human thyroid tumors. Our experiments identify a PPARdelta mechanism that induces cell proliferation through cyclin E1 and is regulated by growth factor and lipid signals. The data argue for systematic investigation of PPARdelta antagonists as antineoplastic agents and implicate altered PPARdelta-cyclin E1 signaling in thyroid and other carcinomas. PMID:18701481

Zeng, Lingchun; Geng, Yan; Tretiakova, Maria; Yu, Xuemei; Sicinski, Peter; Kroll, Todd G

2008-08-15

115

Di(2-ethylhexyl) phthalate induces apoptosis through peroxisome proliferators-activated receptor-gamma and ERK 1/2 activation in testis of Sprague-Dawley rats.  

PubMed

Di(2-ethylhexyl) phthalate (DEHP) is a well-known hepatic and reproductive toxicant whose toxicity may be mediated by peroxisome proliferators-activated receptor (PPAR). This study examined the effects of DEHP on the expression of PPAR-regulated genes involved in testicular cells apoptosis. Sprague-Dawley male rats were treated orally with 250, 500, or 750 mg/kg/d DEHP for 28 d, while control rats were given corn oil. The levels of cell cycle regulators (pRb, cyclins, CDKs, and p21) and apoptosis-related proteins were analyzed by Western blot analysis. The role of PPAR-gamma (PPAR-gamma), class B scavenger receptor type 1 (SR-B1), and ERK1/2 was further studied to examine the signaling pathway for DEHP-induced apoptosis. Results showed that the levels of pRB, cyclin D, CDK2, cyclin E, and CDK4 were significantly lower in rats given 500 and 750 mg/kg/d DEHP, while levels of p21 were significantly higher in rat testes. Dose-dependent increases in PPAR-gamma and RXRalpha proteins were observed in testes after DEHP exposure, while there was a significant decrease in RXRgamma protein levels. In addition to PPAR-gamma, DEHP also significantly increased SR-B1 mRNA and phosphorylated ERK1/2 protein levels. Furthermore, DEHP treatment induced pro-caspase-3 and cleavage of its substrate protein, poly(ADP-ribose) polymerase (PARP), in a dose-dependent manner. Data suggest that DEHP exposure may induce the expression of apoptosis-related genes in testes through induction of PPAR-gamma and activation of the ERK1/2 pathway. PMID:17654247

Ryu, Ju Young; Whang, Jung; Park, Hyeyoung; Im, Ji Young; Kim, Jeonga; Ahn, Mee Young; Lee, Jaewon; Kim, Hyung Sik; Lee, Byung Mu; Yoo, Sun Dong; Kwack, Seung Jun; Oh, Jae Ho; Park, Kui Lea; Han, Soon Young; Kim, Seung Hee

2007-08-01

116

Transmucosal Gastric Leak Induced by Proton Pump Inhibitors  

Microsoft Academic Search

Despite their remarkable safety profile and lack of clinical side effects, proton pump inhibitors (PPIs) induce a transmucosal\\u000a gastric leak to non-electrolyte probes of various sizes. The ex vivo addition of PPIs to isolated rat gastric corpus increases\\u000a transmucosal permeability in a dose-dependent manner, which corresponds with PPIs’ dose-dependent inhibition of acid secretion.\\u000a Upon the addition of omeprazole, lansoprazole, or esomeprazole,

Lisa J. Murray; Melissa Gabello; David S. Rudolph; Christopher P. Farrell; Melissa Morgan; Aaron P. Martin; James C. Underwood; M. Carmen Valenzano; James M. Mullin

2009-01-01

117

Tissue Factor Pathway Inhibitor Release Induced by Defibrotide and Heparins  

Microsoft Academic Search

We evaluated the release of tissue factor pathway inhibitor (TFPI) induced by defibrotide (DF), a single-stranded, negatively charged polydeoxyribonucleotide extracted from mammalian organ. Ten normal volunteers were injected with an intravenous bolus of 400 mg DF and 2,000 IU unfractionated heparin (UFH). In addition, three volunteers were also injected with an intravenous bolus of 2,000 anti-Xa U of two low-molecular-weight

Giuseppe Cella; Alessandra Sbarai; Gabriella Mazzaro; Giovanna Motta; Paolo Carraro; Giuseppe M. Andreozzi; Debra A. Hoppensteadt; Jawed Fareed

2001-01-01

118

Hydroxyproline as an Inhibitor of Auxin-induced Cell Elongation  

Microsoft Academic Search

AUXIN-INDUCED cell elongation can be inhibited by a variety of substances1. Among these inhibitors are the ammo-acid antagonists canavanine2, beta-2-thienylalanine3 and ethionine4,5. This has been taken as evidence that protein synthesis is necessary for cell elongation6. Recently, Steward et al.7 have presented evidence that hydroxy-L-proline can also be an amino-acid antagonist. The growth of carrot callus explants could be blocked

Robert Cleland

1963-01-01

119

Stereoisomers ginsenosides-20(S)-Rg? and -20(R)-Rg? differentially induce angiogenesis through peroxisome proliferator-activated receptor-gamma.  

PubMed

Ginsenosides are considered the major constituents that are responsible for most of the pharmacological actions of ginseng. However, some ginsenosides exist as stereoisomeric pairs, detailed and molecular exposition based on the structural differences of ginsenoside stereoisomers has not been emphasized in most studies. Here we explore the functional differences of ginsenoside Rg? stereoisomers on angiogenesis. In this study, we demonstrated the distinctive differential angiogenic activities of 20(S)-Rg? and 20(R)-Rg? stereoisomers. 20(S)-Rg? at micromolar concentration promotes human endothelial cells proliferation, migration and tube formation in vitro, as well as ex vivo endothelial sprouting. The effects induced by 20(S)-Rg? are significantly more potent than 20(R)-Rg?. These effects are partially mediated through the activation of AKT/ERK-eNOS signaling pathways. Moreover, knockdown of peroxisome proliferator-activated receptor-gamma (PPAR?) by specific small interference RNA abolished the 20(S)-Rg?-induced angiogenesis, indicating that PPAR? is responsible for mediating the angiogenic activity of Rg?. Using reporter gene assay, the PPAR? agonist activity of 20(S)-Rg? has been found 10-fold higher than that of 20(R)-Rg?. Computer modeling also revealed the differential binding is due to the chiral center of 20(S)-Rg? can form a critical hydrogen bond with Tyr473 of PPAR? ligand binding domain. The present study elucidated the differential angiogenic effects of Rg? stereoisomers by acting as agonist of PPAR?. The results shed light on the structural difference between two ginsenoside stereoisomers that can lead to significant differential physiological outcomes which should be carefully considered in the future development of ginsenoside-based therapeutics. PMID:22234331

Kwok, Hoi-Hin; Guo, Guan-Lun; Lau, Justin Kai-Chi; Cheng, Yuen-Kit; Wang, Jiang-Rong; Jiang, Zhi-Hong; Keung, Man-Hong; Mak, Nai-Ki; Yue, Patrick Ying-Kit; Wong, Ricky Ngok-Shun

2012-01-04

120

Transcription factors Krüppel-like factor 6 and peroxisome proliferator-activated receptor-{gamma} mediate high glucose-induced thioredoxin-interacting protein.  

PubMed

We demonstrated recently that thioredoxin-interacting protein (Txnip) and the transcription factor Krüppel-like factor 6 (KLF6) were up-regulated in both in vivo and in vitro models of diabetic nephropathy, thus promoting renal injury. Conversely, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have been shown to be renoprotective. Hence, this study was undertaken to determine whether Txnip expression is regulated by the transcription factors KLF6 and PPAR-gamma. By using siRNAs and overexpressing constructs, the role of KLF6 and PPAR-gamma in Txnip transcriptional regulation was determined in human kidney proximal tubule cells and in streptozocin-induced diabetes mellitus in Sprague-Dawley rats, in vitro and in vivo models of diabetic nephropathy, respectively. KLF6 overexpression increased Txnip expression and promoter activity, which was inhibited by concurrent exposure to PPAR-gamma agonists. In contrast, reduced expression of KLF6 by siRNA or exposure to PPAR-gamma agonists attenuated high glucose-induced Txnip expression and promoter activity. KLF6-Txnip promoter binding was decreased in KLF6-silenced cells, whereas PPAR-gamma agonists increased PPAR-gamma-Txnip promoter binding. Indeed, silencing of KLF6 increased PPAR-gamma expression, suggesting endogenous regulation of PPAR-gamma expression by KLF6. Moreover, renal KLF6 and Txnip expression increased in rats with diabetes mellitus and was inhibited by PPAR-gamma agonist treatment; however, KLF6 expression did not change in HK-2 cells exposed to PPAR-gamma agonists. Hence, Txnip expression and promoter activity are mediated via divergent effects of KLF6 and PPAR-gamma transcriptional regulation. PMID:19808645

Qi, Weier; Chen, Xinming; Holian, John; Tan, Christina Y R; Kelly, Darren J; Pollock, Carol A

2009-10-01

121

Transcription Factors Kr?ppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-? Mediate High Glucose-Induced Thioredoxin-Interacting Protein  

PubMed Central

We demonstrated recently that thioredoxin-interacting protein (Txnip) and the transcription factor Krüppel-like factor 6 (KLF6) were up-regulated in both in vivo and in vitro models of diabetic nephropathy, thus promoting renal injury. Conversely, peroxisome proliferator-activated receptor-? (PPAR-?) agonists have been shown to be renoprotective. Hence, this study was undertaken to determine whether Txnip expression is regulated by the transcription factors KLF6 and PPAR-?. By using siRNAs and overexpressing constructs, the role of KLF6 and PPAR-? in Txnip transcriptional regulation was determined in human kidney proximal tubule cells and in streptozocin-induced diabetes mellitus in Sprague-Dawley rats, in vitro and in vivo models of diabetic nephropathy, respectively. KLF6 overexpression increased Txnip expression and promoter activity, which was inhibited by concurrent exposure to PPAR-? agonists. In contrast, reduced expression of KLF6 by siRNA or exposure to PPAR-? agonists attenuated high glucose-induced Txnip expression and promoter activity. KLF6-Txnip promoter binding was decreased in KLF6-silenced cells, whereas PPAR-? agonists increased PPAR-?-Txnip promoter binding. Indeed, silencing of KLF6 increased PPAR-? expression, suggesting endogenous regulation of PPAR-? expression by KLF6. Moreover, renal KLF6 and Txnip expression increased in rats with diabetes mellitus and was inhibited by PPAR-? agonist treatment; however, KLF6 expression did not change in HK-2 cells exposed to PPAR-? agonists. Hence, Txnip expression and promoter activity are mediated via divergent effects of KLF6 and PPAR-? transcriptional regulation.

Qi, Weier; Chen, Xinming; Holian, John; Tan, Christina Y.R.; Kelly, Darren J.; Pollock, Carol A.

2009-01-01

122

Study on cow ghee versus soybean oil on 7,12-dimethylbenz(a)-anthracene induced mammary carcinogenesis & expression of cyclooxygenase-2 & peroxisome proliferators activated receptor- ? in rats  

PubMed Central

Background & objectives Breast cancer is a leading cause of cancer death in women; dietary fat is the one of the factors that influences its incidence. In the present study we investigated the effect of feeding cow ghee versus soybean oil on 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary cancer in rat and expression of cyclooxygenase-2 and peroxisome proliferators activated receptor- ? (PPAR-?) in mammary gland. Methods Two groups of 21 day old female rats (30 each) were fed for 44 wk diet containing cow ghee or soybean oil (10%). The animals were given DMBA (30mg/kg body weight) through oral intubation after 5 wk feeding. Another two groups (8 each) fed similarly but not given DMBA served as control for the gene expression study. Results In DMBA treated groups, the animal fed soybean oil had higher tumour incidence (65.4%), tumour weight (6.18 g) and tumour volume (6285 mm3) compared to those fed cow ghee (26.6%, 1.67 g, 1925 mm3, respectively). Tumour latency period was 23 wk on soybean oil compared to 27 wk on cow ghee. Histological analysis of tumours showed that the progression of carcinogenesis was more rapid on soybean oil than on cow ghee. The expression of cyclooxygenase-2 was observed only in DMBA treated rats and it was significantly less on cow ghee than on soybean oil. The expression of PPAR-? was significantly more on cow ghee than on soybean oil. Interpretation & conclusions Our results show that dietary cow ghee opposed to soybean oil attenuates mammary carcinogenesis induced by DMBA; and the effect is mediated by decreased expression of cyclooxygenase-2 and increased expression of PPAR-? in the former group.

Rani, Rita; Kansal, Vinod K.

2011-01-01

123

Natural Senescence of Pea Leaves (An Activated Oxygen-Mediated Function for Peroxisomes).  

PubMed Central

We studied the activated oxygen metabolism of peroxisomes in naturally and dark-induced senescent leaves of pea (Pisum sativum L.). Peroxisomes were purified from three different types of senescent leaves and the activities of different peroxisomal and glyoxysomal enzymes were measured. The activities of the O2-- and H2O2-producing enzymes were enhanced by natural senescence. Senescence also produced an increase in the generation of active oxygen species (O2- and H2O2) in leaf peroxisomes and in the activities of two glyoxylate-cycle marker enzymes. A new fraction of peroxisomes was detected at an advanced stage of dark-induced senescence. Electron microscopy revealed that this new peroxisomal fraction varied in size and electron density. During senescence, the constitutive Mn-superoxide dismutase (SOD) activity of peroxisomes increased and two new CuZn-SODs were induced, one of which cross-reacted with an antibody against glyoxysomal CuZn- SOD. This fact and the presence of glyoxylate-cycle enzymes support the idea that foliar senescence is associated with the transition of peroxisomes into glyoxysomes. Our results indicate that natural senescence causes the same changes in peroxisome-activated oxygen metabolism as dark-induced senescence, and reinforce the hypothesis of an effective role of peroxisomes and their activated oxygen metabolism in this stage of the life cycle.

Pastori, G. M.; Del Rio, L. A.

1997-01-01

124

Peroxisome Proliferator-Activated Receptor-g Ligands Reduce Neuronal Inducible Nitric Oxide Synthase Expression and Cell Death In Vivo  

Microsoft Academic Search

Expression of the inducible form of nitric oxide synthase (iNOS) in brain may contribute to neurotoxicity in Alzheimer's disease (AD). Expression of iNOS can be induced in cerebellar granule cells (CGCs) in vivo as well as in vitro, allowing these cells to be used to study regulation of neuronal iNOS expression. We report here that microinjection of bacterial lipopolysaccharide and

Michael T. Heneka; Thomas Klockgether; Douglas L. Feinstein

2000-01-01

125

Role of the PAS1 gene of Pichia pastoris in peroxisome biogenesis  

PubMed Central

Several groups have reported the cloning and sequencing of genes involved in the biogenesis of yeast peroxisomes. Yeast strains bearing mutations in these genes are unable to grow on carbon sources whose metabolism requires peroxisomes, and these strains lack morphologically normal peroxisomes. We report the cloning of Pichia pastoris PAS1, the homologue (based on a high level of protein sequence similarity) of the Saccharomyces cerevisiae PAS1. We also describe the creation and characterization of P. pastoris pas1 strains. Electron microscopy on the P. pastoris pas1 cells revealed that they lack morphologically normal peroxisomes, and instead contain membrane-bound structures that appear to be small, mutant peroxisomes, or "peroxisome ghosts." These "ghosts" proliferated in response to induction on peroxisome-requiring carbon sources (oleic acid and methanol), and they were distributed to daughter cells. Biochemical analysis of cell lysates revealed that peroxisomal proteins are induced normally in pas1 cells. Peroxisome ghosts from pas1 cells were purified on sucrose gradients, and biochemical analysis showed that these ghosts, while lacking several peroxisomal proteins, did import varying amounts of several other peroxisomal proteins. The existence of detectable peroxisome ghosts in P. pastoris pas1 cells, and their ability to import some proteins, stands in contrast with the results reported by Erdmann et al. (1991) for the S. cerevisiae pas1 mutant, in which they were unable to detect peroxisome-like structures. We discuss the role of PAS1 in peroxisome biogenesis in light of the new information regarding peroxisome ghosts in pas1 cells.

1994-01-01

126

Role of the PAS1 gene of Pichia pastoris in peroxisome biogenesis.  

PubMed

Several groups have reported the cloning and sequencing of genes involved in the biogenesis of yeast peroxisomes. Yeast strains bearing mutations in these genes are unable to grow on carbon sources whose metabolism requires peroxisomes, and these strains lack morphologically normal peroxisomes. We report the cloning of Pichia pastoris PAS1, the homologue (based on a high level of protein sequence similarity) of the Saccharomyces cerevisiae PAS1. We also describe the creation and characterization of P. pastoris pas1 strains. Electron microscopy on the P. pastoris pas1 cells revealed that they lack morphologically normal peroxisomes, and instead contain membrane-bound structures that appear to be small, mutant peroxisomes, or "peroxisome ghosts." These "ghosts" proliferated in response to induction on peroxisome-requiring carbon sources (oleic acid and methanol), and they were distributed to daughter cells. Biochemical analysis of cell lysates revealed that peroxisomal proteins are induced normally in pas1 cells. Peroxisome ghosts from pas1 cells were purified on sucrose gradients, and biochemical analysis showed that these ghosts, while lacking several peroxisomal proteins, did import varying amounts of several other peroxisomal proteins. The existence of detectable peroxisome ghosts in P. pastoris pas1 cells, and their ability to import some proteins, stands in contrast with the results reported by Erdmann et al. (1991) for the S. cerevisiae pas1 mutant, in which they were unable to detect peroxisome-like structures. We discuss the role of PAS1 in peroxisome biogenesis in light of the new information regarding peroxisome ghosts in pas1 cells. PMID:7962088

Heyman, J A; Monosov, E; Subramani, S

1994-12-01

127

How Peroxisomes Affect Aflatoxin Biosynthesis in Aspergillus Flavus  

PubMed Central

In filamentous fungi, peroxisomes are crucial for the primary metabolism and play a pivotal role in the formation of some secondary metabolites. Further, peroxisomes are important site for fatty acids ?-oxidation, the formation of reactive oxygen species and for their scavenging through a complex of antioxidant activities. Oxidative stress is involved in different metabolic events in all organisms and it occurs during oxidative processes within the cell, including peroxisomal ?-oxidation of fatty acids. In Aspergillus flavus, an unbalance towards an hyper-oxidant status into the cell is a prerequisite for the onset of aflatoxin biosynthesis. In our preliminary results, the use of bezafibrate, inducer of both peroxisomal ?-oxidation and peroxisome proliferation in mammals, significantly enhanced the expression of pex11 and foxA and stimulated aflatoxin synthesis in A. flavus. This suggests the existence of a correlation among peroxisome proliferation, fatty acids ?-oxidation and aflatoxin biosynthesis. To investigate this correlation, A. flavus was transformed with a vector containing P33, a gene from Cymbidium ringspot virus able to induce peroxisome proliferation, under the control of the promoter of the Cu,Zn-sod gene of A. flavus. This transcriptional control closely relates the onset of the antioxidant response to ROS increase, with the proliferation of peroxisomes in A. flavus. The AfP33 transformant strain show an up-regulation of lipid metabolism and an higher content of both intracellular ROS and some oxylipins. The combined presence of a higher amount of substrates (fatty acids-derived), an hyper-oxidant cell environment and of hormone-like signals (oxylipins) enhances the synthesis of aflatoxins in the AfP33 strain. The results obtained demonstrated a close link between peroxisome metabolism and aflatoxin synthesis.

Reverberi, Massimo; Punelli, Marta; Smith, Carrie A.; Zjalic, Slaven; Scarpari, Marzia; Scala, Valeria; Cardinali, Giorgia; Aspite, Nicaela; Pinzari, Flavia; Payne, Gary A.; Fabbri, Anna A.; Fanelli, Corrado

2012-01-01

128

A Polypeptide from Tomato Leaves Induces Wound-Inducible Proteinase Inhibitor Proteins  

Microsoft Academic Search

Defensive genes in plants can be activated by several different types of nonpeptide signaling molecules. An endogenous polypeptide, consisting of 18 amino acids, was isolated from tomato leaves and was able at very low concentrations to induce the Synthesis of two wound-inducible proteinase inhibitor proteins when supplied to young tomato plants. The sequence of the polypeptide was determined, and an

Gregory Pearce; Daniel Strydom; Scott Johnson; Clarence A. Ryan

1991-01-01

129

Peroxisome proliferator-activated receptor delta regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury.  

PubMed

Cerebral vascular endothelial cell (CEC) degeneration significantly contributes to blood-brain barrier (BBB) breakdown and neuronal loss after cerebral ischemia. Recently, emerging data suggest that peroxisome proliferator-activated receptor delta (PPARdelta) activation has a potential neuroprotective role in ischemic stroke. Here we report for the first time that PPARdelta is significantly reduced in oxygen-glucose deprivation (OGD)-induced mouse CEC death. Interestingly, PPARdelta overexpression can suppress OGD-induced caspase-3 activity, Golgi fragmentation, and CEC death through an increase of bcl-2 protein levels without change of bcl-2 mRNA levels. To explore the molecular mechanisms, we have identified that upregulation of PPARdelta can alleviate ODG-activated microRNA-15a (miR-15a) expression in CECs. Moreover, we have demonstrated that bcl-2 is a translationally repressed target of miR-15a. Intriguingly, gain- or loss-of-miR-15a function can significantly reduce or increase OGD-induced CEC death, respectively. Furthermore, we have identified that miR-15a is a transcriptional target of PPARdelta. Consistent with the in vitro findings, we found that intracerebroventricular infusion of a specific PPARdelta agonist, GW 501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid), significantly reduced ischemia-induced miR-15a expression, increased bcl-2 protein levels, and attenuated caspase-3 activity and subsequent DNA fragmentation in isolated cerebral microvessels, leading to decreased BBB disruption and reduced cerebral infarction in mice after transient focal cerebral ischemia. Together, these results suggest that PPARdelta plays a vascular-protective role in ischemia-like insults via transcriptional repression of miR-15a, resulting in subsequent release of its posttranscriptional inhibition of bcl-2. Thus, regulation of PPARdelta-mediated miR-15a inhibition of bcl-2 could provide a novel therapeutic strategy for the treatment of stroke-related vascular dysfunction. PMID:20445066

Yin, Ke-Jie; Deng, Zhen; Hamblin, Milton; Xiang, Yi; Huang, Huarong; Zhang, Jifeng; Jiang, Xiaodan; Wang, Yanzhuang; Chen, Y Eugene

2010-05-01

130

Telmisartan-induced inhibition of vascular cell proliferation beyond angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma activation.  

PubMed

We investigated the ability of angiotensin II type 1 (AT1) receptor blockers with peroxisome proliferator-activated receptor (PPAR)-gamma agonist activity (telmisartan and irbesartan) and AT1 receptor blockers devoid of PPARgamma agonist activity (eprosartan and valsartan) to inhibit vascular cell proliferation studied in the absence of angiotensin II stimulation. Telmisartan and, to a lesser extent, irbesartan inhibited proliferation of human aortic vascular smooth muscle cells in a dose-dependent fashion, whereas eprosartan and valsartan did not. To investigate the role of PPARgamma in the antiproliferative effects of telmisartan, we studied genetically engineered NIH3T3 cells that express PPARgamma. Pioglitazone inhibited proliferation of NIH3T3 cells expressing PPARgamma but had little effect on control NIH3T3 cells that lack PPARgamma. In contrast, telmisartan inhibited proliferation equally in NIH3T3 with and without PPARgamma. Valsartan failed to inhibit proliferation of either cell line. In addition, telmisartan inhibited proliferation equally in aortic smooth muscle cells derived from mice with targeted knockout of PPARgamma in the smooth muscle and from control mice, whereas valsartan had no effect on cell proliferation. Telmisartan, but not valsartan, reduced phosphorylation of AKT but not extracellular signal-regulated kinase otherwise induced by exposure to serum of quiescent human smooth muscle cells, quiescent mice smooth muscle cells lacking PPARgamma, or quiescent Chinese hamster ovary-K1 cells lacking the AT1 receptor. In summary, the antiproliferative effects of telmisartan in the absence of exogenously supplemented angiotensin II involve more than just AT1 receptor blockade and do not require activation of PPARgamma. It might be postulated that inhibition of AKT activation is a mechanism mediating the antiproliferative effects of telmisartan, including in cells lacking AT1 receptors or PPARgamma. PMID:19822796

Yamamoto, Koichi; Ohishi, Mitsuru; Ho, Christopher; Kurtz, Theodore W; Rakugi, Hiromi

2009-10-12

131

PARP inhibitors attenuate chemotherapy-induced painful neuropathy.  

PubMed

Chemotherapy-induced peripheral neuropathy (CIPN) is a major toxicity of chemotherapy treatment for which no therapy is approved. Poly(ADP-ribose) polymerase (PARP)1/2 are nuclear enzymes activated upon DNA damage, and PARP1/2 inhibition provides resistance against DNA damage. A role for PARP inhibition in sensory neurotransmission has also been established. PARP inhibitors attenuate pain-like behaviors and neuropathy-associated decreased peripheral nerve function in diabetic models. The hypothesis tested was that PARP inhibition protects against painful neuropathy. The objective of this study was to investigate whether the novel, selective PARP1/2 inhibitors (ABT-888 and related analogues) would attenuate development of mechanical allodynia in vincristine-treated rats. PARP inhibitors were dosed for 2 days, and then co-administered with vincristine for 12 days. Mechanical allodynia was observed in rats treated with vincristine. PARP1/2 inhibition significantly attenuated development of mechanical allodynia and reduced poly ADP-ribose (PAR) activation in rat skin. The data presented here show that PARP inhibition attenuates vincristine-induced mechanical allodynia in rats, and supports that PARP inhibition may represent a novel therapeutic approach for CIPN. PMID:22971094

Brederson, Jill-Desiree; Joshi, Shailen K; Browman, Kaitlin E; Mikusa, Joseph; Zhong, Chengmin; Gauvin, Donna; Liu, Xuesong; Shi, Yan; Penning, Thomas D; Shoemaker, Alex R; Giranda, Vincent L

2012-09-01

132

Peroxisomal cholesterol biosynthesis and Smith-Lemli-Opitz syndrome  

SciTech Connect

Smith-Lemli-Opitz syndrome (SLOS), caused by 7-dehydrocholesterol-reductase (DHCR7) deficiency, shows variable severity independent of DHCR7 genotype. To test whether peroxisomes are involved in alternative cholesterol synthesis, we used [1-{sup 14}C]C24:0 for peroxisomal {beta}-oxidation to generate [1-{sup 14}C]acetyl-CoA as cholesterol precursor inside peroxisomes. The HMG-CoA reductase inhibitor lovastatin suppressed cholesterol synthesis from [2-{sup 14}C]acetate and [1-{sup 14}C]C8:0 but not from [1-{sup 14}C]C24:0, implicating a peroxisomal, lovastatin-resistant HMG-CoA reductase. In SLOS fibroblasts lacking DHCR7 activity, no cholesterol was formed from [1-{sup 14}C]C24:0-derived [1-{sup 14}C]acetyl-CoA, indicating that the alternative peroxisomal pathway also requires this enzyme. Our results implicate peroxisomes in cholesterol biosynthesis but provide no link to phenotypic variation in SLOS.

Weinhofer, Isabelle [Center for Brain Research, Medical University of Vienna, Vienna (Austria); Kunze, Markus [Center for Brain Research, Medical University of Vienna, Vienna (Austria); Stangl, Herbert [Department of Medical Chemistry, Medical University of Vienna, Vienna (Austria); Porter, Forbes D. [National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (United States); Berger, Johannes [Center for Brain Research, Medical University of Vienna, Vienna (Austria)]. E-mail: johannes.berger@meduniwien.ac.at

2006-06-23

133

Colorado potato beetles ( leptinotarsa decemlineata) adapt to proteinase inhibitors induced in potato leaves by methyl jasmonate  

Microsoft Academic Search

Potato plants were treated with gaseous methyl jasmonate (MJ) to obtain leaves with high induced levels of cysteine and aspartic proteinase inhibitors. Induced papain inhibitor activity was estimated at 4% of total protein. Other conditions produced leaves with low and moderate levels of this inhibitor. Development of Colorado potato beetle larvae was similar when they were reared on leaves containing

Caroline J. Bolter; Maarten A. Jongsma

1995-01-01

134

Angiotensin-converting enzyme inhibitor-induced unilateral tongue angioedema.  

PubMed

Angioedema is a frequently reported side effect of angiotensin-converting enzyme inhibitors. The literature suggests that immunosuppressed transplant patients are at an increased risk for this adverse condition. A 62-year-old African American man presented with acute unilateral angioedema attributed to angiotensin-converting enzyme inhibitor initiation. A PubMed literature search regarding unilateral angioedema produced only 3 reported cases confirming an uncommon presentation of an otherwise common adverse drug event. The cases raised questions regarding evidence-based management of drug-induced angioedema, effectiveness of current medical management regimens and the potential of other treatment options. Our objective was to review the presentation, diagnosis and acute management of a common adverse drug effect based on an uncommon patient presentation. PMID:22986608

Kuhlen, James Lee; Forcucci, Jessica

2012-11-01

135

ACE Inhibitor-Induced Angioedema of the Bowel  

PubMed Central

Angiotensin converting enzyme inhibitor ACEI-induced angioedema of the intestine is a rare occurrence and often unrecognized complication of ACEI. We present a case of a 45-year-old Hispanic female with angioedema of the small bowel progressing to facial and oral pharyngeal angioedema. Patients are typically middle-aged females on ACEI therapy who present to the emergency department with abdominal pain, nausea, vomiting, and diarrhea. This is a diagnosis of exclusion, and physicians must have a high index of suspicion to make the diagnosis. Symptoms typically resolve within 24–48 hours after ACE inhibitor withdrawal. Recognizing these signs and symptoms, and discontinuing the medication, can save a patient from unnecessary, costly, and invasive procedures.

Campbell, Tabitha; Peckler, Bradley; Hackstadt, Raleigh David; Payor, Austin

2010-01-01

136

Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death.  

PubMed

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth leading cause of cancer death in the western world, with a 5-year survival rate below 5%. Murine double minute 2 (Mdm2) is an important negative regulator of the tumor suppressor p53. Reactivation of wild-type p53 is a promising treatment strategy, and inhibitors of Mdm2 have already entered clinical trials. To investigate the effects of Mdm2 inhibitors in PDAC, we used a murine cell line platform with a genetically defined status of p53. Here, we describe that Mdm2 inhibitors can act on a subset of murine PDAC cell lines p53 independently. Furthermore, we observed that Mdm2 inhibitors increase the sensitivity of murine PDAC cell lines toward topoisomerase II inhibitors by inducing effector caspase-independent cell death. The combination of Mdm2 inhibitors with topoisomerase II inhibitors acts independent of the survival factor NF?B/RelA. Mechanistically, Mdm2 inhibitors increase topoisomerase II inhibitor-induced DNA double-strand breaks. We show that Mdm2 binds to Nbs1 of the Mre11-Rad50-Nijmegen breakage syndrome (Nbs) 1 DNA repair complex. In addition, we provide evidence that Mdm2 inhibitors delay DNA repair. These findings may help to design novel therapeutic strategies to overcome therapeutic resistance of PDAC. PMID:23115126

Conradt, Laura; Henrich, Annika; Wirth, Matthias; Reichert, Maximilian; Lesina, Marina; Algül, Hana; Schmid, Roland M; Krämer, Oliver H; Saur, Dieter; Schneider, Günter

2012-11-26

137

Dual targeting of peroxisomal proteins  

PubMed Central

Cellular compartmentalization into organelles serves to separate biological processes within the environment of a single cell. While some metabolic reactions are specific to a single organelle, others occur in more than one cellular compartment. Specific targeting of proteins to compartments inside of eukaryotic cells is mediated by defined sequence motifs. To achieve multiple targeting to different compartments cells use a variety of strategies. Here, we focus on mechanisms leading to dual targeting of peroxisomal proteins. In many instances, isoforms of peroxisomal proteins with distinct intracellular localization are encoded by separate genes. But also single genes can give rise to differentially localized proteins. Different isoforms can be generated by use of alternative transcriptional start sites, by differential splicing or ribosomal read-through of stop codons. In all these cases different peptide variants are produced, of which only one carries a peroxisomal targeting signal. Alternatively, peroxisomal proteins contain additional signals that compete for intracellular targeting. Dual localization of proteins residing in both the cytoplasm and in peroxisomes may also result from use of inefficient targeting signals. The recent observation that some bona fide cytoplasmic enzymes were also found in peroxisomes indicates that dual targeting of proteins to both the cytoplasm and the peroxisome might be more widespread. Although current knowledge of proteins exhibiting only partial peroxisomal targeting is far from being complete, we speculate that the metabolic capacity of peroxisomes might be larger than previously assumed.

Ast, Julia; Stiebler, Alina C.; Freitag, Johannes; Bolker, Michael

2013-01-01

138

Autophagy induced by farnesyltransferase inhibitors in cancer cells.  

PubMed

The mechanisms of action of farnesyltransferase inhibitors (FTIs) involve Rheb and the phosphatidylinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. mTOR in particular plays a key role in the regulation of autophagy. Collectively, the literature suggests that FTIs very likely induce autophagy, but thus far there have been no reports that FTIs affect this process relevant to cancer cell biology. We hypothesized that FTIs can induce autophagy. In this study, we found that the FTIs manumycin A, FTI-276, and lonafarnib induced autophagy in two human cancer cell lines. We also found that neither inhibition of apoptosis with a pan-caspase inhibitor nor inhibition of autophagy increased the number of clones of lonafarnib-treated U2OS osteosarcoma cells that formed in soft agar. Although whether autophagy is a cell death or cell survival mechanism after FTI treatment remains unresolved, our data show that cancer cells apparently can shift between apoptosis and autophagy once they are committed to die after FTI treatment. PMID:18769123

Pan, Jingxuan; Chen, Bo; Su, Chun-Hui; Zhao, Ruiying; Xu, Zhi-Xiang; Sun, Lily; Lee, Mong-Hong; Yeung, Sai-Ching Jim

2008-10-21

139

Peroxisome Proliferator-Activated Receptor -?/?, -? Agonists and Resveratrol Modulate Hypoxia Induced Changes in Nuclear Receptor Activators of Muscle Oxidative Metabolism  

PubMed Central

PPAR-?, PPAR-?, and PPAR-?, and RXR in conjunction with PGC-1? and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR), and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C2C12 muscle myoblasts displayed a reduction of PGC-1?, PPAR-?, and RXR-? mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1? protein was reduced, and PPAR-? protein increased. The addition of a PPAR-? agonist (L165,041) for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1?, RXR-?, PPAR-?, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-?, PPAR-? mRNA, and PPAR-? and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.

Regnault, Timothy R. H.; Zhao, Lin; Chiu, Jacky S. S.; Gottheil, Stephanie K.; Foran, Allison; Yee, Siu-Pok

2010-01-01

140

?-Carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor ? expression and reactive oxygen species production in MCF7 cancer cells  

Microsoft Academic Search

Although the pharmacological role of ?-carotene in the prevention and treatment of many cancer cells has received increasing attention, the molecular mechanisms underlying such chemopreventive activity are not clear. Since peroxisome proliferator-activated receptor ? (PPAR-?) has been implicated in regulating breast cancer cell differentiation and apoptosis, the effects of ?-carotene on the PPAR-?-mediated pathway and its association with reactive oxygen

Yanhong Cui; Zhongbing Lu; Lin Bai; Zhenhua Shi; Wen-en Zhao; Baolu Zhao

2007-01-01

141

Terminal Differentiation of Human Liposarcoma Cells Induced by Ligands for Peroxisome Proliferator-Activated Receptor gamma and the Retinoid X Receptor  

Microsoft Academic Search

Induction of terminal differentiation represents a promising therapeutic approach to certain human malignancies. The peroxisome proliferator-activated receptor gamma (PPARgamma ) and the retinoid X receptor alpha (RXRalpha ) form a heterodimeric complex that functions as a central regulator of adipocyte differentiation. Natural and synthetic ligands for both receptors have been identified. We demonstrate here that PPARgamma is expressed at high

Peter Tontonoz; Samuel Singer; Barry M. Forman; Pasha Sarraf; Jonathan A. Fletcher; Christopher D. M. Fletcher; Regina P. Brun; Elisabetta Mueller; Soner Altiok; Heather Oppenheim; Ronald M. Evans; Bruce M. Spiegelman

1997-01-01

142

Peroxisome Senescence in Human Fibroblasts  

Microsoft Academic Search

The molecular mechanisms of peroxisome biogenesis have begun to emerge; in contrast, relatively little is known about how the organelle functions as cells age. In this report, we characterize age-related changes in peroxisomes of human cells. We show that aging compromises peroxiso- mal targeting signal 1 (PTS1) protein import, affecting in particular the critical antioxidant enzyme catalase. The number and

Julie E. Legakis; Jay I. Koepke; Chris Jedeszko; Ferdous Barlaskar; Laura J. Terlecky; Holly J. Edwards; Paul A. Walton; Stanley R. Terlecky

2002-01-01

143

Peroxisome Metabolism and Cellular Aging  

PubMed Central

The essential role of peroxisomes in fatty acid oxidation, anaplerotic metabolism, and hydrogen peroxide turnover is well established. Recent findings suggest these and other related biochemical processes governed by the organelle may also play a critical role in regulating cellular aging. The goal of this review is to summarize and integrate into a model, the evidence that peroxisome metabolism actually helps define the replicative and chronological age of a eukaryotic cell. In this model, peroxisomal reactive oxygen species (ROS) are seen as altering organelle biogenesis and function, and eliciting changes in the dynamic communication networks that exist between peroxisomes and other cellular compartments. At low levels, peroxisomal ROS activate an anti-aging program in the cell; at concentrations beyond a specific threshold, a pro-aging course is triggered.

Titorenko, Vladimir I.; Terlecky, Stanley R.

2010-01-01

144

The NADPH oxidase inhibitor apocynin (acetovanillone) induces oxidative stress  

SciTech Connect

Apocynin (acetovanillone) is often used as a specific inhibitor of NADPH oxidase. In N11 glial cells, apocynin induced, in a dose-dependent way, a significant increase of both malonyldialdehyde level (index of lipid peroxidation) and lactate dehydrogenase release (index of a cytotoxic effect). Apocynin evoked also, in a significant way, an increase of H{sub 2}O{sub 2} concentration and a decrease of the intracellular glutathione/glutathione disulfide ratio, accompanied by augmented efflux of glutathione and glutathione disulfide. Apocynin induced the activation of both pentose phosphate pathway and tricarboxylic acid cycle, which was blocked when the cells were incubated with glutathione together with apocynin. The cell incubation with glutathione prevented also the apocynin-induced increase of malonyldialdehyde generation and lactate dehydrogenase leakage. Apocynin exerted an oxidant effect also in a cell-free system: indeed, in aqueous solution, it evoked a faster oxidation of the thiols glutathione and dithiothreitol, and elicited the generation of reactive oxygen species, mainly superoxide anions. Our results suggest that apocynin per se can induce an oxidative stress and exert a cytotoxic effect in N11 cells and other cell types, and that some effects of apocynin in in vitro and in vivo experimental models should be interpreted with caution.

Riganti, Chiara [Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, Via Santena 5/bis, 10126 Turin (Italy); Costamagna, Costanzo [Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, Via Santena 5/bis, 10126 Turin (Italy); Bosia, Amalia [Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, Via Santena 5/bis, 10126 Turin (Italy); Ghigo, Dario [Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, Via Santena 5/bis, 10126 Turin (Italy)]. E-mail: dario.ghigo@unito.it

2006-05-01

145

Zebra Mussel Spawning Is Induced in Low Concentrations of Putative Serotonin Reuptake Inhibitors  

Microsoft Academic Search

Serotonin (5-hydroxytryptamine, 5HT) and its receptor ligands induce both oocyte maturation and spawning in zebra mussels (Dreissena polymorpha). The selective serotonin reuptake inhibitors (SSRIs) fluvoxa- mine (\\

PETER P. FONG

1998-01-01

146

Peroxisomal alterations in Alzheimer's disease.  

PubMed

In Alzheimer's disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I-II, III-IV, and V-VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal ?-oxidation, in cases with stages V-VI pathology compared with those modestly affected (stages I-II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology. PMID:21594711

Kou, Jianqiu; Kovacs, Gabor G; Höftberger, Romana; Kulik, Willem; Brodde, Alexander; Forss-Petter, Sonja; Hönigschnabl, Selma; Gleiss, Andreas; Brügger, Britta; Wanders, Ronald; Just, Wilhelm; Budka, Herbert; Jungwirth, Susanne; Fischer, Peter; Berger, Johannes

2011-05-19

147

Troglitazone, a peroxisome proliferator-activated receptor ? ligand, induces growth inhibition and apoptosis of HepG2 human liver cancer cells  

Microsoft Academic Search

AIM: To examine the effect of troglitazone, a peroxisome proliferator-activated receptor ? (PPAR?) ligand, on the proliferation and apoptosis of human liver cancer cells. METHODS: Liver cancer cell line HepG2 was cultured and treated with troglitazone. Cell proliferation was detected by 3-(4-,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay; apoptosis was detected by flow cytometry and terminal deoxynucleotidyl transferase- mediated nick end labeling

Yan-Ming Zhou; Wen YH; Kang XY; Qian HH; Yang JM; Yin-Hao Wen; Xiao-Yan Kang; Hai-Hua Qian; Jia-Mei Yang; Zheng-Feng Yin

2008-01-01

148

Peroxisome Proliferator-Activated Receptor Induces NADPH Oxidase Activity in Macrophages, Leading to the Generation of LDL with PPAR Activation Properties  

Microsoft Academic Search

Abstract—Peroxisome,proliferator–activated receptors (PPARs) are nuclear receptors controlling lipid and glucose metabolism as well as inflammation. PPARs are expressed in macrophages, cells that also generate reactive oxygen species (ROS). In this study, we investigated whether PPARs regulate ROS production in macrophages. Different PPAR-, but not PPAR- agonists, increased the production of ROS (H2O2 and O2 .) in human and murine macrophages.

