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1

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

PubMed

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 (15dPGJ2) 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 15dPGJ2 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. PMID:15707588

Tsao, Wei-Chia; Wu, Hsiao-Mei; Chi, Kwan-Hwa; Chang, Ying-Hsin; Lin, Wan-Wan

2005-03-10

2

NADH induces the generation of superoxide radicals in leaf peroxisomes. [Pisum sativum L  

SciTech Connect

In peroxisomes isolated from pea leaves (Pisum sativum L.) the production of superoxide free radicals (O{sub 2}{sup {minus}}) by xanthine and NADH was investigated. In peroxisomal membranes, 100 micromolar NADH induced the production of O{sub 2}{sup {minus}} radicals. In the soluble fractions of peroxisomes, no generation of O{sub 2}{sup {minus}} radicals was observed by incubation with either NADH or xanthine, although xanthine oxidase was found located predominantly in the matrix of peroxisomes. The failure of xanthine to induce superoxide generation was probably due to the inability to fully suppress the endogenous Mn-superoxide dismutase activity by inhibitors which were inactive against xanthine oxidase. The generation of superoxide radicals in leaf peroxisomes together with the recently described production of these oxygen radicals in glyoxysomes suggests that O{sub 2}{sup {minus}} generation could be a common metabolic property of peroxisomes and further supports the existence of active oxygen-related roles for peroxisomes in cellular metabolism.

del Rio, L.A.; Sandalio, L.M.; Palma, J.M. (Unidad de Bioquimica Vegetal, Granada (Spain)); Fernandez, V.M.; Ruperez, F.L. (Instituto de Catalisis, Madrid (Spain))

1989-03-01

3

HYDROGEN PEROXIDE INDUCED OXIDATION OF PEROXISOMAL MALATE SYNTHASE AND CATALASE.  

E-print Network

Page 1 HYDROGEN PEROXIDE INDUCED OXIDATION OF PEROXISOMAL MALATE SYNTHASE AND CATALASE. Pria Anand1-6100 E-mail: robdon@gwu.edu Short title: Oxidation of Peroxisomal Malate Synthase and Catalase * Revised Manuscript (Unmarked) Click here to view linked References #12;Page 2 Abbreviations CAT , catalase; MS

Simha, Rahul

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

Discrete Targeting Signals Direct Pmp47 to Oleate-induced Peroxisomes in Saccharomyces cerevisiae*  

E-print Network

Discrete Targeting Signals Direct Pmp47 to Oleate-induced Peroxisomes in Saccharomyces cerevisiae 75390-9041 Pmp47 is a peroxisomal membrane protein consisting of six transmembrane domains (TMDs). We for peroxisomal tar- geting, and similar basic targeting motifs have been found in other peroxisomal membrane

Brand, Paul H.

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. PMID:18776129

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

2009-01-01

7

FEBS J . Author manuscript Visfatin is induced by peroxisome proliferator-activated receptor gamma in  

E-print Network

FEBS J . Author manuscript Page /1 11 Visfatin is induced by peroxisome proliferator/PBEF/NAMPT. The nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR) exerts anti-inflammatory effects

Boyer, Edmond

8

Peroxisome Proliferator-Activated Receptor-/ Protects Against Chemically Induced Liver Toxicity in Mice  

E-print Network

Peroxisome Proliferator-Activated Receptor- / Protects Against Chemically Induced Liver Toxicity M. Ward,5 Frank J. Gonzalez,4 and Jeffrey M. Peters1-3 Potential functional roles for the peroxisome bind- ing to peroxisome proliferator response elements, leading to increased expression of PPAR target

Omiecinski, Curtis

9

PEX11? induces peroxisomal gene expression and alters peroxisome number during early Xenopus laevis development  

Microsoft Academic Search

Background  Peroxisomes are organelles whose roles in fatty acid metabolism and reactive oxygen species elimination have contributed much\\u000a attention in understanding their origin and biogenesis. Many studies have shown that de novo peroxisome biogenesis is an important regulatory process, while yeast studies suggest that total peroxisome numbers are in\\u000a part regulated by proteins such as Pex11, which can facilitate the division

Mark A Fox; Logan A Walsh; Michelle Nieuwesteeg; Sashko Damjanovski

2011-01-01

10

Expression level of methanol-inducible peroxisomal proteins and peroxisome morphology are affected by oxygen conditions and mitochondrial respiratory pathway function in the methylotrophic yeast Candida boidinii.  

PubMed

In the methylotrophic yeast, Candida boidinii, methanol-inducible peroxisomal proteins, for example alcohol oxidase (AOD), dihydroxyacetone synthase (DAS), and peroxisomal glutathione peroxidase (Pmp20), were induced only under aerobic conditions, while expression of PMP47 encoding peroxisomal integral membrane protein Pmp47 was independent of oxygen conditions. Expression of the methanol-inducible peroxisomal enzymes was repressed by inhibition of the mitochondrial respiratory chain. In the respiratory-deficient (?0) mutant strain, their induction was at very low levels despite the presence of oxygen, whereas the expression of PMP47 was unaffected. Taken together, these facts indicate that C. boidinii can sense oxygen conditions, and that mitochondrial respiratory function may have a profound effect on induction of methanol-inducible gene expression of peroxisomal proteins. Peroxisome morphology was also affected by oxygen conditions and respiratory function. Under hypoxic conditions or respiration-inhibited conditions, cells induced by methanol contained small peroxisomes, indicating that peroxisome biogenesis and the protein import machinery were not affected by oxygen conditions but that peroxisome morphology was dependent on induction of peroxisomal matrix proteins. PMID:23448597

Fujimura, Shuki; Yurimoto, Hiroya; Kurimoto, Shota; Matsufuji, Yoshimi; Ito, Takashi; Hayakawa, Takashi; Tomizuka, Noboru; Sakai, Yasuyoshi; Nakagawa, Tomoyuki

2013-06-01

11

Hydrogen peroxide induced oxidation of peroxisomal malate synthase and catalase  

Microsoft Academic Search

Peroxisomes contain oxidases that produce H2O2, which can result in protein oxidation. To test the vulnerability of peroxisomal proteins to oxidation in vivo the organelles were isolated from castor bean endosperm incubated with H2O2. When peroxisomes were exposed to H2O2in vivo, the peroxisomal proteins exhibited an increase in carbonylation as detected in avidin blots of biotin hydrazide derivatized samples. Biotin-tagged

Pria Anand; Yoon Kwak; Rahul Simha; Robert P. Donaldson

2009-01-01

12

Endothelial Peroxisomal Dysfunction and Impaired Pexophagy Promotes Oxidative Damage in Lipopolysaccharide-Induced Acute Kidney Injury  

PubMed Central

Abstract Aims: We examined that (a) how the endotoxic stress affects peroxisomal function and autophagic degradation of peroxisomes—pexophagy, (b) how a superimposed dysfunction of lysosomes and pexophagy modifies responses to lipopolysaccharide (LPS), and (c) the mechanisms of peroxisomal contribution to renal injury. To accomplish this, we used lysosome-defective Lyst-mice in vivo and primary endothelial cells in vitro, and compared the responses with wild-type (WT) littermates. Results: LPS induced pexophagic degradation, followed by proliferation of peroxisomes in WT mice, which was abolished in Lyst-mice. Lyst-mice exhibited impaired activation of catalase, which together with preserved hydrogen peroxide-generating ?-oxidation resulted in redox disequilibrium. LPS treatment induced a heightened inflammatory response, increased oxidative damage, and aggravated renal injury in Lyst-mice. Similarly, as in vivo, LPS-activated lysosomal (LYS) pexophagy and transiently repressed peroxisomes in vitro, supported by reduced peroxisomal density in the vicinity of lysosomes. Peroxisomal dynamics was also abolished in lysosome-defective cells, which accumulated peroxisomes with compromised functions and intraorganellar redox imbalance. Innovation: We demonstrated that pexophagy is a default response to endotoxic injury. However, when LYS dysfunction (a frequent companion of chronic diseases) is superimposed, recycling and functioning of peroxisomes are impaired, and an imbalance between hydrogen peroxide-generating ?-oxidation and hydrogen peroxide-detoxifying catalase ensues, which ultimately results in peroxisomal burnout. Conclusion: Our data strongly suggest that pexophagy, a cellular mechanism per se, is essential in functional maintenance of peroxisomes during LPS exposure. Inhibition of pexophagy results in accumulation of impaired peroxisomes, redox disequilibrium, and aggravated renal damage. Antioxid. Redox Signal. 19, 211–230. PMID:23088293

Ratliff, Brian B.; Bohr, Stefan; Nadel, Ellen; Chen, Jun; Xavier, Sandhya; Chander, Praveen; Goligorsky, Michael S.

2013-01-01

13

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

2009-03-01

14

PPAR? activation induces N(?)-Lys-acetylation of rat liver peroxisomal multifunctional enzyme type 1.  

PubMed

Peroxisomes are ubiquitous subcellular organelles that participate in metabolic and disease processes, with few of its proteins undergoing posttranslational modifications. As the role of lysine-acetylation has expanded into the cellular intermediary metabolism, we used a combination of differential centrifugation, organelle isolation by linear density gradient centrifugation, western blot analysis, and peptide fingerprinting and amino acid sequencing by mass spectrometry to investigate protein acetylation in control and ciprofibrate-treated rat liver peroxisomes. Organelle protein samples isolated by density gradient centrifugation from PPAR?-agonist treated rat liver screened with an anti-N(?)-acetyl lysine antibody revealed a single protein band of 75 kDa. Immunoprecipitation with this antibody resulted in the precipitation of a protein from the protein pool of ciprofibrate-induced peroxisomes, but not from the protein pool of non-induced peroxisomes. Peptide mass fingerprinting analysis identified the protein as the peroxisomal multifunctional enzyme type 1. In addition, mass spectrometry-based amino acid sequencing resulted in the identification of unique peptides containing 4 acetylated-Lys residues (K¹??, K¹?³, K¹??, and K??³). This is the first report that demonstrates posttranslational acetylation of a peroxisomal enzyme in PPAR?-dependent proliferation of peroxisomes in rat liver. PMID:24092543

Contreras, Miguel A; Alzate, Oscar; Singh, Avtar K; Singh, Inderjit

2014-02-01

15

Molecular basis of non-responsiveness to peroxisome proliferators: the guinea-pig PPARalpha is functional and mediates peroxisome proliferator-induced hypolipidaemia.  

PubMed Central

The guinea pig does not undergo peroxisome proliferation in response to peroxisome proliferators, in contrast with other rodents. To understand the molecular basis of this phenotype, the peroxisome proliferator activated receptor alpha (PPARalpha) from guinea-pig liver was cloned; it encodes a protein of 467 amino acid residues that is similar to rodent and human PPARalpha. The guinea-pig PPARalpha showed a high substitution rate: maximum likelihood analysis was consistent with rodent monophyly, but could not exclude rodent polyphyly (P approximately 0.06). The guinea-pig PPARalpha cDNA was expressed in 293 cells and mediated the induction of the luciferase reporter gene by the peroxisome proliferator, Wy-14,643, dependent on the presence of a peroxisome proliferator response element. Moreover the PPARalpha RNA and protein were expressed in guinea-pig liver, although at lower levels than in a species which is responsive to peroxisome proliferators, the mouse. To determine whether the guinea-pig PPARalpha mediated any physiological effects, guinea pigs were exposed to two selective PPARalpha agonists, Wy-14, 643 and methylclofenapate; both compounds induced hypolipidaemia. Thus the guinea pig is a useful model for human responses to peroxisome proliferators. PMID:9620871

Bell, A R; Savory, R; Horley, N J; Choudhury, A I; Dickins, M; Gray, T J; Salter, A M; Bell, D R

1998-01-01

16

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

PubMed Central

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, Dingzhi; Ning, Wei; Xie, Dianren; Guo, Lixia; DuBois, Raymond N.

2014-01-01

17

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

2012-02-23

18

Characteristics of the peroxisome proliferator activated receptor ? (PPAR?) ligand induced apoptosis in colon cancer cells  

Microsoft Academic Search

Background: Involvement of peroxisome proliferator activated receptor ? (PPAR?) in the growth response of colon cancer cells has been suggested.Aims: To investigate the characteristics of PPAR? induced apoptosis in colon cancer cells.Methods: The effects of ligands for each of the PPAR subtypes (?, ?, and ?) on DNA synthesis and cell viability were examined in HT-29 colon cancer cells. Modulation

T Shimada; K Kojima; K Yoshiura; H Hiraishi; A Terano

2002-01-01

19

Peroxisome Proliferator-Activated Receptor Protects Against Alcohol-Induced Liver Damage  

E-print Network

Peroxisome Proliferator-Activated Receptor Protects Against Alcohol-Induced Liver Damage Tamie alcoholic liver disease are not completely understood, but lipid accumulation seems to be central. To investi- gate the roles of PPAR in alcoholic liver injury, wild-type and PPAR -null mice were continuously

Omiecinski, Curtis

20

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

PubMed Central

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 regulated in response to abiotic stress. We sought to test the hypothesis that promoting peroxisome proliferation in Arabidopsis thaliana by over expression of one PEX11 family member, PEX11e, would give increased resistance to salt stress. We could demonstrate up regulation of PEX11e by salt stress and increased peroxisome number by both PEX11e over expression and salt stress, however our experiments failed to find a correlation between PEX11e over expression and increased peroxisome metabolic activity or resistance to salt stress. This suggests that although peroxisome proliferation may be a consequence of salt stress, it does not affect the ability of Arabidopsis plants to tolerate saline conditions. PMID:20195524

Mitsuya, Shiro; El-Shami, Mahmoud; Sparkes, Imogen A.; Charlton, Wayne L.; De Marcos Lousa, Carine; Johnson, Barbara; Baker, Alison

2010-01-01

21

Obesity and Breast Cancer: The Roles of Peroxisome Proliferator-Activated Receptor-? and Plasminogen Activator Inhibitor-1  

PubMed Central

Breast cancer is the most prominent cancer among females in the United States. There are a number of risk factors associated with development of breast cancer, including consumption of a high-fat diet and obesity. Plasminogen activator inhibitor-1 (PAI-1) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer. As a key mediator of adipogenesis and regulator of adipokine production, peroxisome proliferator-activated receptor-? (PPAR-?) is involved in PAI-1 expression from adipose tissue. We summarize the current knowledge linking PPAR-? and PAI-1 expression to high-fat diet and obesity in the risk of breast cancer. PMID:19672469

Carter, Jennifer C.; Church, Frank C.

2009-01-01

22

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

23

Kupffer cells suppress perfluorononanoic acid-induced hepatic peroxisome proliferator-activated receptor ? expression by releasing cytokines.  

PubMed

Kupffer cells (KCs) have been demonstrated to play a role in the regulation of intra-hepatic lipid metabolism through the synthesis and secretion of biologically active products. The involvement of KCs in the disturbance of lipid metabolism that induced by perfluorononanoic acid (PFNA), a known agonist of the peroxisome proliferator-activated receptor alpha (PPAR?), was investigated in this study. Rats were exposed to PFNA or PFNA combined with gadolinium chloride, an inhibitor of KCs, for 14 days. PFNA exposure dose-dependently increased absolute and relative liver weights, induced triglyceride accumulation, up-regulated the expression of both SERBP-1c and PPAR?, and stimulated the release of TNF? and IL-1?. Inactivation of KCs markedly lowered TNF? and IL-1? level, enhanced PFNA-induced expression of PPAR? and its target genes, and reduced liver triglyceride levels. In vitro, PFNA-induced expression of PPAR? in primary cultured hepatocytes was suppressed by recombinant rat TNF? and IL-1?. However, inhibition of the NF-?B pathway prevented this. Transient transfection and promoter analysis further revealed that these two cytokines and NF-?B were coordinately involved in the suppression of PPAR? promoter activity. Our data demonstrate that TNF? and IL-1? released from KCs following PFNA exposure can suppress the expression of PPAR? via NF-?B pathway, which partially contribute to the evident accumulation of triglycerides in rat liver. PMID:22648072

Fang, Xuemei; Zou, Shanshan; Zhao, Yuanyuan; Cui, Ruina; Zhang, Wei; Hu, Jiayue; Dai, Jiayin

2012-10-01

24

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

25

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

26

Clofibrate-induced increases in peroxisomal proteins: effect on synthesis, degradation, and mRNA activity  

SciTech Connect

The effect of clofibrate on the polypeptide composition of peroxisomes was determined. A simple method was developed for the isolation of peroxisomes with a purity of 90-95% using sedimentation in a metrizamide gradient. The specific activities of HD did not change with clofibrate treatment so that the increases in enzyme activities are solely due to increases in protein amounts. The hepatic concentration of HD increased 63 times. The HD synthesis rate, as measured by the incorporation of (/sup 3/H)leucine, increased 74 times, so that the increase in the synthesis was sufficient to account for the increase in protein. Clofibrate caused no discernible change in the degradation rate of HD labeled with (/sup 14/C)bicarbonate. The half-life of HD was approximately 2 days. The translatable mRBA coding for HD increased 55 times. This value is not significantly different from the increase in HD protein or in HD synthesis. This observation was also true for several other peroxisomal proteins. Therefore, clofibrate causes an increase in the mRNA activity, which increases the synthesis of HD leading to an accumulation of protein and enzyme activity. The kinetics of the clofibrate-induced changes in HD synthesis rate, protein level, and enzymatic activity was analyzed using a simple model which included the half-lives of the drug, mRNA, and protein. The best fit of the model to the data gave an mRNA half-life of 10 hours and a protein half-life of 1.8 days, with no significant change by clofibrate.

Mortensen, R.M.

1983-01-01

27

Mechanisms of peroxisome proliferator-induced DNA hypomethylation in rat liver?  

PubMed Central

Genomic hypomethylation is a consistent finding in both human and animal tumors and mounting experimental evidence suggests a key role for epigenetic events in tumorigenesis. Furthermore, it has been suggested that early changes in DNA methylation and histone modifications may serve as sensitive predictive markers in animal testing for carcinogenic potency of environmental agents. Alterations in metabolism of methyl donors, disturbances in activity and/or expression of DNA methyltransferases, and presence of DNA single-strand breaks could contribute to the loss of cytosine methylation during carcinogenesis; however, the precise mechanisms of genomic hypomethylation induced by chemical carcinogens remain largely unknown. This study examined the mechanism of DNA hypomethylation during hepatocarcinogenesis induced by peroxisome proliferators WY-14,643 (4-chloro-6-(2,3-xylidino)-pyrimidynylthioacetic acid) and DEHP (di-(2-ethylhexyl)phthalate), agents acting through non-genotoxic mode of action. In the liver of male Fisher 344 rats exposed to WY-14,643 (0.1% (w/w), 5 months), the level of genomic hypomethylation increased by ~2-fold, as compared to age-matched controls, while in the DEHP group (1.2% (w/w), 5 months) DNA methylation did not change. Global DNA hypomethylation in livers from WY-14,643 group was accompanied by the accumulation of DNA single-strand breaks, increased cell proliferation, and diminished expression of DNA methyltransferase 1, while the metabolism of methyl donors was not affected. In contrast, none of these parameters changed significantly in rats fed DEHP. Since WY-14,643 is much more potent carcinogen than DEHP, we conclude that the extent of loss of DNA methylation may be related to the carcinogenic potential of the chemical agent, and that accumulation of DNA single-strand breaks coupled to the increase in cell proliferation and altered DNA methyltransferase expression may explain genomic hypomethylation during peroxisome proliferator-induced carcinogenesis. PMID:18639561

Pogribny, Igor P.; Tryndyak, Volodymyr P.; Boureiko, Anna; Melnyk, Stepan; Bagnyukova, Tetyana V.; Montgomery, Beverly; Rusyn, Ivan

2008-01-01

28

Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reverses the adverse effects of diet-induced obesity on oocyte quality.  

PubMed

Obesity and its physiological consequences are increasingly prevalent among women of reproductive age and are associated with infertility. To investigate, female mice were fed a high-fat diet until the onset of insulin resistance, followed by assessments of ovarian gene expression, ovulation, fertilization, and oocyte developmental competence. We report defects to ovarian function associated with diet-induced obesity (DIO) that result in poor oocyte quality, subsequently reduced blastocyst survival rates, and abnormal embryonic cellular differentiation. To identify critical cellular mediators of ovarian responses to obesity induced insulin resistance, DIO females were treated for 4 d before mating with an insulin-sensitizing pharmaceutical: glucose and lipid-lowering AMP kinase activator, 5-aminoimidazole 4-carboxamide-riboside, 30 mg/kg.d; sodium salicylate, IkappaK inhibitor that reverses insulin resistance, 50 mg/kg.d; or peroxisome proliferator activated receptor-gamma agonist rosiglitazone, 10 mg/kg.d. 5-aminoimidazole 4-carboxamide-riboside or sodium salicylate treatment did not have significant effects on the reproductive parameters examined. However, embryonic development to the blastocyst stage was significantly improved when DIO mice were treated with rosiglitazone, effectively repairing development rates. Rosiglitazone also normalized DIO-associated abnormal blastomere allocation to the inner cell mass. Such improvements to oocyte quality were coupled with weight loss, improved glucose metabolism, and changes in ovarian mRNA expression of peroxisome proliferator activated receptor-regulated genes, Cd36, Scarb1, and Fabp4 cholesterol transporters. These studies demonstrate that peri-conception treatment with select insulin-sensitizing pharmaceuticals can directly influence ovarian functions and ultimately exert positive effects on oocyte developmental competence. Improved blastocyst quality in obese females treated with rosiglitazone before mating indicates that peroxisome proliferator activated receptor-gamma is a key target for metabolic regulation of ovarian function and oocyte quality. PMID:18276752

Minge, Cadence E; Bennett, Brenton D; Norman, Robert J; Robker, Rebecca L

2008-05-01

29

Alkylthioacetic acid (3-thia fatty acids)--a new group of non-beta-oxidizable, peroxisome-inducing fatty acid analogues. I. A study on the structural requirements for proliferation of peroxisomes and mitochondria in rat liver.  