Elisabeth Teissier; Atsushi Nohara; Giulia Chinetti; Rejane Paumelle; Bertrand Cariou; Jean-Charles Fruchart; Ralf P. Brandes; Ajay Shah; Bart Staels

2004-01-01

149

Peroxisome proliferator-activated receptor ? ligands, 15-deoxy-?12,14-prostaglandin J2, and ciglitazone, induce growth inhibition and cell cycle arrest in hepatic oval cells  

Microsoft Academic Search

There is growing evidence to show that hepatic oval cells contribute to liver regeneration, dysplastic nodule formation, and hepato-carcinogenesis. Peroxisome proliferator-activated receptors (PPARs) and their ligands play an important role in cell growth, inflammatory responses, and liver pathogenesis including fibrosis and cancer. However, little is known about the role of PPAR?\\/its ligands in the growth and differentiation of hepatic oval

Jidong Cheng; Hideji Nakamura; Hiroyasu Imanishi; Weidong Liu; Takayuki Morisaki; Toshihiro Sugiyama; Toshikazu Hada

2004-01-01

150

Peroxisome proliferator activated receptor ? (PPAR?) and PPAR gamma coactivator (PGC1?) induce carnitine palmitoyltransferase IA (CPT1A) via independent gene elements  

Microsoft Academic Search

Long chain fatty acids and pharmacologic ligands for the peroxisome proliferator activated receptor alpha (PPAR?) activate expression of genes involved in fatty acid and glucose oxidation including carnitine palmitoyltransferase-1A (CPT-1A) and pyruvate dehydrogenase kinase 4 (PDK4). CPT-1A catalyzes the transfer of long chain fatty acids from acyl-CoA to carnitine for translocation across the mitochondrial membranes and is an initiating step

Shulan Song; Ramy R. Attia; Sara Connaughton; Melissa I. Niesen; Gene C. Ness; Marshall B. Elam; Roderick T. Hori; George A. Cook; Edwards A. Park

2010-01-01

151

Stress inducible proteinase inhibitor diversity in Capsicum annuum  

PubMed Central

Background Wound-inducible Pin-II Proteinase inhibitors (PIs) are one of the important plant serine PIs which have been studied extensively for their structural and functional diversity and relevance in plant defense against insect pests. To explore the functional specialization of an array of Capsicum annuum (L.) proteinase inhibitor (CanPIs) genes, we studied their expression, processing and tissue-specific distribution under steady-state and induced conditions. Inductions were performed by subjecting C. annuum leaves to various treatments, namely aphid infestation or mechanical wounding followed by treatment with either oral secretion (OS) of Helicoverpa armigera or water. Results The elicitation treatments regulated the accumulation of CanPIs corresponding to 4-, 3-, and 2-inhibitory repeat domains (IRDs). Fourty seven different CanPI genes composed of 28 unique IRDs were identified in total along with those reported earlier. The CanPI gene pool either from uninduced or induced leaves was dominated by 3-IRD PIs and trypsin inhibitory domains. Also a major contribution by 4-IRD CanPI genes possessing trypsin and chymotrypsin inhibitor domains was specifically revealed in wounded leaves treated with OS. Wounding displayed the highest number of unique CanPIs while wounding with OS treatment resulted in the high accumulation of specifically CanPI-4, -7 and ?10. Characterization of the PI protein activity through two dimensional gel electrophoresis revealed tissue and induction specific patterns. Consistent with transcript abundance, wound plus OS or water treated C. annuum leaves exhibited significantly higher PI activity and isoform diversity contributed by 3- and 4-IRD CanPIs. CanPI accumulation and activity was weakly elicited by aphid infestation yet resulted in the higher expression of CanPI-26, -41 and ?43. Conclusions Plants can differentially perceive various kinds of insect attacks and respond appropriately through activating plant defenses including regulation of PIs at transcriptional and post-translational levels. Based on the differentially elicited CanPI accumulation patterns, it is intriguing to speculate that generating sequence diversity in the form of multi-IRD PIs is a part of elaborative plant defense strategy to obtain a diverse pool of functional units to confine insect attack.

2012-01-01

152

Further evidence for the involvement of inhibition of cell proliferation and development in thymic and splenic atrophy induced by the peroxisome proliferator perfluoroctanoic acid in mice.  

PubMed

We recently demonstrated that severe thymic and splenic atrophy occur upon dietary treatment of mice with potent peroxisome proliferators (PPs), e.g. perfluorooctanoic acid (PFOA), WY-14,643, nafenopin, and di(2-ethylhexyl)phthalate (DEHP). In the present study, we investigated this phenomenon further employing a relative inert PP, PFOA. Comparison of the dose-dependencies and time-courses indicated that the peroxisome proliferative effect occurred prior to atrophy of both the thymus and spleen. However, following withdrawal of PFOA from the diet, the weight of the thymus and spleen rapidly returned to normal within 10 and 5 days, respectively, in contrast to the more persistent peroxisome proliferation. Furthermore, the changes in thymus and spleen weight upon PFOA treatment and the following withdrawal from diet paralleled the changes in total thymocyte and splenocyte counts, respectively. It was found previously that the decreases in the thymocyte populations present in the S and G2/M phases, as well as in the number of CD4+CD8+ cells upon PFOA treatment, were the most dramatic, perhaps reflecting inhibition of thymocyte proliferation in connection with thymocyte development. Here, the recovery of thymocytes began with increases in the populations in these same phases of the cell cycle, with CD4+CD8+ cells recovering most rapidly, lending further support to our previous hypothesis. The possible relationship of these immunotoxic effects of PPs to the changes they cause in fatty acid metabolism is discussed. PMID:11597582

Yang, Q; Xie, Y; Eriksson, A M; Nelson, B D; DePierre, J W

2001-10-15

153

Peroxisome biogenesis and molecular defects in peroxisome assembly disorders  

Microsoft Academic Search

Peroxisome assembly in mammals requires more than 14 genes. So far, we have isolated seven complementation groups (CGs) of\\u000a peroxisome biogenesis-defective Chinese hamster ovary (CHO) cell mutants, Z65, Z24\\/ZP107, ZP92, ZP105\\/ZP139, ZP109, ZP110,\\u000a ZP114. Two peroxin cDNAs, PEX2 and PEX6, were first cloned by genetic phenotype-complementation assay using Z65 and ZP92, respectively, and were shown to be responsible\\u000a for peroxisome

Yukio Fujiki; Kanji Okumoto; Hidenori Otera; Shigehiko Tamura

2000-01-01

154

Selective HDAC1/HDAC2 inhibitors induce neuroblastoma differentiation.  

PubMed

While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation. PMID:23706636

Frumm, Stacey M; Fan, Zi Peng; Ross, Kenneth N; Duvall, Jeremy R; Gupta, Supriya; VerPlank, Lynn; Suh, Byung-Chul; Holson, Edward; Wagner, Florence F; Smith, William B; Paranal, Ronald M; Bassil, Christopher F; Qi, Jun; Roti, Giovanni; Kung, Andrew L; Bradner, James E; Tolliday, Nicola; Stegmaier, Kimberly

2013-05-23

155

The peroxisome: still a mysterious organelle  

PubMed Central

More than half a century of research on peroxisomes has revealed unique features of this ubiquitous subcellular organelle, which have often been in disagreement with existing dogmas in cell biology. About 50 peroxisomal enzymes have so far been identified, which contribute to several crucial metabolic processes such as ?-oxidation of fatty acids, biosynthesis of ether phospholipids and metabolism of reactive oxygen species, and render peroxisomes indispensable for human health and development. It became obvious that peroxisomes are highly dynamic organelles that rapidly assemble, multiply and degrade in response to metabolic needs. However, many aspects of peroxisome biology are still mysterious. This review addresses recent exciting discoveries on the biogenesis, formation and degradation of peroxisomes, on peroxisomal dynamics and division, as well as on the interaction and cross talk of peroxisomes with other subcellular compartments. Furthermore, recent advances on the role of peroxisomes in medicine and in the identification of novel peroxisomal proteins are discussed.

Fahimi, H. Dariush

2008-01-01

156

Synthetic peptides for use as inhibitors of neurotransmitter secretion and as inducers of cellular relaxation  

US Patent & Trademark Office Database

The present invention describes materials and methods related to synthetic peptides which block the secretion of neurotransmitters and induce muscle relaxation, and use of said peptides as inhibitors of neurotransmitter secretion and muscle contraction, and as inducers of muscle relaxation.

2012-11-27

157

Polyunsaturated fatty acids regulate lipogenic and peroxisomal gene expression by independent mechanisms  

Microsoft Academic Search

Polyunsaturated fatty acids of the (n-6) and (n-3) families uniquely coordinate hepatic lipid synthesis and oxidation by suppressing the transcription of hepatic genes encoding lipogenic and glycolytic enzymes while concomitantly inducing the activity of enzymes in mitochondrial and peroxisomal fatty acid oxidation. Recently a group of fatty acid activated nuclear transcription factors termed peroxisome proliferator activated receptors (PPARs) were cloned.

S. D. Clarke; M. Turini; D. Jump

1997-01-01

158

Targeting Neurite Growth Inhibitors to Induce CNS Regeneration  

Microsoft Academic Search

Prominent among the several endogenous inhibitors known to limit recovery and plasticity after CNS injury are Nogo (neurite outgrowth inhibitor) and MAG (myelin associated glycoprotein). The effects of these inhibitors on axonal regeneration can be reduced by administratio n of specific antagonists, some of which are commercially available for experimental investigation. There are three aspects of therapeutic manipulations: targeting the

Abba J. Kastin; Weihong Pan

2005-01-01

159

Proteasome inhibitor MG-132 induces MCPIP1 expression.  

PubMed

The proteasome is a protein complex responsible for the degradation of polyubiquitin-tagged proteins. Besides the removal of target proteins, the proteasome also participates in the regulation of gene transcription in both proteolytic and non-proteolytic fashion. In this study the effect of proteasome inhibition on the basal expression of monocyte chemotactic protein-1 induced protein 1 (MCPIP1) was examined. Treatment of HepG2 or HeLa cells with proteasome inhibitor MG-132 resulted in a significant increase of MCPIP1 expression, both at mRNA and protein level. Interestingly, MG-132 did not alter MCPIP1 stability. Instead, the observed protein increase was blocked by actinomycin D, suggesting the involvement of de novo mRNA synthesis in the increase of MCPIP1 protein following MG-132 treatment. Using several inhibitors we determined the participation of extracellular-signal-regulated kinase 1/2 and p38 kinases in MCPIP1 upregulation by MG-132. Our findings show for the first time the impact of proteasome inhibition on MCPIP1 protein expression by modulation of the activity of intracellular signaling pathways. Overexpression of MCPIP1-myc protein decreased the viability of HeLa cells but not HepG2 cells, which correlates with the increased susceptibility of HeLa cells to MG-132 toxicity. Notably, both MG-132 treatment and MCPIP1-myc overexpression led to the activation of apoptosis, as revealed by the induction of caspases 3/7 in both types of cell lines. This suggests the involvement of MCPIP1 upregulation in toxic properties of proteasome inhibition, which is an acknowledged approach to the treatment of several cancer types. PMID:23551903

Skalniak, Lukasz; Koj, Aleksander; Jura, Jolanta

2013-05-07

160

Inducible nitric oxide: an autoregulatory feedback inhibitor of vascular inflammation.  

PubMed

Inducible nitric oxide (iNO) is produced at sites of vascular inflammation by resident and nonresident vascular wall cells, but its role in the inflammatory process is not known. In this study, we show that a novel function of iNO is to terminate inflammatory processes. We find that iNO produced by murine macrophage-like cells, RAW264.7, can inhibit cytokine-induced endothelial cell activation in a separated and mixed endothelial-RAW264.7 coculture system. Both iNO production and endothelial VCAM-1 expression were induced simultaneously with bacterial LPS and murine-specific IFN-gamma. Inhibition of iNO synthase (iNOS) activity with N omega-monomethyl-L-arginine in endothelial-RAW264.7 cocultures, stimulated with murine-specific IFN-gamma and LPS, decreased iNO production by 86%, augmented VCAM-1 and iNOS expression in endothelial and RAW264.7 cells, respectively, and increased monocyte adhesion to the endothelial cell surface. Transient transfection studies using various VCAM-1 promoter constructs demonstrated that inhibitory effects of iNO on VCAM-1 gene transcription were mediated, in part, by inhibitory effects of iNO on kappa B cis-acting elements. Immunofluorescence studies using an Ab to the RelA (p65) subunit of nuclear factor-kappa B revealed that iNO inhibited the activation of nuclear factor-kappa B. These studies indicate that iNO attenuates iNOS expression in macrophages and inhibits monocyte adhesion to endothelial cells, and suggest that endogenously derived iNO may be an important autoregulatory inhibitor of vascular inflammation. PMID:9712068

Peng, H B; Spiecker, M; Liao, J K

1998-08-15

161

Import of stably folded proteins into peroxisomes.  

PubMed Central

By virtue of their synthesis in the cytoplasm, proteins destined for import into peroxisomes are obliged to traverse the single membrane of this organelle. Because the targeting signal for most peroxisomal matrix proteins is a carboxy-terminal tripeptide sequence (SKL or its variants), these proteins must remain import competent until their translation is complete. We sought to determine whether stably folded proteins were substrates for peroxisomal import. Prefolded proteins stabilized with disulfide bonds and chemical cross-linkers were shown to be substrates for peroxisomal import, as were mature folded and disulfide-bonded IgG molecules containing the peroxisomal targeting signal. In addition, colloidal gold particles conjugated to proteins bearing the peroxisomal targeting signal were translocated into the peroxisomal matrix. These results support the concept that proteins may fold in the mammalian cytosol, before their import into the peroxisome, and that protein unfolding is not a prerequisite for peroxisomal import. Images

Walton, P A; Hill, P E; Subramani, S

1995-01-01

162

Yeast peroxisomes multiply by growth and division  

PubMed Central

Peroxisomes can arise de novo from the endoplasmic reticulum (ER) via a maturation process. Peroxisomes can also multiply by fission. We have investigated how these modes of multiplication contribute to peroxisome numbers in Saccharomyces cerevisiae and the role of the dynamin-related proteins (Drps) in these processes. We have developed pulse-chase and mating assays to follow the fate of existing peroxisomes, de novo–formed peroxisomes, and ER-derived preperoxisomal structures. We find that in wild-type (WT) cells, peroxisomes multiply by fission and do not form de novo. A marker for the maturation pathway, Pex3-GFP, is delivered from the ER to existing peroxisomes. Strikingly, cells lacking peroxisomes as a result of a segregation defect do form peroxisomes de novo. This process is slower than peroxisome multiplication in WT cells and is Drp independent. In contrast, peroxisome fission is Drp dependent. Our results show that peroxisomes multiply by growth and division under our assay conditions. We conclude that the ER to peroxisome pathway functions to supply existing peroxisomes with essential membrane constituents.

Motley, Alison M.; Hettema, Ewald H.

2007-01-01

163

Transmucosal gastric leak induced by proton pump inhibitors.  

PubMed

Despite their remarkable safety profile and lack of clinical side effects, proton pump inhibitors (PPIs) induce a transmucosal gastric leak to non-electrolyte probes of various sizes. The ex vivo addition of PPIs to isolated rat gastric corpus increases transmucosal permeability in a dose-dependent manner, which corresponds with PPIs' dose-dependent inhibition of acid secretion. Upon the addition of omeprazole, lansoprazole, or esomeprazole, a small decrease in transepithelial resistance and the concomitant stimulation of short circuit current was observed. Additionally, transepithelial flux of (14)C-[D]-mannitol (MW 182.17) across the gastric mucosa increased by a mean of 68% immediately following the addition of 200 microM omeprazole. This flux increase was bidirectional. Omeprazole also increased the paracellular permeability to larger radiolabeled probes, including (14)C-sucrose (MW 342.3) and (14)C-polyethylene glycol (MW 4,000) by 118% and 350%, respectively. However, the flux of still larger probes, 10,000 and 70,000 MW dextrans, was not increased. Because PPIs are so widely used and are assumed to be innocuous, this transmucosal gastric leak must be further investigated, as it may carry considerable biomedical implications. PMID:19015985

Murray, Lisa J; Gabello, Melissa; Rudolph, David S; Farrell, Christopher P; Morgan, Melissa; Martin, Aaron P; Underwood, James C; Valenzano, M Carmen; Mullin, James M

2008-11-18

164

Role of inhibitor of apoptosis protein in gentamicin-induced cochlear hair cell damage.  

PubMed

Apoptotic cell death is considered to play a key role in gentamicin-induced cochlear hair cell loss. Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis that can prevent activation of effector caspases. This study was designed to investigate the possible involvement of X-linked inhibitor of apoptosis protein (XIAP) in hair cell death due to gentamicin. Basal turn organ of Corti explants from postnatal day (p) p3 or p4 rats were maintained in tissue culture and were exposed to 35 muM gentamicin for up to 48 h. Effects of specific XIAP inhibitors on gentamicin-induced hair cell loss and caspase-3 activation were examined. XIAP inhibitors increased gentamicin-induced hair cell loss but an inactive analog had no effect. Caspase-3 activation was primarily observed at 36 or 48 h in gentamicin-treated hair cells, whereas caspase-3 activation peaked at 24-36 h when explants were treated with gentamicin and an XIAP inhibitor. The inhibitors alone had no effect on hair cells. Finally, a caspase-3 inhibitor decreased caspase-3 activation and hair cell loss induced by gentamicin and an XIAP inhibitor, but caspase-8 and -9 inhibitors did not. The results indicate that XIAP normally acts to decrease caspase-3 activation and hair cell loss during gentamicin ototoxicity, as part of a protective response to potentially damaging stimuli. PMID:17869439

Tabuchi, K; Pak, K; Chavez, E; Ryan, A F

2007-08-02

165

Pex11? deficiency impairs peroxisome elongation and division and contributes to nonalcoholic fatty liver in mice.  

PubMed

Hepatic triglyceride (TG) accumulation is considered to be a prerequisite for developing nonalcoholic fatty liver (NAFL). Peroxisomes have many important functions in lipid metabolism, including fatty acid ?-oxidization. However, the pathogenic link between NAFL and peroxisome biogenesis remains unclear. To examine the molecular and physiological functions of the Pex11? gene, we disrupted this gene in mice. Body weights and hepatic TG concentrations in Pex11?(-/-) mice were significantly higher than those in wild-type (WT) mice fed a normal or a high-fat diet. Hepatic TG concentrations in fasted Pex11?(-/-) mice were significantly higher than those in fasted WT mice. Plasma TG levels increased at lower rates in Pex11?(-/-) mice than in WT mice after treatment with the lipoprotein lipase inhibitor tyloxapol. The number of peroxisomes was lower in the livers of Pex11?(-/-) mice than in those of WT mice. Ultrastructural analysis showed that small and regular spherically shaped peroxisomes were more prevalent in Pex11?(-/-) mice fed normal chow supplemented without or with fenofibrate. We observed a significantly higher ratio of empty peroxisomes containing only PMP70, a peroxisome membrane protein, but not catalase, a peroxisome matrix protein, in Pex11?(-/-) mice. The mRNA expression levels of peroxisomal fatty acid oxidation-related genes (ATP-binding cassette, subfamily D, member 2, and acyl-CoA thioesterase 3) were significantly higher in WT mice than those in Pex11?(-/-) mice under fed conditions. Our results demonstrate that Pex11? deficiency impairs peroxisome elongation and abundance and peroxisomal fatty acid oxidation, which contributes to increased lipid accumulation in the liver. PMID:23169785

Weng, Huachun; Ji, Xu; Naito, Yukiko; Endo, Kosuke; Ma, Xiao; Takahashi, Rie; Shen, Chunshen; Hirokawa, Go; Fukushima, Yasue; Iwai, Naoharu

2012-11-20

166

TSC on the peroxisome controls mTORC1.  

PubMed

mTOR is a central controller that integrates many inputs to regulate cell growth and ensure cellular homeostasis. The mTORC1 inhibitor TSC (tuberous sclerosis complex) on the peroxisome is found to inhibit mTORC1 in response to endogenous reactive oxygen species. Thus, mTOR may avoid confounding different inputs by sensing them at different cellular locations. PMID:24084861

Benjamin, Don; Hall, Michael N

2013-10-01

167

COX2 inhibitors block chemotherapeutic agent-induced apoptosis prior to commitment in hematopoietic cancer cells  

Microsoft Academic Search

Enzymatic inhibitors of pro-inflammatory cyclooxygenase-2 (COX-2) possess multiple anti-cancer effects, including chemosensitization. These effects are not always linked to the inhibition of the COX-2 enzyme. Here we analyze the effects of three COX-2 enzyme inhibitors (nimesulide, NS-398 and celecoxib) on apoptosis in different hematopoietic cancer models. Surprisingly, COX-2 inhibitors strongly prevent apoptosis induced by a panel of chemotherapeutic agents. We

Claudia Cerella; Cyril Sobolewski; Sébastien Chateauvieux; Estelle Henry; Michael Schnekenburger; Jenny Ghelfi; Mario Dicato; Marc Diederich

2011-01-01

168

Further evidence for the involvement of inhibition of cell proliferation and development in thymic and splenic atrophy induced by the peroxisome proliferator perfluoroctanoic acid in mice 3 3 Abbreviations: PFOA, perfluorooctanoic acid; PP, peroxisome proliferator; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; and DEHP, di(2-ethylhexyl)phthalate  

Microsoft Academic Search

We recently demonstrated that severe thymic and splenic atrophy occur upon dietary treatment of mice with potent peroxisome proliferators (PPs), e.g. perfluorooctanoic acid (PFOA), WY-14,643, nafenopin, and di(2-ethylhexyl)phthalate (DEHP). In the present study, we investigated this phenomenon further employing a relative inert PP, PFOA. Comparison of the dose-dependencies and time-courses indicated that the peroxisome proliferative effect occurred prior to atrophy

Qian Yang; Yi Xie; Anna Messing Eriksson; B. Dean Nelson; Joseph W DePierre

2001-01-01

169

The importomer—A peroxisomal membrane complex involved in protein translocation into the peroxisome matrix  

Microsoft Academic Search

The import of proteins into the peroxisome matrix is an essential step in peroxisome biogenesis, which is critical for normal functioning of most eukaryotic cells. The translocation of proteins across the peroxisome membrane and the dynamic behavior of the import receptors during the import cycle is facilitated by several peroxisome–membrane-associated protein complexes, one of which is called the importomer complex

Naganand Rayapuram; Suresh Subramani

2006-01-01

170

Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction in Adolescents: A Review.  

ERIC Educational Resources Information Center

|Objective: To review the existing literature on selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction in adolescents. Method: A literature review of SSRI-induced adverse effects in adolescents focusing on sexual dysfunction was done. Nonsexual SSRI-induced adverse effects were compared in adult and pediatric populations.…

Scharko, Alexander M.

2004-01-01

171

Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction in Adolescents: A Review.  

ERIC Educational Resources Information Center

Objective: To review the existing literature on selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction in adolescents. Method: A literature review of SSRI-induced adverse effects in adolescents focusing on sexual dysfunction was done. Nonsexual SSRI-induced adverse effects were compared in adult and pediatric populations.…

Scharko, Alexander M.

2004-01-01

172

Inhibitors  

MedlinePLUS

... message, please visit this page: About CDC.gov . Hemophilia Share Compartir Add this to... Añadir en... Favorites Delicious Digg Google Bookmarks Inhibitors People with hemophilia have a higher quality of life today than ...

173

Membranes of rat liver peroxisomes.  

PubMed

Membranes of liver peroxisomes from rats fed with clofibrate were purified in a discontinuous gradient using a zonal rotor. The preparation consists of round or oval vesicles mostly devoid of nucleoids with a diameter ranging from 70-700 nm; open sheets are found very infrequently. Mitochondrial profiles as well as vesicles containing cytochemically demonstrable glucose 6-phosphatase are scarce; accordingly, glucose 6-phosphatase is nearly undetectable biochemically. Monoamine oxidase is absent in peroxisomal membranes. Cytochrome b5 is found in a concentration of 0.3 nmoles/mg protein, an order of magnitude comparable to the content of endoplasmic reticulum membranes. Reduction of this cytochrome with palmitoyl-CoA is possible only after recombination of the membranes with the soluble peroxisomal matrix fraction. PMID:6263829

Hüttinger, M; Pavelka, M; Goldenberg, H; Kramar, R

1981-01-01

174

Apoptotic action of peroxisome proliferator-activated receptor-gamma activation in human non small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation.  

PubMed

Peroxisome proliferator-activated receptor (PPAR)-gamma ligands have been shown to inhibit human lung cancers by inducing apoptosis and differentiation. In the present study, we elucidated the apoptotic mechanism of PPARgamma activation in human lung cancers by using a novel PPARgamma agonist, 1-(trans-methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-(1H-indene-2-carboxylic acid ethyl ester (KR-62980), and rosiglitazone. PPARgamma activation selectively inhibited cell viability of non-small-cell lung cancer with little effect on small-cell lung cancer and normal lung cells. The cell death induced by PPARgamma activation presented apoptotic features of oligonucleosomal DNA fragmentation in A549 human non-small-cell lung cancer cell line. Reactive oxygen species (ROS) production was accompanied by increased expression of proline oxidase (POX), a redox enzyme expressed in mitochondria, upon incubation with the agonists. POX RNA interference treatment blocked PPARgamma-induced ROS formation and cytotoxicity, suggesting that POX plays a functional role in apoptosis through ROS formation. The apoptotic effects by the agonists were antagonized by bisphenol A diglycidyl ether, a PPARgamma antagonist, and by knockdown of PPARgamma expression, indicating the involvement of PPARgamma in these actions. The results of the present study suggest that PPARgamma activation induces apoptotic cell death in non-small-cell lung carcinoma mainly through ROS formation via POX induction. PMID:17535976

Kim, Ki Young; Ahn, Jin Hee; Cheon, Hyae Gyeong

2007-05-29

175

Effects of Inflammation on Peroxisomal Enzyme Activity, Catalase Synthesis and Lipid Metabolism.  

National Technical Information Service (NTIS)

The activity of hepatic peroxisomal enzymes, catalase, urate oxidase, D-amino acid oxidase, hydroxy acid oxidase, and carnitine acetyltransferase were serially measured following a turpentine-induced sterile inflammatory lesion in rats. The ensuing depres...

P. G. Canonico W. Rill E. Ayala

1977-01-01

176

Peroxisomes and sexual development in fungi  

PubMed Central

Peroxisomes are versatile and dynamic organelles that are essential for the development of most eukaryotic organisms. In fungi, many developmental processes, such as sexual development, require the activity of peroxisomes. Sexual reproduction in fungi involves the formation of meiotic-derived sexual spores, often takes place inside multicellular fruiting bodies and requires precise coordination between the differentiation of multiple cell types and the progression of karyogamy and meiosis. Different peroxisomal functions contribute to the orchestration of this complex developmental process. Peroxisomes are required to sustain the formation of fruiting bodies and the maturation and germination of sexual spores. They facilitate the mobilization of reserve compounds via fatty acid ?-oxidation and the glyoxylate cycle, allowing the generation of energy and biosynthetic precursors. Additionally, peroxisomes are implicated in the progression of meiotic development. During meiotic development in Podospora anserina, there is a precise modulation of peroxisome assembly and dynamics. This modulation includes changes in peroxisome size, number and localization, and involves a differential activity of the protein-machinery that drives the import of proteins into peroxisomes. Furthermore, karyogamy, entry into meiosis and sorting of meiotic-derived nuclei into sexual spores all require the activity of peroxisomes. These processes rely on different peroxisomal functions and likely depend on different pathways for peroxisome assembly. Indeed, emerging studies support the existence of distinct import channels for peroxisomal proteins that contribute to different developmental stages.

Peraza-Reyes, Leonardo; Berteaux-Lecellier, Veronique

2013-01-01

177

Peroxisome Degradation by Microautophagy in Pichia pastoris: Identification of Specific Steps and Morphological Intermediates  

PubMed Central

We used the dye N-(3-triethylammoniumpropyl)-4-(p-diethylaminophenylhexatrienyl) pyridinium dibromide (FM4-64) and a fusion protein, consisting of the green fluorescent protein appended to the peroxisomal targeting signal, Ser-Lys-Leu (SKL), to label the vacuolar membrane and the peroxisomal matrix, respectively, in living Pichia pastoris cells and followed by fluorescence microscopy the morphological and kinetic intermediates in the vacuolar degradation of peroxisomes by microautophagy and macroautophagy. Structures corresponding to the intermediates were also identified by electron microscopy. The kinetics of appearance and disappearance of these intermediates is consistent with a precursor–product relationship between intermediates, which form the basis of a model for microautophagy. Inhibitors affecting different steps of microautophagy did not impair peroxisome delivery to the vacuole via macroautophagy, although inhibition of vacuolar proteases affected the final vacuolar degradation of green fluorescent protein (S65T mutant version [GFP])-SKL via both autophagic pathways. P. pastoris mutants defective in peroxisome microautophagy (pag mutants) were isolated and characterized for the presence or absence of the intermediates. These mutants, comprising 6 complementation groups, support the model for microautophagy. Our studies indicate that the microautophagic degradation of peroxisomes proceeds via specific intermediates, whose generation and/or processing is controlled by PAG gene products, and shed light on the poorly understood phenomenon of peroxisome homeostasis.

Sakai, Yasuyoshi; Koller, Antonius; Rangell, Linda K.; Keller, Gilbert A.; Subramani, Suresh

1998-01-01

178

Peroxisomes, oxidative stress, and inflammation  

PubMed Central

Peroxisomes are intracellular organelles mediating a wide variety of biosynthetic and biodegradative reactions. Included among these are the metabolism of hydrogen peroxide and other reactive species, molecules whose levels help define the oxidative state of cells. Loss of oxidative equilibrium in cells of tissues and organs potentiates inflammatory responses which can ultimately trigger human disease. The goal of this article is to review evidence for connections between peroxisome function, oxidative stress, and inflammation in the context of human health and degenerative disease. Dysregulated points in this nexus are identified and potential remedial approaches are presented.

Terlecky, Stanley R; Terlecky, Laura J; Giordano, Courtney R

2012-01-01

179

Proteasome inhibitor MG132 induces C6 glioma cell apoptosis via oxidative stress  

Microsoft Academic Search

Aim:Proteasome inhibitors have been found to suppress glioma cell proliferation and induce apoptosis, but the mechanisms are not fully elucidated. In this study we investigated the mechanisms underlying the apoptosis induced by the proteasome inhibitor MG-132 in glioma cells.Methods:C6 glioma cells were used. MTT assay was used to analyze cell proliferation. Proteasome activity was assayed using Succinyl-LLVY-AMC, and intracellular ROS

Wen-hai Fan; Yi Hou; Fan-kai Meng; Xiao-fei Wang; Yi-nan Luo; Peng-fei Ge

2011-01-01

180

The Catalase Inhibitor Sodium Azide Reduces Ethanol-Induced Locomotor Activity  

Microsoft Academic Search

SANCHIS-SEGURA, C., M. MIQUEL, M. CORREA AND C. M. G. ARAGON. The catalase inhibitor sodium azide reduces ethanol-induced locomotor activity. ALCOHOL 19(1) 37–42, 1999.—The involvement of brain catalase in modulating the psychopharmacological effects of ethanol was investigated by examining ethanol-induced locomotor activity in sodium azide-treated mice. Mice were pretreated with IP injections of the catalase inhibitor sodium azide (5, 10,

Carles Sanchis-Segura; Marta Miquel; Mercè Correa; Carlos M. G Aragon

1999-01-01

181

Kupffer cell oxidant production is central to the mechanism of peroxisome proliferators  

Microsoft Academic Search

Increased cell proliferation most likely plays a key role in peroxisome proliferator-induced liver cancer. Recently, Kupffer cells were shown to be responsible for Wy-14,643- induced cell proliferation. However, the mechanism by which peroxisome proliferators activate Kupffer cells is unknown. Since gut-derived endotoxin is a known activator of Kupffer cells, the hypothesis that it is involved was evaluated. Increased cell proliferation

Michelle L. Rose; Chantal A. Rivera; Blair U. Bradford; Lee M. Graves; Russell C. Cattley; Robert Schoonhoven; James A. Swenberg; Ronald G. Thurman

1999-01-01

182

Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis  

Microsoft Academic Search

In the present study we have explored the sensitivity of ovarian cancer cells to TRAIL and proteasome inhibitors. Particularly,\\u000a we have explored the capacity of proteasome inhibitors to bypass TRAIL resistance of ovarian cancer cells. For these studies\\u000a we have used the A2780 ovarian cancer cell line and its chemoresistant derivatives A2780\\/DDP and A2780\\/ADR, providing evidence\\u000a that: (i) the three

Ernestina Saulle; Alessia Petronelli; Luca Pasquini; Eleonora Petrucci; Gualtiero Mariani; Mauro Biffoni; Gianluigi Ferretti; Giovanni Scambia; Pierluigi Benedetti-Panici; Francesco Cognetti; Robin Humphreys; Cesare Peschle; Ugo Testa

2007-01-01

183

Peroxisome Proliferator-activated Receptor ? Coactivator 1 (PGC-1)- and Estrogen-related Receptor (ERR)-induced Regulator in Muscle 1 (PERM1) Is a Tissue-specific Regulator of Oxidative Capacity in Skeletal Muscle Cells.  

PubMed

Mitochondrial oxidative metabolism and energy transduction pathways are critical for skeletal and cardiac muscle function. The expression of genes important for mitochondrial biogenesis and oxidative metabolism are under the control of members of the peroxisome proliferator-activated receptor ? coactivator 1 (PGC-1) family of transcriptional coactivators and the estrogen-related receptor (ERR) subfamily of nuclear receptors. Perturbations in PGC-1 and/or ERR activities have been associated with alterations in capacity for endurance exercise, rates of muscle atrophy, and cardiac function. The mechanism(s) by which PGC-1 and ERR proteins regulate muscle-specific transcriptional programs is not fully understood. We show here that PGC-1? and ERRs induce the expression of a so far uncharacterized muscle-specific protein, PGC-1- and ERR-induced regulator in muscle 1 (Perm1), which regulates the expression of selective PGC-1/ERR target genes. Perm1 is required for the basal as well as PGC-1?-enhanced expression of genes with roles in glucose and lipid metabolism, energy transfer, and contractile function. Silencing of Perm1 in cultured myotubes compromises respiratory capacity and diminishes PGC-1?-induced mitochondrial biogenesis. Our findings support a role for Perm1 acting downstream of PGC-1? and ERRs to regulate muscle-specific pathways important for energy metabolism and contractile function. Elucidating the function of Perm1 may enable novel approaches for the treatment of disorders with compromised skeletal muscle bioenergetics, such as mitochondrial myopathies and age-related/disease-associated muscle atrophies. PMID:23836911

Cho, Yoshitake; Hazen, Bethany C; Russell, Aaron P; Kralli, Anastasia

2013-07-08

184

NF?B inhibitors induce cell death in glioblastomas.  

PubMed

Identification of novel target pathways in glioblastoma (GBM) remains critical due to poor prognosis, inefficient therapies and recurrence associated with these tumors. In this work, we evaluated the role of nuclear-factor-kappa-B (NF?B) in the growth of GBM cells, and the potential of NF?B inhibitors as antiglioma agents. NF?B pathway was found overstimulated in GBM cell lines and in tumor specimens compared to normal astrocytes and healthy brain tissues, respectively. Treatment of a panel of established GBM cell lines (U138MG, U87, U373 and C6) with pharmacological NF?B inhibitors (BAY117082, parthenolide, MG132, curcumin and arsenic trioxide) and NF?B-p65 siRNA markedly decreased the viability of GBMs as compared to inhibitors of other signaling pathways such as MAPKs (ERK, JNK and p38), PKC, EGFR and PI3K/Akt. In addition, NF?B inhibitors presented a low toxicity to normal astrocytes, indicating selectivity to cancerous cells. In GBMs, mitochondrial dysfunction (membrane depolarization, bcl-xL downregulation and cytochrome c release) and arrest in the G2/M phase were observed at the early steps of NF?B inhibitors treatment. These events preceded sub-G1 detection, apoptotic body formation and caspase-3 activation. Also, NF?B was found overstimulated in cisplatin-resistant C6 cells, and treatment of GBMs with NF?B inhibitors overcame cisplatin resistance besides potentiating the effects of the chemotherapeutics, cisplatin and doxorubicin. These findings support NF?B as a potential target to cell death induction in GBMs, and that the NF?B inhibitors may be considered for in vivo testing on animal models and possibly on GBM therapy. PMID:21040711

Zanotto-Filho, Alfeu; Braganhol, Elizandra; Schröder, Rafael; de Souza, Luís Henrique T; Dalmolin, Rodrigo J S; Pasquali, Matheus A Bittencourt; Gelain, Daniel Pens; Battastini, Ana Maria Oliveira; Moreira, José Cláudio Fonseca

2010-10-30

185

Angiotensin Converting Enzyme Inhibitor-induced Gastrointestinal Angioedema: A Case Series and Literature Review.  

PubMed

GOALS:: The objective of this study was to better understand the presenting signs and symptoms of angiotensin converting enzyme (ACE) inhibitor-induced gastrointestinal angioedema, review the medical literature related to this condition, and bring this diagnosis to the attention of clinicians. BACKGROUND:: Angioedema occurs in 0.1% to 0.7% of patients treated with ACE inhibitors and ACE inhibitors account for 20% to 30% of all angioedema cases presenting to emergency departments. However, only recently have ACE inhibitors been recognized as a cause of angioedema of the gastrointestinal tract. Patients with this disease present with one or more episodes of abdominal pain associated with nausea, vomiting, and/or diarrhea. STUDY:: We present four cases of ACE inhibitor-induced gastrointestinal angioedema seen at a single institution and review the literature of other case reports. RESULTS:: Review of the medical literature identified 27 case reports of ACE inhibitor-induced angioedema of the gastrointestinal tract. Multiple ACE inhibitors were implicated in these case reports suggesting that this disease is a class effect of ACE inhibitors. In cases where the race of the patient was stated, 50% were identified as being African American. Ascities was described as a radiographic finding in 16 of 27 cases. There were no reported cases of paracentesis or ascitic fluid analysis described in any of the identified case reports. CONCLUSIONS:: This series highlights ascites as a key feature that distinguishes ACE inhibitor-induced gastrointestinal angioedema from infectious enteritis. This series also confirms the increased incidence of this condition among African American women, an unpredictable interval between medication initiation and the development of symptoms, and the heightened probability of symptom recurrence if ACE inhibitors are not discontinued. ACE inhibitor-induced gastrointestinal angioedema is a rare cause of acute abdominal complaints, but is likely underdiagnosed and should be considered in the differential diagnosis of all individuals taking ACE inhibitors with such symptoms. Early recognition of ACE inhibitor-induced gastrointestinal angioedema may avoid recurrent episodes or costly, invasive evaluations. PMID:23751839

Benson, Brian C; Smith, Carin; Laczek, Jeffrey T

2013-06-01

186

The Expression of GPIHBP1, an Endothelial Cell Binding Site for Lipoprotein Lipase and Chylomicrons, Is Induced by Peroxisome Proliferator-Activated Receptor-?  

PubMed Central

Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), a protein in the lymphocyte antigen 6 (Ly-6) family, plays a key role in the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1 binds lipoprotein lipase and chylomicrons and is expressed along the luminal surface of microvascular endothelial cells. Lipolysis is known to be regulated by metabolic factors and is controlled at multiple levels, including the number of LPL binding sites on capillaries. Here, we tested the possibility that GPIHBP1 expression could be regulated by dietary perturbations and by peroxisome proliferator-activated receptors (PPARs). Gpihbp1 transcript levels in the heart and in brown and white adipose tissue increased with fasting and returned toward baseline after refeeding. A PPAR? agonist increased Gpihbp1 expression in adipose tissue, heart, and skeletal muscle, whereas PPAR? and PPAR? agonists had no effect. Gpihbp1 was expressed in endothelial cells of embryoid bodies generated from mouse embryonic stem cells, and Gpihbp1 expression in embryoid bodies was up-regulated by a PPAR? agonist. Sequences upstream from exon 1 of Gpihbp1 contain a strong PPAR binding site, and that site exhibited activity in a luciferase reporter assay. Gpihbp1 transcript levels in brown and white adipose tissue were lower in endothelial cell PPAR? knockout mice than in littermate control mice, suggesting that PPAR? regulates Gpihbp1 expression in vivo. We conclude that GPIHBP1 is regulated by dietary factors and by PPAR?.

Davies, Brandon S. J.; Waki, Hironori; Beigneux, Anne P.; Farber, Emily; Weinstein, Michael M.; Wilpitz, Damien C.; Tai, Li-Jung; Evans, Ronald M.; Fong, Loren G.; Tontonoz, Peter; Young, Stephen G.

2008-01-01

187

Arabidopsis LON2 is necessary for peroxisomal function and sustained matrix protein import.  

PubMed

Relatively little is known about the small subset of peroxisomal proteins with predicted protease activity. Here, we report that the peroxisomal LON2 (At5g47040) protease facilitates matrix protein import into Arabidopsis (Arabidopsis thaliana) peroxisomes. We identified T-DNA insertion alleles disrupted in five of the nine confirmed or predicted peroxisomal proteases and found only two-lon2 and deg15, a mutant defective in the previously described PTS2-processing protease (DEG15/At1g28320)-with phenotypes suggestive of peroxisome metabolism defects. Both lon2 and deg15 mutants were mildly resistant to the inhibitory effects of indole-3-butyric acid (IBA) on root elongation, but only lon2 mutants were resistant to the stimulatory effects of IBA on lateral root production or displayed Suc dependence during seedling growth. lon2 mutants displayed defects in removing the type 2 peroxisome targeting signal (PTS2) from peroxisomal malate dehydrogenase and reduced accumulation of 3-ketoacyl-CoA thiolase, another PTS2-containing protein; both defects were not apparent upon germination but appeared in 5- to 8-d-old seedlings. In lon2 cotyledon cells, matrix proteins were localized to peroxisomes in 4-d-old seedlings but mislocalized to the cytosol in 8-d-old seedlings. Moreover, a PTS2-GFP reporter sorted to peroxisomes in lon2 root tip cells but was largely cytosolic in more mature root cells. Our results indicate that LON2 is needed for sustained matrix protein import into peroxisomes. The delayed onset of matrix protein sorting defects may account for the relatively weak Suc dependence following germination, moderate IBA-resistant primary root elongation, and severe defects in IBA-induced lateral root formation observed in lon2 mutants. PMID:19748917

Lingard, Matthew J; Bartel, Bonnie

2009-09-11

188

Induction of anti-trout lauric acid hydroxylase immunoreactive proteins by peroxisome proliferators in bluegill and catfish  

Microsoft Academic Search

Various chemicals such as phthalate esters, hypolipidemic drugs, solvents like trichloroethylene, and certain herbicides have been identified as peroxisome proliferating agents (PPAs). In many vertebrates, species- and even gender-specific sensitivities to peroxisome proliferation (PP) and toxicity, have been described and may correlate with inducibility of lauric acid hydroxylase activity. Little is known about PP in fish. The rainbow trout does

M. L. Haasch

1996-01-01

189

Protection against cisplatin-induced nephrotoxicity in the rat by inducers and an inhibitor of glutathione S-transferase.  