PubMed

The induction of peroxisome proliferation was examined in rat liver after administration of equal concentrations (1 mmol/kg body weight) of 1,10-bis(carboxymethylthiodecane) (BCMTD), 1-mono(carboxymethylthiotetradecane) (CMTTD), 1-mono(carboxymethylthiooctane) (CMTO), 1-mono(carboxyethylthiotetradecane) (CETTD), palmitic acid and hexadecanedioic acid (HDDA). BCMTD, a non-beta-oxidizable and non-omega-oxidizable sulphur-substituted fatty acid analogue was considerably more potent than CMTTD (only non-beta-oxidizable) in inducing enlargement of the liver and increasing peroxisomal activities (monitored by peroxisomal beta-oxidation, palmitoyl-CoA hydrolase and catalase activities). Morphometric analysis of randomly selected hepatocytes revealed that BCMTD and CMTTD treatment increased the number and size of peroxisomes and the relative volume fraction of the peroxisomes. All these cellular responses were more marked with BCMTD than compared with CMTTD. CMTO, a non-beta-oxidizable fatty acid analogue containing a lower hydrophobic alkyl-end than CMTTD and CETTD (a beta-oxidizable fatty acid analogue), showed a slight increase (1.4-1.8-fold) of peroxisomal beta-oxidation and caused marginally morphological changes of peroxisomes compared with CMTTD and BCMTD. The most striking effect of the alkylthiopropionic acid (CETTD) was an enhancement of the hepatic triacylglycerol level. Palmitic acid and hexadecanedioic acid only marginally affected the peroxisomal activities, but no morphological changes of peroxisomes and fat droplets were observed. The presented data strongly suggest that a minimal structural requirement for a peroxisome proliferator may be (1) a carboxylic acid group linked to (2) a hydrophobic backbone which (3) cannot be beta-oxidized i.e., the fatty acid analogues have a sulphur atom in the beta-position. It is also conceivable that blockage for omega-oxidation may potentiate the peroxisome-proliferating activities in as much as BCMTD was more potent than CMTTD. Two mitochondrial marker enzymes, carnitine palmitoyltransferase and succinate phenazine methosulphate oxidoreductase were differently affected after administration of the investigated compounds. Furthermore, BCMTD and CMTTD as well as HDDA treatments increased the number of mitochondria, but the mitochondria tended to be smaller. The overall results presented here indicate that the structural requirements for proliferation of mitochondria are not identical to those for proliferation of peroxisomes. PMID:2758028

Berge, R K; Aarsland, A; Kryvi, H; Bremer, J; Aarsaether, N

1989-08-22

30

Peroxisome proliferator-activated receptor ? ligand-induced growth inhibition of human hepatocellular carcinoma  

PubMed Central

Peroxisome proliferator-activated receptor ? (PPAR?) ligands have been implicated in the growth inhibition and differentiation of certain human cancers with diverse tissue origin. In this study, expression of PPAR? in human hepatocellular carcinoma (HCC) and the effect of PPAR? ligands on HCC cells were investigated in vitro using Hep G2, HuH-7, KYN-1 and KYN-2 cell lines. All cell lines were found to express functionally active PPAR? and a marked growth inhibition was induced by thiazolidinedione ligands troglitazone, and pioglitazone as well as with its natural ligand 15-deoxy-?12,14-prostaglandin J 2. The growth inhibitory effect was associated with a dose-dependent inhibition of DNA synthesis, cell cycle progression and ? fetoprotein expression. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11401318

Rumi, M A K; Sato, H; Ishihara, S; Kawashima, K; Hamamoto, S; Kazumori, H; Okuyama, T; Fukuda, R; Nagasue, N; Kinoshita, Y

2001-01-01

31

Regulation of peroxisome proliferator-activated receptor ?/? expression and activity levels by toll-like receptor agonists and MAP kinase inhibitors in rat astrocytes.  

PubMed

Peroxisome proliferator-activated receptor ?/? (PPAR?/?) is a potential regulator of neuroinflammation. Toll-like receptors (TLR) are innate immunity-related receptors of inflammatory stimuli. In the present report, we evaluate the molecular mechanisms of regulation of mRNA, protein, and transcriptional activity levels of PPAR?/? by agonists of TLR4, TLR1/2, and TLR5, using lipopolysaccharide (LPS), peptidoglycan, and flagellin, respectively. We found that these stimuli increase the PPAR?/? levels in astrocytes. Expression and activity of PPAR?/? are separately regulated by inhibitors of p38, MEK1/2, extracellular signal-regulated kinases 1/2, and c-Jun N-terminal Kinase mitogen-activated protein kinases. The LPS-induced kinetics of PPAR?/? expression is similar to that of the proinflammatory gene cyclooxygenase 2. Moreover, for both genes the expression depends on nuclear factor kappa-light-chain-enhancer of activated B cells and p38, and is induced after inhibition of protein synthesis. The up-regulation of the expression after inhibition of protein synthesis signifies the participation of a labile protein in regulation of PPAR?/? expression. In contrast to cyclooxygenase 2, the cycloheximide-sensitive PPAR?/? expression was not responsive to nuclear factor kappa-light-chain-enhancer of activated B cells inhibition. Measurements of PPAR?/? mRNA stability showed that the PPAR?/? mRNA levels are regulated post-transcriptionally. We found that in LPS-stimulated astrocytes, the half-life of PPAR?/? mRNA was 50 min. Thus, we demonstrate that PPAR?/? expression and activity are regulated in TLR agonist-stimulated astrocytes by mechanisms that are widely used for regulation of proinflammatory genes. Protein expression level of nuclear receptor PPAR?/? is important for functions of this transcription factor. We investigate the regulatory mechanisms of PPAR?/? in rat primary astrocytes stimulated by agonists of toll-like receptors (TLR): TLR4, TLR1/2, and TLR5. Expression, activity, mRNA stability, and superinduction of PPAR?/? were up-regulated after TLR stimulation. These processes are sensitive to MAPKs and NF-kB inhibitors. Superinduction is up-regulation of mRNA expression after inhibition of protein synthesis. PMID:24806616

Chistyakov, Dmitry V; Aleshin, Stepan; Sergeeva, Marina G; Reiser, Georg

2014-08-01

32

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

33

Evidence for Peroxisome Proliferator-Activated Receptor (PPAR) -Independent Peroxisome Proliferation: Effects of  

E-print Network

Evidence for Peroxisome Proliferator-Activated Receptor (PPAR) -Independent Peroxisome online at http://www.molpharm.org ABSTRACT Peroxisome proliferators are a diverse group of compounds that these agents induce their pleio- tropic effects exclusively via agonism of peroxisome prolifera- tor

Omiecinski, Curtis

34

Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-? activation in human monocytes  

PubMed Central

Objective Angiotensin II type 1 receptor (AT1) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT1. To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-? (PPAR?)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPAR?-stimulating activity. Methods Human circulating monocytes and monocytic THP-1 (human acute monocytic leukemia cell line) cells were exposed to 50 ng/ml LPS with or without pre-incubation with telmisartan. AT1 mRNA and protein expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The expression of pro-inflammatory factors was determined by real-time PCR, western blot analysis and ELISA. PPAR? activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPAR? gene silencing. Results In human monocytes, telmisartan significantly attenuated the LPS-induced expression of pro-inflammatory factors, the release of pro-inflammatory cytokines and prostaglandin E2, nuclear factor-?B activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-?, inhibitor of ?B-?, monocyte chemotactic protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression and MCP-1-directed migration. Telmisartan also stimulated the expression of the PPAR? target genes cluster of differentiation 36 and ATP-binding cassette subfamily G member 1 in monocytes. The anti-inflammatory effects of telmisartan were prevented by both PPAR? antagonism and PPAR? gene silencing. Anti-inflammatory effects of ARBs correlated with their PPAR? agonist potency. Conclusion Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a major extent through the PPAR? activation pathway and may be beneficial for the treatment of cardiovascular and metabolic disorders in which inflammation plays a major role. PMID:22124178

Pang, Tao; Benicky, Julius; Wang, Juan; Orecna, Martina; Sanchez-Lemus, Enrique; Saavedra, Juan M.

2011-01-01

35

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...

36

Evaluation of peroxisome proliferator-activated receptor agonists on interleukin-5-induced eosinophil differentiation.  

PubMed

Peroxisome proliferator-activated receptor (PPAR) agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists has been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report that PPAR agonists can inhibit the differentiation of several cell types. To date, no studies have examined the effects of PPAR agonists on interleukin-5 (IL-5) -induced eosinophil differentiation from haemopoietic progenitor cells. Non-adherent mononuclear cells or CD34(+) cells isolated from the peripheral blood of allergic subjects were grown for 2 weeks in Methocult(®) cultures with IL-5 (10 ng/ml) and IL-3 (25 ng/ml) in the presence of 1-1000 nm PPAR? agonist (GW9578), PPAR?/? agonist (GW501516), PPAR? agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony-forming units (Eo/B CFU) was quantified by light microscopy. The signalling mechanism involved was assessed by phosphoflow. Blood-extracted CD34(+) cells cultured with IL-5 or IL-5 + IL-3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 nm, P < 0·01) but not GW9578 or GW501516. In addition, rosglitazone significantly inhibited IL-5-induced phosphorylation of extracellular signal-regulated kinase 1/2. We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro, mediated by attenuation of the extracellular signal-regulated kinase 1/2 signalling pathway. These findings indicate that the PPAR? agonist can attenuate tissue eosinophilia by interfering with local differentiative responses. PMID:24628018

Smith, Steven G; Hill, Mike; Oliveria, John-Paul; Watson, Brittany M; Baatjes, Adrian J; Dua, Benny; Howie, Karen; Campbell, Heather; Watson, Rick M; Sehmi, Roma; Gauvreau, Gail M

2014-07-01

37

Inhibition of aldose reductase ameliorates diet?induced nonalcoholic steatohepatitis in mice via modulating the phosphorylation of hepatic peroxisome proliferator-activated receptor ?.  

PubMed

Aldose reductase (AR) is involved in the pathogenesis of nonalcoholic steatohepatitis. This study aimed to determine the mechanism by which AR affects the development of murine diet?induced nonalcoholic steatohepatitis. Steatohepatitis was induced in C57BL/6 mice by administration of a methionine?choline?deficient (MCD) diet, a commonly used nutrition?induced model of steatohepatitis. Hematoxylin and eosin staining was used for histological analyses. Western blot analyses were used to determine protein expression levels and quantitative polymerase chain reaction was used to analyze mRNA expression levels. The results showed that the AR protein expression level was significantly higher in C57BL/6 mice fed the MCD diet than in mice fed the control diet. Diet?induced hepatic steatosis and necroinflammation were attenuated in the MCD diet?fed mice treated with the AR inhibitor, zopolrestat. The ameliorating effect of AR inhibition on steatohepatitis was associated with decreased levels of serum alanine aminotransferase and hepatic lipoperoxides, reduced expression of phosphorylated peroxisome proliferator?activated receptor (PPAR)? and increased mRNA expression of acyl coenzyme A oxidase. These data indicated that induction of hepatic AR expression in mice with steatohepatitis resulted in the phosphorylation of PPAR? and suppression of PPAR? activity. Inhibition of AR decreased lipid accumulation and inflammation in the liver, at least in part through the modulation of PPAR? phosphorylation and PPAR? transcriptional activity. PMID:25333350

Chen, Tong; Shi, Duanyu; Chen, Jinfeng; Yang, Yanxue; Qiu, Mengguang; Wang, Wei; Qiu, Longxin

2015-01-01

38

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...