PubMed

In an attempt to decrease cisplatin-induced nephrotoxicity, glutathione S-transferase (GST) inducers and a GST inhibitor were combined with cisplatin and administered to rats. t-Stilbene oxide (t-SO) and propylthiouracil (PTU) were the GST inducers, and ketoprofen was the GST inhibitor. Combinations of these GST inducers and the inhibitor with cisplatin decreased cisplatin-induced nephrotoxicity. The drug combinations with cisplatin inhibited the cisplatin-induced increase in urinary total GST activity. The combination of t-SO with cisplatin increased total GST activity in the kidney, compared to levels in the cisplatin only group. The t-SO combination recovered the cisplatin alone-induced decrease in GST-alpha activity to control levels. However, glutathione peroxidase (GSHpx) activity after the t-SO combination was ever further reduced compared to the cisplatin alone-induced decrease. The combination of PTU, with cisplatin increased total GST, GST-alpha and GSHpx activity, compared to the cisplatin alone group. However, PTU severely decreased the glutathione (GSH) level. The combination of ketoprofen with cisplatin normalized GST-mu and -alpha activity, and elevated the cisplatin-induced decrease of GSHpx activity and GSH. These findings suggest that ketoprofen decreases cisplatin-induced nephrotoxicity. PMID:8068032

Sadzuka, Y; Shimizu, Y; Takino, Y; Hirota, S

1994-08-01

190

Xenobiotic-Induced Hepatocyte Proliferation Associated with Constitutive Active/Androstane Receptor (CAR) or Peroxisome Proliferator-Activated Receptor ? (PPAR?) Is Enhanced by Pregnane X Receptor (PXR) Activation in Mice  

PubMed Central

Xenobiotic-responsive nuclear receptors pregnane X receptor (PXR), constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor ? (PPAR?) play pivotal roles in the metabolic functions of the liver such as xenobiotics detoxification and energy metabolism. While CAR or PPAR? activation induces hepatocyte proliferation and hepatocarcinogenesis in rodent models, it remains unclear whether PXR activation also shows such effects. In the present study, we have investigated the role of PXR in the xenobiotic-induced hepatocyte proliferation with or without CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and phenobarbital, or PPAR? activation by Wy-14643 in mice. Treatment with TCPOBOP or phenobarbital increased the percentage of Ki-67-positive nuclei as well as mRNA levels of cell proliferation-related genes in livers as expected. On the other hand, treatment with the PXR activator pregnenolone 16?-carbonitrile (PCN) alone showed no such effects. Surprisingly, PCN co-treatment significantly augmented the hepatocyte proliferation induced by CAR activation with TCPOBOP or phenobarbital in wild-type mice but not in PXR-deficient mice. Intriguingly, PXR activation also augmented the hepatocyte proliferation induced by Wy-14643 treatment. Moreover, PCN treatment increased the RNA content of hepatocytes, suggesting the induction of G0/G1 transition, and reduced mRNA levels of Cdkn1b and Rbl2, encoding suppressors of cell cycle initiation. Our present findings indicate that xenobiotic-induced hepatocyte proliferation mediated by CAR or PPAR? is enhanced by PXR co-activation despite that PXR activation alone does not cause the cell proliferation in mouse livers. Thus PXR may play a novel and unique role in the hepatocyte/liver hyperplasia upon exposure to xenobiotics.

Numakura, Yuki; Kodama, Susumu; Miyata, Masaaki; Yamazoe, Yasushi; Yoshinari, Kouichi

2013-01-01

191

Xenobiotic-induced hepatocyte proliferation associated with constitutive active/androstane receptor (CAR) or peroxisome proliferator-activated receptor ? (PPAR?) is enhanced by pregnane X receptor (PXR) activation in mice.  

PubMed

Xenobiotic-responsive nuclear receptors pregnane X receptor (PXR), constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor ? (PPAR?) play pivotal roles in the metabolic functions of the liver such as xenobiotics detoxification and energy metabolism. While CAR or PPAR? activation induces hepatocyte proliferation and hepatocarcinogenesis in rodent models, it remains unclear whether PXR activation also shows such effects. In the present study, we have investigated the role of PXR in the xenobiotic-induced hepatocyte proliferation with or without CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and phenobarbital, or PPAR? activation by Wy-14643 in mice. Treatment with TCPOBOP or phenobarbital increased the percentage of Ki-67-positive nuclei as well as mRNA levels of cell proliferation-related genes in livers as expected. On the other hand, treatment with the PXR activator pregnenolone 16?-carbonitrile (PCN) alone showed no such effects. Surprisingly, PCN co-treatment significantly augmented the hepatocyte proliferation induced by CAR activation with TCPOBOP or phenobarbital in wild-type mice but not in PXR-deficient mice. Intriguingly, PXR activation also augmented the hepatocyte proliferation induced by Wy-14643 treatment. Moreover, PCN treatment increased the RNA content of hepatocytes, suggesting the induction of G0/G1 transition, and reduced mRNA levels of Cdkn1b and Rbl2, encoding suppressors of cell cycle initiation. Our present findings indicate that xenobiotic-induced hepatocyte proliferation mediated by CAR or PPAR? is enhanced by PXR co-activation despite that PXR activation alone does not cause the cell proliferation in mouse livers. Thus PXR may play a novel and unique role in the hepatocyte/liver hyperplasia upon exposure to xenobiotics. PMID:23626729

Shizu, Ryota; Benoki, Satoshi; Numakura, Yuki; Kodama, Susumu; Miyata, Masaaki; Yamazoe, Yasushi; Yoshinari, Kouichi

2013-04-23

192

Protective effect of inducible nitric oxide synthase inhibitor on pancreas transplantation in rats  

Microsoft Academic Search

AIM: To investigate the effect of inducible nitric oxide synthase inhibitor, aminoguanidine, on pancreas transplantation in rats. METHODS: A model of pancreas transplantation was established in rats. Streptozotocin-induced diabetic male Wistar rats were randomly assigned to sham-operation control group (n = 6), transplant control group (n = 6), and aminoguanidine (AG) treatment group (n = 18). In the AG group,

Bai-Feng Li; Yong-Feng Liu; Ying Cheng; Ke-Zhong Zhang; Tie-Min Li; Ning Zhao

2007-01-01

193

Assay and Biochemical Properties of the Proteinase Inhibitor-inducing Factor, a Wound Hormone 1  

PubMed Central

An assay has been developed for the proteinase inhibitor-inducing factor (PIIF), a wound hormone. PIIF is present in tomato (Lycopersicum esculentum var. Bonnie Best) leaf extracts and induces accumulation of proteinase Inhibitor I when the extracts are supplied briefly to excised leaves that are subsequently incubated in water under constant light. An active water-soluble crude PIIF solution was conveniently prepared from autoclaved and lyophilized tomato leaves. Accumulation of Inhibitor I, induced by crude PIIF, is linear, commencing at about 8 to 10 hours after feeding and continues for several hours. Evidence is presented that the PIIF-induced accumulation of Inhibitor I, determined immunologically, is accompanied by the accumulation of other trypsin and chymotrypsin inhibitors, determined enzymatically. The accumulation of Inhibitor I is inhibited by actinomycin D and cycloheximide but not by chloramphenicol or rifampin. PIIF cannot be replaced by traumatin, indoleacetic acid, gibberellic acid, kinetin, ethylene, or abscisic acid. PIIF activity was not destroyed by incubation with a number of proteolytic, carbohydrase, phosphatase, or pyrophosphatase enzymes. The active substance is insoluble in lipid solvents.

Ryan, Clarence A.

1974-01-01

194

A Novel Inhibitor of Inducible Nitric Oxide Synthase, ONO1714, Does Not Ameliorate Hypoxia-induced Pulmonary Hypertension in Rats  

Microsoft Academic Search

A recent study showed that long-term administration of the inducible nitric oxide synthase (iNOS) inhibitor L-NIL reduced\\u000a the development of pulmonary hypertension. The purpose of the present study was to identify the effect of an another iNOS\\u000a inhibitor, ONO-1714, on the development of pulmonary hypertensive vascular changes in chronic hypoxic pulmonary hypertension\\u000a in rats. ONO-1714 was administered to rats exposed

Bao Hua Jiang; Junko Maruyama; Ayumu Yokochi; Yoshihide Mitani; Kazuo Maruyama

2007-01-01

195

[Molecular mechanisms of peroxisome biogenesis in yeasts].  

PubMed

Peroxisomes contain oxidases generating hydrogen peroxide, and catalase degrading this toxic compound. Another characteristic function of each eukaryotic peroxisome, from yeast to man, is fatty acid beta-oxidation. However, in peroxisomes a variety of other metabolic pathways are located. In fungi, peroxisomes contain enzymes involved in catabolism of unusual carbon and nitrogen sources (methanol, purines, D-amino acids, pipecolynic acid, sarcosine, glycolate, spermidine etc) as well as biosynthesis of lysine in yeasts and penicillin in mycelial fungi. Impairment of peroxisomal structure and functions causes many human disorders. The similar defects have been identified in yeast mutants defective in peroxisomal biogenesis. Peroxisomal biogenesis is actively studied during last two decades using uni- and multicellular model systems. It was observed that many aspects of peroxisomal biogenesis and proteins involved in this process display striking similarity between all eukaryotes, from yeasts to humans. Yeast is a convenient model system for this kind of research. Current review summarizes data on molecular events of peroxisomal biogenesis, functions of peroxine proteins, import of peroxisomal matrix and membrane proteins and on mechanisms of peroxisomedivision and inheritance. PMID:22642098

Sibirny?, A A

196

Urate oxidase in peroxisomes from maize root tips  

Microsoft Academic Search

Peroxisomes isolated from maize root tips contained urate oxidase, although the supplementary enzymes allantoinase, allantoicase and NADH-glyoxylate reductase were not detected. Some glutamate-oxalacetate transaminase was present in peroxisomes. Enzymes of two other pathways occuring in plant peroxisomes, namely glycolate metabolism and the glyoxylate cycle, were not present. The root peroxisome thus resembles peroxisomes of the Arum spadix and supports the

Roger W. Parish

1972-01-01

197

The histone deacetylase inhibitor entinostat (SNDX-275) induces apoptosis in Hodgkin lymphoma cells and synergizes with Bcl-2 family inhibitors  

PubMed Central

Objective Based on promising in vitro and in vivo activity of several histone deacetylase inhibitors (HDACi’s) in HL (Hodgkin lymphoma), we investigated SNDX-275, an oral class 1 isoform–selective HDACi in HL-derived cell lines. Materials and Methods Proliferation and cell death were examined by MTS assay, Annexin-V/propidium iodide, and FACS analysis. Gene and protein expression were measured by RT-PCR, Western blotting, and immunohistochemical analysis. A multiplex assay was used to determine cytokines and chemokines. Results SNDX-275 induced cell death in a dose- and time-dependent manner with an IC50 at the sub- and lower micromolar range at 72 hours. At the molecular level, SNDX-275 increased histone H3 acetylation, up-regulated p21 expression, and activated the intrinsic apoptosis pathway by down-regulating the X-linked inhibitor of apoptosis protein (XIAP). SNDX-275 down-regulated the expression of antiapoptotic Bcl-2 and Bcl-xL proteins without altering Mcl-1 or Bax levels. Combination studies demonstrated that two Bcl-2 inhibitors (ABT-737 and obatoclax) significantly enhanced the effect of SNDX-275. SNDX-275 modulated the level of several cytokines and chemokines, including IL-12 p40-70, IP-10, RANTES, IL-13, IL-4, and TARC, and variably induced the cancer/testis antigen expression of MAGE-A4 and survivin in HL cell lines. Conclusions SNDX-275 has antiproliferative activity in HL cell lines, involving several mechanisms: induction of apoptosis, regulation of cytokines and chemokines, and alteration of CTAs. Clinical investigation of SNDX-275 alone or in combination with Bcl-2 inhibitors is warranted in patients with HL. Phase 2 studies with SNDX-275 in HL are ongoing, and future clinical studies should investigate combinations with SNDX-275.

Jona, Adam; Khaskhely, Noor; Buglio, Daniela; Shafer, Jessica A.; Derenzini, Enrico; Bollard, Catherine M.; Medeiros, L. Jeffrey; Illes, Arpad; Ji, Yuan; Younes, Anas

2011-01-01

198

Peroxisome proliferator-activated receptor alpha required for gene induction by dehydroepiandrosterone-3 beta-sulfate.  

PubMed

Peroxisome proliferator-activated receptor alpha (PPAR alpha) mediates the effects of foreign chemical peroxisome proliferators on liver and kidney, including the induction of peroxisomal, mitochondrial, and microsomal enzymes involved in beta-oxidation of fatty acids. However, the role of this receptor in the peroxisome proliferative effects of the endogenous steroid dehydroepiandrosterone (DHEA) is not known. DHEA-3 beta-sulfate fd(DHEA-S) is shown to induce a liver peroxisome proliferative response in rats in vivo at a dose at which DHEA is much less active, which is consistent with cultured hepatocyte studies indicating a requirement for sulfation for the activation of DHEA. Transient transfection experiments demonstrated that in contrast to the prototypic foreign chemical peroxisome proliferator pirinixic acid, DHEA-S and its 17 beta-reduced metabolite, 5-androstene-3 beta, 17 beta-diol-3 beta-sulfate, are inactive in mediating trans-activation by PPAR alpha in COS-1 cells. Two other mammalian PPAR isoforms, gamma and delta/Nucl, were also inactive with respect to DHEA-S trans-activation. To test whether PPAR alpha mediates peroxisomal gene induction by DHEA-S in intact animals, we administered DHEA-S or clofibrate to mice lacking a functional PPAR alpha gene. Both peroxisome proliferators markedly increased hepatic expression of two microsomal cytochrome P450 4A proteins as well as six mRNAs known to be associated with the peroxisomal proliferative response in wild-type mice. In contrast, neither DHEA-S nor clofibrate induced these hepatic proteins and mRNAs in PPAR alpha-deficient mice. Clofibrate-induced expression of kidney CYP4A mRNAs was also blocked in the PPAR alpha gene knockout mice. Thus, despite its unresponsiveness to steroidal peroxisome proliferators in transfection assays, PPAR alpha is obligatory for DHEA-S-stimulated hepatic peroxisomal gene induction. DHEA-S, or one of its metabolites, may thus serve as an important endogenous regulator of liver peroxisomal enzyme expression via a PPAR alpha-mediated pathway. PMID:8700121

Peters, J M; Zhou, Y C; Ram, P A; Lee, S S; Gonzalez, F J; Waxman, D J

1996-07-01

199

Peroxisome induction potential and lipid-regulating activity in rats. Quantitative microscopy and chemical structure-activity relationships.  

PubMed Central

Structurally diverse lipid-regulating agents induce hepatomegaly, hepatic peroxisome proliferation, and hepatocarcinoma in rats by mechanisms not fully understood. Nevertheless the initial hepatic response is a prompt, florid proliferation of peroxisomes. In investigations reported here, changes in the rat hepatic peroxisome compartment were measured by quantitative microscopy to determine chemical structure requirements that relate to peroxisome proliferation and lipid regulation. Aryloxyalkanoic acids plus amide analogs, and thio, benzimidazole, phenylpiperazine, and oxazole derivatives induced peroxisome proliferation and generally decreased plasma triglyceride and total cholesterol levels. These compounds contain an acidic function or are readily metabolized to a chemical with an acidic function. Substitution of the acidic function with an adamantyloxy eliminated peroxisome proliferation and induced contrasting effects on lipid profile, increasing triglycerides and decreasing total cholesterol. A previously unreported, direct correlation emerged between peroxisome proliferation and plasma high-density lipoprotein-cholesterol levels. These effects could not be elicited separately, negating identification of functional groups that could be associated with either activity. Chemical structure and resulting peroxisome proliferation with changes in plasma lipoproteins are therefore closely interrelated in rats. Images Figure 1

McGuire, E. J.; Lucas, J. A.; Gray, R. H.; de la Iglesia, F. A.

1991-01-01

200

Sphingosine kinase 1 is regulated by peroxisome proliferator-activated receptor ? in response to free fatty acids and is essential for skeletal muscle interleukin-6 production and signaling in diet-induced obesity.  

PubMed

We previously demonstrated that sphingosine kinase 1 (Sphk1) expression and activity are up-regulated by exogenous palmitate (PAL) in a skeletal muscle model system and in diet-induced obesity in mice; however, potential functions and in vivo relevance of this have not been addressed. Here, we aimed to determine the mechanism by which PAL regulates SphK1 in muscle, and to determine potential roles for its product, sphingosine-1-phosphate (S1P), in muscle biology in the context of obesity. Cloning and analysis of the mouse Sphk1 promoter revealed a peroxisome proliferator-activated receptor (PPAR) ? cis-element that mediated activation of a reporter under control of the Sphk1 promoter; direct interaction of PPAR? was demonstrated by chromatin immunoprecipitation. PAL treatment induced the proinflammatory cytokine interleukin (IL)-6 in a manner dependent on SphK1, and this was attenuated by inhibition of the sphingosine-1-phosphate receptor 3 (S1PR3). Diet-induced obesity in mice demonstrated that IL-6 expression in muscle, but not adipose tissue, increased in obesity, but this was attenuated in Sphk1(-/-) mice. Moreover, plasma IL-6 levels were significantly decreased in obese Sphk1(-/-) mice relative to obese wild type mice, and muscle, but not adipose tissue IL-6 signaling was activated. These data indicate that PPAR? regulates Sphk1 expression in the context of fatty acid oversupply and links PAL to muscle IL-6 production. Moreover, this function of SphK1 in diet-induced obesity suggests a potential role for SphK1 in obesity-associated pathological outcomes. PMID:23766515

Ross, Jessica S; Hu, Wei; Rosen, Bess; Snider, Ashley J; Obeid, Lina M; Cowart, L Ashley

2013-06-13

201

Acyldepsipeptide HDAC inhibitor production induced in Burkholderia thailandensis  

PubMed Central

Natural product gene clusters are often tightly regulated, resulting in gene cluster silencing in laboratory fermentation studies. The systematic overexpression of transcription factors (TFs) associated with biosynthetic gene clusters found in the genome of Burkholderia thailandensis E264 identified a set of TFs that, when overexpressed, alter the secondary metabolome of this bacterium. The isolation and characterization of burkholdacs A and B, two new acyldepsitripeptide histone deacetylase inhibitors produced by B. thailandensis overexpressing the TF bhcM is reported.

Biggins, John B.; Gleber, Conrad D.; Brady, Sean F.

2011-01-01

202

Effects of octadecanoid metabolites and inhibitors on induced nicotine accumulation in Nicotiana sylvestris  

Microsoft Academic Search

We examined the effects of inhibitors of the octadecanoid pathway (n-propyl gallate, acetosalicylic acid, salicylhydroxamic acid, methyl salicylate, and antipyrine) on wound- and jasmonate-induced nicotine accumulation and compared the nicotine-inducing ability of exogeneous additions of linolenic acid (18:3) and its methyl ester, linoleic acid (18:2), abscisic acid, traumatic acid, and methyl dihydrojasmonate to the nicotine-inducing ability of exogenous additions of

Ian T. Baldwin; Eric A. Schmelz; Zong-Ping Zhang

1996-01-01

203

Peroxisomal disorders with infantile seizures.  

PubMed

Peroxisomes are organelles responsible for multiple metabolic pathways including the biosynthesis of plasmalogens and the oxidation of branched-chain as well as very-long-chain fatty acids (VLCFAs). Peroxisomal disorders (PDs) are heterogeneous groups of diseases and affect many organs with varying degrees of involvement. Even pathogenetically distinct PDs share some common symptoms. However, several PDs have uniquely characteristic clinical findings. The durations of survival in PDs are also variable. Infants with PDs are usually presented with developmental delay, visual and hearing impairment. Generalized hypotonia is present in severe cases. Epileptic seizures are also a common characteristic of patients with certain PDs. Nonetheless, the classification and evolution of epilepsy in PDs have not been elucidated in detail. Here, we review the relevant literatures and provide an overview of PDs with particular emphasis on the characteristics of seizures in infants. PMID:21397417

Liang, Jao-Shwann; Lu, Jyh-Feng

2011-03-11

204

Reversal of sodium pump inhibitor induced vascular smooth muscle contraction with digibind. Stoichiometry and its implications.  

PubMed

The possibility that a circulating sodium pump inhibitor contributes to the pathogenesis of volume-dependent hypertension via an action on vascular smooth muscle (VSM) is supported by multiple lines of investigation, but remains controversial. We had two goals in this study. The first was to compare the pattern of contractile response of rabbit aorta induced by two candidates, ouabain and a labile sodium pump inhibitor that we have identified in the peritoneal dialysate of volume-expanded hypertensive patients with chronic renal failure. Our second goal was to examine the ability of Digibind, a Fab fragment of antisera directed against digoxin, to reverse VSM contraction induced by both agents. Ouabain induced a concentration-dependent contraction, which was delayed in onset, was gradual, and reached a stable plateau after many hours. The labile sodium pump inhibitor induced a qualitatively similar series of responses. Digibind rapidly reversed the contractile responses to both sodium pump inhibitors, with a rate of relaxation that matched that induced by physical removal of the pump inhibitor from the bath. For ouabain, the Digibind:ouabain stoichiometry was highly predictable. When Digibind was present in a molar concentration equivalent to that of ouabain, or less, it had no effect. When the Digibind concentration was twice that of ouabain, complete relaxation occurred. Although the concentration:VSM response relationship for ouabain was steep, the concentration:effect interaction with Digibind was even more steep. The molar concentration of Digibind required to reverse the effects of the labile endogenous inhibitor from peritoneal dialysate was consistently lower than that for ouabain, which is compatible with either greater potency of the labile factor in VSM or greater affinity for Digibind. These findings are compatible with a role for one or more endogenous sodium pump inhibitors as the determinant of vascular smooth muscle tone in the volume-sensitive hypertension of renal disease. PMID:8834705

Krep, H H; Graves, S W; Price, D A; Lazarus, M; Ensign, A; Soszynski, P A; Hollenberg, N K

1996-01-01

205

Mouse models for peroxisome biogenesis disorders  

Microsoft Academic Search

The gene knockout technology has been applied to generate mice lacking functional peroxisomes. These mice are a model for\\u000a Zellweger syndrome and other peroxisome biogenesis disorders that are lethal in early life. Extensive biochemical, ultrastructural,\\u000a and neurodevelopmental analyses indicate that the peroxisome deficient mice closely mimic the pathology in Zellweger patients\\u000a and will be a very useful tool to elucidate

Myriam Baes

2000-01-01

206

Evolutionary aspects of peroxisomes as cell organelles, and of genes encoding peroxisomal proteins  

Microsoft Academic Search

Peroxisomes are present in most eukaryotic cell types, and have different enzymatic content and metabolic functions throughout the life scale. The endosymbiotic origin of these DNA-devoid organelles is supported by evolutionary data concerning genes encoding not only most peroxisomal proteins, but also several transcriptional factors regulating their expression such as peroxisome proliferator-activated receptors.

Norbert Latruffe; Joseph Vamecq

2000-01-01

207

Effect of cyclooxygenase inhibitors on pentylenetetrazol (PTZ)-induced convulsions: Possible mechanism of action.  

PubMed

Cyclooxygenase (COX) is reported to play a significant role in neurodegenerative and neuropsychiatric disorders, and may play a significant role in the pathogenesis of epilepsy. Various neurotransmitter abnormalities, especially of GABA and glutamate, have been reported to play a key role in the pathophysiology of epilepsy. The objective of the present study was to elucidate the effect of cyclooxygenase inhibitors on pentylenetetrazol (PTZ)-induced (80 mg/kg) convulsions in mice with possible mechanism of action. Various COX-inhibitors were administered 45 min prior to the PTZ administration. Onset, duration of clonic convulsions and percentage mortality/recovery were recorded. Pretreatment with COX-inhibitors aspirin (10 and 20 mg/kg, p.o.), naproxen (7 and 14 mg/kg, p.o.), nimesulide (1-5 mg/kg, p.o.) or rofecoxib (1-4 mg/kg, p.o.) dose-dependently showed protection against PTZ-induced convulsions. COX-2 inhibitors were more effective as compared to non-selective COX-inhibitors. Rofecoxib (1 mg/kg) or nimesulide (1 mg/kg) also enhanced the sub-protective effect of diazepam or muscimol showing GABAergic modulation of COX-2 inhibitors. COX-2 inhibitors also antagonized the effect of flumazenil (4 mg/kg)- against PTZ-induced convulsions further confirming the GABAergic mechanism. In conclusion, the results of the present study strongly suggest the possible role of cyclooxygenase isoenzymes in the pathophysiology of epilepsy and the use of COX-inhibitors as an adjuvant therapy in the treatment of epilepsy. PMID:16844276

Dhir, Ashish; Naidu, Pattipati S; Kulkarni, Shrinivas K

2006-07-17

208

Epithelial tissue hyperplasia induced by the RAF inhibitor PF-04880594 is attenuated by a clinically well-tolerated dose of the MEK inhibitor PD-0325901.  

PubMed

Clinical trials of selective RAF inhibitors in patients with melanoma tumors harboring activated BRAFV600E have produced very promising results, and a RAF inhibitor has been approved for treatment of advanced melanoma. However, about a third of patients developed resectable skin tumors during the course of trials. This is likely related to observations that RAF inhibitors activate extracellular signal-regulated kinase (ERK) signaling, stimulate proliferation, and induce epithelial hyperplasia in preclinical models. Because these findings raise safety concerns about RAF inhibitor development, we further investigated the underlying mechanisms. We showed that the RAF inhibitor PF-04880594 induces ERK phosphorylation and RAF dimerization in those epithelial tissues that undergo hyperplasia. Hyperplasia and ERK hyperphosphorylation are prevented by treatment with the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD-0325901 at exposures that extrapolate to clinically well-tolerated doses. To facilitate mechanistic and toxicologic studies, we developed a three-dimensional cell culture model of epithelial layering that recapitulated the RAF inhibitor-induced hyperplasia and reversal by MEK inhibitor in vitro. We also showed that PF-04880594 stimulates production of the inflammatory cytokine interleukin 8 in HL-60 cells, suggesting a possible mechanism for the skin flushing observed in dogs. The complete inhibition of hyperplasia by MEK inhibitor in epithelial tissues does not seem to reduce RAF inhibitor efficacy and, in fact, allows doubling of the PF-04880594 dose without toxicity usually associated with such doses. These findings indicated that combination treatment with MEK inhibitors might greatly increase the safety and therapeutic index of RAF inhibitors for the treatment of melanoma and other cancers. PMID:22752429

Torti, Vince R; Wojciechowicz, Donald; Hu, Wenyue; John-Baptiste, Annette; Evering, Winston; Troche, Gabriel; Marroquin, Lisa D; Smeal, Tod; Yamazaki, Shinji; Palmer, Cynthia L; Burns-Naas, Leigh Ann; Bagrodia, Shubha

2012-07-02

209

Colchicine-Induced Apoptosis Was Prevented by Glycogen Synthase Kinase3 Inhibitors in PC12 Cells  

Microsoft Academic Search

The purpose of this study was to examine whether glycogen synthase kinase-3 (GSK-3) is involved in colchicine-induced cell\\u000a death in PC12 cells by using GSK inhibitors. Colchicine increased apoptotic cell death with morphological changes characterized\\u000a by cell shrinkage and nuclear condensation or fragmentation. GSK-3 inhibitors such as alsterpaullone, SB216763, and AR-A014418\\u000a prevented colchicine-induced cell death and caspase-3 activation. These results

Tsuneo Takadera; Yu Nakajima; Yuki Kanai

2010-01-01

210

Inhibitors of animal phospholipase A 2 enzymes are selective inhibitors of auxin-dependent growth. Implications for auxin-induced signal transduction  

Microsoft Academic Search

.   Auxin and elicitors reportedly activate phospolipase A. A number of inhibitors known to inhibit animal phospholipase A2 were tested for their ability to inhibit hormone and fusicoccin-induced growth. To this end, growth induced by indolyl-3-acetic\\u000a acid and 2,4-dichlorophenoxyacetic acid in hypocotyl segments of etiolated zucchini (Cucurbita pepo L.) seedlings was determined in the presence of the inhibitors nordihydroguajaretic acid

Günther F. E. Scherer; Bernd Arnold

1997-01-01

211

RIP1 protein-dependent assembly of a cytosolic cell death complex is required for inhibitor of apoptosis (IAP) inhibitor-mediated sensitization to lexatumumab-induced apoptosis.  

PubMed

Searching for new strategies to trigger apoptosis in rhabdomyosarcoma (RMS), we investigated the effect of two novel classes of apoptosis-targeting agents, i.e. monoclonal antibodies against TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (mapatumumab) and TRAIL receptor 2 (lexatumumab) and small-molecule inhibitors of inhibitor of apoptosis (IAP) proteins. Here, we report that IAP inhibitors synergized with lexatumumab, but not with mapatumumab, to reduce cell viability and to induce apoptosis in several RMS cell lines in a highly synergistic manner (combination index <0.1). Cotreatment-induced apoptosis was accompanied by enhanced activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and caspase-dependent apoptosis. In addition, IAP inhibitor and lexatumumab cooperated to stimulate the assembly of a cytosolic complex containing RIP1, FADD, and caspase-8. Importantly, knockdown of RIP1 by RNA interference prevented the formation of the RIP1·FADD·caspase-8 complex and inhibited subsequent activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and apoptosis upon treatment with IAP inhibitor and lexatumumab. In addition, RIP1 silencing rescued clonogenic survival of cells treated with the combination of lexatumumab and IAP inhibitor, thus underscoring the critical role of RIP1 in cotreatment-induced apoptosis. By comparison, the TNF?-blocking antibody Enbrel had no effect on IAP inhibitor/lexatumumab-induced apoptosis, indicating that an autocrine TNF? loop is dispensable. By demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent but TNF?-independent manner in RMS cells, our findings substantially advance our understanding of IAP inhibitor-mediated regulation of TRAIL-induced cell death. PMID:22927431

Basit, Farhan; Humphreys, Robin; Fulda, Simone

2012-08-27

212

A Wound-Inducible Potato Proteinase Inhibitor Gene Expressed in Non-Tuber-Bearing Species Is Not Sucrose Inducible 1  

PubMed Central

Sequences homologous to a potato cathepsin D inhibitor cDNA, p749, were identified in the genomic DNA of tomato (Lycopersicon esculentum) and of two non-tuber-bearing potato species (Solanum etuberosum and S. brevidens) by means of Southern blot analysis. The expression of these p749 genes in leaves was induced at the RNA level in response to wounding. High levels of p749 transcripts were detected in polyadenylated RNA extracted from locally wounded leaves 12 h after wounding. Systemic induction of the cathepsin D inhibitor gene also occurred in nonwounded leaves of wounded plants. Both potato and tomato leaves treated with the oligosaccharide chitosan showed an induced accumulation of p749 transcripts. Even though the cathepsin D inhibitor genes from tomato and from non-tuber-bearing potato species are wound inducible, they could not be induced in leaf explants cultured on medium containing very high concentrations of sucrose. Only leaf explants from the tuber-bearing potato (S. tuberosum) accumulated p749 transcripts when cultured on high sucrose medium. A sequence related to the 22-kD potato proteinase inhibitor cDNA, p34021, was identified in tomato by means of genomic Southern blot analysis. Northern blot hybridization showed that p34021 transcripts accumulated in potato (S. tuberosum) leaf explants, but not in tomato explants, when cultured on high sucrose medium. This study demonstrates that the expression of a potato cathepsin D inhibitor gene in tomato and in non-tuber-bearing potato species is wound inducible, but not sucrose inducible. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Hansen, Joel D.; Hannapel, David J.

1992-01-01

213

VEGFR2 and Src kinase inhibitors suppress Andes virus-induced endothelial cell permeability.  

PubMed

Hantaviruses predominantly infect human endothelial cells and, in the absence of cell lysis, cause two diseases resulting from increased vascular permeability. Andes virus (ANDV) causes a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). ANDV infection enhances the permeability of endothelial cells in response to vascular endothelial growth factor (VEGF) by increasing signaling responses directed by the VEGFR2-Src-VE-cadherin pathway, which directs adherens junction (AJ) disassembly. Here we demonstrate that inhibiting pathway-specific VEGFR2 and Src family kinases (SFKs) blocks ANDV-induced endothelial cell permeability. Small interfering RNA (siRNA) knockdown of Src within ANDV-infected endothelial cells resulted in an ?70% decrease in endothelial cell permeability compared to that for siRNA controls. This finding suggested that existing FDA-approved small-molecule kinase inhibitors might similarly block ANDV-induced permeability. The VEGFR2 kinase inhibitor pazopanib as well as SFK inhibitors dasatinib, PP1, bosutinib, and Src inhibitor 1 dramatically inhibited ANDV-induced endothelial cell permeability. Consistent with their kinase-inhibitory concentrations, dasatinib, PP1, and pazopanib inhibited ANDV-induced permeability at 1, 10, and 100 nanomolar 50% inhibitory concentrations (IC(50)s), respectively. We further demonstrated that dasatinib and pazopanib blocked VE-cadherin dissociation from the AJs of ANDV-infected endothelial cells by >90%. These findings indicate that VEGFR2 and Src kinases are potential targets for therapeutically reducing ANDV-induced endothelial cell permeability and, as a result, capillary permeability during HPS. Since the functions of VEGFR2 and SFK inhibitors are already well defined and FDA approved for clinical use, these findings rationalize their therapeutic evaluation for efficacy in reducing HPS disease. Endothelial cell barrier functions are disrupted by a number of viruses that cause hemorrhagic, edematous, or neurologic disease, and as a result, our findings suggest that VEGFR2 and SFK inhibitors should be considered for regulating endothelial cell barrier functions altered by additional viral pathogens. PMID:21177802

Gorbunova, Elena E; Gavrilovskaya, Irina N; Pepini, Timothy; Mackow, Erich R

2010-12-22

214

Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization.  

PubMed

RAF kinases have a prominent role in cancer. Their mode of activation is complex but critically requires dimerization of their kinase domains. Unexpectedly, several ATP-competitive RAF inhibitors were recently found to promote dimerization and transactivation of RAF kinases in a RAS-dependent manner and, as a result, undesirably stimulate RAS/ERK pathway-mediated cell growth. The mechanism by which these inhibitors induce RAF kinase domain dimerization remains unclear. Here we describe bioluminescence resonance energy transfer-based biosensors for the extended RAF family that enable the detection of RAF dimerization in living cells. Notably, we demonstrate the utility of these tools for profiling kinase inhibitors that selectively modulate RAF dimerization and for probing structural determinants of RAF dimerization in vivo. Our findings, which seem generalizable to other kinase families allosterically regulated by kinase domain dimerization, suggest a model whereby ATP-competitive inhibitors mediate RAF dimerization by stabilizing a rigid closed conformation of the kinase domain. PMID:23685672

Lavoie, Hugo; Thevakumaran, Neroshan; Gavory, Gwenaëlle; Li, John J; Padeganeh, Abbas; Guiral, Sébastien; Duchaine, Jean; Mao, Daniel Y L; Bouvier, Michel; Sicheri, Frank; Therrien, Marc

2013-05-19

215

Inhibition of Interleukin-1?-Induced Group IIA Secretory Phospholipase A2 Expression by Peroxisome Proliferator-Activated Receptors (PPARs) in Rat Vascular Smooth Muscle Cells: Cooperation between PPAR? and the Proto-Oncogene BCL-6?  

PubMed Central

The inflammation that occurs during atherosclerosis is characterized by the release of large amounts of group IIA secretory phospholipase A2 (sPLA2-IIA). This study was designed to define the function of the three peroxisome proliferator-activated receptors (PPARs) on sPLA2 expression in vascular smooth muscle cells (VSMCs). We found that PPAR ligands decreased sPLA2-IIA activity and inhibited mRNA accumulation under inflammatory conditions. Furthermore, interleukin-1?-induced sPLA2-IIA promoter activity was inhibited by the three PPAR ligands and in a similar way when cells were cotransfected with PPAR?, PPAR?, or PPAR?, plus retinoid X receptor ? (RXR?). Our study revealed that the regulation of sPLA2-IIA gene transcription by PPAR?/RXR and PPAR?/RXR heterodimers requires an interaction with a PPAR response element (PPRE) of the sPLA2-IIA promoter. In contrast, PPAR? operates through a PPRE-independent mechanism. In addition, we demonstrated that VSMCs expressed the transcriptional repressor BCL-6. Overexpression of BCL-6 markedly reduced sPLA2-IIA promoter activity in VSMCs, while a dominant negative form of BCL-6 abrogated sPLA2 repression by PPAR?. The PPAR? agonist induced a BCL-6 binding to the sPLA2 promoter in VSMCs under inflammatory conditions. The knockdown of BCL-6 by short interfering RNA abolished the inhibitory effect of the PPAR? ligand on sPLA2 activity and prostaglandin E2 release. Thus, the inhibition of sPLA2-IIA activity by PPAR? agonists may provide a promising approach to impacting the initiation and progression of atherosclerosis.

Ravaux, Lucas; Denoyelle, Chantal; Monne, Claire; Limon, Isabelle; Raymondjean, Michel; El Hadri, Khadija

2007-01-01

216

Inhibition of cyclooxygenase-2 prevents adverse effects induced by phosphodiesterase type 4 inhibitors in rats  

PubMed Central

BACKGROUND AND PURPOSE Phosphodiesterase type 4 (PDE4) inhibitors such as roflumilast are currently being developed as anti-inflammatory treatments for chronic airway disorders. However, high doses of PDE4 inhibitors have also been linked to several side effects in different animal species, including pro-inflammatory effects in the rat. Here, we analysed PDE4-related toxicological findings in a rat model and how these side effects might be therapeutically prevented. EXPERIMENTAL APPROACH Wistar rats were treated orally once daily with 10 mg·kg?1 roflumilast for 4 days. Macroscopic changes were monitored throughout the study and further parameters were analysed at the end of the experiment on day 5. In addition, the effects of concomitant treatment with cyclooxygenase (COX) inhibitors were assessed. KEY RESULTS Supratherapeutical treatment with roflumilast induced marked body and spleen weight loss, diarrhea, increased secretory activity of the harderian glands, leukocytosis, increased serum cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels, and histopathological changes in thymus, spleen, mesentery and mesenteric lymph nodes. All these toxicological findings could be prevented by the non-steroidal anti-inflammatory drug (NSAID) and non-selective COX inhibitor, diclofenac, given orally. Similar protective effects could be achieved by the COX-2 selective inhibitor lumiracoxib, whereas the COX-1 selective inhibitor SC-560 was generally not effective. CONCLUSIONS AND IMPLICATIONS Treatment with an NSAID inhibiting COX-2 prevents the major effects found after subchronic overdosing with the PDE4-specific inhibitor roflumilast. If this effect translates into humans, such combined treatment may increase the therapeutic window of PDE4 inhibitors, currently under clinical development.

Peter, D; Goggel, R; Colbatzky, F; Nickolaus, P

2011-01-01

217

COX-2 inhibitors block chemotherapeutic agent-induced apoptosis prior to commitment in hematopoietic cancer cells.  

PubMed

Enzymatic inhibitors of pro-inflammatory cyclooxygenase-2 (COX-2) possess multiple anti-cancer effects, including chemosensitization. These effects are not always linked to the inhibition of the COX-2 enzyme. Here we analyze the effects of three COX-2 enzyme inhibitors (nimesulide, NS-398 and celecoxib) on apoptosis in different hematopoietic cancer models. Surprisingly, COX-2 inhibitors strongly prevent apoptosis induced by a panel of chemotherapeutic agents. We selected U937 cells as a model of sensitive cells for further studies. Here, we provide evidence that the protective effect is COX-independent. No suppression of the low basal prostaglandin (PG)E(2) production may be observed upon treatment by COX-2 inhibitors. Besides, the non-active celecoxib analog 2,5-dimethyl-celecoxib is able to protect from apoptosis as well. We demonstrate early prevention of the stress-induced apoptotic signaling, prior to Bax/Bak activation. This preventive effect fits with an impairment of the ability of chemotherapeutic agents to trigger apoptogenic stress. Accordingly, etoposide-induced DNA damage is strongly attenuated in the presence of COX-2 inhibitors. In contrast, COX-2 inhibitors do not exert any anti-apoptotic activity when cells are challenged with physiological stimuli (anti-Fas, TNF? or Trail) or with hydrogen peroxide, which do not require internalization and/or are not targeted by chemoresistance proteins. Altogether, our findings show a differential off-target anti-apoptotic effect of COX-2 inhibitors on intrinsic vs. extrinsic apoptosis at the very early steps of intracellular signaling, prior to commitment. The results imply that an exacerbation of the chemoresistance phenomena may be implicated. PMID:21745461

Cerella, Claudia; Sobolewski, Cyril; Chateauvieux, Sébastien; Henry, Estelle; Schnekenburger, Michael; Ghelfi, Jenny; Dicato, Mario; Diederich, Marc

2011-06-24

218

Tissue factor pathway inhibitor 2 is induced by thrombin in human macrophages.  