39

Role of peroxisome proliferator-activated receptor-a (PPARa) in bezafibrate-induced hepatocarcinogenesis and cholestasis  

E-print Network

Role of peroxisome proliferator-activated receptor-a (PPARa) in bezafibrate be addressed Email: jmp21@psu.edu Prolonged administration of peroxisome proliferators to rodents typically leads to hepatocarcinogenesis. Peroxisome proliferator-activated receptor-a (PPARa) is required

Omiecinski, Curtis

40

Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator-Activated Receptor Activity  

Microsoft Academic Search

Background—Angiotensin type 1 receptor (AT1R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator-activated receptor- (PPAR )i s the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPAR function by ARBs. Methods and Results—The ARBs irbesartan and telmisartan (10 mol\\/L)

Michael Schupp; Jürgen Janke; Ronald Clasen; Thomas Unger; Ulrich Kintscher

41

An oxidative and salinity stress induced peroxisomal ascorbate peroxidase from Avicennia marina: Molecular and functional characterization  

Microsoft Academic Search

APX (EC, 1.11.1.11) has a key role in scavenging ROS and in protecting cells against their toxic effects in algae and higher plants. A cDNA encoding a peroxisomal ascorbate peroxidase, Am-pAPX1, was isolated from salt stressed leaves of Avicennia marina (Forsk.) Vierh. by EST library screening and its expression in the context of various environmental stresses was investigated. Am-pAPX1 contains

Kumaresan Kavitha; Gayatri Venkataraman; Ajay Parida

2008-01-01

42

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

43

Peroxisomal Localization of Hypoxia-Inducible Factors and Hypoxia-Inducible Factor Regulatory Hydroxylases in Primary Rat Hepatocytes Exposed to Hypoxia-Reoxygenation  

PubMed Central

Many signals involved in pathophysiology are controlled by hypoxia-inducible factors (HIFs), transcription factors that induce expression of hypoxia-responsive genes. HIFs are post-translationally regulated by a family of O2-dependent HIF hydroxylases: four prolyl 4-hydroxylases and an asparaginyl hydroxylase. Most of these enzymes are abundant in resting liver, which is itself unique because of its physiological O2 gradient, and they can exist in both nuclear and cytoplasmic pools. In this study, we analyzed the cellular localization of endogenous HIFs and their regulatory hydroxylases in primary rat hepatocytes cultured under hypoxia-reoxygenation conditions. In hepatocytes, hypoxia targeted HIF-1? to the peroxisome, rather than the nucleus, where it co-localized with von Hippel-Lindau tumor suppressor protein and the HIF hydroxylases. Confocal immunofluorescence microscopy demonstrated that the HIF hydroxylases translocated from the nucleus to the cytoplasm in response to hypoxia, with increased accumulation in peroxisomes on reoxygenation. These results were confirmed via immunotransmission electron microscopy and Western blotting. Surprisingly, in resting liver tissue, perivenous localization of the HIF hydroxylases was observed, consistent with areas of low pO2. In conclusion, these studies establish the peroxisome as a highly relevant site of subcellular localization and function for the endogenous HIF pathway in hepatocytes. PMID:17003483

Khan, Zahida; Michalopoulos, George K.; Stolz, Donna Beer

2006-01-01

44

Subchronic exposure to high-dose ACE-inhibitor moexipril induces catalase activity in rat liver.  

PubMed

The long-term clinical effects of ACE-inhibitors have similarities with those of both fibrates and glitazones, activators of peroxisome proliferator activator receptor (PPAR) alpha and gamma, respectively. The antioxidant enzyme catalase, a heme protein that degrades hydrogen peroxide, is found at high concentrations in peroxisomes. Catalase activity is one of the recognized surrogate markers indicative of PPAR activation in the rat liver. The purpose of the study was to establish the effect of moexipril on catalase activity and to compare it with the effect of both saline controls and that of the known PPAR agonist clofibrate (positive control). Three groups of seven rats were used. All substances were applied i.p. daily for 5 days, followed by a 2-day break. The cycle was repeated eight times. After the final cycle (day 56) the animals were sacrificed and liver tissue collected. The number of catalase positive cells in both moexipril group (95% CI 57-61) and clofibrate group (95% CI 72-80) is higher than in controls (95% CI 3-16) (p < or = 0.01). The number of catalase positive cells in the clofibrate group is higher than in the moexipril group (p < or = 0.01). High-dose subchronic exposure to the ACE-inhibitor moexipril induces catalase activity in the rat liver to an extent comparable to fibrates. We suggest that some of the long-term advantages of ACE inhibitor use - beyond mere BP lowering - might be due to a PPAR mediated effect. PMID:16311918

Adeghate, E; Hasan, M Y; Ponery, A S; Nurulain, S M; Petroianu, G A

2005-12-01

45

Induction of Nuclear Translocation of Constitutive Androstane Receptor by Peroxisome Proliferator-activated  

E-print Network

Induction of Nuclear Translocation of Constitutive Androstane Receptor by Peroxisome Proliferator Peroxisome proliferators activate nuclear receptor peroxi- some proliferator-activated receptor (PPAR diverse synthetic compounds, desig- nated as peroxisome proliferators, induce a set of highly pre

Omiecinski, Curtis

46

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. PMID:22441164

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

47

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

PubMed

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. PMID:22441164

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

2012-06-01

48

Hesperetin glucuronides induce adipocyte differentiation via activation and expression of peroxisome proliferator-activated receptor-?.  

PubMed

In previous reports, hesperidin, a flavonoid glucoside from citrus fruit, is hydrolyzed to hesperetin, an aglycone of hesperidin, and converted to the hesperetin glucuronides (H7-OG and H3'-OG) in vivo and depresses blood glucose levels. But there are no reports on the activity of hesperetin glucuronides. To determine the activity of hesperetin glucuronides, H7-OG and H3'-OG were synthesized and peroxisome proliferator-activated receptor-? (PPAR?) agonist activity was observed at 250 ?M. These glucuronides accelerated the differentiation of 3T3-L1 cells into adipocytes at 10 ?M. Furthermore, H7-OG showed additive effects in reporter gene assays and caused noncompetitive reactions in time-resolved fluorescence resonance energy transfer assays with a thiazolidinedione derivative. Our results indicated that hesperetin glucuronides activated PPAR?, accelerated adipocyte differentiation. PMID:25036134

Gamo, Kanae; Miyachi, Hiroyuki; Nakamura, Kayoko; Matsuura, Nobuyasu

2014-01-01

49

4-Hydroxydocosahexaenoic acid, a potent peroxisome proliferator-activated receptor {gamma} agonist alleviates the symptoms of DSS-induced colitis  

SciTech Connect

(5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) and antidiabetic agent as has been previously reported. As PPAR{gamma} agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice when compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.

Yamamoto, Keiko [Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543 (Japan); Ninomiya, Yuichi; Iseki, Mioko [Division of Translational Research, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan); Nakachi, Yutaka; Kanesaki-Yatsuka, Yukiko [Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan); Yamanoue, Yu; Itoh, Toshimasa [Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan); Nishii, Yasuho [Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan); Petrovsky, Nikolai [Diabetes and Endocrinology, Flinders Medical Centre, Bedford Park, SA 5042 (Australia); Okazaki, Yasushi [Division of Translational Research, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan); Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241 (Japan)], E-mail: okazaki@saitama-med.ac.jp

2008-03-14

50

Peroxisome Proliferator Activator Receptor (PPAR)-? Ligand, but Not PPAR-?, Ameliorates Cyclophosphamide-Induced Oxidative Stress and Inflammation in Rat Liver  

PubMed Central

Hepatoprotective potential of peroxisome proliferator activator receptor (PPAR)-? and -? agonists, fenofibrate (FEN), and pioglitazone (PIO), respectively, against cyclophosphamide (CP)-induced toxicity has been investigated in rat. FEN and PIO (150 and 10?mg/kg/day, resp.) were given orally for 4 weeks. In separate groups, CP (150?mg/kg, i.p.) was injected as a single dose 5 days before the end of experiment, with or without either PPAR agonist. CP induced hepatotoxicity, as it caused histopathological alterations, with increased serum alanine and aspartate transaminases, total bilirubin, albumin, alkaline phosphatase and lactate dehydrogenase. CP caused hepatic oxidative stress, indicated by decrease in tissue reduced glutathione, with increase in malondialdehyde and nitric oxide levels. CP also caused decrease in hepatic antioxidant enzyme levels, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Furthermore, CP increased serum and hepatic levels of the inflammatory marker tumor necrosis factor (TNF)-?, evaluated using ELISA. Preadministration of PIO, but not FEN, prior to CP challenge improved hepatic function and histology, and significantly reversed oxidative and inflammatory parameters. In conclusion, activation of PPAR-?, but not PPAR-?, conferred protection against CP-induced hepatotoxicity, via activation of antioxidant and anti-inflammatory mechanisms, and may serve as supplement during CP chemotherapy. PMID:24803924

El-Sheikh, Azza A. K.; Rifaai, Rehab A.

2014-01-01

51

Proteinase Inhibitor-inducing Factor in Plant Leaves  

PubMed Central

Thirty-nine plant species representing 20 families from the four major divisions of plants were surveyed for the presence of proteinase inhibitor-inducing factor activity in leaves or other tissues. Tissue juices were assayed for their capacity to induce accumulation of proteinase inhibitor I in excised tomato (Lycopersico esculentum) leaves. In tissues of only 2 of the 39 species was proteinase inhibitor-inducing factor-like activity not found. The activity was absent in cabbage leaves and celery stalks. Fruiting bodies from one of three fungi genera assayed contained exceptionally large quantities of proteinase inhibitor-inducing factor-like activity. Extracts from Agraricus campestris fruiting bodies contained over 20 times more activity than tomato leaf juice. The survey confirms that substances with proteinase inhibitor-inducing factor-like activity are widespread in the plant kingdom. PMID:16658956

McFarland, Douglas; Ryan, Clarence A.

1974-01-01

52

Identification and immunogold localization of a novel bromegrass (Bromus inermis Leyss) peroxisome channel protein induced by ABA, cold and drought stresses, and late embryogenesis.  

PubMed

A cDNA (BG-15) was isolated through differential screening of a cDNA library made from an ABA-treated bromegrass (Bromus inermis Leyss) suspension cell culture. The 819 bp pair cDNA encoded a 174 amino acid polypeptide with a calculated molecular mass of 18.08 kD and isolectric point of 7.50. The deduced amino acid sequences for the cDNA were 29.5% and 32.6% homologous to the known amino acid-selective channel proteins of the chloroplastic outer membrane in pea and barley, but were highly homologous (55.6% to 83.2%) to the putative membrane channel proteins from rice and Arabidopsis. Immunogold localization demonstrated that the channel protein encoded by this cDNA was present on the peroxisome membrane. High stringency southern analysis revealed that 1 to 2 copies of the peroxisomal channel protein (PCP) genes were present in the bromegrass genome. Northern and Western blots revealed that the PCP gene was responsive to both cold and drought stresses, and was rapidly induced by ABA (75 microM). The transcript of the PCP gene also accumulated during late embryogenesis, but declined rapidly during germination. Data taken together, responsiveness of the PCP to cold and drought stresses, and accumulation during late embryogenesis suggest this novel peroxisomal channel protein is associated with sugar and fatty acid metabolism through fatty acid import or succinate export from peroxisome during desiccation tolerance and energy metabolism. PMID:16226403

Wu, Guohai; Robertson, Albert J; Zheng, Ping; Liu, Xunjia; Gusta, Lawrence V

2005-12-19

53

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. PMID:14676330

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

54

Activation of Peroxisome Proliferator-Activated Receptor ? Inhibits Streptozotocin-Induced Diabetic Nephropathy Through Anti-Inflammatory Mechanisms in Mice  

PubMed Central

OBJECTIVE Activation of the nuclear hormone receptor peroxisome proliferator–activated receptor (PPAR)-? has been shown to improve insulin resistance, adiposity, and plasma HDL levels. Several studies have reported that activation of PPAR? is atheroprotective; however, the role of PPAR? in renal function remains unclear. Here, we report the renoprotective effects of PPAR? activation in a model of streptozotocin-induced diabetic nephropathy. RESEARCH DESIGN AND METHODS Eight-week-old male C57BL/6 mice were divided into three groups: 1) nondiabetic control mice, 2) diabetic mice, and 3) diabetic mice treated with the PPAR? agonist GW0742 (1 mg/kg/day). GW0742 was administered by gavage for 8 weeks after inducing diabetes. RESULTS GW0742 decreased urinary albumin excretion without altering blood glucose levels. Macrophage infiltration, mesangial matrix accumulation, and type IV collagen deposition were substantially attenuated by GW0742. The gene expression of inflammatory mediators in the kidney cortex, such as monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN), was also suppressed. In vitro studies demonstrated that PPAR? activation increased the expression of anti-inflammatory corepressor B-cell lymphoma-6, which subsequently suppressed MCP-1 and OPN expression. CONCLUSIONS These findings uncover a previously unrecognized mechanism for the renoprotective effects of PPAR? agonists and support the concept that PPAR? agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy. PMID:21270242

Matsushita, Yuichi; Ogawa, Daisuke; Wada, Jun; Yamamoto, Noriko; Shikata, Kenichi; Sato, Chikage; Tachibana, Hiromi; Toyota, Noriko; Makino, Hirofumi

2011-01-01

55

Rosiglitazone-Induced Mitochondrial Biogenesis in White Adipose Tissue Is Independent of Peroxisome Proliferator-Activated Receptor ? Coactivator-1?  