PubMed

Tissue factor pathway inhibitor 2 (TFPI2) is a serine protease inhibitor critical for the regulation of extracellular matrix remodeling and atherosclerotic plaque stability. Previously, we demonstrated that TFPI2 expression is increased in monocytes from patients with familial combined hyperlipidemia (FCH). To gain insight into the molecular mechanisms responsible for this upregulation, we examined TFPI2 expression in THP-1 macrophages exposed to lipoproteins and thrombin. Our results showed that TFPI2 expression was not affected by treatment with very low density lipoproteins (VLDL), but was induced by thrombin (10 U/ml) in THP-1 (1.9-fold increase, p<0.001) and human monocyte-derived macrophages (2.3-fold increase, p<0.005). The specificity of the inductive effect was demonstrated by preincubation with the thrombin inhibitors hirudin and PPACK, which ablated thrombin effects. TFPI2 induction was prevented by pre-incubation with MEK1/2 and JNK inhibitors, but not by the EGF receptor antagonist AG1478. In the presence of parthenolide, an inhibitor of NF?B, but not of SR-11302, a selective AP-1 inhibitor, thrombin-mediated TFPI2 induction was blunted. Our results also show that thrombin treatment increased ERK1/2, JNK and I?B? phosphorylation. Finally, we ruled out the possibility that TFPI2 induction by thrombin was mediated by COX-2, as preincubation with a selective COX-2 inhibitor did not prevent the inductive effect. In conclusion, thrombin induces TFPI2 expression by a mechanism involving ERK1/2 and JNK phosphorylation, leading finally to NFkB activation. In the context of atherosclerosis, thrombin-induced macrophage TFPI2 expression could represent a means of avoiding excessive activation of matrix metalloproteases at sites of inflammation. PMID:21515313

Pou, Jordi; Rebollo, Alba; Piera, Lídia; Merlos, Manuel; Roglans, Núria; Laguna, Juan C; Alegret, Marta

2011-04-15

219

The Kinase Inhibitor Sorafenib Induces Cell Death through a Process Involving Induction of Endoplasmic Reticulum Stress  

Microsoft Academic Search

Sorafenib is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells. Recently, we demonstrated that sorafenib diminishes Mcl-1 protein expression by inhibiting translation through a MEK1\\/2-ERK1\\/2 signaling-independent mechanism and that this phenomenon plays a key func- tional role in sorafenib-mediated lethality. Here, we report that inducible expression of constitutively active MEK1 fails to protect cells from

Mohamed Rahmani; Eric Maynard Davis; Timothy Ryan Crabtree; Joseph Reza Habibi; Tri K. Nguyen; Paul Dent; Steven Grant

2007-01-01

220

Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine — a PDE1 inhibitor  

Microsoft Academic Search

Enhancing cyclic nucleotides signaling by inhibition of phosphodiesterases (PDEs) is known to be beneficial in disorders associated with cognitive decline. The present study was designed to investigate the effect of vinpocetine (PDE1 inhibitor) on intracerebroventricular (i.c.v.) streptozotocin induced experimental sporadic dementia of Alzheimer's type. Infusion of streptozotocin impaired learning and memory, increased oxidative–nitritive stress and induced cholinergic hypofunction in rats.

Rahul Deshmukh; Vivek Sharma; Sidharth Mehan; Nidhi Sharma; K. L. Bedi

2009-01-01

221

Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients  

Microsoft Academic Search

Background: Tamoxifen may induce uterine abnormalities of clinical concern. Our aim was to compare early uterine changes occurring in postmenopausal breast cancer patients treated in first- line with tamoxifen or third generation aromatase inhibitors. We also assessed the effect of aroma- tase inhibitors on tamoxifen-induced uterine changes. Patients and methods: Seventy-seven consecutive postmenopausal breast cancer patients scheduled to start endocrine

L. Morales; D. Timmerman; P. Neven; M. L. Konstantinovic; A. Carbonez; S. Van Huffel; L. Ameye; C. Weltens; M.-R. Christiaens; I. Vergote; R. Paridaens

2005-01-01

222

MAP KINASE ERK 1/2 INHIBITORS INDUCE DYSMORPHOLOGY IN MOUSE WHOLE EMBRYO CULTURE  

EPA Science Inventory

ROSEN, M.B. and E. S. HUNTER. Reproductive Toxicology Division, NHEERL, ORD, U.S. EPA, Research Triangle Park, North Carolina. MAP kinase Erk1/2 inhibitors induce dysmorphology in mouse whole embryo culture. MAP Kinase signal transduction is associated with a variety ...

223

Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia  

Microsoft Academic Search

The phosphodiesterase inhibitor, ibudilast, has many effects on lymphocytes, endothelial cells, and glial cells. We examined the neuroprotective role of ibudilast in neuron and microglia co-cultures. Ibudilast significantly suppressed neuronal cell death induced by the activation of microglia with lipopolysaccharide (LPS) and interferon (IFN)-?. To examine the mechanisms by which ibudilast exerts a neuroprotective role against the activation of microglia,

Tetsuya Mizuno; Tohru Kurotani; Yukio Komatsu; Jun Kawanokuchi; Hideki Kato; Norimasa Mitsuma; Akio Suzumura

2004-01-01

224

Effects of Neutrophil Elastase Inhibitor on Bleomycin-Induced Pulmonary Fibrosis in Mice  

Microsoft Academic Search

Neutrophils play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). To elu- cidate the possible involvement of neutrophil elastase (NE) in pulmonary fibrosis, we investigated the efficacy of a new specific NE inhibitor (ONO-5046 ? Na) in a murine model of human IPF, bleomy- cin-induced pulmonary fibrosis. Bronchoalveolar lavage (BAL) and histopathological analysis were performed on bleomycin-treated

YASUYUKI TAOOKA; AKIHIRO MAEDA; KEIKO HIYAMA; SHINICHI ISHIOKA; MICHIO YAMAKIDO

225

The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) mediates interaction with extracellular signal-regulated kinase 5 and PPARgamma1 transcriptional activation: involvement in flow-induced PPARgamma activation in endothelial cells.  

PubMed

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that form a subfamily of the nuclear receptor gene family. Since both flow and PPARgamma have atheroprotective effects and extracellular signal-regulated kinase 5 (ERK5) kinase activity is significantly increased by flow, we investigated whether ERK5 kinase regulates PPARgamma activity. We found that activation of ERK5 induced PPARgamma1 activation in endothelial cells (ECs). However, we could not detect PPARgamma phosphorylation by incubation with activated ERK5 in vitro, in contrast to ERK1/2 and JNK, suggesting a role for ERK5 as a scaffold. Endogenous PPARgamma1 was coimmunoprecipitated with endogenous ERK5 in ECs. By mammalian two-hybrid analysis, we found that PPARgamma1 associated with ERK5a at the hinge-helix 1 region of PPARgamma1. Expressing a hinge-helix 1 region PPARgamma1 fragment disrupted the ERK5a-PPARgamma1 interaction, suggesting a critical role for hinge-helix 1 region of PPARgamma in the ERK5-PPARgamma interaction. Flow increased ERK5 and PPARgamma1 activation, and the hinge-helix 1 region of the PPARgamma1 fragment and dominant negative MEK5beta significantly reduced flow-induced PPARgamma activation. The dominant negative MEK5beta also prevented flow-mediated inhibition of tumor necrosis factor alpha-mediated NF-kappaB activation and adhesion molecule expression, including vascular cellular adhesion molecule 1 and E-selectin, indicating a physiological role for ERK5 and PPARgamma activation in flow-mediated antiinflammatory effects. We also found that ERK5 kinase activation was required, likely by inducing a conformational change in the NH(2)-terminal region of ERK5 that prevented association of ERK5 and PPARgamma1. Furthermore, association of ERK5a and PPARgamma1 disrupted the interaction of SMRT and PPARgamma1, thereby inducing PPARgamma activation. These data suggest that ERK5 mediates flow- and ligand-induced PPARgamma activation via the interaction of ERK5 with the hinge-helix 1 region of PPARgamma. PMID:15367687

Akaike, Masashi; Che, Wenyi; Marmarosh, Nicole-Lerner; Ohta, Shinsuke; Osawa, Masaki; Ding, Bo; Berk, Bradford C; Yan, Chen; Abe, Jun-ichi

2004-10-01

226

A newly discovered function of peroxisomes  

PubMed Central

In plants, peroxisomes are the organelles involved in various metabolic processes and physiological functions including ?-oxidation, mobilization of seed storage lipids, photorespiration, and hormone biosynthesis. We have recently shown that, in fungi and plants, peroxisomes play a vital role in biosynthesis of biotin, an essential cofactor required for various carboxylation and decarboxylation reactions. In fungi, the mutants defective in peroxisomal protein import exhibit biotin auxotrophy. The fungal BioF protein, a 7-keto-8-aminopelargonic acid (KAPA) synthase catalyzing the conversion of pimeloyl-CoA to KAPA in biotin biosynthesis, contains the peroxisomal targeting sequence 1 (PTS1), and its peroxisomal targeting is required for biotin biosynthesis. In plants, biotin biosynthesis is essential for embryo development. We have shown that the peroxisomal targeting sequences of the BioF proteins are conserved throughout the plant kingdom, and the Arabidopsis thaliana BioF protein is indeed localized in peroxisomes. Our findings suggest that peroxisomal localization of the BioF protein is evolutionarily conserved among eukaryotes, and required for biotin biosynthesis and plant growth and development.

Maruyama, Jun-ichi; Yamaoka, Shohei; Matsuo, Ichiro; Tsutsumi, Nobuhiro; Kitamoto, Katsuhiko

2012-01-01

227

Peroxisomal targeting signals in green algae.  

PubMed

Peroxisomal enzymatic proteins contain targeting signals (PTS) to enable their import into peroxisomes. These targeting signals have been identified as PTS1 and PTS2 in mammalian, yeast, and higher plant cells; however, no PTS2-like amino acid sequences have been observed in enzymes from the genome database of Cyanidiochyzon merolae (Bangiophyceae), a primitive red algae. In studies on the evolution of PTS, it is important to know when their sequences came to be the peroxisomal targeting signals for all living organisms. To this end, we identified a number of genes in the genome database of the green algae Chlamydomonas reinhardtii, which contains amino acid sequences similar to those found in plant PTS. In order to determine whether these sequences function as PTS in green algae, we expressed modified green fluorescent proteins (GFP) fused to these putative PTS peptides under the cauliflower mosaic virus 35S promoter. To confirm whether granular structures containing GFP-PTS fusion proteins accumulated in the peroxisomes of Closterium ehrenbergii, we observed these cells after the peroxisomes were stained with 3, 3'-diaminobenzidine. Our results confirm that the GFP-PTS fusion proteins indeed accumulated in the peroxisomes of these green algae. These findings suggest that the peroxisomal transport system for PTS1 and PTS2 is conserved in green algal cells and that our fusion proteins can be used to visualize peroxisomes in live cells. PMID:19214701

Shinozaki, Akiko; Sato, Nagisa; Hayashi, Yasuko

2009-02-12

228

Regulation of breast cancer resistant protein by peroxisome proliferator-activated receptor ? in human brain microvessel endothelial cells.  

PubMed

Breast cancer resistance protein (BCRP/ABCG2), an ATP-binding cassette (ABC) membrane-associated drug efflux transporter, is known to localize at the blood-brain barrier (BBB) and can significantly restrict xenobiotic permeability in the brain. The objective of this study is to investigate the regulation of BCRP functional expression by peroxisome proliferator-activated receptor alpha (PPAR?), a ligand-activated transcription factor primarily involved in lipid metabolism, in a cerebral microvascular endothelial cell culture system (hCMEC/D3), representative of human BBB. We demonstrate that PPAR?-selective ligands (i.e., clofibrate, GW7647) significantly induce BCRP mRNA and protein expression in a time- and concentration-dependent manner, whereas pharmacological inhibitors (i.e., MK886, GW6471) prevent this induction. Using [(3)H]mitoxantrone, an established BCRP substrate, we observe a significant reduction in its cellular accumulation by monolayer cells treated with clofibrate, suggesting increased BCRP efflux activity. In addition, we show a significant decrease in BCRP protein expression and function when PPAR? is down-regulated by small interfering RNA. Applying chromatin immunoprecipitation and quantitative real-time polymerase chain reaction, we observe that clofibrate treatment increases PPAR? binding to the peroxisome proliferator response element within the ABCG2 gene promoter. This study provides the first evidence of direct BCRP regulation by PPAR? in a human in vitro BBB model and suggests new targeting strategies for either improving drug brain bioavailability or increasing neuroprotection. PMID:22266374

Hoque, Md Tozammel; Robillard, Kevin R; Bendayan, Reina

2012-01-19

229

A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS.  

PubMed

Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signalling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by peroxisomal biogenesis factors 19 and 5 (PEX19 and PEX5), respectively, and peroxisome-localized TSC functioned as a Rheb GTPase-activating protein (GAP) to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, and abrogated peroxisome localization, Rheb GAP activity and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS, and peroxisome-localization-deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for the TSC in responding to ROS at the peroxisome, and identify the peroxisome as a signalling organelle involved in regulation of mTORC1. PMID:23955302

Zhang, Jiangwei; Kim, Jinhee; Alexander, Angela; Cai, Shengli; Tripathi, Durga Nand; Dere, Ruhee; Tee, Andrew R; Tait-Mulder, Jacqueline; Di Nardo, Alessia; Han, Juliette M; Kwiatkowski, Erica; Dunlop, Elaine A; Dodd, Kayleigh M; Folkerth, Rebecca D; Faust, Phyllis L; Kastan, Michael B; Sahin, Mustafa; Walker, Cheryl Lyn

2013-08-18

230

Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells  

Microsoft Academic Search

Purpose  Alterations in ceramide metabolism have been reported in prostate cancer (PCa), resulting in escape of cancer cells from ceramide-induced\\u000a apoptosis. Specifically, increased expression of lysosomal acid ceramidase (AC) has been shown in some primary PCa tissues\\u000a and in several PCa cell lines. To determine if this represents a novel therapeutic target, we designed and synthesized LCL204,\\u000a a lysosomotropic analog of

David H. Holman; Lorianne S. Turner; Ahmed El-Zawahry; Saeed Elojeimy; Xiang Liu; Jacek Bielawski; Zdzislaw M. Szulc; Kristi Norris; Youssef H. Zeidan; Yusuf A. Hannun; Alicja Bielawska; James S. Norris

2008-01-01

231

Effect of metabolic inhibitors on lauric acid-induced hemolysis  

Microsoft Academic Search

Lauric acid reduced osmotic RBC fragility at low salt concentrations and caused hemolysis under normotonic conditions. KCN inhibited the hemolytic effect of l.a. under normotonic but did not influence its action under hypotonic conditions. It is concluded that l.a.-induced hemolysis requires penetration of the f.a. into a deep membrane pool whereas binding of l.a. in the superficial RBC-membrane pool is

Elisabeth Bachmann; Gerhard Zbinden

1973-01-01

232

Age-dependent roles of peroxisomes in the hippocampus of a transgenic mouse model of Alzheimer's disease  

PubMed Central

Background Alzheimer’s Disease (AD) is a progressive neurodegenerative disease, especially affecting the hippocampus. Impairment of cognitive and memory functions is associated with amyloid ?-peptide-induced oxidative stress and alterations in lipid metabolism. In this scenario, the dual role of peroxisomes in producing and removing ROS, and their function in fatty acids ?-oxidation, may be critical. This work aims to investigating the possible involvement of peroxisomes in AD onset and progression, as studied in a transgenic mouse model, harboring the human Swedish familial AD mutation. We therefore characterized the peroxisomal population in the hippocampus, focusing on early, advanced, and late stages of the disease (3, 6, 9, 12, 18 months of age). Several peroxisome-related markers in transgenic and wild-type hippocampal formation were comparatively studied, by a combined molecular/immunohistochemical/ultrastructural approach. Results Our results demonstrate early and significant peroxisomal modifications in AD mice, compared to wild-type. Indeed, the peroxisomal membrane protein of 70 kDa and acyl-CoA oxidase 1 are induced at 3 months, possibly reflecting the need for efficient fatty acid ?-oxidation, as a compensatory response to mitochondrial dysfunction. The concomitant presence of oxidative damage markers and the altered expression of antioxidant enzymes argue for early oxidative stress in AD. During physiological and pathological brain aging, important changes in the expression of peroxisome-related proteins, also correlating with ongoing gliosis, occur in the hippocampus. These age- and genotype-based alterations, strongly dependent on the specific marker considered, indicate metabolic and/or numerical remodeling of peroxisomal population. Conclusions Overall, our data support functional and biogenetic relationships linking peroxisomes to mitochondria and suggest peroxisomal proteins as biomarkers/therapeutic targets in pre-symptomatic AD.

2013-01-01

233

Encapsulation-Induced Stress Helps Saccharomyces cerevisiae Resist Convertible Lignocellulose Derived Inhibitors  

PubMed Central

The ability of macroencapsulated Saccharomyces cerevisiae CBS8066 to withstand readily and not readily in situ convertible lignocellulose-derived inhibitors was investigated in anaerobic batch cultivations. It was shown that encapsulation increased the tolerance against readily convertible furan aldehyde inhibitors and to dilute acid spruce hydrolysate, but not to organic acid inhibitors that cannot be metabolized anaerobically. Gene expression analysis showed that the protective effect arising from the encapsulation is evident also on the transcriptome level, as the expression of the stress-related genes YAP1, ATR1 and FLR1 was induced upon encapsulation. The transcript levels were increased due to encapsulation already in the medium without added inhibitors, indicating that the cells sensed low stress level arising from the encapsulation itself. We present a model, where the stress response is induced by nutrient limitation, that this helps the cells to cope with the increased stress added by a toxic medium, and that superficial cells in the capsules degrade convertible inhibitors, alleviating the inhibition for the cells deeper in the capsule.

Westman, Johan O.; Manikondu, Ramesh Babu; Franzen, Carl Johan; Taherzadeh, Mohammad J.

2012-01-01

234

Activation of Peroxisome Proliferator-Activated Receptor ?/? Inhibits Lipopolysaccharide-Induced Cytokine Production in Adipocytes by Lowering Nuclear Factor-?B Activity via Extracellular Signal-Related Kinase 1/2  

PubMed Central

OBJECTIVE—Chronic activation of the nuclear factor-?B (NF-?B) in white adipose tissue leads to increased production of pro-inflammatory cytokines, which are involved in the development of insulin resistance. It is presently unknown whether peroxisome proliferator–activated receptor (PPAR) ?/? activation prevents inflammation in adipocytes. RESEARCH DESIGN AND METHODS AND RESULTS—First, we examined whether the PPAR?/? agonist GW501516 prevents lipopolysaccharide (LPS)-induced cytokine production in differentiated 3T3-L1 adipocytes. Treatment with GW501516 blocked LPS-induced IL-6 expression and secretion by adipocytes and the subsequent activation of the signal transducer and activator of transcription 3 (STAT3)–Suppressor of cytokine signaling 3 (SOCS3) pathway. This effect was associated with the capacity of GW501516 to impede LPS-induced NF-?B activation. Second, in in vivo studies, white adipose tissue from Zucker diabetic fatty (ZDF) rats, compared with that of lean rats, showed reduced PPAR?/? expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-?B DNA-binding activity. Furthermore, IL-6 expression and NF-?B DNA-binding activity was higher in white adipose tissue from PPAR?/?-null mice than in wild-type mice. Because mitogen-activated protein kinase–extracellular signal–related kinase (ERK)1/2 (MEK1/2) is involved in LPS-induced NF-?B activation in adipocytes, we explored whether PPAR?/? prevented NF-?B activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2 phosphorylation by LPS. Furthermore, white adipose tissue from animal showing constitutively increased NF-?B activity, such as ZDF rats and PPAR?/?-null mice, also showed enhanced phospho-ERK1/2 levels. CONCLUSIONS—These findings indicate that activation of PPAR?/? inhibits enhanced cytokine production in adipocytes by preventing NF-?B activation via ERK1/2, an effect that may help prevent insulin resistance.

Rodriguez-Calvo, Ricardo; Serrano, Lucia; Coll, Teresa; Moullan, Norman; Sanchez, Rosa M.; Merlos, Manuel; Palomer, Xavier; Laguna, Juan C.; Michalik, Liliane; Wahli, Walter; Vazquez-Carrera, Manuel

2008-01-01

235

Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis  

PubMed Central

Histone deacetylase (HDAC) inhibitors are emerging as effective therapies in the treatment of cancer, and the role of HDACs in the regulation of promoters is rapidly expanding. GRP78/BiP is a stress inducible endoplasmic reticulum (ER) chaperone with anti-apoptotic properties. We present here the mechanism for repression of the Grp78 promoter by histone deacetylase 1 (HDAC1). Our studies reveal that HDAC inhibitors specifically induce GRP78, and the induction level is amplified by ER stress. Through mutational analysis, we have identified the minimal Grp78 promoter and specific elements responsible for HDAC-mediated repression. We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275, but also by exogenous overexpression and siRNA knockdown of specific HDACs. We present the results of chromatin immunoprecipitation analysis that reveals the binding of HDAC1 to the Grp78 promoter before but not after ER stress. Furthermore, overexpression of GRP78 confers resistance to HDAC inhibitor induced apoptosis in cancer cells and, conversely, suppression of GRP78 sensitizes them to HDAC inhibitor. These results define HDAC inhibitors as new agents that upregulate GRP78 without concomitantly inducing the ER or heat shock stress response, and suppression of GRP78 in tumors may provide a novel, adjunctive option to enhance anti-cancer therapies that utilize these compounds.

Baumeister, Peter; Dong, Dezheng; Fu, Yong; Lee, Amy S.

2009-01-01

236

Evidence for a peroxisome proliferator-activated receptor (PPAR)-mediated mechanism for conjugated linoleic acid (CLA)  

Microsoft Academic Search

We have previously shown that a mixture of conjugated derivatives of linoleic acid (CLA) induces peroxisome proliferator-responsive enzymes and modulates hepatic lipid metabolism in vivo. The present studies demonstrate that CLA is a high affinity ligand and activator of peroxisome proliferator-activated receptor (PPAR) with high specificity for the PPAR? subtype. Moreover, CLA induces accumulation of PPAR-responsive mRNAs in a rat

Silvia Yolanda Moya Camarena

1998-01-01

237

NOVEL ATYPICAL PKC INHIBITORS PREVENT VASCULAR ENDOTHELIAL GROWTH FACTOR-INDUCED BLOOD-RETINAL BARRIER DYSFUNCTION  

PubMed Central

SYNOPSIS Pro-inflammatory cytokines and growth factors such as vascular endothelial growth factor (VEGF) contribute to the loss of the blood-retinal barrier (BRB) and subsequent macular edema in various retinal pathologies. VEGF signaling requires conventional PKC (PKC?) activity; however, PKC? inhibition only partially prevents VEGF-induced endothelial permeability and does not affect pro-inflammatory cytokine-induced permeability suggesting the involvement of alternative signaling pathways. Here, we provide evidence for the involvement of atypical protein kinase C (aPKC) signaling in VEGF-induced endothelial permeability and identify a novel class of inhibitors of aPKC that prevent BRB breakdown in vivo. Genetic and pharmacological manipulations of aPKC isoforms were used to assess their contribution to endothelial permeability in culture. A chemical library was screened using an in vitro kinase assay to identify novel small molecule inhibitors and further medicinal chemistry was performed to delineate a novel pharmacophore. We demonstrate that aPKC isoforms are both sufficient and required for VEGF-induced endothelial permeability. Furthermore, these specific, potent, non-competitive, small molecule inhibitors prevented VEGF-induced tight junction internalization and retinal endothelial permeability in response to VEGF in both primary culture and in rodent retina. These data suggest that aPKC inhibition with 2-amino-4-phenyl-thiophene derivatives may be developed to preserve the BRB in retinal diseases such as diabetic retinopathy or uveitis and the blood-brain barrier (BBB) in the presence of brain tumors.

Titchenell, Paul M.; Lin, Cheng-Mao; Keil, Jason M.; Sundstrom, Jeffrey M.; Smith, Charles D.; Antonetti, David A.

2013-01-01

238

Wound-Inducible Proteinase Inhibitors in Pepper. Differential Regulation upon Wounding, Systemin, and Methyl Jasmonate1  

PubMed Central

Seven small (approximately 6,000 D) wound-inducible proteinase inhibitor proteins were isolated from leaves of pepper (Capsicum annuum) plants that are members of the potato inhibitor II family. N-terminal sequences obtained indicated that the pepper leaf proteinase inhibitors (PLPIs) exhibit homology to two GenBank accessions that code for preproteins containing three isoinhibitors domains each that, when post-translationally processed, can account for the mixture of isoinhibitors that are reported herein from pepper leaves. A constitutive level of PLPI proteins was found in pepper leaves, and these levels increased up to 2.6-fold upon wounding of the lower leaves. Exposing intact plants to methyl jasmonate vapors induced the accumulation of PLPIs. Supplying excised young pepper plants with water through the cut stems induced PLPI proteins to levels higher than those found in intact plants, but with high variability. Supplying the excised plants with systemin did not result in an increase of PLPI levels that were statistically higher than levels found in excised plants. Gel-blot analyses of PLPI induction revealed the presence of two mRNA bands, having slightly different mobilities in agarose gels. Only the low Mr mRNA is present in untreated control plants, and it appears to be responsible for the constitutive levels of PLPI found in leaves. Both mRNA species are wound- and methyl jasmonate-inducible. Only the low- Mr species is weakly induced by systemin, indicating a differential expression of the two PLPI species.

Moura, Daniel S.; Ryan, Clarence A.

2001-01-01

239

Inhibition of carcinogen-induced chromosomal aberrations by an anticarcinogenic protease inhibitor.  

PubMed Central

It was hypothesized that chemicals- and radiation-induced carcinogenesis might require at least two specific chromosomal events that must coincide within a single target cell: (i) induction of chromosomal changes, possibly mutations, that are recessive and therefore latent in diploid somatic cells and (ii) aberrant mitotic segregation events that will convert the heterozygous cell, created by the first process, into a homozygous or hemizygous cell through chromosomal rearrangements. Hence, we tested the prediction that an inhibitor of induced carcinogenesis may inhibit one or both of these chromosomal events by studying the effects of antipain, a protease inhibitor and known inhibitor of carcinogenesis, on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced mutagenesis, chromosomal aberrations, sister chromatid exchanges, and cell killing in V79 Chinese hamster cells. We show that antipain inhibited MNNG-induced chromosomal exchanges and all other chromosomal aberrations exclusively. This results leads us to postulate that MNNG-induced DNA lesions cause chromosomal aberrations which arise through an antipain-sensitive cellular process, that some chromosomal rearrangement is a rate-limiting step in carcinogenesis, and that mutagenesis alone, if required, is not sufficient to accomplish carcinogenesis. Images

Kinsella, A R; Radman, M

1980-01-01

240

Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content  

PubMed Central

To examine the mechanism by which fish oil protects against fat-induced insulin resistance, we studied the effects of control, fish oil, and safflower oil diets on peroxisomal content, fatty acyl-CoA, diacylglycerol, and ceramide content in rat liver and muscle. We found that, in contrast to control and safflower oil-fed rats, fish oil feeding induced a 150% increase in the abundance of peroxisomal acyl-CoA oxidase and 3-ketoacyl-CoA thiolase in liver but lacked similar effects in muscle. This was paralleled by an almost twofold increase in hepatic peroxisome content (both P < 0.002 vs. control and safflower). These changes in the fish oil-fed rats were associated with a more than twofold lower hepatic triglyceride/diacylglycerol, as well as intramuscular triglyceride/fatty acyl-CoA, content. In conclusion, these data strongly support the hypothesis that n-3 fatty acids protect against fat-induced insulin resistance by serving as peroxisome proliferator-activated receptor-? ligands and thereby induce hepatic, but not intramuscular, peroxisome proliferation. In turn, an increased hepatic ?-oxidative capacity results in lower hepatic triglyceride/diacylglycerol and intramyocellular triglyceride/fatty acyl-CoA content.

Neschen, Susanne; Moore, Irene; Regittnig, Werner; Yu, Chun Li; Wang, Yanlin; Pypaert, Marc; Petersen, Kitt Falk; Shulman, Gerald I.

2010-01-01

241

Identification of peroxisomal targeting signals located at the carboxy terminus of four peroxisomal proteins  

PubMed Central

As part of an effort to understand how proteins are imported into the peroxisome, we have sought to identify the peroxisomal targeting signals in four unrelated peroxisomal proteins: human catalase, rat hydratase:dehydrogenase, pig D-amino acid oxidase, and rat acyl-CoA oxidase. Using gene fusion experiments, we have identified a region of each protein that can direct heterologous proteins to peroxisomes. In each case, the peroxisomal targeting signal is contained at or near the carboxy terminus of the protein. For catalase, the peroxisomal targeting signal is located within the COOH-terminal 27 amino acids of the protein. For hydratase:dehydrogenase, D-amino acid oxidase, and acyl-CoA oxidase, the targeting signals are located within the carboxy- terminal 15, 14, and 15 amino acids, respectively. A tripeptide of the sequence Ser-Lys/His-Leu is present in each of these targeting signals as well as in the peroxisomal targeting signal identified in firefly luciferase (Gould, S.J., G.-A. Keller, and S. Subramani. 1987. J. Cell Biol. 105:2923-2931). When the peroxisomal targeting signal of the hydratase:dehydrogenase is mutated so that the Ser-Lys-Leu tripeptide is converted to Ser-Asn-Leu, it can no longer direct proteins to peroxisomes. We suggest that this tripeptide is an essential element of at least one class of peroxisomal targeting signals.

1988-01-01

242

Human peroxisomal targeting signal-1 receptor restores peroxisomal protein import in cells from patients with fatal peroxisomal disorders.  

PubMed

Two peroxisomal targeting signals, PTS1 and PTS2, are involved in the import of proteins into the peroxisome matrix. Human patients with fatal generalized peroxisomal deficiency disorders fall into at least nine genetic complementation groups. Cells from many of these patients are deficient in the import of PTS1-containing proteins, but the causes of the protein-import defect in these patients are unknown. We have cloned and sequenced the human cDNA homologue (PTS1R) of the Pichia pastoris PAS8 gene, the PTS1 receptor (McCollum, D., E. Monosov, and S. Subramani. 1993. J. Cell Biol. 121:761-774). The PTS1R mRNA is expressed in all human tissues examined. Antibodies to the human PTS1R recognize this protein in human, monkey, rat, and hamster cells. The protein is localized mainly in the cytosol but is also found to be associated with peroxisomes. Part of the peroxisomal PTS1R protein is tightly bound to the peroxisomal membrane. Antibodies to PTS1R inhibit peroxisomal protein-import of PTS1-containing proteins in a permeabilized CHO cell system. In vitro-translated PTS1R protein specifically binds a serine-lysine-leucine-peptide. A PAS8-PTS1R fusion protein complements the P. pastoris pas8 mutant. The PTS1R cDNA also complements the PTS1 protein-import defect in skin fibroblasts from patients--belonging to complementation group two--diagnosed as having neonatal adrenoleukodystrophy or Zellweger syndrome. The PTS1R gene has been localized to a chromosomal location where no other peroxisomal disorder genes are known to map. Our findings represent the only case in which the molecular basis of the protein-import deficiency in human peroxisomal disorders is understood. PMID:7790377

Wiemer, E A; Nuttley, W M; Bertolaet, B L; Li, X; Francke, U; Wheelock, M J; Anné, U K; Johnson, K R; Subramani, S

1995-07-01

243

Hepatocellular peroxisome proliferation and DNA synthesis in Wistar rats treated with herbicide fluazifop.  

PubMed

The aim of this study was to determine the effect of herbicide fluazifop, on the early occurring changes in rat liver regarded as hepatic markers of peroxisome proliferators (PPs). Fluazifop was administered orally to male Wistar rats at increasing doses from 5.6 to 891 mg/kg body weight per day for 1, 2, 4, 7 and 14 consecutive days and peroxisome proliferation, induction of some peroxisome-associated enzymes and mitogenesis (S-phase, M-phase and percentage of binucleated hepatocytes) were studied. Short-term treatment of rats with fluazifop resulted in hepatomegaly due to time dependent proliferation of smooth endoplasmic reticulum (SER) and peroxisomes. The increase in the number of peroxisomes in the hepatocytes was supported by an increase in peroxisomal palmitoyl-CoA oxidation and catalase activity. In contrast to other PPs fluazifop induced low rate of rcplicative DNA synthesis and did not affect mitoses (M-phase). DNA synthesis was accompanied by the appearance of binucleated hepatocytes. Thus, we can conclude that fluazifop produces in male Wistar rats hepatomegaly due to cellular hypertrophy. The threshold dose for palmitoyl-CoA oxidation and DNA synthesis was 112 and 223 mg/kg body weight per day, respectively. The value for hepatomegaly and catalase activity was 56 mg/kg body weight per day. The results presented in this paper demonstrated that fluazifop can be classified as a weak rodent PPs. PMID:12167308

Kostka, Grazyna; Palut, Danuta; Ludwicki, Jan K; Kope?-Szlezak, Joanna; Wiadrowska, Bozena; Lembowicz, Krystyna

2002-09-16

244

Labeling of peroxisomes with green fluorescent protein in living P. pastoris cells.  

PubMed

We exploited the light-activated fluorescent properties of the green fluorescent protein (GFP) of the jellyfish Aequorea victoria for studies on the peroxisomal sorting of polypeptides. GFP and GFP-SKL (containing a C-terminal, tripeptide peroxisomal targeting signal, SKL) were expressed from a methanol-inducible, alcohol oxidase (AOX1) promoter in the methylotrophic yeast Pichia pastoris. GFP was cytosolic, whereas the GFP-SKL fusion protein was targeted to peroxisomes, as demonstrated by biochemical fractionation of organelles on Nycodenz gradients. Neither GFP nor GFP-SKL affected the viability of yeast cells but both were fluorescent on excitation with 395-nm UV light. The subcellular locations of GFP and GFP-SKL in living yeast cells were monitored by fluorescence microscopy and their fluorescence was coupled to photo-oxidation of diaminobenzidine (DAB), resulting in the deposition of electron-dense oxidized DAB at intracellular locations of GFP derivatives. This photooxidation procedure permitted facile ultrastructural localization of GFP in cells by electron microscopy, and provided further evidence that GFP produced in P. pastoris is cytosolic, whereas GFP-SKL is peroxisomal. The GFP-SKL fusion protein is therefore a versatile reporter for the peroxisomal compartment, with many applications for studies involving peroxisomal import and biogenesis. PMID:8666743

Monosov, E Z; Wenzel, T J; Lüers, G H; Heyman, J A; Subramani, S

1996-06-01

245

Inhibition of peroxisome-proliferator-activated receptor (PPAR)alpha by MK886.  

PubMed Central

Although MK886 was originally identified as an inhibitor of 5-lipoxygenase activating protein (FLAP), recent data demonstrate that this activity does not underlie its ability to induce apoptosis [Datta, Biswal and Kehrer (1999) Biochem. J. 340, 371--375]. Since FLAP is a fatty-acid binding protein, it is conceivable that MK886 may affect other such proteins. A family of nuclear receptors that are activated by fatty acids and their metabolites, the peroxisome-proliferator-activated receptors (PPARs), have been implicated in apoptosis and may represent a target for MK886. The ability of MK886 to inhibit PPAR-alpha, -beta and -gamma activity was assessed using reporter assay systems (peroxisome-proliferator response element--luciferase). Using a transient transfection system in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells and human lung adenocarcinoma A549 cells, 10--20 microM MK886 inhibited Wy14,643 activation of PPAR alpha by approximately 80%. Similar inhibition of PPAR alpha by MK886 was observed with a stable transfection reporter system in CV-1 cells. Only minimal inhibitory effects were seen on PPAR beta and PPAR gamma. MK886 inhibited PPAR alpha by a non-competitive mechanism as shown by its effects on the binding of arachidonic acid to PPAR alpha protein, and a dose-response study using a transient transfection reporter assay in COS-1 cells. An assay assessing PPAR ligand-receptor interactions showed that MK886 prevents the conformational change necessary for active-complex formation. The expression of keratin-1, a protein encoded by a PPAR alpha-responsive gene, was reduced by MK886 in a culture of mouse primary keratinocytes, suggesting that PPAR inhibition has functional consequences in normal cells. Although Jurkat cells express all PPAR isoforms, various PPAR alpha and PPAR gamma agonists were unable to prevent MK886-induced apoptosis. This is consistent with MK886 functioning as a non-competitive inhibitor of PPAR alpha, but may also indicate that PPAR alpha is not directly involved in MK886-induced apoptosis. Although numerous PPAR activators have been identified, the results show that MK886 can inhibit PPAR alpha, making it the first compound identified to have such an effect.

Kehrer, J P; Biswal, S S; La, E; Thuillier, P; Datta, K; Fischer, S M; Vanden Heuvel, J P

2001-01-01

246

Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system?  

Microsoft Academic Search

One of the many functions of liver peroxisomes is the ?-oxidation of long-chain fatty acids. It is essential for the continuation of peroxisomal ?-oxidation that a redox shuttle system exist across the peroxisomal membrane to reoxidize NADH. We propose that this redox shuttle system consists of a substrate cycle between lactate and pyruvate. Here we present evidence that purified peroxisomal

Grant B. McClelland; Savita Khanna; Gilda F González; C. Eric Butz; George A. Brooks

2003-01-01

247

Farnesyltransferase inhibitors induce DNA damage via reactive oxygen species in human cancer cells.  

PubMed

Farnesyltransferase inhibitors (FTIs) possess antitumor activity. Based on recent findings, we hypothesized that FTIs induce reactive oxygen species (ROS) that damage DNA, leading to DNA damage responses. To test this hypothesis, we investigated the effects of FTIs on the generation of ROS, DNA double-strand breaks (DSB), DNA damage responses, and RhoB, and the effects of quenching ROS on these FTI effects. We evaluated four FTIs in human cancer cell lines of different tissue origins. We found that FTIs induced ROS and DSBs. Suppressing expression of the beta-subunit of farnesyltransferase with siRNA did not induce ROS, but slightly attenuated the ROS induced by FTIs. N-acetyl-L-cysteine (NAC), but not caspase inhibitors, blocked FTI-induced DSBs, suggesting that the DSBs were caused by ROS and did not result from apoptosis. The DSBs led to DNA damage responses. H2AX became phosphorylated and formed nuclear foci. The DNA-damage-sensing molecules involved were probably ataxia-telangiectasia mutated protein (ATM) and DNA-dependent protein kinase (DNA-PK) but not ATM- and Rad3-related protein (ATR). Key components of the homologous recombination and nonhomologous end joining repair pathways (DNA-PK, BRCA1, and NBS1) underwent phosphorylation and formed nuclear foci. RhoB, a mediator of the antineoplastic effect of FTIs and a protein inducible by DNA damage, was increased by FTIs. This increase was blocked by NAC. We concluded that FTIs induced oxidative DNA damage by inducing ROS and initiated DNA damage responses, including RhoB induction, and there was a complex relationship among FTIs, farnesyltransferase, ROS, and RhoB. Our data also imply that inhibitors of DNA repair may accentuate the clinical efficacy of FTIs. PMID:15867362

Pan, Jingxuan; She, Miaorong; Xu, Zhi-Xiang; Sun, Lily; Yeung, Sai-Ching Jim

2005-05-01

248

HMG-CoA reductase inhibitors inhibit rat propylthiouracil-induced goiter by modulating the ras-MAPK pathway  

Microsoft Academic Search

The aim of this study was to evaluate in vivo the antiproliferative effect of an inhibitor of isoprenoids metabolism, lovastatin, in an experimental model of propylthiouracil-induced goiter. In thyroid cells, thyrotropin (TSH)-induced proliferation requires active isoprenoid synthesis, and the HMG-CoA reductase inhibitors have antiproliferative effects in vitro. Propylthiouracil treatment (PTU) of rats led to thyroid hypertrophy and hyperplasia by TSH-induced

Chiara Laezza; Gherardo Mazziotti; Laura Fiorentino; Patrizia Gazzerro; Giuseppe Portella; Diego Gerbasio; Carlo Carella; Giuseppe Matarese; Maurizio Bifulco

2006-01-01

249

Peroxisomal acyl-CoA synthetases.  

PubMed

Peroxisomes carry out many essential lipid metabolic functions. Nearly all of these functions require that an acyl group-either a fatty acid or the acyl side chain of a steroid derivative-be thioesterified to coenzyme A (CoA) for subsequent reactions to proceed. This thioesterification, or "activation", reaction, catalyzed by enzymes belonging to the acyl-CoA synthetase family, is thus central to cellular lipid metabolism. However, despite our rather thorough understanding of peroxisomal metabolic pathways, surprisingly little is known about the specific peroxisomal acyl-CoA synthetases that participate in these pathways. Of the 26 acyl-CoA synthetases encoded by the human and mouse genomes, only a few have been reported to be peroxisomal, including ACSL4, SLC27A2, and SLC27A4. In this review, we briefly describe the primary peroxisomal lipid metabolic pathways in which fatty acyl-CoAs participate. Then, we examine the evidence for presence and functions of acyl-CoA synthetases in peroxisomes, much of which was obtained before the existence of multiple acyl-CoA synthetase isoenzymes was known. Finally, we discuss the role(s) of peroxisome-specific acyl-CoA synthetase isoforms in lipid metabolism. PMID:22366061

Watkins, Paul A; Ellis, Jessica M

2012-02-17

250

Peroxisomal acyl-CoA synthetases  

PubMed Central

Peroxisomes carry out many essential lipid metabolic functions. Nearly all of these functions require that an acyl group – either a fatty acid or the acyl side chain of a steroid derivative – be thioesterified to coenzyme A (CoA) for subsequent reactions to proceed. This thioesterification, or “activation”, reaction, catalyzed by enzymes belonging to the acyl-CoA synthetase (ACS) family, is thus central to cellular lipid metabolism. However, despite our rather thorough understanding of peroxisomal metabolic pathways, surprisingly little is known about the specific peroxisomal ACSs that participate in these pathways. Of the 26 ACSs encoded by the human and mouse genomes, only a few have been reported to be peroxisomal, including ACSL4, ACSVL1 (FATP2), and FATP4. In this review, we briefly describe the primary peroxisomal lipid metabolic pathways in which fatty acyl-CoAs participate. Then, we examine the evidence for presence and functions of ACSs in peroxisomes, much of which was obtained before the existence of multiple ACS isoenzymes was known. Finally, we discuss the role(s) of peroxisome-specific ACS isoforms in lipid metabolism.

Watkins, Paul A.; Ellis, Jessica M.

2012-01-01

251

The role of peroxisomal fatty acyl-CoA beta-oxidation in bile acid biosynthesis  

SciTech Connect

The physiological role of the peroxisomal fatty acyl-CoA beta-oxidizing system (FAOS) is not yet established. We speculated that there might be a relationship between peroxisomal degradation of long-chain fatty acids in the liver and the biosynthesis of bile acids. This was investigated using (1-{sup 14}C)butyric acid and (1-{sup 14}C)lignoceric acid as substrates of FAOS in mitochondria and peroxisomes, respectively. The incorporation of ({sup 14}C)lignoceric acid into primary bile acids was approximately four times higher than that of ({sup 14}C)butyric acid (in terms of C-2 units). The pools of these two fatty acids in the liver were exceedingly small. The incorporations of radioactivity into the primary bile acids were strongly inhibited by administration of aminotriazole, which is a specific inhibitor of peroxisomal FAOS in vivo. Aminotriazole inhibited preferentially the formation of cholate, the major primary bile acid, from both ({sup 14}C)lignoceric acid and ({sup 14}C)butyric acid, rather than the formation of chenodeoxycholate. The former inhibition was about 70% and the latter was approximately 40-50%. In view of reports that cholate is biosynthesized from endogenous cholesterol, the above results indicate that peroxisomal FAOS may have an anabolic function, supplying acetyl CoA for bile acid biosynthesis.

Hayashi, H.; Miwa, A. (Josai Univ., Saitama (Japan))

1989-11-01

252

The histone deacetylase inhibitor vorinostat prevents TNF?-induced necroptosis by regulating multiple signaling pathways.  

PubMed

Histone deacetylase (HDAC) inhibitors are novel anticancer reagents that have recently been reported to have anti-inflammatory and neuroprotective effects; however, the mechanisms underlying their activities are largely undefined. The data from this study show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can protect L929 cells from TNF?-induced necroptosis. This effect involves multiple mechanisms, including the upregulation of cFLIPL expression, the enhanced activation of NF?B and p38 MAPK, and the inactivation of JNK. In addition, SAHA could initiate cell autophagy by inhibiting Akt and mTOR, which also play important roles in protecting cells from necroptosis. Because cell necroptosis is important for inflammation-related deterioration and neurodegenerative disease, our results indicate that preventing cell necrosis may be an important mechanism through which HDAC inhibitor compounds exert their anti-inflammatory or neuroprotective effects. PMID:23708756

Wang, Di; Zhao, Ming; Chen, Guozhu; Cheng, Xiang; Han, Xiaoxi; Lin, Song; Zhang, Xuhui; Yu, Xiaodan

2013-11-01

253

Inhibition of etoposide-induced apoptosis with peptide aldehyde inhibitors of proteasome.  

PubMed Central

Recent investigations have indicated the involvement of proteasome in programmed cell death. The present studies show that although peptide aldehyde inhibitors of proteasome are by themselves weak inducers of apoptosis, they inhibit the apoptotic effect of the anticancer drug etoposide in rat thymocytes. Acetyl-Leu-Leu-norvalinal (LLnV-al) and other related peptide aldehydes inhibited the increase in caspase activity and DNA fragmentation that followed treatment with etoposide and their effect was related to their potency as proteasome inhibitors. To inhibit etoposide-induced apoptosis, LLnV-al must be present within 3 h of treatment with etoposide, in the same way as the inhibitor of protein synthesis cycloheximide must be. Etoposide caused a rapid accumulation of p53 protein that was not inhibited by LLnV-al, which was also a strong inducer of p53. Peptide aldehydes were also weak activators of caspase activity, suggesting that the same mechanism, i.e. the blocking of proteasome function, both triggers apoptosis and inhibits the effect of etoposide. These results are consistent with a model in which proteasome is selectively involved in the pathway used by etoposide to induce cell suicide.

Stefanelli, C; Bonavita, F; Stanic, I; Pignatti, C; Farruggia, G; Masotti, L; Guarnieri, C; Caldarera, C M

1998-01-01

254

Effects of cytochrome P450 inhibitors and inducers on the metabolism and pharmacokinetics of ospemifene.  

PubMed

Purpose: The objectives were to determine the cytochrome P450 (CYP) enzymes involved in the metabolism of ospemifene and its main hydroxylated metabolites and to examine the effects of CYP inhibitors and inducers on ospemifene pharmacokinetics. Methods: In vitro metabolism studies were conducted using human liver microsomes; CYP-selective inhibitors and CYP-specific substrates were used to determine the roles of nine CYP isoforms in ospemifene metabolism. Two Phase 1 clinical trials were conducted in healthy postmenopausal women; crossover designs examined the effects of pretreatment with the CYP modulators rifampicin, ketoconazole, fluconazole and omeprazole on ospemifene pharmacokinetics. Results: Although several CYP inhibitors decreased the in vitro formation of ospemifene metabolites, none of them completely blocked metabolism. Roles for CYP3A4, CYP2C9, CYP2C19 and CYP2B6 in the metabolism of ospemifene and its two main metabolites, 4--hydroxyospemifene and 4'-hydroxyospemifene, were confirmed. The in vivo experiments demonstrated that ospemifene serum concentrations were decreased by rifampicin pretreatment, increased by ketoconazole or fluconazole pretreatment, and minimally affected by omeprazole pretreatment. Conclusions: The clinical pharmacokinetic findings and in vitro data suggest that CYP3A4 is important for ospemifene metabolism, but other CYP isoforms and metabolic pathways also contribute. Strong CYP3A or CYP2C9 inducers (e.g. rifampicin) would be expected to decrease the exposure to ospemifene. Ospemifene should be used with caution when coadministered with the modest CYP3A inhibitor ketoconazole and should not be coadministered with the potent CYP3A/CYP2C9/CYP2C19 inhibitor fluconazole. The potent CYP2C19 inhibitor omeprazole is unlikely to cause clinically significant changes in ospemifene pharmacokinetics. Copyright © 2013 John Wiley & Sons, Ltd. PMID:23852652

Lehtinen, Terhi; Tolonen, Ari; Turpeinen, Miia; Uusitalo, Jouko; Vuorinen, Jouni; Lammintausta, Risto; Pelkonen, Olavi; Scheinin, Mika

2013-08-15

255

Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.  

PubMed Central

Constitutive cyclooxygenase (COX-1; prostaglandin-endoperoxide synthase, EC 1.14.99.1) is present in cells under physiological conditions, whereas COX-2 is induced by some cytokines, mitogens, and endotoxin presumably in pathological conditions, such as inflammation. Therefore, we have assessed the relative inhibitory effects of some nonsteroidal antiinflammatory drugs on the activities of COX-1 (in bovine aortic endothelial cells) and COX-2 (in endotoxin-activated J774.2 macrophages) in intact cells, broken cells, and purified enzyme preparations (COX-1 in sheep seminal vesicles; COX-2 in sheep placenta). Similar potencies of aspirin, indomethacin, and ibuprofen against the broken cell and purified enzyme preparations indicated no influence of species. Aspirin, indomethacin, and ibuprofen were more potent inhibitors of COX-1 than COX-2 in all models used. The relative potencies of aspirin and indomethacin varied only slightly between models, although the IC50 values were different. Ibuprofen was more potent as an inhibitor of COX-2 in intact cells than in either broken cells or purified enzymes. Sodium salicylate was a weak inhibitor of both COX isoforms in intact cells and was inactive against COX in either broken cells or purified enzyme preparations. Diclofenac, BW 755C, acetaminophen, and naproxen were approximately equipotent inhibitors of COX-1 and COX-2 in intact cells. BF 389, an experimental drug currently being tested in humans, was the most potent and most selective inhibitor of COX-2 in intact cells. Thus, there are clear pharmacological differences between the two enzymes. The use of such models of COX-1 and COX-2 activity will lead to the identification of selective inhibitors of COX-2 with presumably less side effects than present therapies. Some inhibitors had higher activity in intact cells than against purified enzymes, suggesting that pure enzyme preparations may not be predictive of therapeutic action. Images Fig. 1

Mitchell, J A; Akarasereenont, P; Thiemermann, C; Flower, R J; Vane, J R

1993-01-01

256

Neuroprotective effect of cyclooxygenase inhibitors in ICV-STZ induced sporadic Alzheimer's disease in rats.  

PubMed

Sporadic Alzheimer's disease is an age-related neurological and psychiatric disorder characterized by impaired energy metabolism. Oxidative stress and neuroinflammation have been implicated in pathophysiology of sporadic type of dementia. The central streptozotocin administration induces behavioral and biochemical alterations resembling those in sporadic type of Alzheimer's patients. The present study was designed to investigate the effects of chronic pretreatment with cyclooxygenase-1 or cyclooxygenase-2 or cyclooxygenase-3 selective inhibitors on cognitive dysfunction and oxidative stress markers in intracerebroventricular streptozotocin-treated rats. Chronic treatment with valeryl salicylate (5 and 10 mg/kg, i.p.) and etoricoxib (5 and 10 mg/kg, i.p.) on a daily basis for a period of 21 days, beginning 1 h prior to first intracerebroventricular streptozotocin injection, significantly improved streptozotocin-induced cognitive impairment. However, phenacetin (20 and 40 mg/kg, i.p.) failed to restore the cognitive performances of streptozotocin-treated rats. Besides, improving cognitive dysfunction, chronic administration of highly selective cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors (valeryl salicylate and etoricoxib, respectively), but not cyclooxygenase-3 inhibitor (phenacetin), significantly reduced elevated malondialdehyde, nitrite levels, and restored reduced glutathione and superoxide dismutase levels. Furthermore, cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors significantly increased the survival of pyramidal neurons. In summary, we demonstrate for the first time that both cyclooxygenase-1 and cyclooxygenase-2 isoforms, but not cyclooxygenase-3, are involved in the progression of neuronal damage in intracerebroventricular streptozotocin-treated rats. PMID:21701788

Dhull, Dinesh Kumar; Jindal, Ankur; Dhull, Rakesh K; Aggarwal, Saurabh; Bhateja, Deepak; Padi, Satyanarayana S V

2011-06-24

257

Effects of selective cyclooxygenase inhibitors on ischemia/reperfusion-induced hepatic microcirculatory dysfunction in mice.  

PubMed

We examined the effects of selective cyclooxygenase (COX) inhibition on hepatic warm ischemia/reperfusion (I/R) injury in mice. A selective COX-1 inhibitor, SC-560, selective COX-2 inhibitors, NS-398 and celecoxib, and indomethacin were administered 30 min before ischemia. Four hours after reperfusion, an in vivo microscopic study showed that I/R caused significant accumulation of leukocytes adhering to the hepatic microvessels and nonperfused sinusoids. Levels of plasma alanine transaminase (ALT) and tumor necrosis factor (TNF)-alpha also showed increases. SC-560, NS-398, celecoxib and indomethacin significantly reduced hepatic responses to I/R including microcirculatory dysfunction and release of ALT and TNF-alpha. Moreover, the effects of the thromboxane (TX) A(2) (TXA(2)) synthase inhibitor OKY-046 and the TXA(2) receptor antagonist S-1452 on hepatic responses to I/R exhibited results similar to those obtained with COX inhibitors. These results suggest that COX-1 and COX-2 contribute to I/R-induced hepatic microvascular and hepatocellular injury partly through TNF-alpha production, and that TXs derived from COX are partly responsible for I/R-induced liver injury. PMID:12928598

Ito, Y; Katagiri, H; Ishii, K; Kakita, A; Hayashi, I; Majima, M

258

Identification of peroxisomal targeting signals located at the carboxy terminus of four peroxisomal proteins  

Microsoft Academic Search

As part of an effort to understand how pro- teins are imported into the peroxisome, we have sought to identify the peroxisomal targeting signals in four unrelated peroxisomal proteins: human catalase, rat hydratase:dehydrogenase, pig o-amino acid oxi- dase, and rat acyl-CoA oxidase. Using gene fusion ex- periments, we have identified a region of each protein that can direct heterologous proteins

Stephen John Gould; Gilbert-Andre Keller; Suresh Subramani

1988-01-01

259

The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances taxol-induced cell death in breast cancer  

Microsoft Academic Search

Purpose  The histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) enhances taxol-induced antitumor effects\\u000a against some human cancer cells. The aim of this study is to investigate whether SAHA can enhance taxol-induced cell death\\u000a against human breast cancer cells and to illustrate the mechanism in detail.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  A panel of eight human breast cancer cell lines and an immortalized human breast epithelial

Yi-kang Shi; Zhong-hua Li; Xi-qian Han; Ji-hu Yi; Zhen-hua Wang; Jing-li Hou; Cong-ran Feng; Qing-hong Fang; Hui-hui Wang; Peng-fei Zhang; Feng-shan Wang; Jie Shen; Peng Wang

2010-01-01

260

TNF ? is involved in neuropathic pain induced by nucleoside reverse transcriptase inhibitor in rats  

PubMed Central

In patients with HIV/AIDS, neuropathic pain is a common neurological complication. Infection with the HIV itself may lead to neuropathic pain, and painful symptoms are enhanced when patients are treated with nucleoside reverse transcriptase inhibitors (NRTI). The mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In the current studies, we tested the role of TNF? in antiretroviral drug-induced neuropathic pain. We administered 2?,3?-dideoxycytidine (ddC, one of the NRTIs) systemically to induce mechanical allodynia. We found that ddC induced overexpression of both mRNA and proteins of GFAP and TNF? in the spinal dorsal horn. TNF? was colocalized with GFAP in the spinal dorsal horn and with NeuN in the DRG. Knockdown of TNF? with siRNA blocked the mechanical allodynia induced by ddC. Intrathecal administration of glial inhibitor or recombinant TNF soluble receptor, reversed mechanical allodynia induced by ddC. These results suggest that TNF? is involved in NRTI-induced neuropathic pain.

Zheng, Xuexing; Ouyang, Handong; Liu, Shue; Mata, Marina; Fink, David J.; Hao, Shuanglin

2011-01-01

261

PS-341 and Histone Deacetylase Inhibitor Synergistically Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells  

PubMed Central

Proteasome inhibitor PS-341 (also known as Bortezomib) and histone deacetylase (HDAC) inhibitors have emerged as novel therapeutic agents for a variety of malignancies. In this study, we examined whether PS-341 and the HDAC inhibitor trichostatin A (TSA) induced apoptosis in head and neck squamous cell carcinoma (HNSCC), a common and lethal malignancy. We found that, while TSA treatment alone did not induce apoptosis in HNSCC cells, it significantly enhanced PS-341-induced apoptosis in HNSCC cells in vitro. Consistently, TSA significantly improved PS-341-mediated inhibition of HNSCC tumor growth in nude mice. Mechanistically, we found that TSA increased PS-341-induced Noxa expression and caspase activation in HNSCC cells. The knock-down of Noxa significantly reduced apoptosis induced by co-treatment of PS-341 and TSA. Taken together, our results provide new insight into the mechanisms of synergistic antitumor activity of PS-341 and HDAC inhibitor regimen, offering a new therapeutic strategy for HNSCC patients.

Kim, JinKoo; Guan, Jean; Chang, Insoon; Chen, Xiaohong; Han, Demin; Wang, Cun-Yu

2010-01-01

262

A Sycamore Cell Wall Polysaccharide and a Chemically Related Tomato Leaf Polysaccharide Possess Similar Proteinase Inhibitor-Inducing Activities 1  

PubMed Central

A large pectic polysaccharide, called rhamnogalacturonan I, that is solubilized by a fungal endo-?-1,4-polygalacturonase from the purified walls of suspension-cultured sycamore cells possesses proteinase inhibitor-inducing activity similar to that of the proteinase inhibitor-inducing factor, a pectic-like oligosaccharide fraction isolated from tomato leaves. This suggests that the proteinase inhibitor-inducing activity resides in particular polysaccharide fragments which can be released when plant cell walls are exposed to appropriate enzyme degradation as a result of either wounding or pest attack.

Ryan, Clarence A.; Bishop, Paul; Pearce, Gregory; Darvill, Alan G.; McNeil, Michael; Albersheim, Peter

1981-01-01

263

Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis.  

PubMed

Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through increased expression of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins, enzymes that remodel collagen at the metastatic site and recruit bone marrow-derived cells (BMDCs) to the metastatic niche. We investigated the effect of two chemically and mechanistically distinct HIF inhibitors, digoxin and acriflavine, on breast cancer metastatic niche formation. Both drugs blocked the hypoxia-induced expression of LOX and LOXL proteins, collagen cross-linking, CD11b? BMDC recruitment, and lung metastasis in an orthotopic breast cancer model. Patients with HIF-1 ?-overexpressing breast cancers are at increased risk of metastasis and mortality and our results suggest that such patients may benefit from aggressive therapy that includes a HIF inhibitor. PMID:22231744

Wong, Carmen Chak-Lui; Zhang, Huafeng; Gilkes, Daniele M; Chen, Jasper; Wei, Hong; Chaturvedi, Pallavi; Hubbi, Maimon E; Semenza, Gregg L

2012-01-10

264

The COX inhibitors indomethacin and meloxicam exhibit anti-emetic activity against cisplatin-induced emesis in piglets  

Microsoft Academic Search

We analysed the effects of four cyclooxygenases (COX) inhibitors on cisplatin-induced emesis in piglets. Ninety-five animals receiving cisplatin (5.5mgkg?1, i.v.) were observed for 60h. One hour prior to cisplatin, controls (n=29) were dosed with a saline solution while experimental animals received an i.v. or i.p. injection of one of the COX inhibitors. Additional injections of COX inhibitor were given at

V Girod; J Dapzol; M Bouvier; L Grélot

2002-01-01

265

Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis  

Microsoft Academic Search

Cardiac apoptosis has been considered an important contributing factor to heart failure. Several subcellular mechanisms, including\\u000a increased protein phosphatase 1 activity, have been suggested to induce apoptosis. Protein phosphatase 1 is regulated by an\\u000a endogenous inhibitor-1 (I-1) that is activated upon phosphorylation at threonine 35 via protein kinase A. Here, we tested\\u000a whether cardiac-specific overexpression of a constitutively active (T35D,

Guoli Chen; Xiaoyang Zhou; Stela Florea; Jiang Qian; Wenfeng Cai; Zhiguo Zhang; Guo-Chang Fan; John Lorenz; Roger J. Hajjar; Evangelia G. Kranias

2010-01-01

266

HMG-CoA reductase inhibitors induce apoptosis in mouse proximal tubular cells in primary culture  

Microsoft Academic Search

HMG-CoA reductase inhibitors induce apoptosis in mouse proximal tubular cells in primary culture. Renal cyst formation in polycystic diseases or after nephron reduction is attributed to enhanced tubular cell proliferation with unbalanced cell death. The induction of tubular cell death could be effective to reduce renal cyst formation. In this study, we examined the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)

Osamu Iimura; François Vrtovsnik; Fabiola Terzi; Gérard Friedlander

1997-01-01

267

Phospholipase C inhibitors attenuate arrhythmias induced by kappa-receptor stimulation in the isolated rat heart.  

PubMed

To determine whether the phospholipase C (PLC)/inositol 1,4,5 trisphosphate (IP3)/Ca2+ pathway mediates cardiac arrhythmias induced by kappa-opioid receptor stimulation, the effects of U50,488H, a selective kappa-opioid receptor agonist, on cardiac rhythm in a isolated perfused rat heart, intracellular calcium ([Ca2+]i) in a single ventricular myocyte and IP3 production in myocytes were studied in the presence and absence of PLC inhibitors. U50,488H, the effects of which had been shown to be abolished by a selective kappa-receptor antagonist, nor-binaltorphimine, induced arrhythmias dose-dependently and increased both [Ca2+]i and IP3-production in the heart. More importantly, the effects of U50,488H were blocked by PLC inhibitors, neomycin and streptomycin. To further confirm the selectivity of action of the PLC inhibitor, the effects of another PLC inhibitor U73122 and its inactive structural analog, U73343, on cardiac rhythm in the isolated perfused rat heart were compared. The former did, while the latter did not, block the arrhythmogenic effect of U50,488H. We also determined whether the effects of kappa-receptor stimulation involves a pertussis toxin (PTX)-sensitive G-protein. We found that pretreatment with PTX at 4 microg/l for 10 min, a treatment shown to affect PTX sensitive G-protein-mediated functions, attenuated significantly the U50,488H-induced arrhythmias. The present study provides evidence that kappa-receptor stimulation-induced cardiac arrhythmias involves, at least partly, the PLC/IP3/Ca2+ pathway as well as a PTX sensitive G-protein. PMID:9799662

Bian, J S; Zhang, W M; Xia, Q; Wong, T M

1998-10-01

268

In Vivo Excitotoxicity Induced by Ouabain, a Na+\\/K+ATPase Inhibitor  

Microsoft Academic Search

The susceptibility of immature rat brain to neurotoxicity of N-methyl-d-aspartate (NMDA) has provided a widely used in vivo paradigm to study excitotoxicity relevant to acute neurodegenerative diseases such as cerebral ischemia. In this study, in vivo excitotoxicity was induced via injection of ouabain (1 mM\\/0.5 ?L), a Na+\\/K+-ATPase-inhibitor, into neonatal rat brain and compared with NMDA injection. The aim of

Wouter B Veldhuis; Mario van der Stelt; Florence Delmas; Brigitte Gillet; Gerrit A Veldink; Johannes F G Vliegenthart; Klaas Nicolay; Peter R Bär

2003-01-01

269

The Effects of a Selective cAMP Phosphodiesterase Inhibitor, Rolipram, on Methamphetamine-Induced Behavior  

Microsoft Academic Search

The effects of rolipram, a selective cAMP phosphodiesterase inhibitor, on locomotor activity, rearing, and stereotyped behavior (sniffing, repetitive head movements) induced by methamphetamine (MAP) over 1 hour were investigated in rats. Coadministration of rolipram (4 mg\\/kg IP) significantly attenuated the responses of locomotor activity, rearing and repetitive head movements to MAP (2, 4 or 8 mg\\/kg IP). Rolipram (0.5, 1,

Masaomi Iyo; Yohko Maeda; Toshiya Inada; Yoshie Kitao; Hajime Sasaki; Susumu Fukui

1995-01-01

270

Apoptosis-inducing antitumor efficacy of hexokinase II inhibitor in hepatocellular carcinoma.  

PubMed

Hypoxia stimulates hepatocellular carcinoma (HCC) cell growth via hexokinase (HK) II induction, and alternatively, HK II inhibition induces apoptosis by activating mitochondrial signaling. This study was to investigate whether the induction of HK II by hypoxia is associated with enhanced mitochondrial stability and to confirm the apoptosis-inducing efficacy of HK II inhibitor in an in vivo model of HCC. Mitochondrial stability was examined by treating isolated mitochondria with deoxycholate, a permeability-enhancing agent. Alteration of permeability transition pore complex composition was analyzed by immunoprecipitation and immunoblotting. An in vivo model of HCC was established in C3H mice i.d. implanted with MH134 cells. The antitumor efficacy of i.p. given 3-bromopyruvate (3-BrPA), a HK II inhibitor, was evaluated by measuring tumor volumes and quantifying apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining and (99m)Tc-hydrazinonicotinamide-Annexin V scans. Hypoxia enhanced mitochondrial stability, and this was inhibited by 3-BrPA treatment. In particular, HK II levels in permeability transition pore complex immunoprecipitates were reduced after 3-BrPA treatment. In mice treated with 3-BrPA, mean tumor volumes and tumor volume growth were found to be significantly reduced. Moreover, percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly increased in 3-BrPA-treated mice, and this apoptosis-inducing efficacy was reflected in vivo by (99m)Tc-hydrazinonicotinamide-Annexin V imaging. Our results show that hypoxia enhances mitochondrial stability via HK II induction and that HK II inhibitor treatment exhibits an in vivo antitumor effect by inducing apoptosis. Therefore, HK II inhibitors may be therapeutically useful for the treatment of advanced infiltrative hypovascular HCCs, which are growing in a hypoxic environment. PMID:17876052

Kim, Won; Yoon, Jung-Hwan; Jeong, Jae-Min; Cheon, Gi-Jeong; Lee, Tae-Sup; Yang, Jong-In; Park, Su-Cheol; Lee, Hyo-Suk

2007-09-01

271

The Rho-kinase inhibitor, fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats  

Microsoft Academic Search

This study aimed to investigate the effect of the Rho-kinase inhibitor fasudil on the development of diabetic nephropathy and clarify a contribution of the Rho\\/Rho-kinase pathway to the pathogenesis of diabetic nephropathy. Diabetes was induced in male Sprague–Dawley rats with an intraperitoneal injection of streptozotocin. Animals were then divided into the following 4 groups; normal control rats, diabetic rats, diabetic

Atsushi Gojo; Kazunori Utsunomiya; Kanta Taniguchi; Tamotsu Yokota; Shoh Ishizawa; Yasushi Kanazawa; Hideaki Kurata; Naoko Tajima

2007-01-01

272

Posttranslational Regulatory Control of Trehalase Induced by Nutrients, Metabolic Inhibitors, and Physical Agents in Pachysolen tannophilus  

Microsoft Academic Search

Soto, T., Fernandez, J., Vicente-Soler, J., Cansado, J., and Gacto, M. 1996. Posttranslational regulatory control of trehalase induced by nutrients, metabolic inhibitors, and physical agents inPachysolen tannophilus. Fungal Genetics and Biology20,143–151. Trehalase activity in the yeastPachysolen tannophilusis due to a single enzyme with highest activity during exponential growth on glucose. Derepressed cells enhanced markedly the level of trehalase activity upon

Teresa Soto; Juana Fernandez; Jero Vicente-Soler; Jose Cansado; Mariano Gacto

1996-01-01

273

Tyrosine protein kinase inhibitors prevent activation of cardiac swelling-induced chloride current  

Microsoft Academic Search

The effect of tyrosine protein kinase inhibitors on the swelling-induced chloride current (ICl-swelling of dog atrial myocytes was studied using the whole-cell patch-clamp recording technique. Currents were measured during hyperpolarizing voltage ramps with potassium currents blocked by cesium. Osmolarity was varied using mannitol. Exposure to hypotonic solution (˜249 mosmol\\/kg) activated ICl-swelling. Hypertonic solution (˜ 363mosmol\\/kg) was used to shrink swollen

Steve Sorota

1995-01-01

274

Beneficial effects of the synthetic trypsin inhibitor camostate in cerulein-induced acute pancreatitis in rats  

Microsoft Academic Search

The therapeutic effect and the mechanism of action of the synthetic trypsin inhibitor camostate were studied in a rat model of acute interstitial pancreatitis induced by four subcutaneous injections of 20 µg\\/kg body weight of cerulein at hourly intervals. Rats with acute pancreatitis were given either 100 mg\\/kg body weight camostate or volume- and pH-adjusted water via an orogastric tube

Makoto Otsuki; Satoshi Tani; Yoshinori Okabayashi; Masatoshi Fuji; Takahiko Nakamura; Takashi Fujisawa; Hiroshi Itoh

1990-01-01

275

Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor1 DNA-Binding Activity  

Microsoft Academic Search

The identification of small molecules that inhibit the sequence- specific binding of transcription factors to DNA is an attractive approach for regulation of gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that controls genes involved in glycolysis, angiogenesis, migration, and invasion, all ofwhichareimportantfortumorprogressionandmetastasis.To identify inhibitors of HIF-1 DNA-binding activity, we expressed truncated HIF-1A and HIF-1B proteins containing the basic-

Dehe Kong; Eun Jung Park; Andrew G. Stephen; Maura Calvani; John H. Cardellina; Robert J. Fisher; Robert H. Shoemaker; Giovanni Melillo

2005-01-01

276

T-1095, a renal Na +-glucose transporter inhibitor, improves hyperglycemia in streptozotocin-induced diabetic rats  

Microsoft Academic Search

The effect of T-1095, an inhibitor of renal glucose reabsorption, on hyperglycemia and the expression of Na+-glucose cotransporters (SGLTs) and facilitative glucose transporter 2 (GLUT2) in streptozotocin (STZ)-induced diabetic rats was examined. There was an elevation of blood glucose, hemoglobin A1c (HbA1c), kidney weight, and urinary excretion of both glucose and albumin in STZ rats. Administration of 0.03% and 0.1%

Tetsuya Adachi; Koichiro Yasuda; Yoshimasa Okamoto; Nobuyuki Shihara; Akira Oku; Kiichiro Ueta; Kazuyuki Kitamura; Akira Saito; Toshio Iwakura; Yuichiro Yamada; Hideki Yano; Yutaka Seino; Kinsuke Tsuda

2000-01-01

277

Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors  

Microsoft Academic Search

Objective To determine the effect of matrix metalloproteinase (MMP) inhibitors in mono-iodoacetate-induced arthritis in rats.Design The ability of compounds to inhibit MMPs in vitro was assessed kinetically using a quenched fluorescent substrate. Rats were injected with iodoacetate intraarticularly in one knee joint and damage to the tibial plateau was evaluated from digitized images captured using an image analyser and by

M. J. Janusz; E. B. Hookfin; S. A. Heitmeyer; J. F. Woessner; A. J. Freemont; J. A. Hoyland; K. K. Brown; L. C. Hsieh; N. G. Almstead; B. De; M. G. Natchus; S. Pikul; Y. O. Taiwo

2001-01-01

278

Vascular Endothelial Growth Factor Inhibitor-Induced Hypertension: Basics for Primary Care Providers  

PubMed Central

Frequently, primary care providers continue to manage the overall medical care of cancer patients. With newer and often more potent antitumor agents, patients may present to their local physicians with drug-induced toxicities such as hypertension induced by vascular endothelial growth factor (VEGF) inhibitors. It is imperative that these healthcare providers are aware of basic aspects of this drug class, as its use has increased significantly in the last several years. Uncontrolled or malignant hypertension due to these agents should be recognized readily and treated early to prevent more severe outcomes. This overview provides a brief background on the role of VEGF and angiogenesis in tumor metabolism as well as theories of the mechanism of VEGF inhibitors and hypertension. Helpful clinical practice aspects including the types of inhibitors used in the United States and their pharmacologic characteristics will be discussed. Also, diagnosis and treatment of hypertension induced by vascular endothelial growth factors are reviewed. A summary of key aspects of this drug class and hypertension is included.

Escalante, Carmen P.; Zalpour, Ali

2011-01-01

279

Effects of inhibitors on 1-methyladenine induced maturation of starfish oocytes  

NASA Astrophysics Data System (ADS)

1-methladenine (1-MA) induces starfish oocytes maturation via surface reaction followed by the appearance of a cytoplasmic maturation factor which in turn induces germinal vesicle breakdown (GVBD) to resume meiosis. Cellular mechanisms involved in GVBD were investigated by microinjection of metabolic inhibitors. Colchicine (Co) inhibited maturation, cytochalasin-B (CB) delayed GVBD and actinomycin-D-(Act-D) and puromycin (Pu) had no effect. It appears that the microtubule and the microfilament systems are associated with the nuclear membrane dissolution during the process of oocyte maturation of starfish.

Lee, Harold H.; Xu, Quanhan

1986-12-01

280

The Proteasome Inhibitor PS341 Inhibits Growth, Induces Apoptosis, and Overcomes Drug Resistance in Human Multiple Myeloma Cells1  

Microsoft Academic Search

Human multiple myeloma (MM) is a presently incurable hematological malignancy, and novel biologically based therapies are urgently needed. Proteasome inhibitors represent a novel potential anticancer therapy. In this study, we demonstrate that the proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis of human MM cell lines and freshly isolated patient MM cells; inhibits mitogen-activated protein ki- nase growth signaling

Teru Hideshima; Paul Richardson; Dharminder Chauhan; Vito J. Palombella; Peter J. Elliott; Julian Adams; Kenneth C. Anderson

2001-01-01

281

Translation Inhibitors Induce Formation of Cholesterol Ester-Rich Lipid Droplets  

PubMed Central

Lipid droplets (LDs) in non-adipocytes contain triglycerides (TG) and cholesterol esters (CE) in variable ratios. TG-rich LDs are generated when unsaturated fatty acids are administered, but the conditions that induce CE-rich LD formation are less well characterized. In the present study, we found that protein translation inhibitors such as cycloheximide (CHX) induced generation of CE-rich LDs and that TIP47 (perilipin 3) was recruited to the LDs, although the expression of this protein was reduced drastically. Electron microscopy revealed that LDs formed in CHX-treated cells possess a distinct electron-dense rim that is not found in TG-rich LDs, whose formation is induced by oleic acid. CHX treatment caused upregulation of mTORC1, but the CHX-induced increase in CE-rich LDs occurred even when rapamycin or Torin1 was given along with CHX. Moreover, the increase in CE was seen in both wild-type and autophagy-deficient Atg5-null mouse embryonic fibroblasts, indicating that mTORC1 activation and suppression of autophagy are not necessary to induce the observed phenomenon. The results showed that translation inhibitors cause a significant change in the lipid ester composition of LDs by a mechanism independent of mTORC1 signaling and autophagy.

Tatematsu, Tsuyako; Shinohara, Yuki; Maeda, Takashi; Cheng, Jinglei; Fujimoto, Toyoshi

2012-01-01

282

A Novel Sphingosine Kinase Inhibitor Induces Autophagy in Tumor CellsS?  

PubMed Central

The sphingolipids ceramide, sphingosine, and sphingosine 1-phosphate (S1P) regulate cell signaling, proliferation, apoptosis, and autophagy. Sphingosine kinase-1 and -2 (SK1 and SK2) phosphorylate sphingosine to form S1P, shifting the balanced activity of these lipids toward cell proliferation. We have previously reported that pharmacological inhibition of SK activity delays tumor growth in vivo. The present studies demonstrate that the SK2-selective inhibitor 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide (ABC294640) induces nonapoptotic cell death that is preceded by microtubule-associated protein light chain 3 cleavage, morphological changes in lysosomes, formation of autophagosomes, and increases in acidic vesicles in A-498 kidney carcinoma cells. ABC294640 caused similar autophagic responses in PC-3 prostate and MDA-MB-231 breast adenocarcinoma cells. Simultaneous exposure of A-498 cells to ABC294640 and 3-methyladenine, an inhibitor of autophagy, switched the mechanism of toxicity to apoptosis, but decreased the potency of the SK2 inhibitor, indicating that autophagy is a major mechanism for tumor cell killing by this compound. Induction of the unfolded protein response by the proteasome inhibitor N-(benzyloxycarbonyl)leucinylleucinylleucinal Z-Leu-Leu-Leu-al (MG-132) or the heat shock protein 90 inhibitor geldanamycin synergistically increased the cytotoxicity of ABC294640 in vitro. In severe combined immunodeficient mice bearing A-498 xenografts, daily administration of ABC294640 delayed tumor growth and elevated autophagy markers, but did not increase terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells in the tumors. These data suggest that ABC294640 promotes tumor cell autophagy, which ultimately results in nonapoptotic cell death and a delay of tumor growth in vivo. Consequently, ABC294640 may effectively complement anticancer drugs that induce tumor cell apoptosis.

Beljanski, Vladimir; Knaak, Christian

2010-01-01

283

Peroxisomes in dental tissues of the mouse.  

PubMed

Patients with mild forms of peroxisomal biogenesis disorders show facial dysmorphism and exhibit dentition problems accompanied by enamel hypoplasia. However, no information is available on the role of peroxisomes in dental and paradontal tissues. Therefore, we studied the distribution of these organelles, their protein composition and the expression of corresponding genes during dental development and in mature decalcified teeth in mice. Perfusion-fixed heads of mice of different developmental stages (E13.5 to adult) were cut in sagittal direction into two halves and embedded in paraffin for serial sectioning and subsequent peroxidase-based immunohistochemistry or double-immunofluorescence preparations. Frozen, unfixed heads of newborn mice were used for cryosectioning and subsequent laser-assisted microdissection of ameloblasts and odontoblasts, RNA isolation and RT-PCR analysis. Our results revealed the presence of peroxisomes already in the bud stage of dental development. An increase in peroxisome abundance was noted during differentiation of ameloblasts and odontoblasts with the highest number of organelles in Tomes' processes of mature ameloblasts. A strong heterogeneity of peroxisomal enzyme content developed within differentiated dental cell types. A drastic down-regulation of catalase in maturing ameloblasts was noted in contrast to high levels of lipid metabolizing enzymes in peroxisomes of these cells. As known from the literature, differentiated ameloblasts are more prone to oxidative damage which could be explained by the low catalase levels inside of this cell type. PMID:23982811

Stelzig, Ingra; Karnati, Srikanth; Valerius, Klaus Peter; Baumgart-Vogt, Eveline

2013-08-28

284

Isolation and characterization of rat and human cDNAs encoding a novel putative peroxisomal enoyl-CoA hydratase  

SciTech Connect

We have used a PCR-based subtractive hybridization method to identify upregulated cDNAs in the livers of rats treated with a peroxisome proliferator [clofibrate or di(2-ethylhexyl) phthalate]. After four rounds of subtractive hybridization 62 differentially hybridizing clones were partially sequenced and analyzed by sequence homology searching. Of 62, 49 were identical to 14 different upregulated rat sequences in the databank (mostly genes encoding microsomal or peroxisomal enzymes), 4 of 62 were fragments of three previously unknown genes, and 9 of 62 were false positives. Two of the unknown fragments hybridized to a single novel cDNA that was found to be more than 20-fold induced by both peroxisome proliferators. The 36-kDa predicted protein product of this cDNA shows a high degree of sequence homology to enoyl-CoA hydratases of several different species and has a C-terminal peroxisomal targeting sequence. An epitope-tagged protein product of a full-length cDNA was targeted to peroxisomes in a human cell line. We named this gene, which encodes an apparent peroxisomal enoyl-CoA hydratase, ECH1. We have also identified human ECH1 cDNA and mapped its structural gene to 19q13, 3{prime} to the ryanodine receptor, by hybridization to somatic cell hybrid DNA and chromosome 19-specific cosmid arrays. Possible roles for the ECH1 protein product in peroxisomal {beta}-oxidation are discussed. 64 refs., 6 figs., 2 tabs.

Fitzpatrick, D.R.; Germain-Lee, E.; Valle, D.

1995-06-10

285

Evaluation of Protease Inhibitors and an Antioxidant for Treatment of Sulfur Mustard-Induced Toxic Lung Injury.  

National Technical Information Service (NTIS)

Sulfur mustard (SM)-induced lung injury has been associated with protease activation, oxidative injury and inflammatory response culminating in tissue necrosis. The protease inhibitors aprotinin and ilomastat and the antioxidant trolox were evaluated for ...

D. P. Fetterer D. R. Anderson S. L. Taylor W. W. Holmes

2009-01-01

286

An inventory of peroxisomal proteins and pathways in Drosophila melanogaster  

PubMed Central

Peroxisomes are ubiquitous organelles housing a variety of essential biochemical pathways. Peroxisome dysfunction causes a spectrum of human diseases known as peroxisome biogenesis disorders (PBD). While much is known regarding the mechanism of peroxisome biogenesis, it is still unclear how peroxisome dysfunction leads to the disease state. Several recent studies have shown that mutations in Drosophila peroxin genes cause phenotypes similar to those seen in humans with PBDs suggesting that Drosophila might be a useful system to model PBDs. We have analyzed the proteome of Drosophila to identify the proteins involved in peroxisomal biogenesis and homeostasis as well as metabolic enzymes that function within the organelle. The subcellular localization of five of these predicted peroxisomal proteins was confirmed. Similar to C. elegans, Drosophila appears to only utilize the peroxisome targeting signal (PTS) type 1 system for matrix protein import. This work will further our understanding of peroxisomes in Drosophila and add to the usefulness of this emerging model system.

Faust, Joseph E.; Verma, Avani; Peng, Chengwei; McNew, James A.

2012-01-01

287

Novel atypical PKC inhibitors prevent vascular endothelial growth factor-induced blood-retinal barrier dysfunction.  

PubMed

Pro-inflammatory cytokines and growth factors such as VEGF (vascular endothelial growth factor) contribute to the loss of the BRB (blood-retinal barrier) and subsequent macular oedema in various retinal pathologies. VEGF signalling requires PKC? [conventional PKC (protein kinase C)] activity; however, PKC? inhibition only partially prevents VEGF-induced endothelial permeability and does not affect pro-inflammatory cytokine-induced permeability, suggesting the involvement of alternative signalling pathways. In the present study, we provide evidence for the involvement of aPKC (atypical PKC) signalling in VEGF-induced endothelial permeability and identify a novel class of inhibitors of aPKC that prevent BRB breakdown in vivo. Genetic and pharmacological manipulations of aPKC isoforms were used to assess their contribution to endothelial permeability in culture. A chemical library was screened using an in vitro kinase assay to identify novel small-molecule inhibitors, and further medicinal chemistry was performed to delineate a novel pharmacophore. We demonstrate that aPKC isoforms are both sufficient and required for VEGF-induced endothelial permeability. Furthermore, these specific, potent, non-competitive, small-molecule inhibitors prevented VEGF-induced tight junction internalization and retinal endothelial permeability in response to VEGF in both primary culture and in rodent retina. The results of the present study suggest that aPKC inhibition with 2-amino-4-phenyl-thiophene derivatives may be developed to preserve the BRB in retinal diseases such as diabetic retinopathy or uveitis, and the BBB (blood-brain barrier) in the presence of brain tumours. PMID:22721706

Titchenell, Paul M; Lin, Cheng-Mao; Keil, Jason M; Sundstrom, Jeffrey M; Smith, Charles D; Antonetti, David A

2012-09-15

288

Intracoronary administration of a thromboxane A2 synthase inhibitor relieves acetylcholine-induced coronary spasm.  

PubMed

This study sought to clarify the effectiveness of intracoronary administration of a thromboxane (TX) A2 synthase inhibitor, Ozagrel Na, to relieve coronary spasms induced by intracoronary injection of acetylcholine (ACh). An ACh spasm provocation test was performed in 92 consecutive patients with coronary spastic angina using incremental doses of 20, 50, and 80 microg into the right coronary artery, and 20, 50, and 100 microg into the left coronary artery within 20s. A coronary spasm was defined as TIMI 0 or 1 flow and an intracoronary injection of 20 mg Ozagrel Na was administered when it was provoked. Within 2 min of the administration of the TXA2 synthase inhibitor, ACh-induced coronary spasms were relieved (TIMI 3 flow) in 88.1% of procedures without complications. In only 4 cases (4.3%), it took more than 3 min to relieve the coronary spasms. Intracoronary administration of 20mg Ozagrel Na when ACh-induced spasms occurred, shortened the spasm relief time in all 7 patients (200 +/- 59s vs 111 +/- 23s, p < 0.01), improved the maximal ST segment elevation in 5 of them (3.9 +/- 3.7 mm vs 0.7 +/- 1.5 mm, p < 0.05), and stopped chest pain in 4 patients. In 4 patients who had ACh-induced coronary spasm of the left anterior descending artery, the TXB2 concentration in the coronary sinus decreased after intracoronary administration of Ozagrel Na into the left coronary artery (463 +/- 562 vs 96 +/- 45, p < 0.01). In conclusion, intracoronary administration of a TXA2 synthase inhibitor can relieve ACh-induced coronary spasms by inhibiting TXA2 synthesis in the local coronary circulation. PMID:12224820

Sueda, Shozo; Kohno, Hiroaki; Inoue, Katsuji; Fukuda, Hiroshi; Suzuki, Jun; Watanabe, Kouki; Ochi, Naoto; Kawada, Hiroyuki; Uraoka, Tadao

2002-09-01

289

Kidney-specific Overexpression of Sirt1 Protects against Acute Kidney Injury by Retaining Peroxisome Function  

PubMed Central

Sirt1, a NAD-dependent protein deacetylase, is reported to regulate intracellular metabolism and attenuate reactive oxidative species (ROS)-induced apoptosis leading to longevity and acute stress resistance. We created transgenic (TG) mice with kidney-specific overexpression of Sirt1 using the promoter sodium-phosphate cotransporter IIa (Npt2) driven specifically in proximal tubules and investigated the kidney-specific role of Sirt1 in the protection against acute kidney injury (AKI). We also elucidated the role of number or function of peroxisome and mitochondria in mediating the mechanisms for renal protective effects of Sirt1 in AKI. Cisplatin-induced AKI decreased the number and function of peroxisomes as well as mitochondria and led to increased local levels of ROS production and renal tubular apoptotic cells. TG mice treated with cisplatin mitigated AKI, local ROS, and renal tubular apoptotic tubular cells. Consistent with these results, TG mice treated with cisplatin also exhibited recovery of peroxisome number and function, as well as rescued mitochondrial function; however, mitochondrial number was not recovered. Immunoelectron microscopic findings consistently demonstrated that the decrease in peroxisome number by cisplatin in wild type mice was restored in transgenic mice. In HK-2 cells, a cultured proximal tubule cell line, overexpression of Sirt1 rescued the cisplatin-induced cell apoptosis through the restoration of peroxisome number, although the mitochondria number was not restored. These results indicate that Sirt1 overexpression in proximal tubules rescues cisplatin-induced AKI by maintaining peroxisomes number and function, concomitant up-regulation of catalase, and elimination of renal ROS levels. Renal Sirt1 can be a potential therapeutic target for the treatment of AKI.