PubMed Central

Background Thiazolidinediones, a family of insulin-sensitizing drugs commonly used to treat type 2 diabetes, are thought to exert their effects in part by promoting mitochondrial biogenesis in white adipose tissue through the transcriptional coactivator PGC-1? (Peroxisome Proliferator-Activated Receptor ? Coactivator-1?). Methodology/Principal Findings To assess the role of PGC-1? in the control of rosiglitazone-induced mitochondrial biogenesis, we have generated a mouse model that lacks expression of PGC-1? specifically in adipose tissues (PGC-1?-FAT-KO mice). We found that expression of genes encoding for mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle or fatty acid oxidation, was similar in white adipose tissue of wild type and PGC-1?-FAT-KO mice. Furthermore, the absence of PGC-1? did not prevent the positive effect of rosiglitazone on mitochondrial gene expression or biogenesis, but it precluded the induction by rosiglitazone of UCP1 and other brown fat-specific genes in white adipose tissue. Consistent with the in vivo findings, basal and rosiglitazone-induced mitochondrial gene expression in 3T3-L1 adipocytes was unaffected by the knockdown of PGC-1? but it was impaired when PGC-1? expression was knockdown by the use of specific siRNA. Conclusions/Significance These results indicate that in white adipose tissue PGC-1? is dispensable for basal and rosiglitazone-induced mitochondrial biogenesis but required for the rosiglitazone-induced expression of UCP1 and other brown adipocyte-specific markers. Our study suggests that PGC-1? is important for the appearance of brown adipocytes in white adipose tissue. Our findings also provide evidence that PGC-1? and not PGC-1? regulates basal and rosiglitazone-induced mitochondrial gene expression in white adipocytes. PMID:22087241

Pardo, Rosario; Enguix, Natàlia; Lasheras, Jaime; Feliu, Juan E.; Kralli, Anastasia; Villena, Josep A.

2011-01-01

56

Secretory Leukocyte Protease Inhibitor, but not Alpha1 Protease Inhibitor, Blocks Tryptase-induced Bronchoconstriction  

Microsoft Academic Search

Alpha-1-protease inhibitor (?1-PI) and secretory leukocyte protease inhibitor (SLPI) are two natural airway serine protease inhibitors. While inhibition of neutrophil elastase is a function common to both ?1-PI and SLPI, we showed previously that they exhibit different patterns of protection against antigen-induced changes in airway function in allergic sheep. Specifically, the protective effect seen with SLPI was similar to the

R. M. Forteza; A. Ahmed; T. Lee; W. M. Abraham

2001-01-01

57

Peroxisome Proliferator-activated Receptor ?/? Induces Myogenesis by Modulating Myostatin Activity*  

PubMed Central

Classically, peroxisome proliferator-activated receptor ?/? (PPAR?/?) function was thought to be restricted to enhancing adipocyte differentiation and development of adipose-like cells from other lineages. However, recent studies have revealed a critical role for PPAR?/? during skeletal muscle growth and regeneration. Although PPAR?/? has been implicated in regulating myogenesis, little is presently known about the role and, for that matter, the mechanism(s) of action of PPAR?/? in regulating postnatal myogenesis. Here we report for the first time, using a PPAR?/?-specific ligand (L165041) and the PPAR?/?-null mouse model, that PPAR?/? enhances postnatal myogenesis through increasing both myoblast proliferation and differentiation. In addition, we have identified Gasp-1 (growth and differentiation factor-associated serum protein-1) as a novel downstream target of PPAR?/? in skeletal muscle. In agreement, reduced Gasp-1 expression was detected in PPAR?/?-null mice muscle tissue. We further report that a functional PPAR-responsive element within the 1.5-kb proximal Gasp-1 promoter region is critical for PPAR?/? regulation of Gasp-1. Gasp-1 has been reported to bind to and inhibit the activity of myostatin; consistent with this, we found that enhanced secretion of Gasp-1, increased Gasp-1 myostatin interaction and significantly reduced myostatin activity upon L165041-mediated activation of PPAR?/?. Moreover, we analyzed the ability of hGASP-1 to regulate myogenesis independently of PPAR?/? activation. The results revealed that hGASP-1 protein treatment enhances myoblast proliferation and differentiation, whereas silencing of hGASP-1 results in defective myogenesis. Taken together these data revealed that PPAR?/? is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating myostatin activity via a mechanism involving Gasp-1. PMID:22362769

Bonala, Sabeera; Lokireddy, Sudarsanareddy; Arigela, Harikumar; Teng, Serena; Wahli, Walter; Sharma, Mridula; McFarlane, Craig; Kambadur, Ravi

2012-01-01

58

Hsp90 inhibitor induces autophagy and apoptosis in osteosarcoma cells.  

PubMed

Heat shock protein 90 (Hsp90) is constitutively expressed at 2?10?fold higher levels in tumor cells compared to normal cells, suggesting that it may be critically important for tumor cell growth and survival. These features make Hsp90 a potential target for anticancer drug development. Inhibition of Hsp90 activity not only results in rapid degradation of Hsp90 client proteins but also induces apoptosis of various tumor cells. Hsp90 also plays an important role in autophagy. An Hsp90 inhibitor induces autophagy through inhibition of mTOR. It is still under debate whether chemotherapy?induced autophagy in tumor cells is a protective response or is invoked to promote cell death. The aim of this study was to examine the effects of the Hsp90 inhibitor, geldanamycin (GA), on KTHOS osteosarcoma cells. We further examined whether a combination of GA and the autophagy inhibitor 3?methyladenine (3?MA) enhanced GA?induced apoptosis in KTHOS cells. GA had an inhibitory effect on cell proliferation and inhibited the Akt/mTOR signaling pathway in KTHOS cells. GA alone induced autophagy and apoptosis in KTHOS cells, but treatment with a combination of GA and 3?MA suppressed autophagy and induced apoptosis to a much greater extent than GA alone in these cells. It was considered that the autophagy inhibitor 3?MA suppressed a protective mechanism induced by Hsp90 inhibitor in tumor cells and induced apoptosis. Therefore, the combination of an Hsp90 inhibitor and an autophagy inhibitor may be an effective treatment for osteosarcoma because this combination effectively induces apoptotic pathways. PMID:25351442

Mori, Masaki; Hitora, Toshiaki; Nakamura, Osamu; Yamagami, Yoshiki; Horie, Ryosuke; Nishimura, Hideki; Yamamoto, Tetsuji

2015-01-01

59

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. PMID:9009266

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

1997-01-01

60

Genome-Wide Analysis of Effectors of Peroxisome Ramsey A. Saleem1  

E-print Network

Genome-Wide Analysis of Effectors of Peroxisome Biogenesis Ramsey A. Saleem1 , Rose Long-O'Donnell1 Processing, Tampere University of Technology, Tampere, Finland Abstract Peroxisomes are intracellular of fatty acids. Peroxisomes biogenesis can be induced by the presence of peroxisome proliferators

Shmulevich, Ilya

61

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

62

Perfluorooctanoic Acid Induced Developmental Toxicity in the Mouse is Dependent on Expression of Peroxisome Proliferator Activated Receptor-alpha  

Microsoft Academic Search

Perfluorooctanoic acid (PFOA) is a member of a family of perfluorinated chemicals that have a variety of applications. PFOA persists in the environment and is found in wildlife and humans. In mice, PFOA is developmentally toxic producing mortality, delayed eye opening, growth deficits, and altered pubertal maturation. PFOA activates peroxisome proliferators-activated receptor-alpha (PPARa), a pathway critical to the mode of

Barbara D. Abbott; Cynthia J. Wolf; Judith E. Schmid; Kaberi P. Das; Robert D. Zehr; Laurence Helfant; Shoji Nakayama; Andrew B. Lindstrom; Mark J. Strynar; Christopher Lau

2007-01-01

63

ABCD2 Alters Peroxisome Proliferator-Activated Receptor ? Signaling In Vitro, but Does Not Impair Responses to Fenofibrate Therapy in a Mouse Model of Diet-Induced Obesity.  

PubMed

Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) ? ligand that has been widely used as a lipid-lowering agent in the treatment of hypertriglyceridemia. ABCD2 (D2) is a peroxisomal long-chain acyl-CoA transporter that is highly induced by fenofibrate in the livers of mice. To determine whether D2 is a modifier of fibrate responses, wild-type and D2-deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPAR? signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that knockdown of D2 modified genomic responses to fibrate treatment. We next evaluated the impact of D2 on effects of fibrates in a mouse model of diet-induced obesity. Fenofibrate treatment opposed the development of obesity, hypertriglyceridemia, and insulin resistance. However, these effects were unaffected by D2 genotype. We concluded that D2 can modulate genomic responses to fibrates, but that these effects are not sufficiently robust to alter the effects of fibrates on diet-induced obesity phenotypes. PMID:25123288

Liu, Xiaoxi; Liu, Jingjing; Liang, Shuang; Schlüter, Agatha; Fourcade, Stephane; Aslibekyan, Stella; Pujol, Aurora; Graf, Gregory A

2014-11-01

64

Interleukin-6 inhibition of peroxisome proliferator-activated receptor alpha expression is mediated by JAK2- and PI3K-induced STAT1/3 in HepG2 hepatocyte cells.  

PubMed

Interleukin-6 (IL-6) is the major activator of the acute phase response (APR). One important regulator of IL-6-activated APR is peroxisome proliferator-activated receptor alpha (PPAR?). Currently, there is a growing interest in determining the role of PPAR? in regulating APR; however, studies on the molecular mechanisms and signaling pathways implicated in mediating the effects of IL-6 on the expression of PPAR? are limited. We previously revealed that IL-6 inhibits PPAR? gene expression through CAAT/enhancer-binding protein transcription factors in hepatocytes. In this study, we determined that STAT1/3 was the direct downstream molecules that mediated the Janus kinase 2 (JAK2) and phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways in IL-6-induced repression of PPAR?. Treatment of cells with pharmacological inhibitors of JAK2, PI3K, AKT, and mTOR attenuated the inhibitory effect of IL-6 on PPAR? protein in a dose-dependent manner. These inhibitors also decreased the IL-6-induced repression of PPAR? mRNA expression and promoter activity. Overexpression of STAT1 and STAT3 in HepG2 cells cotransfected with a reporter vector containing this PPAR? promoter region revealed that both the expression plasmids inhibited the IL-6-induced repression of PPAR? promoter activity. In the presence of inhibitors of JAK2 and mTOR (AG490 and rapamycin, respectively), IL-6-regulated protein expression and DNA binding of STAT1 and STAT3 were either completely or partially inhibited simultaneously, and the IL-6-induced repression of PPAR? protein and mRNA was also inhibited. This study has unraveled novel pathways by which IL-6 inhibits PPAR? gene transcription, involving the modulation of JAK2/STAT1-3 and PI3K/AKT/mTOR by inducing the binding of STAT1 and STAT3 to STAT-binding sites on the PPAR? promoter. Together, these findings represent a new model of IL-6-induced suppression of PPAR? expression by inducing STAT1 and STAT3 phosphorylation and subsequent down-regulation of PPAR? mRNA expression. PMID:24242046

Chew, Guat-Siew; Myers, Stephen; Shu-Chien, Alexander Chong; Muhammad, Tengku Sifzizul Tengku

2014-03-01

65

Peroxisome proliferator-activated receptor-? activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats  

Microsoft Academic Search

We investigated the effects of a high-fat (HF) diet and peroxisome proliferator-activated receptor (PPAR)-? activation on the intrarenal lipotoxicity associated with the renin–angiotensin system (RAS) and oxidative stress using spontaneously hypertensive (SHR) rats. Male SHR and Wistar–Kyoto (WKY) rats at 8 weeks of age were fed either a normal-fat diet or an HF diet without or with fenofibrate treatment for

Seok Joon Shin; Ji Hee Lim; Sungjin Chung; Dong-Ye Youn; Hyun Wha Chung; Hyung Wook Kim; Jeong-Hwa Lee; Yoon Sik Chang; Cheol Whee Park

2009-01-01

66

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

2011-02-15

67

Tumor necrosis factor inhibitor-induced serositis.  