Hasegawa, Kazuhiro; Wakino, Shu; Yoshioka, Kyoko; Tatematsu, Satoru; Hara, Yoshikazu; Minakuchi, Hitoshi; Sueyasu, Keiko; Washida, Naoki; Tokuyama, Hirobumi; Tzukerman, Maty; Skorecki, Karl; Hayashi, Koichi; Itoh, Hiroshi

2010-01-01

290

Prevention of salt induced hypertension and fibrosis by angiotensin converting enzyme inhibitors in Dahl S rats  

PubMed Central

Background and purpose: In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade. Experimental approach: From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg-1 day-1) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg-1 day-1) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age. Key results: High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by ?80% in brain nuclei and heart and lisinopril by ?60% in the brain and by ?70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta. Conclusion and implication: As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.

Liang, B; Leenen, F H H

2007-01-01

291

Protection against Adverse Biological Effects Induced by Space Radiation by the Bowman-Birk Inhibitor and Antioxidants  

Microsoft Academic Search

Kennedy, A. R., Zhou, Z., Donahue, J. J. and Ware, J. H. Protection against Adverse Biological Effects Induced by Space Radiation by the Bowman-Birk Inhibitor and Antioxi- dants. Radiat. Res. 166, 327-332 (2006). This study was undertaken to evaluate the protective effects of the soybean-derived Bowman-Birk inhibitor (BBI), BBI concentrate (BBIC) and\\/or antioxidants against the adverse biological effects induced by

Ann R. Kennedy; Zhaozong Zhou; Jeremiah J. Donahue; Jeffrey H. Ware

2006-01-01

292

PredPlantPTS1: A Web Server for the Prediction of Plant Peroxisomal Proteins  

PubMed Central

Prediction of subcellular protein localization is essential to correctly assign unknown proteins to cell organelle-specific protein networks and to ultimately determine protein function. For metazoa, several computational approaches have been developed in the past decade to predict peroxisomal proteins carrying the peroxisome targeting signal type 1 (PTS1). However, plant-specific PTS1 protein prediction methods have been lacking up to now, and pre-existing methods generally were incapable of correctly predicting low-abundance plant proteins possessing non-canonical PTS1 patterns. Recently, we presented a machine learning approach that is able to predict PTS1 proteins for higher plants (spermatophytes) with high accuracy and which can correctly identify unknown targeting patterns, i.e., novel PTS1 tripeptides and tripeptide residues. Here we describe the first plant-specific web server PredPlantPTS1 for the prediction of plant PTS1 proteins using the above-mentioned underlying models. The server allows the submission of protein sequences from diverse spermatophytes and also performs well for mosses and algae. The easy-to-use web interface provides detailed output in terms of (i) the peroxisomal targeting probability of the given sequence, (ii) information whether a particular non-canonical PTS1 tripeptide has already been experimentally verified, and (iii) the prediction scores for the single C-terminal 14 amino acid residues. The latter allows identification of predicted residues that inhibit peroxisome targeting and which can be optimized using site-directed mutagenesis to raise the peroxisome targeting efficiency. The prediction server will be instrumental in identifying low-abundance and stress-inducible peroxisomal proteins and defining the entire peroxisomal proteome of Arabidopsis and agronomically important crop plants. PredPlantPTS1 is freely accessible at ppp.gobics.de.

Reumann, Sigrun; Buchwald, Daniela; Lingner, Thomas

2012-01-01

293

Dynein light chain interaction with the peroxisomal import docking complex modulates peroxisome biogenesis in yeast.  

PubMed

Dynein is a large macromolecular motor complex that moves cargo along microtubules. A motor-independent role for the light chain of dynein, Dyn2p, in peroxisome biology in Saccharomyces cerevisiae was suggested from its interaction with Pex14p, a component of the peroxisomal matrix protein import docking complex. Here we show that cells of the yeast Yarrowia lipolytica deleted for the gene encoding the homologue of Dyn2p are impaired in peroxisome function and biogenesis. These cells exhibit compromised growth on medium containing oleic acid as the carbon source, the metabolism of which requires functional peroxisomes. Their peroxisomes have abnormal morphology, atypical matrix protein localization, and an absence of proteolytic processing of the matrix enzyme thiolase, which normally occurs upon its import into the peroxisome. We also show physical and genetic interactions between Dyn2p and members of the docking complex, particularly Pex17p. Together, our results demonstrate a role for Dyn2p in the assembly of functional peroxisomes and provide evidence that Dyn2p acts in cooperation with the peroxisomal matrix protein import docking complex to effect optimal matrix protein import. PMID:23943868

Chang, Jinlan; Tower, Robert J; Lancaster, David L; Rachubinski, Richard A

2013-08-13

294

Phosphodiesterase type IV inhibitors prevent ischemia-reperfusion-induced gastric injury in rats.  

PubMed

The effects of selective inhibitors of phosphodiesterase type IV (PDE4) on ischemia-reperfusion-induced gastric injuries were investigated in rats. Gastric ischemia was induced by applying a small clamp to the celiac artery, and reoxygenation was performed by removal of the clamp. Ischemia-reperfusion produced gastric hemorrhagic injuries and increased the content of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO) activity in gastric mucosa. Rolipram (0.03-0.3 mg/kg, s.c.) and Ro-20-1724 (0.3-3 mg/kg, s.c.) prevented the development of gastric injury in a dose-dependent manner, and it also inhibited the increase in mucosal TNF-alpha content and MPO activity induced by ischemia-reperfusion. The anti-ulcer drug irsogladine (1-10 mg/kg, p.o.), which is known to possess a PDE4 inhibitory action, also inhibited the gastric injury produced by ischemia-reperfusion, as well as the increase in TNF-alpha levels and MPO activity. It is concluded that the ability of PDE4 inhibitors to inhibit cytokine TNF-alpha synthesis and the infiltration of polymorphonuclear leukocytes underlies their gastroprotective effects in ischemia-reperfusion-induced gastric injury. Our experiments suggest that drugs that inhibit PDE4 isoenzyme, such as the anti-ulcer drug irsogladine, may be a useful adjunct therapy for the treatment of the gastric damage that follows ischemia-reperfusion. PMID:15272207

Kyoi, Takashi; Kitazawa, Satoru; Tajima, Koyuki; Zhang, Xin; Ukai, Yojiro

2004-07-01

295

Mitochondrial Permeability Transition Pore Inhibitors Prevent Ethanol-Induced Neuronal Death in Mice.  

PubMed

Ethanol induces brain injury by a mechanism that remains partly unknown. Mitochondria play a key role in cell death processes, notably through the opening of the permeability transition pore (PTP). Here, we tested the effect of ethanol and PTP inhibitors on mitochondrial physiology and cell viability both in vitro and in vivo. Direct addition of ethanol up to 100 mM on isolated mouse brain mitochondria slightly decreased oxygen consumption but did not affect PTP regulation. In comparison, when isolated from ethanol-treated (two doses of 2 g/kg, 2 h apart) 7-day-old mouse pups, brain mitochondria displayed a transient decrease in oxygen consumption but no change in PTP regulation or H(2)O(2) production. Conversely, exposure of primary cultured astrocytes and neurons to 20 mM ethanol for 3 days led to a transient PTP opening in astrocytes without affecting cell viability and to a permanent PTP opening in 10 to 20% neurons with the same percentage of cell death. Ethanol-treated mouse pups displayed a widespread caspase-3 activation in neurons but not in astrocytes and dramatic behavioral alterations. Interestingly, two different PTP inhibitors (namely, cyclosporin A and nortriptyline) prevented both ethanol-induced neuronal death in vivo and ethanol-induced behavioral modifications. We conclude that PTP opening is involved in ethanol-induced neurotoxicity in the mouse. PMID:23268549

Lamarche, Frederic; Carcenac, Carole; Gonthier, Brigitte; Cottet-Rousselle, Cecile; Chauvin, Christiane; Barret, Luc; Leverve, Xavier; Savasta, Marc; Fontaine, Eric

2013-01-01

296

Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70.  

PubMed

Missense mutant proteins, such as those produced in individuals with genetic diseases, are often misfolded and subject to processing by intracellular quality control systems. Previously, we have shown using a yeast system that enzymatic function could be restored to I278T cystathionine beta-synthase (CBS), a cause of homocystinuria, by treatments that affect the intracellular chaperone environment. Here, we extend these studies and show that it is possible to restore significant levels of enzyme activity to 17 of 18 (94%) disease causing missense mutations in human cystathionine beta-synthase (CBS) expressed in Saccharomyces cerevisiae by exposure to ethanol, proteasome inhibitors, or deletion of the Hsp26 small heat shock protein. All three of these treatments induce Hsp70, which is necessary but not sufficient for rescue. In addition to CBS, these same treatments can rescue disease-causing mutations in human p53 and the methylene tetrahydrofolate reductase gene. These findings do not appear restricted to S. cerevisiae, as proteasome inhibitors can restore significant CBS enzymatic activity to CBS alleles expressed in fibroblasts derived from homocystinuric patients and in a mouse model for homocystinuria that expresses human I278T CBS. These findings suggest that proteasome inhibitors and other Hsp70 inducing agents may be useful in the treatment of a variety of genetic diseases caused by missense mutations. PMID:20066033

Singh, Laishram R; Gupta, Sapna; Honig, Nicholaas H; Kraus, Jan P; Kruger, Warren D

2010-01-08

297

Activation of Mutant Enzyme Function In Vivo by Proteasome Inhibitors and Treatments that Induce Hsp70  

PubMed Central

Missense mutant proteins, such as those produced in individuals with genetic diseases, are often misfolded and subject to processing by intracellular quality control systems. Previously, we have shown using a yeast system that enzymatic function could be restored to I278T cystathionine ?-synthase (CBS), a cause of homocystinuria, by treatments that affect the intracellular chaperone environment. Here, we extend these studies and show that it is possible to restore significant levels of enzyme activity to 17 of 18 (94%) disease causing missense mutations in human cystathionine ?-synthase (CBS) expressed in Saccharomyces cerevisiae by exposure to ethanol, proteasome inhibitors, or deletion of the Hsp26 small heat shock protein. All three of these treatments induce Hsp70, which is necessary but not sufficient for rescue. In addition to CBS, these same treatments can rescue disease-causing mutations in human p53 and the methylene tetrahydrofolate reductase gene. These findings do not appear restricted to S. cerevisiae, as proteasome inhibitors can restore significant CBS enzymatic activity to CBS alleles expressed in fibroblasts derived from homocystinuric patients and in a mouse model for homocystinuria that expresses human I278T CBS. These findings suggest that proteasome inhibitors and other Hsp70 inducing agents may be useful in the treatment of a variety of genetic diseases caused by missense mutations.

Singh, Laishram R.; Gupta, Sapna; Honig, Nicholaas H.; Kraus, Jan P.; Kruger, Warren D.

2010-01-01

298

HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats.  

PubMed

Thrombin activates immunocompetent microglia and increases release of inflammatory cytokines under intracerebral hemorrhage (ICH) insults. Also, thrombin injection into the striatum evokes acute necrosis and delayed apoptosis of neurons. A nucleoprotein high-mobility group box 1 (HMGB1) that is released from necrotic cells has been suggested to behave like a cytokine and cause over-facilitation of immune functions. Here we examined the effect of glycyrrhizin, known as an inhibitor of HMGB1, on thrombin-induced injury in rat cortico-striatal slice cultures and in vivo rat ICH model. In slice cultures, thrombin-induced a drastic increase in propidium iodide fluorescence indicating necrotic cell death in the cortical region, and robust shrinkage of the striatal tissue. Glycyrrhizin (10-100 ?M) attenuated thrombin-induced cortical injury in a concentration-dependent manner. The protective effect of glycyrrhizin was not mediated by glucocorticoid receptors or modulation of nitric oxide production, but was reversed by exogenous HMGB1 application. The injury induced by a high concentration of HMGB1 was suppressed by glycyrrhizin. In vivo, unilateral injection of type IV collagenase into rat striatum induced ICH associated with brain edema formation, contralateral paralysis and neuron death. Once daily intraperitoneal administration of glycyrrhizin attenuated ICH-induced edema in both the cortex and the basal ganglia, and improved behavioral performance of rats in forelimb placing. Moreover, glycyrrhizin partially but significantly ameliorated ICH-induced neuron loss inside hematoma. These findings suggest that an HMGB1 inhibitor glycyrrhizin is a potential candidate for a remedy for ICH. PMID:21752338

Ohnishi, Masatoshi; Katsuki, Hiroshi; Fukutomi, Chiharu; Takahashi, Madoka; Motomura, Misato; Fukunaga, Mizuki; Matsuoka, Yasuhiro; Isohama, Yoichiro; Izumi, Yasuhiko; Kume, Toshiaki; Inoue, Atsuko; Akaike, Akinori

2011-07-06

299

Peroxisome Proliferator-Activated Receptor ?/? Cross Talks with E2F and Attenuates Mitosis in HRAS-Expressing Cells  

PubMed Central

The role of peroxisome proliferator-activated receptor ?/? (PPAR?/?) in Harvey sarcoma ras (Hras)-expressing cells was examined. Ligand activation of PPAR?/? caused a negative selection with respect to cells expressing higher levels of the Hras oncogene by inducing a mitotic block. Mitosis-related genes that are predominantly regulated by E2F were induced to a higher level in HRAS-expressing Ppar?/?-null keratinocytes compared to HRAS-expressing wild-type keratinocytes. Ligand-activated PPAR?/? repressed expression of these genes by direct binding with p130/p107, facilitating nuclear translocation and increasing promoter recruitment of p130/p107. These results demonstrate a novel mechanism of PPAR?/? cross talk with E2F signaling. Since cotreatment with a PPAR?/? ligand and various mitosis inhibitors increases the efficacy of increasing G2/M arrest, targeting PPAR?/? in conjunction with mitosis inhibitors could become a suitable option for development of new multitarget strategies for inhibiting RAS-dependent tumorigenesis.

Zhu, Bokai; Khozoie, Combiz; Bility, Moses T.; Ferry, Christina H.; Blazanin, Nicholas; Glick, Adam B.; Gonzalez, Frank J.

2012-01-01

300

Inhibition of Interleukin1 Induced Group IIA Secretory Phospholipase A2 Expression by Peroxisome Proliferator-Activated Receptors (PPARs) in Rat Vascular Smooth Muscle Cells: Cooperation between PPAR  and the ProtoOncogene BCL6  

Microsoft Academic Search

The inflammation that occurs during atherosclerosis is characterized by the release of large amounts of group IIA secretory phospholipase A2 (sPLA2-IIA). This study was designed to define the function of the three peroxisome proliferator-activated receptors (PPARs) on sPLA2 expression in vascular smooth muscle cells (VSMCs). We found that PPAR ligands decreased sPLA2-IIA activity and inhibited mRNA accumulation under inflammatory conditions.

Lucas Ravaux; Chantal Denoyelle; Claire Monne; Isabelle Limon; Michel Raymondjean; Khadija El Hadri

2007-01-01

301

Peroxisomes: the neuropathological consequences of peroxisomal dysfunction in the developing brain.  

PubMed

Peroxisomes are intracellular organelles that perform vital metabolic functions. They have been extensively studied in the hepatic and renal systems, yet their pivotal roles in facilitating central nervous system patterning and in disease pathogenesis are only recently being firmly established by the neuroscience community. Peroxisomal functions including the break-down of long chain fatty acids, the removal of H2O2, and the biosynthesis of ether lipids. The build up of long chain fatty acids and H2O2 is detrimental to cellular function, and ether lipids play roles in maintaining cell membrane structure. These findings have major implications for treatments for the full spectrum of peroxisomal disorders. Here, we provide a timely review highlighting the most important data in recent times linking peroxisomal functions to brain formation, and we describe how peroxisomal deficiency and pathway dysfunction results in neurological deficits, the more severe of which result in life changing disabilities and death. PMID:23830890

Barry, Denis S; O'Keeffe, Gerard W

2013-07-02

302

Including Receptor Flexibility and Induced Fit Effects into the Design of MMP-2 Inhibitors  

PubMed Central

Matrix metalloproteinases (MMPs) comprise a class of flexible proteins required for normal tissue remodeling. Overexpression of MMPs is associated with a wide range of pathophysiological processes, including vascular disease, multiple sclerosis, Alzheimer’s disease, and cancer. Nearly all MMP inhibitors have failed in clinical trials, in part due to lack of specificity. Due to the highly dynamic molecular motions of the MMP-2 binding pockets, the rational drug design of MMP inhibitors has been very challenging. To address these challenges, in the current study we combine computer docking with molecular dynamics (MD) simulations in order to incorporate receptor-flexibility and induced-fit effects into the drug-design process. Our strategy identifies molecular fragments predicted to target multiple MMP-2 binding pockets.

Durrant, Jacob D.; de Oliveira, Cesar Augusto F.; McCammon, J. Andrew

2010-01-01

303

Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells  

PubMed Central

Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.

Gottlicher, Martin; Minucci, Saverio; Zhu, Ping; Kramer, Oliver H.; Schimpf, Annemarie; Giavara, Sabrina; Sleeman, Jonathan P.; Lo Coco, Francesco; Nervi, Clara; Pelicci, Pier Giuseppe; Heinzel, Thorsten

2001-01-01

304

Angiogenesis inhibitor DC101 delays growth of intracerebral glioblastoma but induces morbidity when combined with irradiation.  

PubMed

The combination of irradiation with angiogenic inhibition is increasingly being investigated for treatment of glioblastoma multiforme (GBM). We investigated whether vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor DC101 affects morbidity and tumor growth in irradiated and non-irradiated intracerebral GBM-bearing mice, controlled with sham treatments. End-points were toxicity, morbidity and histology. Irradiation either or not combined, reduced tumor size strongly, whereas DC101 mono-treatment reduced tumor size by 64%. Irradiation delayed morbidity from 5.8 weeks in sham-treated mice to 10.3 weeks. Morbidity after combined treatment occurred after 5.9 weeks. Treatment with angiogenesis inhibitor DC101 delays tumor growth but it induces morbidity, by itself or combined with irradiation. PMID:19473756

Verhoeff, Joost J C; Stalpers, Lukas J A; Van Noorden, Cornelis J F; Troost, Dirk; Ramkema, Marja D; van Bree, Chris; Song, Ji-Ying; Donker, Mila; Chekenya, Martha; Vandertop, W Peter; Richel, Dick J; van Furth, Wouter R

2009-05-26

305

ACE inhibitors can induce circulating antibodies directed to antigens of the superficial epidermal cells.  

PubMed

Drug-induced pemphigus has been reported in patients receiving angiotensin-converting enzyme inhibitors. The aim of this work was to study a group of hypertensive patients without skin diseases treated with angiotensin-converting enzyme (ACE) Inhibitors (I), to verify the presence of serum circulating anti-antibodies. The indirect immunofluorescence showed that 33 sera (52.38%) presented autoantibodies directed to an antigen of the cytoplasm of the superficial epidermal keratinocytes. Two of the 33 positive sera had antibodies to Dsg1 and/or 3 in ELISA. Immunoblot analyses were negative. All the 48 control sera were found to have no circulating antibodies using the three assays. Our results would confirm that ACEI drugs may trigger the production of circulating autoantibodies also in patients without clinical manifestations of pemphigus. PMID:20563876

Cozzani, Emanuele; Rosa, Gian Marco; Drosera, Massimo; Intra, Chiara; Barsotti, Antonio; Parodi, Aurora

2010-06-20

306

Peroxisome proliferator-activated receptor gamma regulates expression of signal transducer and activator of transcription 5A  

SciTech Connect

Signal transducer and activator of transcription 5A (STAT5A) has been shown to be important for terminal differentiation of mammary epithelial cells. In order to understand regulation of expression of STAT5A, the 5' end of the mouse Stat5a gene was isolated. Putative regulatory elements was searched for and several peroxisome proliferator response elements (PPREs) were found, one with high (12/13 nucleotides) and three with less (8-10/13) similarity to the reported consensus sequence. Mouse mammary epithelial HC11 cells were treated with peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligand, the thiazolidinedione (TZD) troglitazone, and an increase in STAT5A protein expression was seen. The 5' flank of Stat5a gene was cloned in a luciferase reporter vector. A concentration dependent activation of the STAT5A-luciferase reporter was detected, when transiently transfected HC11 cells were treated with TZD. The activation could be inhibited by treatment with a PPAR{gamma} antagonist. It has earlier been shown that epidermal growth factor (EGF) induces MAPK phosphorylation of PPAR{gamma} resulting in a less transcriptionally active receptor. In HC11 cells, EGF inhibited TZD induced STAT5A-reporter activity suggesting that our previously reported EGF-mediated suppression of STAT5A expression is mediated in all or partly through inhibition of PPAR{gamma} activity. Furthermore, the MEK inhibitor PD98059 inhibited the EGF effect. All together, data presented suggest that PPAR{gamma} participates in regulation of STAT5A expression.

Olsen, Hanne [Department of Medical Nutrition, Karolinska Institutet, NOVUM, S-141 86 Huddinge (Sweden); Haldosen, Lars-Arne [Department of Medical Nutrition, Karolinska Institutet, NOVUM, S-141 86 Huddinge (Sweden)]. E-mail: Lars-Arne.Haldosen@mednut.ki.se

2006-05-01

307

Angiotensin II induces secretion of plasminogen activator inhibitor 1 and a tissue metalloprotease inhibitor-related protein from rat brain astrocytes  

SciTech Connect

The present study investigates angiotensin (Ang) II effects on secretory protein synthesis in brain astrocytes cultured from neonatal and 21-day-old rats. Ang II-induced changes in the de novo synthesis of (35S)methionine-labeled secretory proteins were visualized using two-dimensional NaDodSO4/PAGE. Astrocytes from 21-day-old rat brain possess specific high-affinity receptors for Ang II. These cells express two Ang II-induced secretory proteins with Mr 55,000 (AISP-55K) and Mr 30,000 (AISP-30K), which were time- and dose-dependent (EC50, 1 nM). (Sar1, Ile8)Ang II (where Sar is sarcosine) inhibited Ang II-induced secretion of AISP-55K but not AISP-30K. N-terminal amino acid sequencing indicates that AISP-55K is identical to rat plasminogen activator inhibitor 1, whereas AISP-30K exhibits 72-81% identity to three closely related proteins: human tissue inhibitor of metalloproteases, a rat phorbol ester-induced protein, and the murine growth-responsive protein 16C8. Immunofluorescent staining with rat plasminogen activator inhibitor 1 antibody was induced in the majority of cells in culture after Ang II treatment of astrocytes from 21-day-old rat brains. Absence of this response to Ang II in astrocytes from neonatal rat brain provides evidence that this action of Ang II on astrocytes is developmentally regulated.

Olson, J.A. Jr.; Shiverick, K.T.; Ogilvie, S.; Buhi, W.C.; Raizada, M.K. (Univ. of Florida College of Medicine, Gainesville (USA))

1991-03-01

308

Matrix metalloproteinase-3 inhibitor retards treadmill running-induced cartilage degradation in rats  

PubMed Central

Introduction The effect of intra-articular injection of matrix metalloproteinase (MMP)-3 inhibitor was investigated in a rat model to understand the role of MMP-3 in cartilage degradation induced by excessive loading from running. Methods A total of 24 male Wistar rats were randomly assigned into groups of sedentary control (SED), high-intensity running (HIR), HIR + low dosage of MMP-3 Inhibitor I (HIRI1), and HIR + high dosage of MMP-3 Inhibitor I (HIRI2). Rats in the HIR, HIRI1 and HIRI2 groups were intensively trained for six weeks on the treadmill. Those in HIRI1 and HIRI2 groups were provided bilateral intra-articular injections of 80 ?L of 0.2 mM and 2 mM MMP-3 Inhibitor I in knee joints once a week, respectively. Blood samples were collected to measure serum MMP-3 level using ELISA. Femoral condyles were collected to observe cartilage characteristics by histochemistry, and MMP-3 as well as collagen II was measured by immunohistochemistry. In addition, cartilage samples were obtained to assess MMP-3 mRNA expression by RT-PCR. Results Histological examination showed osteoarthritic changes in rats after six weeks of high intensity running. In comparison to the SED group, significant decreases in glycosaminoglycans (GAG) and collagen content were found in the HIR group, which corresponded to significant increase in serum MMP-3 level, cartilage MMP-3 activity and gene expression. However, such a degradative process was considerably retarded by intra-articular injection of MMP-3 inhibitor at higher dosage. Statistical differences were found between the HIR and HIRI2 groups with regard to GAG and collagen II content, serum MMP-3 level, cartilage MMP-3 activity and gene expression. Conclusions High-intensity running for six weeks may lead to cartilage degradation in a rat model. It was shown that the chrondroprotective effect was offered by the use of intra-articular injection of MMP-3 inhibitor. MMP-3 acts as the key mediator of this catabolic change under such mechanical condition. The results also showed that MMP-3 selective inhibitor may be an effective option for retarding such osteoarthritic changes.

2011-01-01

309

Histochemical studies on peroxisomes in regenerating proximal tubules of the kidney.  

PubMed Central

Peroxisomes of the regenerating proximal tubules of the rat kidney were investigated after necrosis induced by mercuric chloride. Slices both for light and electron microscopic examinations were incubated in 3,3'-diaminobenzidine (DAB) medium. Peroxisomes were absent in the necrotic epithelium. They appeared on the fourth day of regeneration and later their number increased reaching the normal distribution in the fourth week. They seem to be needed for the functional differentiation of the proximal tubule cells during regeneration. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8

Boti, Z.; Ivanyi, B.; Kobor, J.; Ormos, J.

1979-01-01

310

The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage.  

PubMed

Histone deacetylase (HDAC) inhibitors have been proven to be effective therapeutic agents to kill cancer cells through inhibiting HDAC activity or altering the structure of chromatin. As a potent HDAC inhibitor, depsipeptide not only modulates histone deacetylation but also activates non-histone protein p53 to inhibit cancer cell growth. However, the mechanism of depsipeptide-induced p53 transactivity remains unknown. Here, we show that depsipeptide causes DNA damage through induction of reactive oxygen species (ROS) generation, as demonstrated by a comet assay and by detection of the phosphorylation of H2AX. Depsipeptide induced oxidative stress was confirmed to relate to a disturbance in reduction-oxidation (redox) reactions through inhibition of the transactivation of thioredoxin reductase (TrxR) in human cancer cells. Upon treatment with depsipeptide, p53 phosphorylation at threonine 18 (Thr18) was specifically induced. Furthermore, we also demonstrated that phosphorylation of p53 at Thr18 is required for p53 acetylation at lysine 373/382 and for p21 expression in response to depsipeptide treatment. Our results demonstrate that depsipeptide plays an anti-neoplastic role by generating ROS to elicit p53/p21 pathway activation. PMID:22112863

Wang, Haiying; Zhou, Wen; Zheng, Zhixing; Zhang, Ping; Tu, Bo; He, Qihua; Zhu, Wei-Guo

2011-11-23

311

PPARÁ-DEPENDENT GENE EXPRESSION CHANGES IN THE MOUSE LIVER AFTER EXPOSURE TO PEROXISOME PROLIFERATORS  

EPA Science Inventory

Peroxisome proliferators (PP) are a large class of structurally diverse chemicals that mediate their effects in the liver mainly through the PP-activated receptor ¿ (PPAR?). Development of PP induced hepatocarcinogenesis in mouse liver is known to be dependent on PPAR&#...

312

Oxidative stress, microsomal and peroxisomal fatty acid oxidation in the liver of rats treated with acetone.  

PubMed

Parameters of oxidative stress, microsomal cytochrome P450 activity and peroxisomal fatty acid oxidation were studied in liver of rats following acetone (1% v/v) consumption for 7 days. Acetone treatment increased the activity of catalase and decreased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GTPx), but did not significantly modify the liver content of malondialdehyde (MDA) and reduced glutathione. Also, acetone increased the total content of cytochrome P450, the microsomal lauric acid hydroxylation, aminopyrine N-demethylation and the peroxisomal beta-oxidation of palmitoyl CoA. These effects were similar to those found previously in starved and ethanol-treated rats, supporting the hypothesis that ketone bodies would be the common inducer of microsomal and peroxisomal fatty acid oxidation in these metabolic states. PMID:11301292

Orellana B, M; Guajardo, V; Araya, J; Thieleman, L; Rodrigo, R

2001-04-01

313

AKT inhibitor suppresses hyperthermia-induced Ndrg2 phosphorylation in gastric cancer cells.  

PubMed

Hyperthermia is one of the most effective adjuvant treatments for various cancers with few side effects. However, the underlying molecular mechanisms still are not known. N-myc downstream-regulated gene 2 (NDRG2), a tumor suppressor, has been shown to be involved in diverse cellular stresses including hypoxia, lipotoxicity, etc. In addition, Ndrg2 has been reported to be related to progression of gastric cancer. In the current study, our data showed that the apoptosis rate of MKN28 cells increased relatively rapidly to 13.4% by 24 h after treatment with hyperthermia (42°C for 1 h) compared to 5.1% in control cells (P < 0.05). Nevertheless, there was no obvious change in the expression level of total Ndrg2 during this process. Further investigation demonstrated that the relative phosphorylation levels of Ndrg2 at Ser332, Thr348 increased up to 3.2- and 1.9-fold (hyperthermia group vs control group) at 3 h in MKN28 cells, respectively (P < 0.05). We also found that heat treatment significantly increased AKT phosphorylation. AKT inhibitor VIII (10 µM) decreased the phosphorylation level of Ndrg2 induced by hyperthermia. Accordingly, the apoptosis rate rose significantly in MKN28 cells (16.4%) treated with a combination of AKT inhibitor VIII and hyperthermia compared to that (6.8%) of cells treated with hyperthermia alone (P < 0.05). Taken together, these data demonstrated that Ndrg2 phosphorylation could be induced by hyperthermia in an AKT-dependent manner in gastric cancer cells. Furthermore, AKT inhibitor VIII suppressed Ndrg2 phosphorylation and rendered gastric cancer cells susceptible to apoptosis induced by hyperthermia. PMID:23558861

Tao, Yurong; Guo, Yan; Liu, Wenchao; Zhang, Jian; Li, Xia; Shen, Lan; Ru, Yi; Xue, Yan; Zheng, Jin; Liu, Xinping; Zhang, Jing; Yao, Libo

2013-04-05

314

Inhibitor of Differentiation-3 mediates high fat diet-induced visceral fat expansion  

PubMed Central

Objective Inhibitor of differentiation-3 (Id3) has been implicated in promoting angiogenesis, a key determinant of high fat diet (HFD)-induced visceral adiposity. Yet the role of Id3 in high fat diet (HFD)-induced angiogenesis and visceral adipose expansion is unknown. Methods and Results Id3?/? mice demonstrated a significant attenuation of HFD-induced visceral fat depot expansion compared to WT littermate controls. Importantly, unlike other Id proteins, loss of Id3 did not affect adipose depot size in young mice fed chow diet or differentiation of adipocytes in vitro or in vivo. Contrast enhanced ultrasound revealed a significant attenuation of visceral fat microvascular blood volume in HFD-fed mice null for Id3 compared to WT controls. HFD induced Id3 and VEGFA expression in the visceral stromal vascular fraction (SVF) and Id3?/? mice had significantly lower levels of VEGFA protein in visceral adipose tissue compared to WT. Furthermore, HFD-induced VEGFA expression in visceral adipose tissue was completely abolished by loss of Id3. Consistent with this effect, Id3 abolished E12-mediated repression of VEGFA promoter activity. Conclusions Results identify Id3 as an important regulator of HFD-induced visceral adipose VEGFA expression, microvascular blood volume, and depot expansion. Inhibition of Id3 may have potential as a therapeutic strategy to limit visceral adiposity.

Cutchins, Alexis; Harmon, Daniel B.; Kirby, Jennifer L.; Doran, Amanda C.; Oldham, Stephanie N.; Skaflen, Marcus; Klibanov, Alexander L.; Meller, Nahum; Keller, Susanna R.; Garmey, James; McNamara, Coleen A.

2011-01-01

315

Bridging the Gap between Plant and Mammalian Polyamine Catabolism: A Novel Peroxisomal Polyamine Oxidase Responsible for a Full Back-Conversion Pathway in Arabidopsis1[W][OA  

PubMed Central

In contrast to animals, where polyamine (PA) catabolism efficiently converts spermine (Spm) to putrescine (Put), plants have been considered to possess a PA catabolic pathway producing 1,3-diaminopropane, ?1-pyrroline, the corresponding aldehyde, and hydrogen peroxide but unable to back-convert Spm to Put. Arabidopsis (Arabidopsis thaliana) genome contains at least five putative PA oxidase (PAO) members with yet-unknown localization and physiological role(s). AtPAO1 was recently identified as an enzyme similar to the mammalian Spm oxidase, which converts Spm to spermidine (Spd). In this work, we have performed in silico analysis of the five Arabidopsis genes and have identified PAO3 (AtPAO3) as a nontypical PAO, in terms of homology, compared to other known PAOs. We have expressed the gene AtPAO3 and have purified a protein corresponding to it using the inducible heterologous expression system of Escherichia coli. AtPAO3 catalyzed the sequential conversion/oxidation of Spm to Spd, and of Spd to Put, thus exhibiting functional homology to the mammalian PAOs. The best substrate for this pathway was Spd, whereas the N1-acetyl-derivatives of Spm and Spd were oxidized less efficiently. On the other hand, no activity was detected when diamines (agmatine, cadaverine, and Put) were used as substrates. Moreover, although AtPAO3 does not exhibit significant similarity to the other known PAOs, it is efficiently inhibited by guazatine, a potent PAO inhibitor. AtPAO3 contains a peroxisomal targeting motif at the C terminus, and it targets green fluorescence protein to peroxisomes when fused at the N terminus but not at the C terminus. These results reveal that AtPAO3 is a peroxisomal protein and that the C terminus of the protein contains the sorting information. The overall data reinforce the view that plants and mammals possess a similar PA oxidation system, concerning both the subcellular localization and the mode of its action.

Moschou, Panagiotis N.; Sanmartin, Maite; Andriopoulou, Athina H.; Rojo, Enrique; Sanchez-Serrano, Jose J.; Roubelakis-Angelakis, Kalliopi A.

2008-01-01

316

Charcot-Marie-Tooth disease-associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission.  

PubMed

Mitochondria and peroxisomes can be fragmented by the process of fission. The fission machineries of both organelles share a set of proteins. GDAP1 is a tail-anchored protein of mitochondria and induces mitochondrial fragmentation. Mutations in GDAP1 lead to Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy, and affect mitochondrial dynamics. Here, we show that GDAP1 is also targeted to peroxisomes mediated by the import receptor Pex19. Knockdown of GDAP1 leads to peroxisomal elongation that can be rescued by re-expressing GDAP1 and by missense mutated forms found in CMT patients. GDAP1-induced peroxisomal fission is dependent on the integrity of its hydrophobic domain 1, and on Drp1 and Mff, as is mitochondrial fission. Thus, GDAP1 regulates mitochondrial and peroxisomal fission by a similar mechanism. However, our results reveal also a more critical role of the amino-terminal GDAP1 domains, carrying most CMT-causing mutations, in the regulation of mitochondrial compared to peroxisomal fission. PMID:23628762

Huber, Nina; Guimaraes, Sofia; Schrader, Michael; Suter, Ueli; Niemann, Axel

2013-04-30

317

Phospholipase C Inhibitors Attenuate Arrhythmias Induced by ? -receptor Stimulation in the Isolated Rat Heart  

Microsoft Academic Search

To determine whether the phospholipase C (PLC)\\/inositol 1,4,5 trisphosphate (IP3)\\/Ca2+pathway mediates cardiac arrhythmias induced by?-opioid receptor stimulation, the effects of U50,488H, a selective?-opioid receptor agonist, on cardiac rhythm in a isolated perfused rat heart, intracellular calcium ([Ca2+]i) in a single ventricular myocyte and IP3production in myocytes were studied in the presence and absence of PLC inhibitors. U50,488H, the effects of

Jin-Song Bian; Wei-Min Zhang; Qiang Xia; Tak-Ming Wong

1998-01-01

318

Administration of an aldose reductase inhibitor induces a decrease of collagen fluorescence in diabetic rats.  

PubMed Central

As a consequence of an increased flux through the sorbitol pathway fructose levels rise in various tissues in diabetes. Also, in vitro nonenzymatic fructosylation of protein induces the generation of fluorescence at a rate 10 times greater than glucosylation. The administration of sorbinil, an aldose reductase inhibitor known to lower tissue fructose concentration, to experimental diabetic rats led to a decrease in the fluorescence related to advanced Maillard products in their skin collagen. This effect is consistent with the in vivo occurrence of nonenzymatic fructosylation of collagen. A potential pathogenetic role for this posttranslational modification in diabetic complications should be considered.

Suarez, G; Rajaram, R; Bhuyan, K C; Oronsky, A L; Goidl, J A

1988-01-01

319

Activation of peroxisome proliferators-activated receptor ? (PPAR?) promotes blastocyst hatching in mice.  

PubMed

Prostaglandins participate in a variety of female reproductive processes, including ovulation, fertilization, embryo implantation and parturition. In particular, maternal prostacyclin (PGI(2)) is critical for embryo implantation and the action of PGI(2) is not mediated via its G-protein-coupled membrane receptor, IP, but its nuclear receptor, peroxisome-proliferator-activated receptor ? (PPAR?). Recently, several studies have shown that PGI(2) enhances blastocyst development and/or hatching rate in vitro, and subsequently implantation and live birth rates in mice. However, the mechanism by which PGI(2) improves preimplantation embryo development in vitro remains unclear. Using molecular, pharmacologic and genetic approaches, we show that PGI(2)-induced PPAR? activation accelerates blastocyst hatching in mice. mRNAs for PPAR?, retinoid X receptor (heterodimeric partners of PPAR?) and PGI(2) synthase (PGIS) are temporally induced after zygotic gene activation, and their expression reaches maximum levels at the blastocyst stage, suggesting that functional complex of PPAR? can be formed in the blastocyst. Carbaprostacyclin (a stable analogue of PGI(2)) and GW501516 (a PPAR? selective agonist) significantly accelerated blastocyst hatching but did not increase total cell number of cultured blastocysts. Whereas U51605 (a PGIS inhibitor) interfered with blastocyst hatching, GW501516 restored U51605-induced retarded hatching. In contrast to the improvement of blastocyst hatching by PPAR? agonists, PPAR antagonists significantly inhibited blastocyst hatching. Furthermore, deletion of PPAR? at early stages of preimplantation mouse embryos caused delay of blastocyst hatching, but did not impair blastocyst development. Taken together, PGI(2)-induced PPAR? activation accelerates blastocyst hatching in mice. PMID:21511721

Kang, Hee Jung; Hwang, Soo Jin; Yoon, Jung Ah; Jun, Jin Hyun; Lim, Hyunjung Jade; Yoon, Tae Ki; Song, Haengseok

2011-04-20

320

Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma.  

PubMed Central

BACKGROUND--The cysteinyl leukotrienes may play a central part in the mechanisms of aspirin-sensitive asthma. Previous work has shown that individuals with aspirin-sensitive asthma have high basal urinary LTE4 levels which increase further upon aspirin ingestion, and that sulphidopeptide leukotriene receptor antagonists attenuate aspirin-induced airflow obstruction. If the cysteinyl leukotrienes cause aspirin-induced asthmatic reactions, inhibition of the 5-lipoxygenase pathway should prevent aspirin-induced bronchospasm. This hypothesis has been tested with ZD2138, a specific non-redox 5-lipoxygenase inhibitor. METHODS--Seven subjects (four men) with aspirin-sensitive asthma with baseline FEV1 values > 67% were studied. ZD2138 (350 mg) or placebo was given on two separate occasions two weeks apart in a randomised double blind fashion. A single dose of aspirin was administered four hours after dosing and FEV1 was measured for six hours. Inhibition of the 5-lipoxygenase pathway by ZD2138 was assessed by measurements of urinary LTE4 levels and ex vivo calcium ionophore stimulated LTB4 generation in whole blood, before administration of drug or placebo and at regular time intervals after dosing and aspirin administration. RESULTS--ZD2138 protected against the aspirin-induced reduction in FEV1 with a 20.3 (4.9)% fall in FEV1 following placebo compared with 4.9 (2.9)% following ZD2138. This was associated with 72% inhibition of ex vivo LTB4 generation in whole blood at 12 hours and a 74% inhibition of the rise in urinary LTE4 excretion at six hours after aspirin ingestion. CONCLUSIONS--In aspirin-sensitive asthma the 5-lipoxygenase inhibitor ZD2138 inhibits the fall in FEV1 induced by aspirin and this is associated with substantial inhibition of 5-lipoxygenase.