PubMed

A 46-year-old man with a history of asthma and psoriatic arthritis on adalimumab presented with fever, tachycardia, and hypoxia. He was diagnosed with pleural effusion and started on antibiotics, as it was noted to be an exudative effusion. Patient failed to improve on multiple courses of antibiotics, and his blood and pleural fluid cultures were negative. He was then started on prednisone 1 mg/kg and showed remarkable recovery. He was diagnosed with adalimumab-induced serositis. PMID:23344110

Annapureddy, Narender; Agarwal, Shiv Kumar; Ammakkanavar, Natraj; Kanakadandi, Vijay; Sabharwal, Manpreet S; Sanjani, Hari Priya; Simoes, Priya; Nadkarni, Girish N

2014-01-01

68

Hypoxia inducible factor pathway inhibitors as anticancer therapeutics  

PubMed Central

Hypoxia is a significant feature of solid tumor cancers. Hypoxia leads to a more malignant phenotype that is resistant to chemotherapy and radiation, is more invasive and has greater metastatic potential. Hypoxia activates the hypoxia inducible factor (HIF) pathway, which mediates the biological effects of hypoxia in tissues. The HIF complex acts as a transcription factor for many genes that increase tumor survival and proliferation. To date, many HIF pathway inhibitors indirectly affect HIF but there have been no clinically approved direct HIF inhibitors. This can be attributed to the complexity of the HIF pathway, as well as to the challenges of inhibiting protein–protein interactions. PMID:23573973

Burroughs, Sarah K; Kaluz, Stefan; Wang, Danzhu; Wang, Ke

2013-01-01

69

Wogonin prevents lipopolysaccharide-induced acute lung injury and inflammation in mice via peroxisome proliferator-activated receptor gamma-mediated attenuation of the nuclear factor-kappaB pathway.  

PubMed

Acute lung injury (ALI) from a variety of clinical disorders, characterized by diffuse inflammation, is a cause of acute respiratory failure that develops in patients of all ages. Previous studies reported that wogonin, a flavonoid-like chemical compound which was found in Scutellaria baicalensis, has anti-inflammatory effects in several inflammation models, but not in ALI. Here, the in vivo protective effect of wogonin in the amelioration of lipopolysaccharide (LPS) -induced lung injury and inflammation was assessed. In addition, the in vitro effects and mechanisms of wogonin were studied in the mouse macrophage cell lines Ana-1 and RAW264.7. In vivo results indicated that wogonin attenuated LPS-induced histological alterations. Peripheral blood leucocytes decreased in the LPS-induced group, which was ameliorated by wogonin. In addition, wogonin inhibited the production of several inflammatory cytokines, including tumour necrosis factor-?, interleukin-1? (IL-1?) and IL-6, in the bronchoalveolar lavage fluid and lung tissues after LPS challenge, while the peroxisome proliferator-activated receptor ? (PPAR?) inhibitor GW9662 reversed these effects. In vitro results indicated that wogonin significantly decreased the secretion of IL-6, IL-1? and tumour necrosis factor-? in Ana-1 and RAW264.7 cells, which was suppressed by transfection of PPAR? small interfering RNA and GW9662 treatment. Moreover, wogonin activated PPAR?, induced PPAR?-mediated attenuation of the nuclear translocation and the DNA-binding activity of nuclear factor-?B in vivo and in vitro. In conclusion, all of these results showed that wogonin may serve as a promising agent for the attenuation of ALI-associated inflammation and pathology by regulating the PPAR?-involved nuclear factor-?B pathway. PMID:24766487

Yao, Jing; Pan, Di; Zhao, Yue; Zhao, Li; Sun, Jie; Wang, Yu; You, Qi-Dong; Xi, Tao; Guo, Qing-Long; Lu, Na

2014-10-01

70

Jasmonic acid inducible aspartic proteinase inhibitors from potato.  

PubMed

A new cDNA clone coding for an aspartic proteinase inhibitor homologue was isolated from a potato tuber cDNA library. Southern blot analysis was used to study the structural diversity of the aspartic proteinase inhibitor gene family in several species of the Solanaceae. The existence of sequence-homologous genes was confirmed in the genomic DNA of different potato cultivars (Solanum tuberosum L. cv. Désirée, Pentland Squire and Igor), tomato (Lycopersicon esculentum Mill.), aubergine (S. melongena L.) and a wild type of bittersweet (S. dulcamara L.). Northern blot hybridization of total RNA, isolated from leaves under non-stress conditions, of different solanaceous species and of potato tubers showed that the gene transcripts encoding aspartic proteinase inhibitors occur mainly in potato tubers. The presence of several cathepsin D inhibitor isoforms has been detected at the protein level. At least four isoforms were isolated by affinity chromatography on cathepsin D-Sepharose and characterized. Additionally, exogenous treatment of potato plantlets by jasmonic acid (JA) over a wide range of concentrations (0-100 microM) was performed in a stem node culture in vitro. We demonstrated that the expression of aspartic proteinase inhibitor mRNA was drastically induced in potato shoots at concentrations of 50-100 microM JA. PMID:9055446

Kreft, S; Ravnikar, M; Mesko, P; Pungercar, J; Umek, A; Kregar, I; Strukelj, B

1997-03-01

71

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

2010-04-01

72

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

73

A myosin inhibitor impairs auxin-induced cell division  

Microsoft Academic Search

Summary. The role of myosins for auxin-induced cell division was probed using the inhibitor 2,3-butanedione monoxime in the tobacco cell line VBI-0, where cell elongation and division are axially aligned under the control of auxin. A morphometric analysis revealed that cell division is blocked in a dose-dependent manner, whereas cell expansion continued. In addition, the polarity of terminal cells was

Carola Holweg; Anne Honsel; Peter Nick

2003-01-01

74

Characterization of endoproteases from plant peroxisomes.  

PubMed Central

In this work, the characterization of endoprotease (EP) isoenzymes in peroxisomes is reported for the first time in cell organelles purified from pea leaves (Pisum sativum L.). A comparative analysis of the endo-proteolytic activity in peroxisomes purified from young (15-day-old) and senescent (50-day-old) leaves was carried out. Peroxisomes purified from senescent leaves showed a much higher endo-proteolytic activity than organelles from young plants. A 16 h incubation with exogenous substrates was the threshold time for the detection of a linear increase in the endo-proteolytic activity of peroxisomes from senescent leaves. Three EP isoenzymes (EP2, EP4 and EP5), having molecular masses of 88, 64 and 50 kDa respectively, were found in young plants by using SDS/polyacrylamide-gradient gels co-polymerized with gelatin. However, four additional isoenzymes (EP1, EP3, EP6 and EP7), with molecular masses of 220, 76, 46 and 34 kDa respectively, were detected in senescent plants. All the isoenzymes detected in peroxisomes from both young and senescent leaves were neutral proteases. By using different class-specific inhibitors, the electrophoretically separated EP isoenzymes were characterized as three serine-proteinases (EP1, EP3 and EP4), two cysteine-proteinases (EP2 and EP6) and a metallo-proteinase (EP7), and EP5 might be a metal-dependent serine-proteinase. Moreover, a peroxisomal polypeptide of 64 kDa was recognized by an antibody against a thiol-protease. The serine-proteinase isoenzymes (EP1, EP3 and EP4), which represent approx. 70% of the total EP activity of peroxisomes, showed a notable thermal stability, not being inhibited by incubation at 50 degrees C for 1 h. PMID:9359407

Distefano, S; Palma, J M; Gomez, M; Rio, L A

1997-01-01

75

Endocrine disruption induced by organotin compounds; organotins function as a powerful agonist for nuclear receptors rather than an aromatase inhibitor.  

PubMed

Organotin compounds have been widely used as antifouling biocides for ships and fishing nets, agricultural fungicides and rodent repellents. These widespread uses have resulted in the release of increasing amounts of organotins into the environment. In aquatic invertebrates, particularly marine gastropods, organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), induce irreversible sexual abnormality in females which is termed "imposex" at very low concentrations. Although it has been theorized that these compounds act as potential competitive inhibitors of aromatase, which converts androgen to estrogen, and then increase levels of unconverted androgens in gastropods, their effective concentrations for aromatase inhibition are high. In addition to wildlife, organotins may have various undesirable effects on human health. Contrary to the theory of organotin-induced aromatase inhibition in gastropods, in human choriocarcinoma cells, these compounds markedly enhance estradiol biosynthesis along with the increase of both aromatase activity and 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD I) activity, which converts low-activity estrogen estrone to the biologically more active form estradiol, at the same low concentrations. Although there are many reports describing the potential toxicity of organotins in human and mammals, the critical target molecules for the toxicity of organotin compounds remain unclear. Recently, organotin compounds including TBT and TPT were identified as nanomolar agonists for retinoid X receptor (RXR) and peroxisome proliferator-activated receptor (PPAR) gamma, which are members of the nuclear receptor superfamily. Here, we review the potential genetics action and subsequent toxicity induced by organotins via these nuclear receptors. PMID:18670157

Nakanishi, Tsuyoshi

2008-08-01

76

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

77

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

78

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

2013-05-15

79

Hepatology Research 22 (2002) 5257 Hepatic regeneration in peroxisome proliferator-activated  

E-print Network

Hepatology Research 22 (2002) 52­57 Hepatic regeneration in peroxisome proliferator in revised form 9 April 2001; accepted 1 May 2001 Abstract Peroxisome proliferator activated receptor effects induced by peroxisome proliferators including cell proliferation. In a previous study, we have

Omiecinski, Curtis

80

814 Journal of Lipid Research Volume 41, 2000 Involvement of the peroxisome proliferator-activated  

E-print Network

814 Journal of Lipid Research Volume 41, 2000 Involvement of the peroxisome proliferator of peroxisome proliferator-induced genes en- coding cytosolic (CTE-I), mitochondrial (MTE-I), and peroxi- somal of the peroxisome proliferator-activated receptor in regu- lating long-chain acyl-CoA thioesterases. J. Lipid Res

Omiecinski, Curtis

81

Inhibition of rotavirus ECwt infection in ICR suckling mice by N-acetylcysteine, peroxisome proliferator-activated receptor gamma agonists and cyclooxygenase-2 inhibitors  

PubMed Central

Live attenuated vaccines have recently been introduced for preventing rotavirus disease in children. However, alternative strategies for prevention and treatment of rotavirus infection are needed mainly in developing countries where low vaccine coverage occurs. In the present work, N-acetylcysteine (NAC), ascorbic acid (AA), some nonsteroidal anti-inflammatory drugs (NSAIDs) and peroxisome proliferator-activated receptor gamma (PPAR?) agonists were tested for their ability to interfere with rotavirus ECwt infectivity as detected by the percentage of viral antigen-positive cells of small intestinal villi isolated from ECwt-infected ICR mice. Administration of 6 mg NAC/kg every 8 h for three days following the first diarrhoeal episode reduced viral infectivity by about 90%. Administration of AA, ibuprofen, diclofenac, pioglitazone or rosiglitazone decreased viral infectivity by about 55%, 90%, 35%, 32% and 25%, respectively. ECwt infection of mice increased expression of cyclooxygenase-2, ERp57, Hsc70, NF-?B, Hsp70, protein disulphide isomerase (PDI) and PPAR? in intestinal villus cells. NAC treatment of ECwt-infected mice reduced Hsc70 and PDI expression to levels similar to those observed in villi from uninfected control mice. The present results suggest that the drugs tested in the present work could be assayed in preventing or treating rotaviral diarrhoea in children and young animals. PMID:24037197