Nasser, S M; Bell, G S; Foster, S; Spruce, K E; MacMillan, R; Williams, A J; Lee, T H; Arm, J P

1994-01-01

321

Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis  

PubMed Central

Background Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with pathological processes, in particular tumour development, and is a target for the development of new therapies. We have investigated the anti-angiogenic potential of two naturally occurring stilbene glycosides (compounds 1 and 2) isolated from the medicinal plant Boswellia papyriferai using large and smallvessel-derived endothelial cells. Compound 1 (trans-4',5'-dihydroxy-3-methoxystilbene-5-O-{?-L-rhamnopyranosyl-(1?2)-[?-L-rhamnopyranosyl-(1?6)}-?-D-glucopyranoside was the more hydrophilic and inhibited FGF-2-induced proliferation, wound healing, invasion in Matrigel, tube formation and angiogenesis in large and small vessel-derived endothelial cells and also in the chick chorioallantoic membrane assay. Using a binding assay we were able to show compound 1 reduced binding of FGF-2 to fibroblast growth factor receptors-1 and -2. In all cases the concentration of compound 1 which caused 50% inhibition (IC50) was determined. The effect of compound 1 on EGF and VEGF-induced proliferation was also investigated. Results Compound 1 inhibited all stages of FGF-2 induced angiogenesis with IC50 values in the range 5.8 ± 0.18 – 48.90 ± 0.40 ?M but did not inhibit EGF or VEGF-induced angiogenesis. It also inhibited FGF-2 binding to FGF receptor-1 and -2 with IC50 values of 5.37 ± 1.04 and 9.32 ± 0.082 ?M respectively and with concommotant down-regulation of phosphorylated-ERK-1/-2 expression. Compound 2 was an ineffective inhibitor of angiogenesis despite its structural homology to compound 1. Conclusion Compound 1 inhibited FGF-2 induced angiogenesis by binding to its cognate receptors and is an addition to the small number of natural product inhibitors of angiogenesis

Hussain, Sajjad; Slevin, Mark; Ahmed, Nessar; West, David; Choudhary, Muhammad Iqbal; Naz, Humera; Gaffney, John

2009-01-01

322

Use of a Soluble Epoxide Hydrolase Inhibitor in Smoke-Induced Chronic Obstructive Pulmonary Disease  

PubMed Central

Tobacco smoke-induced chronic obstructive pulmonary disease (COPD) is a prolonged inflammatory condition of the lungs characterized by progressive and largely irreversible airflow limitation attributable to a number of pathologic mechanisms, including bronchitis, bronchiolitis, emphysema, mucus plugging, pulmonary hypertension, and small-airway obstruction. Soluble epoxide hydrolase inhibitors (sEHIs) demonstrated anti-inflammatory properties in a rat model after acute exposure to tobacco smoke. We compared the efficacy of sEHI t-TUCB (trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid) and the phosphodiesterase-4 (PDE4) inhibitor Rolipram (Biomol International, Enzo Life Sciences, Farmingdale, NY) to reduce lung injury and inflammation after subacute exposure to tobacco smoke over a period of 4 weeks. Pulmonary physiology, bronchoalveolar lavage, cytokine production, and histopathology were analyzed to determine the efficacy of sEHI and Rolipram to ameliorate tobacco smoke–induced inflammation and injury in the spontaneously hypertensive rat. Both t-TUCB and Rolipram inhibited neutrophil elevation in bronchoalveolar lavage. sEHI t-TUCB suppressed IFN-?, while improving lung function by reducing tobacco smoke–induced total respiratory resistance and tissue damping (small-airway and peripheral tissue resistance). Increases in tobacco smoke–induced alveolar airspace size were attenuated by t-TUCB. Rolipram inhibited the production of airway mucus. Both t-TUCB and Rolipram inhibited vascular remodeling–related growth factor. These findings suggest that sEHI t-TUCB has therapeutic potential for treating COPD by improving lung function and attenuating the lung inflammation and emphysematous changes caused by tobacco smoke. To the best of our knowledge, this is the first report to demonstrate that sEHI exerts significant protective effects after repeated, subacute tobacco smoke–induced lung injury in a rat model of COPD.

Wang, Lei; Yang, Jun; Guo, Lei; Uyeminami, Dale; Dong, Hua; Hammock, Bruce D.

2012-01-01

323

Salutary effect of NF?B inhibitor and folacin in hyperhomocysteinemia-hyperlipidemia induced vascular dementia.  

PubMed

Dementia of vascular origin or vascular dementia (VaD) is considered as the second commonest form of dementia after Alzheimer's disease (AD). In the last ten years various researchers have reported a strong association of hyperhomocysteinemia (HHcy), hyperlipidemia (HL) and dementia. This study investigates the salutary effect of natrium diethyl dithio carbamate trihydrate (NDDCT), a nuclear factor-kappaB (NF-?B) inhibitor as well as folacin (Vitamin-B(9)) in HHcy-HL induced VaD. l-methionone was used to induce HHcy-HL and associated VaD. Morris water-maze (MWM) was used for testing learning and memory. Vascular system assessment was done by testing endothelial function. Biochemical estimations were performed to assess HHcy (serum homocysteine), HL (serum cholesterol), oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species and brain glutathione), nitric oxide levels (serum nitrite/nitrate) and cholinergic activity (brain acetyl cholinesterase activity). L-methionine treated animals have shown HHcy-HL, endothelial dysfunction, impairment of learning, memory, reduction in serum nitrite/nitrate levels and brain glutathione (GSH) along with increase in serum and brain thiobarbituric acid reactive species (TBARS), and brain acetylcholinesterase activity. NDDCT, folacin and donepezil (positive control) significantly improved HHcy-HL induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. l-methionine induced HHcy-HL has caused VaD development in rats. NF?-B inhibitors and folacin may be considered as potential agents for the management of HHcy-HL induced VaD. PMID:22510463

Sharma, Bhupesh; Singh, Nirmal

2012-04-04

324

Reovirus-Induced Apoptosis Is Preceded by Increased Cellular Calpain Activity and Is Blocked by Calpain Inhibitors  

PubMed Central

The cellular pathways of apoptosis have not been fully characterized; however, calpain, a cytosolic calcium-activated cysteine protease, has been implicated in several forms of programmed cell death. Reoviruses induce apoptosis both in vitro and in vivo and serve as a model for studying virus-induced cell death. We investigated the potential role of calpain in reovirus-induced apoptosis in vitro by measuring calpain activity as well as evaluating the effects of calpain inhibitors. L929 cells were infected with reovirus type 3 Abney (T3A), and calpain activity, measured as cleavage of the fluorogenic calpain substrate Suc-Leu-Leu-Val-Tyr-AMC, was monitored. There was a 1.6-fold increase in calpain activity in T3A-infected cells compared to mock-infected cells; this increase was completely inhibited by preincubation with calpain inhibitor I (N-acetyl-leucyl-leucyl-norleucinal [aLLN]), an active-site inhibitor. Both aLLN and PD150606, a specific calpain inhibitor that interacts with the calcium-binding site, inhibited reovirus-induced apoptosis in L929 cells by 54 to 93%. Apoptosis induced by UV-inactivated reovirus was also reduced 65 to 69% by aLLN, indicating that inhibition of apoptosis by calpain inhibitors is independent of effects on viral replication. We conclude that calpain activation is a component of the regulatory cascade in reovirus-induced apoptosis.

Debiasi, Roberta L.; Squier, Margaret K. T.; Pike, Bobbi; Wynes, Murry; Dermody, Terence S.; Cohen, J. John; Tyler, Kenneth L.

1999-01-01

325

Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes  

PubMed Central

Autophagy is responsible for nonspecific, bulk degradation of cytoplasmic components. Recent work has revealed also that there is specific, autophagic degradation of polyubiquitinated protein aggregates, whose buildup occurs during neurodegenerative disease. Here, we report that simple mono-ubiquitination of normally long-lived cytoplasmic substrates is sufficient to target these substrates for autophagic degradation in mammalian cells. That is, upon their ubiquitination, both small [i.e., red fluorescent protein (RFP)] and large (i.e., peroxisomes) substrates are efficiently targeted to autophagosomes and then degraded within lysosomes upon autophagosome-lysosome fusion. This targeting requires the ubiquitin-binding protein, p62, and is blocked by the Class III phosphatidylinositol 3-kinase (PI3K) inhibitor, 3-methyladenine (3-MA), or by depletion of the autophagy-related-12 (Atg12) protein homolog. Mammalian cells thus use a common pathway involving ubiquitin and p62 for targeting diverse types of substrates for autophagy.

Kim, Peter Kijun; Hailey, Dale Warren; Mullen, Robert Thomas; Lippincott-Schwartz, Jennifer

2008-01-01

326

Plant Density and Nutrient Availability Constrain Constitutive and Wound-induced Expression of Trypsin Inhibitors in Brassica napus  

Microsoft Academic Search

We investigated the effects of plant density on plant size, leaf total soluble protein content, and constitutive and wound-induced levels of proteinaceous trypsin inhibitors in pot-grown Brassica napus seedlings in two greenhouse studies. We manipulated plant density by varying the number of intraspecific neighbors surrounding a target plant in the center of each pot. In general, constitutive and induced levels

Donald F. Cipollini; Joy Bergelson

2001-01-01

327

Autophagy in organelle homeostasis: peroxisome turnover  

PubMed Central

When cells are confronted with an insufficient supply of nutrients in their extracellular fluid, they may begin to cannibalize some of their internal proteins as well as whole organelles for reuse in the synthesis of new components. This process is termed autophagy and it involves the formation of a double-membrane structure within the cell, which encloses the material to be degraded into a vesicle called an autophagosome. The autophagosome subsequently fuses with a lysosome/vacuole whose hydrolytic enzymes degrade the sequestered organelle. Degradation of peroxisomes is a specific type of autophagy, which occurs in a selective manner and has been mostly studied in yeast. Recently, it was reported that a similar selective process of autophagy occurs in mammalian cells with proliferated peroxisomes. Here we discuss characteristics of the autophagy of peroxisomes in mammalian cells and present a comprehensive model of their likely mechanism of degradation on the basis of known and common elements from other systems.

Monastyrska, Iryna; Klionsky, Daniel J.

2006-01-01

328

Extinction of peroxisomal functions in hepatoma cell-fibroblast hybrids  

Microsoft Academic Search

Although peroxisomes are ubiquitous, differences in the number of organelles and in the expression of associated metabolic activities are observed, depending on the cell type. To investigate the control of peroxisomal activity in connection with cell differentiation, we constructed hybrids between two types of cells whose histogenetic origins dictate significant differences in peroxisomal activities: hepatoma cells and fibroblasts, with high

El Bachir Bioukar; Sophie Sarrazin; Marc Conti; Eric Rabetafika; Jean-Paul Carreau; Sophie Dhorne-Pollet; Nicole Raynaud; Jean Deschatrette

1996-01-01

329

PEROXISOMES IN ABSORPTIVE CELLS OF MAMMALIAN SMALL INTESTINE  

PubMed Central

Huge numbers of peroxisomes are present in guinea pig duodenum, jejunum, and ileum, and in rat duodenum. The peroxisomes have been studied by light and electron microscopy, including visualization by incubation in a newly-developed alkaline 3,3' diaminobenzidine (DAB) medium. Electron micrographs of more than 3700 guinea pig peroxisomes have been studied. The diameter of most peroxisomes ranges from 0.15 µ. to 0.25 µ. They often appear in clusters, surrounded by and continuous, in numerous places, with smooth endoplasmic reticulum (ER). The ER is extremely tortuous in these regions. Serial sectioning is valuable for studying the ER-peroxisome relationships but viewing sections at different angles, tilted with a goniometer stage, is more informative. The intimate relations of the two organelles appear the same in tissue fixed in four different fixatives. The peroxisomes may be interpreted as localized dilatations of smooth ER retaining multiple membranous continuities. This interpretation is discussed in light of the turnover data on peroxisomal proteins of rat hepatocytes reported by Poole and colleagues. The very large numbers of peroxisomes in intestinal epithelium lead to speculations concerning their functional significance. They resemble the small peroxisomes described in many other cell types. Although the distinctive relationship of these peroxisomes to the ER is probably more significant than their small size, for practical purposes we propose the term "microperoxisomes" to distinguish these peroxisomes from the better-known larger peroxisomes of liver and kidney.

Novikoff, Phyllis M.; Novikoff, Alex B.

1972-01-01

330

Peroxisomes Are Required for in Vivo Nitric Oxide Accumulation in the Cytosol following Salinity Stress of Arabidopsis Plants1[C][W][OA  

PubMed Central

Peroxisomes are unique organelles involved in multiple cellular metabolic pathways. Nitric oxide (NO) is a free radical active in many physiological functions under normal and stress conditions. Using Arabidopsis (Arabidopsis thaliana) wild type and mutants expressing green fluorescent protein through the addition of peroxisomal targeting signal 1 (PTS1), which enables peroxisomes to be visualized in vivo, this study analyzes the temporal and cell distribution of NO during the development of 3-, 5-, 8-, and 11-d-old Arabidopsis seedlings and shows that Arabidopsis peroxisomes accumulate NO in vivo. Pharmacological analyses using nitric oxide synthase (NOS) inhibitors detected the presence of putative calcium-dependent NOS activity. Furthermore, peroxins Pex12 and Pex13 appear to be involved in transporting the putative NOS protein to peroxisomes, since pex12 and pex13 mutants, which are defective in PTS1- and PTS2-dependent protein transport to peroxisomes, registered lower NO content. Additionally, we show that under salinity stress (100 mm NaCl), peroxisomes are required for NO accumulation in the cytosol, thereby participating in the generation of peroxynitrite (ONOO?) and in increasing protein tyrosine nitration, which is a marker of nitrosative stress.

Corpas, Francisco J.; Hayashi, Makoto; Mano, Shoji; Nishimura, Mikio; Barroso, Juan B.

2009-01-01

331

Cycloheximide as a tool to investigate protein import in peroxisomes: a case study of the subcellular localization of isoprenoid biosynthetic enzymes.  

PubMed

Cytosolic background fluorescence is often observed when native low-abundance peroxisomal proteins carrying a weak peroxisomal targeting sequence are expressed as fluorescent fusion protein using a strong constitutive promoter in transiently transformed plant cells. This cytosolic fluorescence usually comes from the strong expression of the low-abundance proteins exceeding the peroxisome import efficiency. This often results in a misinterpretation of the protein subcellular localization, as there is doubt as to whether proteins are dually targeted to the cytosol and peroxisome or are exclusively localized to peroxisomes. To circumvent this experimental difficulty, the protein peroxisome import study can be optimized by de novo protein synthesis inhibition in transiently transformed cells using the translation inhibitor cycloheximide. This approach was used here successfully for the study of the subcellular localization of distinct plant isoprenoid biosynthetic enzymes, allowing us to clearly demonstrate that 5-phosphomevalonate kinase, mevalonate 5-diphosphate decarboxylase and a short isoform of farnesyl diphosphate synthase from Catharanthus roseus are exclusively localized to peroxisomes. PMID:22459325

Guirimand, Grégory; Simkin, Andrew John; Papon, Nicolas; Besseau, Sébastien; Burlat, Vincent; St-Pierre, Benoit; Giglioli-Guivarc'h, Nathalie; Clastre, Marc; Courdavault, Vincent

2012-03-27

332

A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma.  

PubMed

Renal cell carcinoma (RCC) is resistant to traditional cancer therapies such as radiation therapy and chemotherapy. The use of targeted therapies has improved the clinical outcomes of patients with metastatic RCC. However, most patients acquire resistance against targeted therapies over time. We report that the combination of the novel histone deacetylase (HDAC) inhibitor OBP-801, also known as YM753 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 synergistically inhibits cell growth and induces apoptosis in RCC cells. This combination activated caspase-3, -8 and -9 and the pan-caspase inhibitor zVAD-fmk significantly reduced the apoptotic response to the treatment with OBP-801 and LY294002. Moreover, the combined treatment induced intracellular reactive oxygen species (ROS) and the radical scavenger N-acetyl-L-cysteine (NAC) blocked the intracellular ROS and apoptosis induced by OBP-801 and LY294002. The co-treatment with OBP-801 and LY294002 markedly decreased survivin and the X-linked inhibitor of apoptosis protein (XIAP) protein levels, but Bcl-2 family members were not altered by the OBP-801/LY294002 co-treatment. These alterations were restored by NAC treatment. The transient transfection of survivin and XIAP reduced the apoptotic response to the OBP-801/LY294002 co-treatment. Additionally, OBP-801 was significantly more effective than SAHA, another HDAC inhibitor, in the combination with LY294002 against 786-O cells. Taken together, these results strongly suggest the combination of OBP-801 and LY294002 to be a promising treatment for RCC. PMID:23900601

Yamada, Takeshi; Horinaka, Mano; Shinnoh, Masahide; Yoshioka, Takashi; Miki, Tsuneharu; Sakai, Toshiyuki

2013-07-30

333

Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells.  

PubMed

Kit is a membrane-bound tyrosine kinase and receptor for stem cell factor (SCF) with a crucial role in hematopoiesis. Mutations of KIT occur in almost half of patients with core-binding factor leukemias, in which they have been associated with worse outcome. Development of new compounds targeting Kit may therefore hold promise for therapy. We investigated the activity and mechanism of action of APcK110, a novel Kit inhibitor, in the mastocytosis cell line HMC1.2 (KITV560G and KITD816V), acute myeloid leukemia (AML) lines OCIM2 and OCI/AML3 (both wild-type), and primary samples from patients with AML. We show that (a) APcK110 inhibits proliferation of the mastocytosis cell line HMC1.2 and the SCF-responsive cell line OCI/AML3 in a dose-dependent manner; (b) APcK110 is a more potent inhibitor of OCI/AML3 proliferation than the clinically used Kit inhibitors imatinib and dasatinib and at least as potent as cytarabine; (c) APcK110 inhibits the phosphorylation of Kit, Stat3, Stat5, and Akt in a dose-dependent fashion, showing activity of APcK110 on Kit and its downstream signaling pathways; (d) APcK110 induces apoptosis by cleavage of caspase-3 and poly(ADP-ribose) polymerase; and (e) APcK110 inhibits proliferation of primary AML blasts in a clonogenic assay but does not affect proliferation of normal colony-forming cells. Although APcK110 activity may partly depend on cytokine responsiveness (e.g., SCF) and not exclusively KIT mutation status, it remains a potent inhibitor of AML and mastocytosis cell lines and primary AML samples. APcK110 and similar compounds should be evaluated in clinical trials of patients with AML. PMID:19383925

Faderl, Stefan; Pal, Ashutosh; Bornmann, William; Albitar, Maher; Maxwell, David; Van, Quin; Peng, Zhenghong; Harris, David; Liu, Zhiming; Hazan-Halevy, Inbal; Kantarjian, Hagop M; Estrov, Zeev

2009-04-21

334

The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways.  

PubMed

Although calcineurin inhibitors (CNIs) are very useful in preventing allograft rejection, they can mediate a rapid progression of post-transplantation malignancies. The CNI cyclosporine A (CsA) can promote renal tumor growth through activation of the proto-oncogene ras and over-expression of the angiogenic cytokine VEGF; the ras activation also induces over-expression of the cytoprotective enzyme HO-1, which promotes survival of renal cancer cells. Here, we show that the natural product honokiol significantly inhibited CsA-induced and Ras-mediated survival of renal cancer cells through the down-regulations of VEGF and HO-1. Thus, honokiol treatment may help to prevent tumor-promoting effects of CsA in transplant patients. PMID:23752066

Banerjee, Pallavi; Basu, Aninda; Arbiser, Jack L; Pal, Soumitro

2013-06-07

335

Intracellular serine protease inhibitor SERPINB4 inhibits granzyme M-induced cell death.  

PubMed

Granzyme-mediated cell death is the major pathway for cytotoxic lymphocytes to kill virus-infected and tumor cells. In humans, five different granzymes (i.e. GrA, GrB, GrH, GrK, and GrM) are known that all induce cell death. Expression of intracellular serine protease inhibitors (serpins) is one of the mechanisms by which tumor cells evade cytotoxic lymphocyte-mediated killing. Intracellular expression of SERPINB9 by tumor cells renders them resistant to GrB-induced apoptosis. In contrast to GrB, however, no physiological intracellular inhibitors are known for the other four human granzymes. In the present study, we show that SERPINB4 formed a typical serpin-protease SDS-stable complex with both recombinant and native human GrM. Mutation of the P2-P1-P1' triplet in the SERPINB4 reactive center loop completely abolished complex formation with GrM and N-terminal sequencing revealed that GrM cleaves SERPINB4 after P1-Leu. SERPINB4 inhibited GrM activity with a stoichiometry of inhibition of 1.6 and an apparent second order rate constant of 1.3×10(4) M(-1) s(-1). SERPINB4 abolished cleavage of the macromolecular GrM substrates ?-tubulin and nucleophosmin. Overexpression of SERPINB4 in tumor cells inhibited recombinant GrM-induced as well as NK cell-mediated cell death and this inhibition depended on the reactive center loop of the serpin. As SERPINB4 is highly expressed by squamous cell carcinomas, our results may represent a novel mechanism by which these tumor cells evade cytotoxic lymphocyte-induced GrM-mediated cell death. PMID:21857942

de Koning, Pieter J A; Kummer, J Alain; de Poot, Stefanie A H; Quadir, Razi; Broekhuizen, Roel; McGettrick, Anne F; Higgins, Wayne J; Devreese, Bart; Worrall, D Margaret; Bovenschen, Niels

2011-08-03

336

Intracellular Serine Protease Inhibitor SERPINB4 Inhibits Granzyme M-Induced Cell Death  

PubMed Central

Granzyme-mediated cell death is the major pathway for cytotoxic lymphocytes to kill virus-infected and tumor cells. In humans, five different granzymes (i.e. GrA, GrB, GrH, GrK, and GrM) are known that all induce cell death. Expression of intracellular serine protease inhibitors (serpins) is one of the mechanisms by which tumor cells evade cytotoxic lymphocyte-mediated killing. Intracellular expression of SERPINB9 by tumor cells renders them resistant to GrB-induced apoptosis. In contrast to GrB, however, no physiological intracellular inhibitors are known for the other four human granzymes. In the present study, we show that SERPINB4 formed a typical serpin-protease SDS-stable complex with both recombinant and native human GrM. Mutation of the P2-P1-P1? triplet in the SERPINB4 reactive center loop completely abolished complex formation with GrM and N-terminal sequencing revealed that GrM cleaves SERPINB4 after P1-Leu. SERPINB4 inhibited GrM activity with a stoichiometry of inhibition of 1.6 and an apparent second order rate constant of 1.3×104 M?1s?1. SERPINB4 abolished cleavage of the macromolecular GrM substrates ?-tubulin and nucleophosmin. Overexpression of SERPINB4 in tumor cells inhibited recombinant GrM-induced as well as NK cell-mediated cell death and this inhibition depended on the reactive center loop of the serpin. As SERPINB4 is highly expressed by squamous cell carcinomas, our results may represent a novel mechanism by which these tumor cells evade cytotoxic lymphocyte-induced GrM-mediated cell death.

de Koning, Pieter J. A.; Kummer, J. Alain; de Poot, Stefanie A. H.; Quadir, Razi; Broekhuizen, Roel; McGettrick, Anne F.; Higgins, Wayne J.; Devreese, Bart; Worrall, D. Margaret; Bovenschen, Niels

2011-01-01

337

Pre-treatment with ACE Inhibitor Attenuates Doxorubicin Induced Cardiomyopathy via Preservation of Mitochondrial Function  

PubMed Central

Aims Doxorubicin is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. Angiotensin-converting enzyme (ACE) inhibitors are commonly used as cardioprotective agents and have recently been shown in clinical studies to be efficacious in the prevention of anthracycline induced heart failure. Here we evaluated a mechanism for these protective effects by testing the ability of the ACE inhibitor enalapril to preserve mitochondrial function in a model of chronic doxorubicin treatment in rats. Methods Sprague Dawley rats were divided into three groups and followed for a total of 10 weeks: a) control-untreated, b) Doxorubicin treated (Dox), and c) Doxorubicin + Enalapril treated (DE). Doxorubicin was administered via intraperitoneal injection at weekly intervals from week 2 through week 7. Enalapril was administered in the drinking water of the DE group for the study duration. Results Doxorubicin treatment produced a significant loss in left ventricular contractility (P< 0.05), decrease in mitochondrial function via impairment of state-3 respiration, decrease in the cytosolic fraction of ATP, and up-regulation of free radical production. Enalapril significantly attenuated the decrease in percent fractional shortening (P< 0.05) and prevented the doxorubicin-associated reduction in respiratory efficiency and cytosolic ATP content (P< 0.05). Importantly, enalapril also abolished the robust doxorubicin-induced increase in free radical formation. Conclusions Administration of enalapril attenuates doxorubicin-induced cardiac dysfunction via preservation of mitochondrial respiratory efficiency and reduction in doxorubicin-associated free radical generation.

Hiona, Asimina; Lee, Andrew Stephen; Nagendran, Jayan; Xie, Xiaoyan; Connolly, Andrew J.; Robbins, Robert C.; Wu, Joseph C.

2011-01-01

338

Bowman-Birk protease inhibitor from soybeans enhances cisplatin-induced cytotoxicity in human mesothelioma cells.  

PubMed

Malignant mesothelioma (MM) is an aggressive cancer with no effective treatment options. Enforced expression of the gap junction (GJ) component connexin 43 (Cx43) increases the sensitivity of MM cells to cisplatin. Bowman-Birk protease inhibitor (BBI) induces the restoration of Cx43 in several types of tumor cells. In this study, we examined the capability of BBI to enhance the cytotoxic effect of cisplatin in MM cells via the induction of Cx43. Human MM H28 cells were used. Cell viability was evaluated by a WST-1 assay and proteasomal activity was determined by fluorometric analysis. Protein and mRNA levels were determined by immunoblot analysis and real-time RT-PCR, respectively. GJ function mediated by Cx43 was evaluated using the scrape-loading method. BBI effectively inhibited H28 cell growth in a dose-dependent manner (200-400 ?g/ml). In parallel with the growth inhibition, Cx43 levels (mRNA and protein) and GJ function were elevated by BBI treatment. Knockdown of BBI-induced Cx43 by an antisense nucleotide treatment almost cancelled the growth inhibition. BBI enhanced cisplatin-induced cytotoxicity in H28 cells, and down-regulation of Cx43 by the antisense nucleotide treatment abrogated the enhancing effect of BBI. The induction of Cx43 by BBI contributed to Src inactivation and subsequent induction of Bax. Furthermore, an Src inhibitor (SU6656) also enhanced cisplatin-induced cytotoxicity in H28 cells. These results suggest that BBI improves the cytotoxic efficacy of cisplatin in H28 cells via the inhibition of Src signaling. PMID:22977565

Kashiwagi, Korehito; Virgona, Nantiga; Yamada, Jin; Sato, Ayami; Ota, Masako; Yazawa, Takuya; Yano, Tomohiro

2011-05-12

339

Bowman-Birk protease inhibitor from soybeans enhances cisplatin-induced cytotoxicity in human mesothelioma cells  

PubMed Central

Malignant mesothelioma (MM) is an aggressive cancer with no effective treatment options. Enforced expression of the gap junction (GJ) component connexin 43 (Cx43) increases the sensitivity of MM cells to cisplatin. Bowman-Birk protease inhibitor (BBI) induces the restoration of Cx43 in several types of tumor cells. In this study, we examined the capability of BBI to enhance the cytotoxic effect of cisplatin in MM cells via the induction of Cx43. Human MM H28 cells were used. Cell viability was evaluated by a WST-1 assay and proteasomal activity was determined by fluorometric analysis. Protein and mRNA levels were determined by immunoblot analysis and real-time RT-PCR, respectively. GJ function mediated by Cx43 was evaluated using the scrape-loading method. BBI effectively inhibited H28 cell growth in a dose-dependent manner (200–400 ?g/ml). In parallel with the growth inhibition, Cx43 levels (mRNA and protein) and GJ function were elevated by BBI treatment. Knockdown of BBI-induced Cx43 by an antisense nucleotide treatment almost cancelled the growth inhibition. BBI enhanced cisplatin-induced cytotoxicity in H28 cells, and down-regulation of Cx43 by the antisense nucleotide treatment abrogated the enhancing effect of BBI. The induction of Cx43 by BBI contributed to Src inactivation and subsequent induction of Bax. Furthermore, an Src inhibitor (SU6656) also enhanced cisplatin-induced cytotoxicity in H28 cells. These results suggest that BBI improves the cytotoxic efficacy of cisplatin in H28 cells via the inhibition of Src signaling.

KASHIWAGI, KOREHITO; VIRGONA, NANTIGA; YAMADA, JIN; SATO, AYAMI; OTA, MASAKO; YAZAWA, TAKUYA; YANO, TOMOHIRO

2011-01-01

340

KEAP1-Dependent Synthetic Lethality Induced by AKT and TXNRD1 Inhibitors in Lung Cancer.  

PubMed

Intrinsic resistance to agents targeting phosphoinositide 3-kinase (PI3K)/AKT pathway is one of the major challenges in cancer treatment with such agents. The objective of this study is to identify the genes or pathways that can be targeted to overcome the resistance of non-small cell lung carcinoma (NSCLC) to the AKT inhibitor MK2206, which is currently being evaluated in phase I and II clinical trials. Using a genome-wide siRNA library screening and biologic characterization, we identified that inhibition of thioredoxin reductase-1 (TXNRD1), one of the key antioxidant enzymes, with siRNAs or its inhibitor, auranofin, sensitized NSCLC cells to MK2206 treatment in vitro and in vivo. We found that simultaneous inhibition of TXNRD1 and AKT pathways induced robust reactive oxygen species production, which was involved in c-jun-NH2-kinase (JNK; MAPK8) activation and cell apoptosis. Furthermore, we found that the synthetic lethality interaction between the TXNRD1 and AKT pathways occurred through the KEAP1/NRF2 cellular antioxidant pathway. Finally, we found that synthetic lethality induced by TXNRD1 and AKT inhibitors relied on wild-type KEAP1 function. Our study indicates that targeting the interaction between AKT and TXNRD1 antioxidant pathways with MK2206 and auranofin, a U.S. Food and Drug Administration-approved drug, is a rational strategy to treat lung cancer and that KEAP1 mutation status may offer a predicative biomarker for such combination approaches. Cancer Res; 73(17); 5532-43. ©2013 AACR. PMID:23824739

Dai, Bingbing; Yoo, Suk-Young; Bartholomeusz, Geoffrey; Graham, Ryan A; Majidi, Mourad; Yan, Shaoyu; Meng, Jieru; Ji, Lin; Coombes, Kevin; Minna, John D; Fang, Bingliang; Roth, Jack A

2013-07-03

341

Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency  

PubMed Central

Single-base lesions in DNA are repaired predominantly by base excision repair (BER). DNA polymerase ? (pol ?) is the polymerase of choice in the preferred single-nucleotide BER pathway. The characteristic phenotype of mouse fibroblasts with a deletion of the pol ? gene is moderate hypersensitivity to monofunctional alkylating agents, e.g., methyl methanesulfonate (MMS). Increased sensitivity to MMS is also seen in the absence of pol ? partner proteins XRCC1 and PARP-1, and under conditions where BER efficiency is reduced by synthetic inhibitors. PARP activity plays a major role in protection against MMS-induced cytotoxicity, and cells treated with a combination of non-toxic concentrations of MMS and a PARP inhibitor undergo cell cycle arrest and die by a Chk1-dependent apoptotic pathway. Since BER-deficient cells and tumors are similarly hypersensitive to the clinically used chemotherapeutic methylating agent temozolomide, modulation of DNA damage-induced cell signaling pathways, as well as BER, are attractive targets for potentiating chemotherapy.

Horton, Julie K.; Wilson, Samuel H.

2007-01-01

342

Radiation-induced pulmonary endothelial dysfunction in rats: modification by an inhibitor of angiotensin converting enzyme  

SciTech Connect

The ability of the angiotensin converting enzyme (ACE) inhibitor Captopril to modify radiation-induced pulmonary endothelial dysfunction was determined in male rats sacrificed 2 months after a single dose of 10-30 Gy of /sup 60/Co gamma rays to the right hemithorax. Half of each dose group consumed feed containing 0.12% w/w Captopril (60 mg/kg/day) continuously after irradiation, and half consumed control feed. Four markers of endothelial function were monitored: ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. All data were plotted as dose-response curves, and subjected to linear regression analysis. The Captopril modifying effect was expressed as the ratio of isoeffective doses at a common intermediate response (DRF), or as the ratio of the response curve slopes. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. Captopril exhibited DRF values of 1.4-2.1, and slope ratios of 1.4-5.1 for all four functional markers (p less than 0.05). Thus, the ACE inhibitor Captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats sacrificed 2 months postirradiation. Although the mechanism of Captopril action is not clear at present, these data suggest a novel application for this class of compounds as injury-modifying agents in irradiated lung.

Ward, W.F.; Kim, Y.T.; Molteni, A.; Solliday, N.H.

1988-07-01

343

Inhibitor binding induces active site stabilization of the HCV NS3 protein serine protease domain  

PubMed Central

Few structures of viral serine proteases, those encoded by the Sindbis and Semliki Forest viruses, hepatitis C virus (HCV) and cytomegalovirus, have been reported. In the life cycle of HCV a crucial role is played by a chymotrypsin-like serine protease encoded at the N–terminus of the viral NS3 protein, the solution structure of which we present here complexed with a covalently bound reversible inhibitor. Unexpectedly, the residue in the P2 position of the inhibitor induces an effective stabilization of the catalytic His–Asp hydrogen bond, by shielding that region of the protease from the solvent. This interaction appears crucial in the activation of the enzyme catalytic machinery and represents an unprecedented observation for this family of enzymes. Our data suggest that natural substrates of this serine protease could contribute to the enzyme activation by a similar induced-fit mechanism. The high degree of similarity at the His–Asp catalytic site region between HCV NS3 and other viral serine proteases suggests that this behaviour could be a more general feature for this category of viral enzymes.

Barbato, G.; Cicero, D.O.; Cordier, F.; Narjes, F.; Gerlach, B.; Sambucini, S.; Grzesiek, S.; Matassa, V.G.; De Francesco, R.; Bazzo, R.

2000-01-01

344

Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma  

PubMed Central

Purpose Metastasis is responsible for the death of most cancer patients, yet few therapeutic agents are available which specifically target the molecular events that lead to metastasis. We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma and metastasis (UM). The purpose of this study was to identify therapeutic agents that reverse the phenotypic effects of BAP1 loss in UM. Experimental Design In silico screens were performed to identify therapeutic compounds predicted to differentiate UM cells using Gene Set Enrichment Analysis and Connectivity Map databases. Valproic acid, trichostatin A, LBH-589 and suberoylanilide hydroxamic acid were evaluated for their effects on UM cells using morphologic evaluation, MTS viability assays, BrdU incorporation, flow cytometry, clonogenic assays, gene expression profiling, histone acetylation and ubiquitination assays, and a murine xenograft tumorigenicity model. Results HDAC inhibitors induced morphologic differentiation, cell cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. Valproic acid inhibited the growth of UM tumors in vivo. Conclusions These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of micrometastatic disease in UM.

Landreville, Solange; Agapova, Olga A.; Matatall, Katie A.; Kneass, Zachary T.; Onken, Michael D.; Lee, Ryan S.; Bowcock, Anne M.; Harbour, J. William

2011-01-01

345

Antidiabetic effects of SGLT2-selective inhibitor ipragliflozin in streptozotocin-nicotinamide-induced mildly diabetic mice.  

PubMed

Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption, and inhibition of renal SGLT2 activity represents an innovative strategy for the treatment of hyperglycemia in diabetic patients. The present study investigated the antidiabetic effects of ipragliflozin, a SGLT2-selective inhibitor, in streptozotocin-nicotinamide-induced mildly diabetic mice, which exhibited a mild decline in glucose tolerance associated with the loss of early-phase insulin secretion. Oral administration of ipragliflozin increased urinary glucose excretion in a dose-dependent manner, an effect which was significant at doses of 0.3 mg/kg or higher and lasted over 12 h. In addition, ipragliflozin dose-dependently improved hyperglycemia and glucose intolerance with concomitant decreases in plasma insulin levels without causing hypoglycemia. Once-daily dosing of ipragliflozin (0.1 - 3 mg/kg) for 4 weeks attenuated hyperglycemia, glucose intolerance, and impaired insulin secretion. These results suggest that the SGLT2-selective inhibitor ipragliflozin increases urinary glucose excretion by inhibiting renal glucose reabsorption, improves hyperglycemia in streptozotocin-nicotinamide-induced mildly diabetic mice, and may be useful for treating type 2 diabetes. PMID:22971845

Tahara, Atsuo; Kurosaki, Eiji; Yokono, Masanori; Yamajuku, Daisuke; Kihara, Rumi; Hayashizaki, Yuka; Takasu, Toshiyuki; Imamura, Masakazu; Qun, Li; Tomiyama, Hiroshi; Kobayashi, Yoshinori; Noda, Atsushi; Sasamata, Masao; Shibasaki, Masayuki

2012-08-23

346

Comparison of the effects of various peroxisome proliferators on peroxisomal enzyme activities, DNA synthesis, and apoptosis in rat and human hepatocyte cultures.  

PubMed

Peroxisome proliferators (PPs) are a class of rodent nongenotoxic hepatocarcinogens that cause hepatocyte peroxisome proliferation, increased DNA synthesis, and decreased spontaneous apoptosis. We examined the effects of various PPs such as the hypolipidemic agents clofibric acid (CLO), bezafibrate (BEZA), ciprofibrate (CIPRO), and nafenopin (NAFE) and the plasticizer di-(2-ethylhexyl)phthalate (DEHP) on the various parameters in vitro in rat and human hepatocyte cultures. In rat hepatocyte cultures, after 72 h of treatment with the various PPs at 100-500 microM, a compound-dependent increase in acyl CoA oxidase (ACO) and carnitine acetyl transferase (CAT) activities, markers of peroxisome proliferation, was observed with the following potencies: CIPRO = NAFE > BEZA > CLO > DEHP. A minor (120-150%), but significant, no concentration-dependent increase in DNA synthesis and a marked, no compound-dependent and, with the exception of NAFE, no concentration-dependent 60-80% decrease in spontaneous apoptosis was observed with all tested compounds (50-250 microM) after 48 h of treatment. Inhibition of spontaneous apoptosis in PP-treated versus control rat hepatocyte cultures was also observed morphologically. Furthermore, PPs inhibited transforming growth factor beta (TGFbeta)-induced apoptosis but not tumor necrosis factor alpha (TNFalpha)/alpha Amanitine (alphaAma)-induced apoptosis in rat hepatocyte cultures. In human hepatocyte cultures, the various PPs at 50-500 microM did not affect peroxisomal enzyme activities, DNA synthesis, or spontaneous and induced (TGFbeta or TNFalpha/alphaAma) apoptosis. The compound-dependent peroxisome proliferation but no compound-dependent disruption of the mitogenic/apoptotic balance elicited by PPs in primary rat hepatocyte cultures supports the hypothesis that oxidative stress is directly linked to the hepatocarcinogenic potential of a given PP in rodents and that disruption of the mitogenic/apoptotic balance contributes to the development of PP-induced hepatocarcinogenesis. In addition, the absence of effects of all PPs on both peroxisome proliferation-associated parameters and mitogenic/apoptotic balance supports the hypothesis that human liver cells are refractory to PP-induced hepatocarcinogenesis. PMID:10502499

Goll, V; Alexandre, E; Viollon-Abadie, C; Nicod, L; Jaeck, D; Richert, L

1999-10-01

347

Carbohydrate metabolism is perturbed in peroxisome-deficient hepatocytes due to mitochondrial dysfunction, AMP-activated protein kinase (AMPK) activation, and peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?) suppression.  

PubMed

Hepatic peroxisomes are essential for lipid conversions that include the formation of mature conjugated bile acids, the degradation of branched chain fatty acids, and the synthesis of docosahexaenoic acid. Through unresolved mechanisms, deletion of functional peroxisomes from mouse hepatocytes (L-Pex5(-/-) mice) causes severe structural and functional abnormalities at the inner mitochondrial membrane. We now demonstrate that the peroxisomal and mitochondrial anomalies trigger energy deficits, as shown by increased AMP/ATP and decreased NAD(+)/NADH ratios. This causes suppression of gluconeogenesis and glycogen synthesis and up-regulation of glycolysis. As a consequence, L-Pex5(-/-) mice combust more carbohydrates resulting in lower body weights despite increased food intake. The perturbation of carbohydrate metabolism does not require a long term adaptation to the absence of functional peroxisomes as similar metabolic changes were also rapidly induced by acute elimination of Pex5 via adenoviral administration of Cre. Despite its marked activation, peroxisome proliferator-activated receptor ? (PPAR?) was not causally involved in these metabolic perturbations, because all abnormalities still manifested when peroxisomes were eliminated in a peroxisome proliferator-activated receptor ? null background. Instead, AMP-activated kinase activation was responsible for the down-regulation of glycogen synthesis and induction of glycolysis. Remarkably, PGC-1? was suppressed despite AMP-activated kinase activation, a paradigm not previously reported, and they jointly contributed to impaired gluconeogenesis. In conclusion, lack of functional peroxisomes from hepatocytes results in marked disturbances of carbohydrate homeostasis, which are consistent with adaptations to an energy deficit. Because this is primarily due to impaired mitochondrial ATP production, these L-Pex5-deficient livers can also be considered as a model for secondary mitochondrial hepatopathies. PMID:22002056

Peeters, Annelies; Fraisl, Peter; van den Berg, Sjoerd; Ver Loren van Themaat, Emiel; Van Kampen, Antoine; Rider, Mark H; Takemori, Hiroshi; van Dijk, Ko Willems; Van Veldhoven, Paul P; Carmeliet, Peter; Baes, Myriam

2011-10-14

348

Carbohydrate Metabolism Is Perturbed in Peroxisome-deficient Hepatocytes Due to Mitochondrial Dysfunction, AMP-activated Protein Kinase (AMPK) Activation, and Peroxisome Proliferator-activated Receptor ? Coactivator 1? (PGC-1?) Suppression*  

PubMed Central

Hepatic peroxisomes are essential for lipid conversions that include the formation of mature conjugated bile acids, the degradation of branched chain fatty acids, and the synthesis of docosahexaenoic acid. Through unresolved mechanisms, deletion of functional peroxisomes from mouse hepatocytes (L-Pex5?/? mice) causes severe structural and functional abnormalities at the inner mitochondrial membrane. We now demonstrate that the peroxisomal and mitochondrial anomalies trigger energy deficits, as shown by increased AMP/ATP and decreased NAD+/NADH ratios. This causes suppression of gluconeogenesis and glycogen synthesis and up-regulation of glycolysis. As a consequence, L-Pex5?/? mice combust more carbohydrates resulting in lower body weights despite increased food intake. The perturbation of carbohydrate metabolism does not require a long term adaptation to the absence of functional peroxisomes as similar metabolic changes were also rapidly induced by acute elimination of Pex5 via adenoviral administration of Cre. Despite its marked activation, peroxisome proliferator-activated receptor ? (PPAR?) was not causally involved in these metabolic perturbations, because all abnormalities still manifested when peroxisomes were eliminated in a peroxisome proliferator-activated receptor ? null background. Instead, AMP-activated kinase activation was responsible for the down-regulation of glycogen synthesis and induction of glycolysis. Remarkably, PGC-1? was suppressed despite AMP-activated kinase activation, a paradigm not previously reported, and they jointly contributed to impaired gluconeogenesis. In conclusion, lack of functional peroxisomes from hepatocytes results in marked disturbances of carbohydrate homeostasis, which are consistent with adaptations to an energy deficit. Because this is primarily due to impaired mitochondrial ATP production, these L-Pex5-deficient livers can also be considered as a model for secondary mitochondrial hepatopathies.

Peeters, Annelies; Fraisl, Peter; van den Berg, Sjoerd; Ver Loren van Themaat, Emiel; Van Kampen, Antoine; Rider, Mark H.; Takemori, Hiroshi; van Dijk, Ko Willems; Van Veldhoven, Paul P.; Carmeliet, Peter; Baes, Myriam

2011-01-01

349

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI34051 induces apoptosis in T-cell lymphomas  

Microsoft Academic Search

We have developed a potent, histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 with >200-fold selectivity over the other HDAC isoforms. PCI-34051 induces caspase-dependent apoptosis in cell lines derived from T-cell lymphomas or leukemias, but not in other hematopoietic or solid tumor lines. Unlike broad-spectrum HDAC inhibitors, PCI-34051 does not cause detectable histone or tubulin acetylation. Cells defective in T-cell receptor signaling

S Balasubramanian; J Ramos; W Luo; M Sirisawad; E Verner; J J Buggy

2008-01-01

350

Post-treatment of an NADPH oxidase inhibitor prevents seizure-induced neuronal death.  

PubMed

The present study sought to evaluate the neuroprotective effects of apocynin, an NADPH oxidase assembly inhibitor, on seizure-induced neuronal death. Apocynin, also known as acetovanillone, is a natural organic compound isolated from the root of Canadian hemp (Apocynum cannabium). It has been extensively studied to determine its disease-fighting capabilities and application in several brain insults, such as traumatic brain injury and stroke. Here we tested the hypothesis that post-treatment of apocynin may prevent seizure-induced neuronal death by suppression of NADPH oxidase-mediated superoxide production. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25mg/kg) in male rats. Apocynin (30mg/kg, i.p.) was injected into the intraperitoneal space two hours after seizure onset. A second injection was performed 24h after seizure. To test whether apocynin inhibits NADPH oxidase activation-induced reactive oxygen species (ROS) production, dihydroethidium (dHEt, 5mg/kg, i.p.) was injected before onset of seizure and ROS production was detected five hours after seizure onset. Neuronal oxidative injury (4HNE), neuronal death (Fluoro Jade-B), blood brain barrier (BBB) disruption (IgG leak), neurotrophil infiltration (MPO) and microglia activation (CD11b) in the hippocampus was evaluated at three days after status epilepticus (SE). Pilocarpine-induced seizure increased p47 immunofluorescence in the plasma membrane of hippocampal neurons at 12h post-insult and apocynin treatment prevented this increase. The present study found that apocynin post-treatment decreased ROS production and lipid peroxidation after seizure and decreased the number of degenerating hippocampal neurons. Apocynin also reduced seizure-induced BBB disruption, neurotrophil infiltration and microglial activation. Taken together, the present results suggest that inhibition of NADPH oxidase by apocynin may have a high therapeutic potential to reduce seizure-induced neuronal dysfunction. PMID:23313582

Kim, Jin Hee; Jang, Bong Geom; Choi, Bo Young; Kim, Hyeong Seop; Sohn, Min; Chung, Tae Nyoung; Choi, Hui Chul; Song, Hong Ki; Suh, Sang Won

2013-01-10

351

Paradoxical effects of a selective cyclooxygenase-2 inhibitor, etodolac, on proliferative changes of forestomach in alloxan-induced diabetic rats  

Microsoft Academic Search

A single intravenous injection of alloxan, a non-genotoxic diabetogenic chemical, induces proliferative changes in forestomach mucosa of rats, and some lesions progress to squamous cell carcinoma accompanied with inflammatory change. The present study was conducted to examine the effects of a selective cyclooxygenase-2 (COX-2) inhibitor, etodolac, on the proliferative changes of forestomach mucosa in alloxan-induced diabetic rats. Alloxan-induced diabetic rats

Tomoya Sano; Kiyokazu Ozaki; Yasushi Kodama; Tetsuro Matsuura; Isao Narama

2009-01-01

352

Cox2 is needed but not sufficient for apoptosis induced by Cox2 selective inhibitors in colon cancer cells  

Microsoft Academic Search

The role of Cox-2 in NSAID-induced apoptosis is debated. We studied the role of Cox-2 inhibition in apoptosis induced by a selective Cox-2 inhibitor, SC236 (a structural analogue of celecoxib) in two colon cancer cell lines, HT29 (expressing Cox-2 protein) and HCT116 (not expressing Cox-2 protein). Apoptosis was quantified by flow cytometry. SC236 0–75 µM decreased cell numbers and induced

B. Agarwal; P. Swaroop; P. Protiva; S. V. Raj; H. Shirin; P. R. Holt

2003-01-01

353

Novel peroxisomal protease Tysnd1 processes PTS1- and PTS2-containing enzymes involved in ?-oxidation of fatty acids  

PubMed Central

Peroxisomes play an important role in ?-oxidation of fatty acids. All peroxisomal matrix proteins are synthesized in the cytosol and post-translationally sorted to the organelle. Two distinct peroxisomal signal targeting sequences (PTSs), the C-terminal PTS1 and the N-terminal PTS2, have been defined. Import of precursor PTS2 proteins into the peroxisomes is accompanied by a proteolytic removal of the N-terminal targeting sequence. Although the PTS1 signal is preserved upon translocation, many PTS1 proteins undergo a highly selective and limited cleavage. Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal ?-oxidation. Tysnd1 itself undergoes processing through the removal of the presumably inhibitory N-terminal fragment. Tysnd1 expression is induced by the proliferator-activated receptor ? agonist bezafibrate, along with the increase in its substrates. A model is proposed where the Tysnd1-mediated processing of the peroxisomal enzymes promotes their assembly into a supramolecular complex to enhance the rate of ?-oxidation.

Kurochkin, Igor V; Mizuno, Yumi; Konagaya, Akihiko; Sakaki, Yoshiyuki; Schonbach, Christian; Okazaki, Yasushi

2007-01-01

354

Effect of a Large Dose of Di (2-ethylhexyl) phthalate (DEHP) on Hepatic Peroxisome in Cynomolgus Monkeys (Macaca Fascicularis)  

PubMed Central

To elucidate the effect of a large dose of di (2-ethylhexyl) phthalate (DEHP), a plasticizer and peroxisome proliferator-activated receptor-? (PPAR?) agonist, on hepatic peroxisomes, we orally administered 1,000 mg/kg/day, once daily, to 3 male and 4 female cynomolgus monkeys for 28 days consecutively. Light-microscopic and electron microscopic examinations of the liver were carried out in conjunction with measurement of the hepatic fatty acid ?-oxidation system (FAOS), carnitine acetyltransferase (CAT) and carnitine palmitoyltransferase (CPT) activities, which are peroxisomal and/or mitochondrial enzyme activities. Electron microscopically, enlargement of the mitochondria was observed with lamellar orientation of the cristae along the major axis. Although the number of peroxisomes showed a tendency to increase when compared with those in a biopsied specimen before treatment, no abnormality in morphology was observed. A slight increase in CPT activity was noted at termination. No changes were noted in hepatic FAOS or CAT activity. In conclusion, although repeated oral treatment of cynomolgus monkeys with a large dose of DEHP induced a subtle increase in the numbers of peroxisomes with slight enlargements of the mitochondria, this low-sensitivity response to peroxisome proliferators in cynomolgus monkeys was considered to be closer to the response in humans than that in rodents.

Nakamura, Chika; Minamide, Yoshiyuki; Kudo, Shinobu; Maeda, Hiroshi; Chihaya, Yutaka; Kamimura, Yasuhiro; Miyajima, Hiroaki; Sasaki, Jun; Goryo, Masanobu; Okada, Kosuke

2010-01-01

355

THE SYNTHESIS AND TURNOVER OF RAT LIVER PEROXISOMES  

PubMed Central

Rat liver peroxisomes have been separated according to size by zonal sedimentation. A method is described for calculating the size of the particles from their final position in the gradient. Peroxisomes seem biochemically homogeneous throughout their size distribution. 3 hr after injection of tritiated leucine, the specific radioactivity of catalase is the same in peroxisomes of different sizes, and it remains so for up to 1 wk after administration of the precursor. This observation rules out the possibility that peroxisomes have an extended period of independent growth. If individual particles maintain an independent existence, they must be formed very rapidly. The other possible explanation is that peroxisomes exchange material within the liver cell.

Poole, Brian; Higashi, Tokuhiko; de Duve, Christian

1970-01-01

356

Aborted Autophagy and Nonapoptotic Death Induced by Farnesyl Transferase Inhibitor and LovastatinS?  

PubMed Central

Exposure of the human malignant peripheral nerve sheath tumor cell lines STS-26T, ST88-14, and NF90-8 to nanomolar concentrations of both lovastatin and farnesyl transferase inhibitor (FTI)-1 but not to either drug alone induced cell death. ST88-14 and NF90-8 cells underwent apoptosis, yet dying STS-26T cells did not. FTI-1 cotreatment induced a strong and sustained autophagic response as indicated by analyses of microtubule-associated protein-1 light chain 3 (LC3)-II accumulation in STS-26T cultures. Extensive colocalization of LC3-positive punctate spots was observed with both lysosome-associated membrane protein (LAMP)-1 and LAMP-2 (markers of late endosomes/lysosomes) in solvent or FTI-1 or lovastatin-treated STS-26T cultures but very little colocalization in lovastatin/FTI-1-cotreated cultures. The absence of colocalization in the cotreatment protocol correlated with loss of LAMP-2 expression. Autophagic flux studies indicated that lovastatin/FTI-1 cotreatment inhibited the completion of the autophagic program. In contrast, rapamycin induced an autophagic response that was associated with cytostasis but maintenance of viability. These studies indicate that cotreatment of STS-26T cells with lovastatin and FTI-1 induces an abortive autophagic program and nonapoptotic cell death.

Wojtkowiak, Jonathan W.; Sane, Komal M.; Kleinman, Miriam; Sloane, Bonnie F.; Reiners, John J.

2011-01-01

357

Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses SEB-Induced Lung Inflammation  

PubMed Central

Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB.

McKallip, Robert J.; Hagele, Harriet F.; Uchakina, Olga N.

2013-01-01

358

Renal papillary cytoplasmic granularity and potassium depletion induced by carbonic anhydrase inhibitors in rats.  

PubMed

Renal papillary cytoplasmic granularity (RPCG) induced by carbonic anhydrase inhibitors (CAIs) in rats is characterized by the accumulation of dense secondary lysosomes in epithelial, endothelial, and interstitial cells and may be related to drug-induced potassium depletion. Female Sprague-Dawley rats were given the CAI, acetazolamide, by gavage. Half were supplemented with 1% potassium chloride in the drinking water. Two treated groups were allowed to recover for 1 or 2 mo. Potassium supplementation inhibited RPCG by 80% but produced little amelioration of the mild 13% decrease in serum potassium induced by 200 mg/kg/day acetazolamide for 28 days. Acetazolamide-induced RPCG is reversible because 1- and 2-mo recovery periods decreased the incidence by 75% and 80%, respectively. The results support the hypothesis that RPCG is related to potassium depletion secondary to carbonic anhydrase inhibition. Because supplementation of potassium chloride had little effect on serum potassium, these data suggest that depletion of renal medullary potassium content is important in the pathogenesis of RPCG as previously suggested by others. Other types of diuretics that produce hypokalemia as a side effect may not deplete medullary potassium since RPCG has not been reported in humans or animals given these drugs. PMID:8115822

Owen, R A; Durand-Cavagna, G; Molon-Noblot, S; Boussiquet-Leroux, C; Berry, P H; Tonkonoh, N; Peter, C P; Gordon, L R

359

The multi-targeted kinase inhibitor sunitinib induces apoptosis in colon cancer cells via PUMA.  

PubMed

Constitutive activation of pro-survival kinases has become a promising target of small molecules with an increasing interest in developing multi-targeted agents. The mechanisms underlying the responsiveness to most agents targeting cancer specific survival pathways are still poorly understood but critical for their clinical application. In this study, we found that sunitinib, a small molecule inhibitor of multiple tyrosine kinases including VEGFRs and PDGFRs induces apoptosis and inhibits cell growth in colon cancer cells in cell culture and xenograft models via the BH3-only protein PUMA. Sunitinib treatment induced PUMA transcription via the AKT/FoxO3a axis. PUMA, BH3 mimetics, or 5-Flurourical sensitized colon cancer cells to sunitinib-induced apoptosis. Furthermore, PUMA was induced by sunitinib treatment in xenograft tumors, and deficiency in PUMA significantly suppressed the anti-tumor effects of sunitinib. Our study suggests that PUMA-mediated apoptosis is important for the therapeutic responses to sunitinib, and activation of the mitochondrial pathway by BH3 mimetics or PUMA manipulation may be useful for improving the antitumor activity of sunitinib. Modulation of PUMA and selective Bcl-2 family members might be potential biomarkers for predicting sunitinib responses. PMID:22912816

Sun, Jing; Sun, Quanhong; Brown, Matthew F; Dudgeon, Crissy; Chandler, Julie; Xu, Xiang; Shu, Yongqian; Zhang, Lin; Yu, Jian

2012-08-17

360

The translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice  

PubMed Central

Cachexia, or muscle-wasting syndrome, is one of the major causes of death in patients affected by diseases such as cancer, AIDS and sepsis. However, no effective anti-cachectic treatment is currently available. Here we show that a low dose of pateamine A, an inhibitor of translation initiation, prevents muscle wasting caused by the cytokines interferon ? and tumour necrosis factor ? or by C26-adenocarcinoma tumours. Surprisingly, although high doses of pateamine A abrogate general translation, low doses selectively inhibit the expression of pro-cachectic factors such as inducible nitric oxide synthase. This selectivity depends on the 5?UTR of inducible nitric oxide synthase messenger RNA (mRNA) that, unlike the 5?UTR of MyoD mRNA, promotes the recruitment of inducible nitric oxide synthase mRNA to stress granules, where its translation is repressed. Collectively, our data provide a proof of principle that nontoxic doses of compounds such as pateamine A could be used as novel drugs to combat cachexia-induced muscle wasting.

Di Marco, Sergio; Cammas, Anne; Lian, Xian Jin; Kovacs, Erzsebet Nagy; Ma, Jennifer F.; Hall, Derek T.; Mazroui, Rachid; Richardson, John; Pelletier, Jerry; Gallouzi, Imed Eddine

2012-01-01

361

Phosphodiesterase 5 inhibitors prevent 3,4-methylenedioxymethamphetamine-induced 5-HT deficits in the rat.  

PubMed

Phosphodiesterase 5 (PDE5) inhibitors are often used in combination with club drugs such as 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). We investigated the consequences of such combination in the serotonergic system of the rat. Oral administration of sildenafil citrate (1.5 or 8 mg/kg) increased brain cGMP levels and protected in a dose-dependent manner against 5-hydroxytryptamine depletions caused by MDMA (3 x 5 mg/kg, i.p., every 2 h) in the striatum, frontal cortex and hippocampus without altering the acute hyperthermic response to MDMA. Intrastriatal administration of the protein kinase G (PKG) inhibitor, KT5823 [(9S, 10R, 12R)-2,3,9,10,11,12-Hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid, methyl ester)], suppressed sildenafil-mediated protection. By contrast, the cell permeable cGMP analogue, 8-bromoguanosine cyclic 3',5'-monophosphate, mimicked sildenafil effects further suggesting the involvement of the PKG pathway in mediating sildenafil protection. Because mitochondrial ATP-sensitive K(+) channels are a target for PKG, we next administered the specific mitochondrial ATP-sensitive K(+) channel blocker, 5-hydroxydecanoic acid, 30 min before sildenafil. 5-hydroxydecanoic acid completely reversed the protection afforded by sildenafil, thereby implicating the involvement of mitochondrial ATP-sensitive K(+) channels. Sildenafil also increased Akt phosphorylation, and so the possible involvement of the Akt/endothelial nitric oxide synthase (eNOS)/sGC signalling pathway was analysed. Neither the phosphatidylinositol 3-kinase inhibitor, wortmannin, nor the selective eNOS inhibitor, L-N5-(1-iminoethyl)-L-ornithine dihydrochloride, reversed the protection afforded by sildenafil, suggesting that Akt/eNOS/sGC cascade does not participate in the protective mechanisms. Our data also show that the protective effect of sildenafil can be extended to vardenafil, another PDE5 inhibitor. In conclusion, sildenafil protects against MDMA-induced long-term reduction of indoles by a mechanism involving increased production of cGMP and subsequent activation of PKG and mitochondrial ATP-sensitive K(+) channel opening. PMID:19187094

Puerta, Elena; Hervias, Isabel; Goñi-Allo, Beatriz; Lasheras, Berta; Jordan, Joaquin; Aguirre, Norberto

2009-02-01

362

Tissue Inhibitor of Matrix Metalloproteinase-1 Mediates Erythropoietin-induced Neuroprotection in Hypoxia Ischemia  

PubMed Central

Previous studies have shown that erythropoietin (EPO) is neuroprotective in both in vivo and in vitro models of hypoxia ischemia. However theses studies hold limited clinical translations because the underlying mechanism remains unclear and the key molecules involved in EPO-induced neuroprotection are still to be determined. This study investigated if tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and if its upstream regulator signaling molecule Janus kinase-2 (JAK-2) are critical in EPO-induced neuroprotection. Hypoxia Ischemia (HI) was modeled in-vitro by oxygen and glucose deprivation (OGD) and in-vivo by a modified version of Rice-Vannucci model of HI in 10-day-old rat pups. EPO treated cells were exposed to AG490, an inhibitor of JAK-2 or TIMP-1 neutralizing antibody for 2 hours with OGD. Cell death, phosphorylation of JAK-2 and signal transducers and activators of transcription protein-3 (STAT-3), TIMP-1 expression, and matrix metalloproteinase-9 (MMP-9) activity were measured and compared with normoxic group. Hypoxic ischemic animals were treated one hour following HI and evaluated 48 hours after. Our data showed that EPO significantly increased cell survival, associated with increased TIMP-1 activity, phosphorylation of JAK-2, STAT-3, and decreased MMP-9 activity in vivo and in vitro. EPO’s protective effects were reversed by inhibition of JAK-2 or TIMP-1 in both models. We concluded that JAK-2, STAT-3 and TIMP-1 are key mediators of EPO-induced neuroprotection during hypoxia ischemia injury.

Souvenir, Rhonda; Fathali, Nancy; Ostrowski, Robert P.; Lekic, Tim; Zhang, John H.; Tang, Jiping

2011-01-01

363

Isoflurane-Induced Spatial Memory Impairment in Mice is Prevented by the Acetylcholinesterase Inhibitor Donepezil  

PubMed Central

Although many studies have shown that isoflurane exposure impairs spatial memory in aged animals, there are no clinical treatments available to prevent this memory deficit. The anticholinergic properties of volatile anesthetics are a biologically plausible cause of cognitive dysfunction in elderly subjects. We hypothesized that pretreatment with the acetylcholinesterase inhibitor donepezil, which has been approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease, prevents isoflurane-induced spatial memory impairment in aged mice. In present study, eighteen-month-old mice were administered donepezil (5 mg/kg) or an equal volume of saline by oral gavage with a feeding needle for four weeks. Then the mice were exposed to isoflurane (1.2%) for six hours. Two weeks later, mice were subjected to the Morris water maze to examine the impairment of spatial memory after exposure to isoflurane. After the behavioral test, the mice were sacrificed, and the protein expression level of acetylcholinesterase (AChE), choline acetylase (ChAT) and ?7 nicotinic receptor (?7-nAChR) were measured in the brain. Each group consisted of 12 mice. We found that isoflurane exposure for six hours impaired the spatial memory of the mice. Compared with the control group, isoflurane exposure dramatically decreased the protein level of ChAT, but not AChE or ?7-nAChR. Donepezil prevented isoflurane-induced spatial memory impairments and increased ChAT levels, which were downregulated by isoflurane. In conclusions, pretreatment with the AChE inhibitor donepezil prevented isoflurane-induced spatial memory impairment in aged mice. The mechanism was associated with the upregulation of ChAT, which was decreased by isoflurane.

Wang, Beilei; Xu, Huan; Li, Wen; Chen, Jie; Wang, Xiangrui

2011-01-01

364

Anti-angiogenic activity of sesterterpenes; natural product inhibitors of FGF-2-induced angiogenesis.  

PubMed

Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is of physiological and pathological importance. We have investigated the anti-angiogenic potential of two naturally occurring sesterterpenes, leucosesterterpenone (compound 1) and leucosterlactone (compound 2) isolated from the Himalayan plant Leucosceptrum canum and identified as having biological activity in preliminary screening. Compound 1 inhibited fibroblast growth factor-2-induced proliferation, migration in a wounding assay, chemotaxis and tube formation with small vessel (human dermal) and large vessel (bovine aortic) endothelial cells while compound 2 was largely inactive. Both compounds were also active in an in vivo angiogenic model using the chick chorioallantoic membrane. Neither compounds showed inhibitory activity in the absence of fibroblast growth factor-2. We were able to demonstrate in a binding assay that compounds 1 and 2 bound to the fibroblast growth factor-2 receptor-1 with IC(50) values of 1.4 +/- 0.956 and 132.47 +/- 7.90 muM, respectively, with a concomitant down regulation of phosphorylated ERK1/2 but did not bind to receptor-2. Compound 1 was less hydrophobic than compound 2 and this may contribute to its increased activity. Compound 1 is a new addition to the small number of inhibitors of fibroblast growth factor-2-induced angiogenesis. The compound was a specific inhibitor in that it had no effect on vascular endothelial growth factor or epithelial growth factor-induced angiogenesis. Since angiogenesis is essential for tumour development we conclude that these compounds may have potential as anti-tumour agents. PMID:18330714

Hussain, S; Slevin, M; Matou, S; Ahmed, N; Choudhary, M Iqbal; Ranjit, R; West, D; Gaffney, J

2008-03-11

365

A mammalian steroid action inhibitor spironolactone retards plant growth by inhibition of brassinosteroid action and induces light-induced gene expression in the dark  

Microsoft Academic Search

We screened steroid derivatives and found that spironolactone, an inhibitor of both 17?-hydroxysteroid dehydrogenase (17?-HSD) and aldosterone receptor, is an inhibitor of phytohormone brassinosteroid (BR) action in plants. Under both dark and light growing conditions, spironolactone induced morphological changes in Arabidopsis, characteristic of brassinosteroid-deficient mutants. Spironolactone-treated plants were also nearly restored to the wild-type phenotype by treatment with additional BRs.

Tadao Asami; Keimei Oh; Yusuke Jikumaru; Yukihisa Shimada; Iriko Kaneko; Takeshi Nakano; Suguru Takatsuto; Shozo Fujioka; Shigeo Yoshida

2004-01-01

366

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas.  

PubMed

We have developed a potent, histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 with >200-fold selectivity over the other HDAC isoforms. PCI-34051 induces caspase-dependent apoptosis in cell lines derived from T-cell lymphomas or leukemias, but not in other hematopoietic or solid tumor lines. Unlike broad-spectrum HDAC inhibitors, PCI-34051 does not cause detectable histone or tubulin acetylation. Cells defective in T-cell receptor signaling were still sensitive to PCI-34051-induced apoptosis, whereas a phospholipase C-gamma1 (PLCgamma1)-defective line was resistant. Jurkat cells showed a dose-dependent decrease in PCI-34051-induced apoptosis upon treatment with a PLC inhibitor U73122, but not with an inactive analog. We found that rapid intracellular calcium mobilization from endoplasmic reticulum (ER) and later cytochrome c release from mitochondria are essential for the apoptotic mechanism. The rapid Ca(2+) flux was dependent on PCI-34051 concentration, and was blocked by the PLC inhibitor U73122. Further, apoptosis was blocked by Ca(2+) chelators (BAPTA) and enhanced by Ca(2+) effectors (thapsigargin), supporting this model. These studies show that HDAC8-selective inhibitors have a unique mechanism of action involving PLCgamma1 activation and calcium-induced apoptosis, and could offer benefits including a greater therapeutic index for treating T-cell malignancies. PMID:18256683

Balasubramanian, S; Ramos, J; Luo, W; Sirisawad, M; Verner, E; Buggy, J J

2008-02-07

367

Catalase degradation in sunflower cotyledons during peroxisome transition from glyoxysomal to leaf peroxisomal function. [Helianthus annuus  

SciTech Connect

First order rate constant for the degradation (degradation constants) of catalase in the cotyledons of sunflower (Helianthus annuus L.) were determined by measuring the loss of catalase containing /sup 14/C-labeled heme. During greening of the cotyledons, a period when peroxisomes change from glyoxysomal to leaf peroxisomal function, the degradation of glyoxysomal catalase is significantly slower than during all other stages of cotyledon development in light or darkness. The degradation constant during the transition stage of peroxisome function amounts to 0.205 day/sup -1/ in contrast to the constants ranging from 0.304 day/sup -1/ to 0.515 day/sup -1/ during the other developmental stages. Density labeling experiments comprising labeling of catalase with /sup 2/H/sub 2/O and its isopycnic centrifugation on CsCl gradients demonstrated that the determinations of the degradation constants were not substantially affected by reutilization of /sup 14/C-labeled compounds for catalase synthesis. The degradation constants for both glyoxysomal catalase and catalase synthesized during the transition of peroxisome function do not differ. This was shown by labeling the catalases with different isotopes and measuring the isotope ratio during the development of the cotyledons. The results are inconsistent with the concept that an accelerated and selective degradation of glyoxysomes underlies the change in peroxisome function. The data suggest that catalase degradation is at least partially due to an individual turnover of catalase and does not only result from a turnover of the whole peroxisomes.

Eising, R.; Gerhardt, B.

1987-06-01

368

Hesperetin, a Selective Phosphodiesterase 4 Inhibitor, Effectively Suppresses Ovalbumin-Induced Airway Hyperresponsiveness without Influencing Xylazine/Ketamine-Induced Anesthesia  

PubMed Central

Hesperetin, a selective phosphodiesterase (PDE)4 inhibitor, is present in the traditional Chinese medicine, “Chen Pi.” Therefore, we were interested in investigating its effects on ovalbumin- (OVA-) induced airway hyperresponsiveness, and clarifying its rationale for ameliorating asthma and chronic obstructive pulmonary disease (COPD). Hesperetin was revealed to have a therapeutic (PDE4H/PDE4L) ratio of >11. Hesperetin (10?~?30??mol/kg, intraperitoneally (i.p.)) dose-dependently and significantly attenuated the airway hyperresponsiveness induced by methacholine. It also significantly suppressed the increases in total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-?, and tumor necrosis factor-? in bronchoalveolar lavage fluid (BALF). It dose-dependently and significantly suppressed total and OVA-specific immunoglobulin E levels in the BALF and serum. However, hesperetin did not influence xylazine/ketamine-induced anesthesia, suggesting that hesperetin has few or no emetic effects. In conclusion, the rationales for ameliorating allergic asthma and COPD by hesperetin are anti-inflammation, immunoregulation, and bronchodilation.

Shih, Chung-Hung; Lin, Ling-Hung; Hsu, Hsin-Te; Wang, Kuo-Hsien; Lai, Chi-Yin; Chen, Chien-Ming; Ko, Wun-Chang

2012-01-01

369

A novel potent inhibitor of inducible nitric oxide inhibitor, ONO1714, reduces intestinal ischemia–reperfusion injury in rats  

Microsoft Academic Search

The overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) may contribute to the pathophysiology of intestinal injury induced by ischemia–reperfusion. The aim of the present study was to examine the effect of selective iNOS inhibition by a cyclic amidine analogue, ONO-1714, on reperfusion-induced small intestinal injury and inflammation in rats. Intestinal damage was induced in male Sprague–Dawley

Yuji Naito; Tomohisa Takagi; Hiroshi Ichikawa; Naoya Tomatsuri; Masaaki Kuroda; Yutaka Isozaki; Kazuhiro Katada; Kazuhiko Uchiyama; Satoshi Kokura; Norimasa Yoshida; Takeshi Okanoue; Toshikazu Yoshikawa

2004-01-01

370

Tissue-specific induction of 17‚-hydroxysteroid dehydrogenase type IV by peroxisome proliferator chemicals is dependent on the peroxisome proliferator-activated receptor Æ  

Microsoft Academic Search

Abstract The,17‚-hydroxysteroid dehydrogenase,(17‚-HSD) family of proteins regulates the levels of the active 17‚- hydroxy forms of sex steroids. The expression of 17‚-HSD type IV is induced by peroxisome proliferator chemicals (PPC) in rat liver. In order to characterize more generally the impact of PPC on 17‚-HSD expression, we deter- mined (1) if expression of other members,of the 17‚-HSD family was

L Q Fan; R C Cattley; J C Corton

371

Defects in mouse nephrogenesis induced by selective and non-selective cyclooxygenase-2 inhibitors  

PubMed Central

BACKGROUND AND PURPOSE Deletion of the cyclooxygenase-2 (COX-2) gene causes impairment of kidney development, but the effect of selective inhibitors of COX-2 (coxibs) or the non-selective inhibitors of COX (the classical non-steroidal anti-inflammatory drugs; NSAIDs) on kidney development was less well described. EXPERIMENTAL APPROACH We assessed the effects of equipotent analgesic doses of celecoxib, rofecoxib, valdecoxib, etoricoxib and lumiracoxib and of the NSAIDs, diclofenac and naproxen, on postpartum kidney development in mice, from postnatal day 1 (P1) to P21. KEY RESULTS All the COX inhibitors, at the doses used, blocked COX-2 activity by more than 80% as assayed by PGE2 synthesis in lipopolysaccharide-stimulated mouse blood samples. Rofecoxib, etoricoxib and lumiracoxib exerted the most marked impairment of postpartum kidney development, demonstrated by attenuation of kidney growth, reduction in size of glomeruli, increase in immature superficial glomeruli, thinning of subcapsular cortical mass and reduction in size of juxtamedullary glomeruli. These defects were less severe than those in kidneys from COX-2?/? mice. Administration of diclofenac and naproxen revealed renal defects similar to those after coxib treatment, but both NSAIDs induced greater arrest of immature superficial glomeruli in the outer cortex and increased the number of undifferentiated proliferating cell nuclear antigen-positive cells. Treatment with celecoxib or valdecoxib caused only minimal changes in renal morphology. CONCLUSIONS AND IMPLICATIONS Classical NSAIDs cause similar or even stronger nephrodysgenesis than the coxibs. Also, the ranking of coxibs regarding adverse effects on renal development, using equi-analgesic doses, is rofecoxib = etoricoxib = lumiracoxib > valdecoxib > celecoxib.

Olliges, Anke; Wimmer, Stefanie; Nusing, Rolf M

2011-01-01

372

Natural Product-Based Inhibitors of Hypoxia-Inducible Factor-1 (HIF-1)  

PubMed Central

The transcription factor hypoxia-inducible factor-1 (HIF-1) regulates the expression of more than 70 genes involved in cellular adaptation and survival under hypoxic stress. Activation of HIF-1 is associated with numerous physiological and pathological processes that include tumorigenesis, vascular remodeling, inflammation, and hypoxia/ischemia-related tissue damage. Clinical studies suggested that HIF-1 activation correlates directly with advanced disease stages and treatment resistance among cancer patients. Preclinical studies support the inhibition of HIF-1 as a major molecular target for antitumor drug discovery. Considerable effort is underway, in government laboratories, industry and academia, to identify therapeutically useful small molecule HIF-1 inhibitors. Natural products (low molecular weight organic compounds produced by plants, microbes, and animals) continue to play a major role in modern antitumor drug discovery. Most of the compounds discovered to inhibit HIF-1 are natural products or synthetic compounds with structures that are based on natural product leads. Natural products have also served a vital role as molecular probes to elucidate the pathways that regulate HIF-1 activity. Natural products and natural product-derived compounds that inhibit HIF-1 are summarized in light of their biological source, chemical class, ancd effect on HIF-1 and HIF-mediated gene regulation. When known, the mechanism(s) of action of HIF-1 inhibitors are described. Many of the substances found to inhibit HIF-1 are non-druggable compounds that are too cytotoxic to serve as drug leads. The application of high-throughput screening methods, complementary molecular-targeted assays, and structurally diverse chemical libraries hold promise for the discovery of therapeutically useful HIF-1 inhibitors.

Nagle, Dale G.; Zhou, Yu-Dong

2010-01-01

373

High Throughput Screening for Small Molecule Inhibitors of Heparin-induced Tau Fibril Formation  

PubMed Central

A library of ?51,000 compounds was interrogated by high throughput screening (HTS) using a heparin-induced tau fibrillization assay. HTS was conducted with bacterially expressed recombinant tau fragment K18 and the reaction was monitored by thioflavine T fluorescence. Hits meeting criteria set for selection in HTS were further evaluated in a panel of assays designed (a) to confirm the initial results and (b) to identify possible false positives arising from non-specific mechanisms or assay dependent artifacts. Two 2,3-di(furan-2-yl)-quinoxalines were confirmed as inhibitors of tau fibrillization with IC50s in the low micromolar range (l–3 ?M). Among false positives hits, members of the pyrimidotriazines, benzofurans, porphyrins and anthraquinones, inhibited tau fibrillization by generating peroxides via catalytic redox cycles due to the reducing agent dithiothreitol (DTT) in the assay. This study delineates focused strategies for HTS of tau fibrillization inhibitors that are relevant to drug discovery for Alzheimer's disease and related tauopathies.

Crowe, Alex; Ballatore, Carlo; Hyde, Edward; Trojanowski, John Q.; Lee, Virginia M.-Y.

2009-01-01

374

Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli  

PubMed Central

Modulation of bacterial chromosomal supercoiling is a function of DNA gyrase-catalyzed strand breakage and rejoining. This reaction is exploited by both antibiotic and proteic gyrase inhibitors, which trap the gyrase molecule at the DNA cleavage stage. Owing to this interaction, double-stranded DNA breaks are introduced and replication machinery is arrested at blocked replication forks. This immediately results in bacteriostasis and ultimately induces cell death. Here we demonstrate, through a series of phenotypic and gene expression analyses, that superoxide and hydroxyl radical oxidative species are generated following gyrase poisoning and play an important role in cell killing by gyrase inhibitors. We show that superoxide-mediated oxidation of iron–sulfur clusters promotes a breakdown of iron regulatory dynamics; in turn, iron misregulation drives the generation of highly destructive hydroxyl radicals via the Fenton reaction. Importantly, our data reveal that blockage of hydroxyl radical formation increases the survival of gyrase-poisoned cells. Together, this series of biochemical reactions appears to compose a maladaptive response, that serves to amplify the primary effect of gyrase inhibition by oxidatively damaging DNA, proteins and lipids.

Dwyer, Daniel J; Kohanski, Michael A; Hayete, Boris; Collins, James J

2007-01-01

375

Induction of secretory leukocyte protease inhibitor (SLPI) in estradiol valerate (EV) induced polycystic ovary.  

PubMed

The excessive administration of estradiol valerate induces polycystic ovary syndrome by formation of follicular cysts. Secretory leukocyte protease inhibitor (SLPI) promotes wound healing by decreasing the excessive inflammatory response, stimulating keratinocyte proliferation and increasing collagen deposition through the inhibition of protease activity. In this study, SLPI expression was high in the ovarian stroma, corpus luteum, unilaminar primary follicle, multilaminar primary follicle and granulose layer of the antral follicle in polycystic ovary (PCO) compared to the normal ovary. SLPI was expressed strongly in the theca around the cyst in PCO compared to the mature follicle in the normal ovary. The levels of SLPI mRNA and protein expression were higher in PCO than in the normal ovary, and the level of MMP-2 expression was lower in PCO. These results showed that the formation of a cyst was initiated from a multilaminar primary follicle and SLPI expression was increased depending on the morphological changes in the follicle and ovarian stroma. Therefore, an increase in SLPI may be related to the suppression of tissue disruption, and act as a protease inhibitor in PCO, suggesting that SLPI increases independently of the estrogen concentration in pathological tissues. PMID:21910062

Park, Jin-Ju; Bae, Chun Sik; Choi, Baik-Dong; Jeong, Soon-Jeong; Wang, Guanlin; Lim, Do-Seon; Kim, Byung-Ock; Cho, Young-Sik; Kim, Sun-Ju; Jeong, Moon-Jin

2011-09-11

376

Integrated Analysis of Drug-Induced Gene Expression Profiles Predicts Novel hERG Inhibitors  

PubMed Central

Growing evidence suggests that drugs interact with diverse molecular targets mediating both therapeutic and toxic effects. Prediction of these complex interactions from chemical structures alone remains challenging, as compounds with different structures may possess similar toxicity profiles. In contrast, predictions based on systems-level measurements of drug effect may reveal pharmacologic similarities not evident from structure or known therapeutic indications. Here we utilized drug-induced transcriptional responses in the Connectivity Map (CMap) to discover such similarities among diverse antagonists of the human ether-à-go-go related (hERG) potassium channel, a common target of promiscuous inhibition by small molecules. Analysis of transcriptional profiles generated in three independent cell lines revealed clusters enriched for hERG inhibitors annotated using a database of experimental measurements (hERGcentral) and clinical indications. As a validation, we experimentally identified novel hERG inhibitors among the unannotated drugs in these enriched clusters, suggesting transcriptional responses may serve as predictive surrogates of cardiotoxicity complementing existing functional assays.

Babcock, Joseph J.; Du, Fang; Xu, Kaiping; Wheelan, Sarah J.; Li, Min

2013-01-01

377

Amelioration of cisplatin-induced mouse renal lesions by a cyclooxygenase (COX)-2 selective inhibitor.  

PubMed

In this study, we investigated the effects of the cyclooxygenase (COX)-2 selective inhibitor, meloxicam, on cisplatin-induced inflammation, oxidative stress and renal lesions in BALB/c mice. A single cisplatin injection (13mg/kg, i.p.) significantly increased plasma creatinine, blood urea nitrogen and urinary glucose accompanied by a concomitant increase in COX-2 mRNA and COX-2 protein levels. These changes in renal lesion parameters were diminished by simultaneous treatment of meloxicam (0.7mg/kg/day in drinking water). The expression of oxidative stress markers, p47(phox), p67(phox), hemoxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and 4-hydroxy-2-nonenal (4-HNE)-modified protein were increased with cisplatin injection. Simultaneous treatment of meloxicam with cisplatin significantly inhibited the increase in p47(phox), HO-1 and 4-HNE-modified protein. The phosphorylation of extracellular regulated kinase (ERK) and c-jun-N-terminal kinase (JNK) were increased with cisplatin injection, but these changes were inhibited by meloxicam. Moreover, concomitant meloxicam treatment also prevented the cisplatin-induced infiltration of macrophages to the tubulointerstitial area. These results suggest that meloxicam can ameliorate cisplatin-induced mouse renal lesions, potentially through the inhibition of inflammatory and oxidative stress responses. PMID:23747596

Honma, Shigeyoshi; Takahashi, Naho; Shinohara, Masahiro; Nakamura, Kazuki; Mitazaki, Satoru; Abe, Sumiko; Yoshida, Makoto

2013-06-04

378

The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor on Noise- Induced Hearing Loss  

PubMed Central

Objective(s): Noise-induced hearing loss (NIHL) is the major cause of acquired hearing loss. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, is a non- steroidal anti- inflammatory drug (NSAID) with known antioxidant and antineoplastic activity. Therefore, we monitored the extent of temporary noise- induced threshold shifts (TTS) and cochlear damage caused by high level 4- kHz noise exposure to verify the differences with those pretreated with celecoxib. Materials and Methods: Ten male albino guinea pigs (300-350 g in weight) were randomly allocated into two groups: the primal group was exposed to 4- kHz octave band noise at 102 dB SPL for 3 hrs (group 1, n=5); the latter pretreated with 50 mg/ kg celecoxib for 3 days, then exposed to noise (group 2, n=5). Before exposure and one hr after noise exposure, threshold shifts were evaluated with auditory brainstem responses (ABR) and finally the animals were euthanized for histological evaluation. Results: Comparing the threshold shifts before/after noise exposure with those pretreated, we found out that TTS caused by noise exposure did not show significant mitigation by celecoxib. By observing the organ of Corti at lower middle turn of cochlea in celecoxib pretreated group, considerable hair cell loss was discovered. Conclusion: The current study clearly confirmed that celecoxib had no attenuation against temporary noise-induced hearing loss.

Pourbakht, Akram

2013-01-01

379

Amplification of CRKL induces transformation and EGFR inhibitor resistance in human non small cell lung cancers  

PubMed Central

We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non-small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortalized human airway epithelial cells promoted anchorage independent growth and tumorigenicity. Oncogenic CRKL activates SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in EGFR mutant cells induces resistance to gefitinib by activating ERK and AKT signaling. We identified CRKL amplification in an EGFR inhibitor treated lung adenocarcinoma that was not present prior to treatment. These observations show that CRKL overexpression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.

Cheung, Hiu Wing; Du, Jinyan; Boehm, Jesse S.; He, Frank; Weir, Barbara A.; Wang, Xiaoxing; Butaney, Mohit; Sequist, Lecia V.; Luo, Biao; Engelman, Jeffrey A.; Root, David E.; Meyerson, Matthew; Golub, Todd R.; Janne, Pasi A.; Hahn, William C.

2011-01-01

380

Human and mouse induced pluripotent stem cells are differentially reprogrammed in response to kinase inhibitors.  

PubMed

Conventional human induced pluripotent stem cells (hiPSCs), reprogrammed from somatic cells by induced expression of Oct4, Sox2, Klf4, and c-Myc, are phenotypically different from mouse embryonic stem cells (ESCs). In mice, culture in N2B27 serum-free 2i media (mitogen-activated protein kinase/extracellular signal-regulated kinase and glycogen synthase kinase 3 inhibitors; PD0325901 and CHIR99021) plus leukemia inhibitory factor (LIF) (2i+LIF medium) enriches for germline competent ESCs. Here, we demonstrate that flat-shaped hiPSC colonies can be reprogrammed into bowl-shaped multi-potent stem cells (2i-hiPSCs) by using 2i+LIF medium. Mechanical dissociation of 2i-hiPSC colonies enables stable maintenance for >20 passages. Importantly, gene expression profiling demonstrated that 2i-hiPSCs more closely resemble primitive neural stem cells (PNSCs). Notably, this 2i-induced phenotype was generated from conventional hiPSCs, but not human ESCs (hESCs), thus correlating with the observation of neuroectodermal SOX1-positive colonies in conventional hiPSCs, but not hESCs in 2i+LIF medium. Thus, 2i-hiPSCs, which are nonteratoma forming PNSCs, may repr