Guerrero, Carlos Arturo; Pardo, Paula; Rodriguez, Victor; Guerrero, Rafael; Acosta, Orlando

2013-01-01

82

Administration of the peroxisomal proliferator-activated receptor {gamma} agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment  

SciTech Connect

Purpose: We hypothesized that administration of the anti-inflammatory peroxisomal proliferator-activated receptor {gamma} (PPAR{gamma}) agonist pioglitazone (Pio) to adult male rats would inhibit radiation-induced cognitive impairment. Methods and Materials: Young adult male F344 rats received one of the following: (1) fractionated whole brain irradiation (WBI); 40 or 45 Gy {gamma}-rays in 4 or 4.5 weeks, respectively, two fractions per week and normal diet; (2) sham-irradiation and normal diet; (3) WBI plus Pio (120 ppm) before, during, and for 4 or 54 weeks postirradiation; (4) sham-irradiation plus Pio; or (5) WBI plus Pio starting 24h after completion of WBI. Results: Administration of Pio before, during, and for 4 or 54 weeks after WBI prevented Radiation-induced cognitive impairment. Administration of Pio for 54 weeks starting after completion of fractionated WBI substantially but not significantly reduced Radiation-induced cognitive impairment. Conclusions: These findings offer the promise of improving the quality of life and increasing the therapeutic window for brain tumor patients.

Zhao Weiling [Department of Radiation Oncology, Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Payne, Valerie [Department of Radiation Oncology, Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Tommasi, Ellen [Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Diz, Debra I. [Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Hsu, F.-C. [Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Robbins, Mike E. [Department of Radiation Oncology, Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (United States)]. E-mail: mrobbins@wfubmc.edu

2007-01-01

83

Light control of peroxisome proliferation during Arabidopsis photomorphogenesis  

PubMed Central

Peroxisomes are multifunctional organelles whose abundance and metabolic activities differ depending on the species, cell type, developmental stage and prevailing environmental conditions.1 However, little is known about the signaling pathways that control these variations, especially in plants. Our laboratory recently investigated the regulatory role of light in changes in peroxisome abundance and identified a phytochrome A-dependent pathway responsible for the proliferation of peroxisomes during dark-to-light transition in Arabidopsis seedlings. Light induces peroxisome proliferation at least in part through upregulating the PEX11b gene, which encodes a peroxisomal membrane protein that mediates the early stages of peroxisome multiplication. Activation of PEX11b requires the far-red light receptor phyA, as well as the bZIP transcription factor HYH, which binds directly to the promoter of PEX11b. We conclude that during photomorphogenesis, both the import of leaf-peroxisome enzymes from the cytosol and the induction of peroxisome proliferation take place to prepare seedlings for photosynthesis and photorespiration. In addition to light, other plant peroxisome proliferators may also exert their functions by targeting members of the PEX11 gene family for transcriptional activation. PMID:19704562

Desai, Mintu

2008-01-01

84

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORa (PPARa) AGONISTS DIFFERENTIALLY REGULATE INHIBITOR OF DNA BINDING (ID2) EXPRESSION IN RODENTS AND HUMAN CELLS  

EPA Science Inventory

Abstract Inhibitor of DNA binding (Id2) is a member of the helix-loop-helix (HLH) transcription factor family whose members play important roles in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones,...

85

Cell death is induced by ciglitazone, a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonist, independently of PPAR{gamma} in human glioma cells  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Greater than 30 {mu}M ciglitazone induces cell death in glioma cells. Black-Right-Pointing-Pointer Cell death by ciglitazone is independent of PPAR{gamma} in glioma cells. Black-Right-Pointing-Pointer CGZ induces cell death by the loss of MMP via decreased Akt. -- Abstract: Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPAR{gamma} in CGZ-induced cell death was examined. At concentrations of greater than 30 {mu}M, CGZ, a synthetic PPAR{gamma} agonist, activated caspase-3 and induced apoptosis in T98G cells. Treatment of T98G cells with less than 30 {mu}M CGZ effectively induced cell death after pretreatment with 30 {mu}M of the PPAR{gamma} antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPAR{gamma} was down-regulated cells by siRNA, lower concentrations of CGZ (<30 {mu}M) were sufficient to induce cell death, although higher concentrations of CGZ ( Greater-Than-Or-Slanted-Equal-To 30 {mu}M) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPAR{gamma}. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPAR{gamma} in glioma cells, by down-regulating Akt activity and inducing MMP collapse.

Lee, Myoung Woo; Kim, Dae Seong; Kim, Hye Ryung; Kim, Hye Jin; Yang, Jin Mo; Ryu, Somi; Noh, Yoo Hun; Lee, Soo Hyun; Son, Meong Hi; Jung, Hye Lim; Yoo, Keon Hee [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)] [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Koo, Hong Hoe, E-mail: hhkoo@skku.edu [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Sung, Ki Woong, E-mail: kwsped@skku.edu [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2012-01-06

86

Plant Peroxisomes: Biogenesis and Function  

PubMed Central

Peroxisomes are eukaryotic organelles that are highly dynamic both in morphology and metabolism. Plant peroxisomes are involved in numerous processes, including primary and secondary metabolism, development, and responses to abiotic and biotic stresses. Considerable progress has been made in the identification of factors involved in peroxisomal biogenesis, revealing mechanisms that are both shared with and diverged from non-plant systems. Furthermore, recent advances have begun to reveal an unexpectedly large plant peroxisomal proteome and have increased our understanding of metabolic pathways in peroxisomes. Coordination of the biosynthesis, import, biochemical activity, and degradation of peroxisomal proteins allows for highly dynamic responses of peroxisomal metabolism to meet the needs of a plant. Knowledge gained from plant peroxisomal research will be instrumental to fully understanding the organelle’s dynamic behavior and defining peroxisomal metabolic networks, thus allowing the development of molecular strategies for rational engineering of plant metabolism, biomass production, stress tolerance, and pathogen defense. PMID:22669882

Hu, Jianping; Baker, Alison; Bartel, Bonnie; Linka, Nicole; Mullen, Robert T.; Reumann, Sigrun; Zolman, Bethany K.

2012-01-01

87

The PEROXIN11 Protein Family Controls Peroxisome Proliferation in Arabidopsis[W  

PubMed Central

PEROXIN11 (PEX11) is a peroxisomal membrane protein in fungi and mammals and was proposed to play a major role in peroxisome proliferation. To begin understanding how peroxisomes proliferate in plants and how changes in peroxisome abundance affect plant development, we characterized the extended Arabidopsis thaliana PEX11 protein family, consisting of the three phylogenetically distinct subfamilies PEX11a, PEX11b, and PEX11c to PEX11e. All five Arabidopsis PEX11 proteins target to peroxisomes, as demonstrated for endogenous and cyan fluorescent protein fusion proteins by fluorescence microscopy and immunobiochemical analysis using highly purified leaf peroxisomes. PEX11a and PEX11c to PEX11e behave as integral proteins of the peroxisome membrane. Overexpression of At PEX11 genes in Arabidopsis induced peroxisome proliferation, whereas reduction in gene expression decreased peroxisome abundance. PEX11c and PEX11e, but not PEX11a, PEX11b, and PEX11d, complemented to significant degrees the growth phenotype of the Saccharomyces cerevisiae pex11 null mutant on oleic acid. Heterologous expression of PEX11e in the yeast mutant increased the number and reduced the size of the peroxisomes. We conclude that all five Arabidopsis PEX11 proteins promote peroxisome proliferation and that individual family members play specific roles in distinct peroxisomal subtypes and environmental conditions and possibly in different steps of peroxisome proliferation. PMID:17220199

Orth, Travis; Reumann, Sigrun; Zhang, Xinchun; Fan, Jilian; Wenzel, Dirk; Quan, Sheng; Hu, Jianping

2007-01-01

88

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

2013-01-01

89

An aqueous extract of Salacia oblonga root, a herb-derived peroxisome proliferator-activated receptor-alpha activator, by oral gavage over 28 days induces gender-dependent hepatic hypertrophy in rats  

Microsoft Academic Search

Activation of peroxisome proliferator-activated receptor (PPAR)-alpha by natural and synthetic chemicals induces hepatic hypertrophy. An aqueous extract of Salacia oblonga root (SOW) is an Ayurvedic medicine with anti-diabetic and anti-obesity properties. In the present study, it was found that SOW (100, 300 and 900mg\\/kg, once daily by oral gavage over a 28 day period) elicited dose-related increases in liver weight

Xianglu Rong; Moon Sun Kim; Ning Su; Suping Wen; Yukimi Matsuo; Johji Yamahara; Michael Murray; Yuhao Li

2008-01-01

90

Prenatal and perinatal diagnosis of peroxisomal disorders  

Microsoft Academic Search

Summary Peroxisomes play an essential role in human cellular metabolism. Peroxisomal disorders, a group of genetic diseases caused by peroxisomal dysfunction, can be classified into three groups: (1) disorders of peroxisome biogenesis with a generalized loss of peroxisomal functions (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, hyperpipecolic acidaemia); (2) disorders with a loss of multiple peroxisomal functions (rhizomelic chondrodysplasia punctata

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

1989-01-01

91

Peroxisome mosaicism in the livers of peroxisomal deficiency patients  

Microsoft Academic Search

Peroxisomal deficiency disorders, which are genetically transmitted, are assumed to be expressed in all cells, and the use of cultured skin fibroblasts for diagnosis and research is based on this assumption. We describe three patients with clinical, biochemical, and microscopic evidence of a peroxisomal disorder. However, their liver displays mosaicism, i.e., parenchymal cells with peroxisomes are adjacent to cells without

Marc Espeel; Hanna Mandel; Florence Poggi; Jan A. M. Smeitink; Ronald J. A. Wanders; Ingrid Kerckaert; Rudolf B. H. Schutgens; Jean-marie Saudubray; Bwee-tien Poll-the; Frank Roels

1995-01-01

92

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

2013-01-01

93

Electrolyte and Acid-base disturbances induced by clacineurin inhibitors.  

PubMed

Nephrotoxicity is the most common and clinically significant adverse effect of calcineurin inhibitors. Cyclosporine and tacrolimus nephrotoxicity is manifested by both acute azotemia and chronic progressive renal disease and tubular zdysfunction. An elevation in the plasma potassium concentration due to reduced efficiency of urinary potassium excretion is common in cyclosporine-treated patients; it may be severe and potentially life-threatening with concurrent administration of an angiotensin converting enzyme inhibitor, which diminishes aldosterone release. Tubular injury induced by cyclosporine can also impair acid excretion. This may be presented as a hyperchloremic metabolic acidosis associated with decreased aldosterone activity and suppression of ammonium excretion by hyperkalemia. Some patients treated with cyclosporine develop hypophosphatemia due to urinary phosphate wasting. Renal magnesium wasting is also common presumably due to drug effects on magnesium reabsorption. Hypomagnesemia has also been implicated as a contributor to the nephrotoxicity associated with cyclosporine. Both cyclosporine and tacrolimus are associated with hypercalciuria. Attention must be paid to drug dose, side effects, and drug interactions to minimize toxicity and maximize efficacy. PMID:24459511

Lee, Chang Hwa; Kim, Gheun-Ho

2007-12-01

94

Peroxisome proliferator-activated receptors ?/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus  

PubMed Central

Background Status epilepticus induces subcellular changes that may lead to neuronal cell death in the hippocampus. However, the mechanism of seizure-induced neuronal cell death remains unclear. The mitochondrial uncoupling protein 2 (UCP2) is expressed in selected regions of the brain and is emerged as an endogenous neuroprotective molecule in many neurological disorders. We evaluated the neuroprotective role of UCP2 against seizure-induced hippocampal neuronal cell death under experimental status epilepticus. Methods In Sprague–Dawley rats, kainic acid (KA) was microinjected unilaterally into the hippocampal CA3 subfield to induce prolonged bilateral seizure activity. Oxidized protein level, translocation of Bcl-2, Bax and cytochrome c between cytosol and mitochondria, and expression of peroxisome proliferator-activated receptors ? (PPAR?) and UCP2 were examined in the hippocampal CA3 subfield following KA-induced status epilepticus. The effects of microinjection bilaterally into CA3 area of a PPAR? agonist, rosiglitazone or a PPAR? antagonist, GW9662 on UCP2 expression, induced superoxide anion (O2· -) production, oxidized protein level, mitochondrial respiratory chain enzyme activities, translocation of Bcl-2, Bax and cytochrome c, and DNA fragmentation in bilateral CA3 subfields were examined. Results Increased oxidized proteins and mitochondrial or cytosol translocation of Bax or cytochrome c in the hippocampal CA3 subfield was observed 3–48?h after experimental status epilepticus. Expression of PPAR? and UCP2 increased 12–48?h after KA-induced status epilepticus. Pretreatment with rosiglitazone increased UCP2 expression, reduced protein oxidation, O2· - overproduction and dysfunction of mitochondrial Complex I, hindered the translocation of Bax and cytochrome c, and reduced DNA fragmentation in the CA3 subfield. Pretreatment with GW9662 produced opposite effects. Conclusions Activation of PPAR? upregulated mitochondrial UCP2 expression, which decreased overproduction of reactive oxygen species, improved mitochondrial Complex I dysfunction, inhibited mitochondrial translocation of Bax and prevented cytosolic release of cytochrome c by stabilizing the mitochondrial transmembrane potential, leading to amelioration of apoptotic neuronal cell death in the hippocampus following status epilepticus. PMID:22849356

2012-01-01

95

Selective HDAC1/HDAC2 Inhibitors Induce Neuroblastoma Differentiation  

PubMed Central

Summary 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

2013-01-01

96

Peroxisome proliferator-activated receptor activating hypoglycemic effect of Gardenia jasminoides Ellis aqueous extract and improvement of insulin sensitivity in steroid induced insulin resistant rats  

PubMed Central

Background The active components of Gardenia (Gardenia jasminoides Ellis, GJ) exhibit a hypoglycemic effect by improving insulin secretion and lowering plasma lipids. In the present study, we fed a water extract of gardenia to steroid-induced insulin-resistant (SIIR) rats and observed changes in signaling proteins in order to elucidate the mechanisms of the insulin-sensitizing effect of GJ and evaluate its possibility as an insulin-sensitizing agent. Methods Normal Wistar rats were randomly divided into a control group (i.e., saline) and experimental groups (GJ 100 and 200 mg/kg). Blood samples were taken at 0, 30, and 60 min for plasma glucose assay in order to determine the optimal dose to induce the hypoglycemic effect. SIIR rats were then randomly divided into a control group (i.e., saline) and an experimental group (optimal dose of gardenia extract) to observe the insulin-sensitizing effect of the extract. Finally, western blot analysis was performed to detect intracellular signaling proteins to elucidate the mechanisms of the insulin-sensitization effect of GJ. Results The normal Wistar rats in the GJ 200 mg/kg group exhibited significant hypoglycemic activity. Meanwhile, the SIIR rats had higher plasma glucose levels than normal rats. There was no obvious change in insulin level, but the insulin sensitivity index and homeostasis model assessment index were significantly elevated. Meanwhile, a significant hypoglycemic effect was observed with GJ 200 mg/kg. In addition, intracellular signaling proteins including insulin receptor substrate-1 (IRS-1) and peroxisome proliferator-activated receptor (PPAR?) were elevated in muscle cells. Conclusions The optimal dose of GJ aqueous extract of 200 mg/kg exerts a PPAR?-activating hypoglycemic effect and improves insulin resistance in SIIR rats. Therefore, it is a potential insulin-sensitizing agent in type 2 diabetes mellitus with insulin resistance. PMID:24438349

2014-01-01

97

Peroxisome-proliferator-activated receptor-alpha activation protects brain capillary endothelial cells from oxygen-glucose deprivation-induced hyperpermeability in the blood-brain barrier.  

PubMed

That promising neuroprotectants failed to demonstrate benefit against stroke highlights the great difficulties to translate preclinical pharmacological effects in clinical outcomes. Part of this hurdle implies the complex response to injury of the neurovascular unit increasing the cerebrovascular permeability at the level of the blood-brain barrier (BBB). Previous studies reported neuroprotection in animal models upon activation of the nuclear receptor PPARalpha(peroxisome proliferator-activated receptor)alpha, but the cellular targets at the BBB level remain largely unexplored. Here, to study whether PPAR-alpha activation acts on BBB permeability, we adapted a mouse BBB cell model to ischaemic conditions at the stage of occlusion defined in vitro as oxygen-glucose deprivation (OGD). This model consists of a co-culture of brain capillary endothelial cells (ECs) on a filter insert placed upon a rat glial cell culture. The EC monolayer permeability increase induced by 4 h of OGD was significantly restricted after treatment with the PPAR-alpha agonist fenofibric acid (FA) 24 h before or at the onset of OGD. Treatments of separated ECs or glial cells showed that this protective effect was conferred by BBB ECs but not glial cells. Furthermore, co-cultures with ECs from PPAR-alpha-deficient mice revealed that FA had no effect on OGD-induced hyperpermeability. No transcriptional modulation of classical PPAR-alpha target genes such as SOD, ICAM-1, VCAM-1, ACO, CPT-1, PDK-4 or ET-1 was observed in wild type mouse ECs. In conclusion, these results suggest that part of the preventive PPAR-alpha-mediated protection may occur via BBB ECs by limiting hyperpermeability. PMID:19534718

Mysiorek, Caroline; Culot, Maxime; Dehouck, Lucie; Derudas, Bruno; Staels, Bart; Bordet, Régis; Cecchelli, Roméo; Fenart, Laurence; Berezowski, Vincent

2009-08-01

98

Proteinase Inhibitor-inducing Factor in Plant Leaves: A Phylogenetic Survey.  

PubMed

Thirty-nine plant species representing 20 families from the four major divisions of plants were surveyed for the presence of proteinase inhibitor-inducing factor activity in leaves or other tissues. Tissue juices were assayed for their capacity to induce accumulation of proteinase inhibitor I in excised tomato (Lycopersico esculentum) leaves. In tissues of only 2 of the 39 species was proteinase inhibitor-inducing factor-like activity not found. The activity was absent in cabbage leaves and celery stalks. Fruiting bodies from one of three fungi genera assayed contained exceptionally large quantities of proteinase inhibitor-inducing factor-like activity. Extracts from Agraricus campestris fruiting bodies contained over 20 times more activity than tomato leaf juice. The survey confirms that substances with proteinase inhibitor-inducing factor-like activity are widespread in the plant kingdom. PMID:16658956

McFarland, D; Ryan, C A

1974-11-01

99

Analysis of the Bioactivity of Magnetically Immunoisolated Peroxisomes  

PubMed Central

Peroxisomes produce reactive oxygen species (ROS), which may participate in biotransformations of innate biomolecules and xenobiotics. Isolating functional peroxisomes with low levels of contaminants would be a useful tool to investigate biotransformations occurring in these organelles that are usually confounded with biotransformations occurring in other co-isolated organelles. Here we immunoisolate peroxisomes, demonstrate that the impurity level after isolation is low and that peroxisomes retain their biological activity. In this method, an antibody targeting a 70 kDa peroxisomal membrane protein was immobilized to silanized magnetic iron oxide beads (1–4 ?m in diameter) coated with Protein A. Peroxisomes from L6 rat myoblast homogenates were magnetically captured, washed and then analyzed for subcellular composition using enzymatic assays. Based on the ratio of peroxisomal to lysosomal activity, the retained fraction is 70-fold enriched relative to the unretained fraction. Similarly, the ratio of peroxisomal activity to mitochondrial content suggests that the retained fraction is >30-fold enriched relative to the unretained fraction. H2O2 production from the ?-oxidation of palmitoyl-CoA demonstrated that the isolated peroxisomal fraction was biologically active. Capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) analysis confirmed that the immunopurified fractions were capable of transforming the anti-cancer drug doxorubicin and the fatty acid analog, BODIPY 500/510 C1C12. Besides its use to investigate peroxisome biotransformations in health and disease, the combination of magnetic immunoisolation with CE-LIF could be widely applicable to investigate subcellular specific biotransformations of xenobiotics occurring at immunoisolated subcellular compartments. PMID:22065344

Wang, Yaohua; Taylor, Thane H.; Arriaga, Edgar A.

2011-01-01

100

Toward Understanding Plant Peroxisome Proliferation  

PubMed Central

Plant peroxisomes are highly dynamic organelles that adapt to environmental variation by altering their number, but the molecular basis for plant peroxisome proliferation is largely unknown. To begin understanding how this fundamental cell biological process is controlled in plants, we recently characterized the Arabidopsis homologues of the yeast Pex11p protein, which is involved in peroxisome proliferation via an unknown mechanism. Using a combination of fluorescence microscopy, immunobiochemistry, overexpression and loss-of-function studies, and heterologous gene expression in yeast cells, we showed that all five Arabidopsis PEX11 proteins target to peroxisomal membranes and promote peroxisome proliferation with partial redundancy and specificity. A subset of the dynamin-related proteins (DRPs) is also involved with peroxisome division in plants, yeast, and mammals. Future experiments should focus on addressing the biochemical function of PEX11 and using new tools to uncover additional components of the peroxisome proliferation pathways, especially those that are unique to plants. PMID:19704631

2007-01-01

101

Valproic Acid and Other HDAC Inhibitors Induce Microglial Apoptosis and Attenuate Lipopolysaccharide- induced Dopaminergic Neurotoxicity  

PubMed Central

Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation. Other HDAC inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson’s disease. PMID:17850978

Chen, Po See; Wang, Chao-Chuan; Bortner, Carl D.; Peng, Giia-Sheun; Wu, Xuefei; Pang, Hao; Lu, Ru-Band; Gean, Po-Wu; Chuang, De-Maw; Hong, Jau-Shyong

2009-01-01

102

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

103

Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs.  

PubMed

Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) and cyclooxygenase inhibitor that is frequently used as a research tool to study the process of adipocyte differentiation. Treatment of various preadipocyte cell lines with micromolar concentrations of indomethacin in the presence of insulin promotes their terminal differentiation. However, the molecular basis for the adipogenic actions of indomethacin had remained unclear. In this report, we show that indomethacin binds and activates peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor known to play a pivotal role in adipogenesis. The concentration of indomethacin required to activate PPARgamma is in good agreement with that required to induce the differentiation of C3H10T1/2 cells to adipocytes. We demonstrate that several other NSAIDs, including fenoprofen, ibuprofen, and flufenamic acid, are also PPARgamma ligands and induce adipocyte differentiation of C3H10T1/2 cells. Finally, we show that the same NSAIDs that activate PPARgamma are also efficacious activators of PPARalpha, a liver-enriched PPAR subtype that plays a key role in peroxisome proliferation. Interestingly, several NSAIDs have been reported to induce peroxisomal activity in hepatocytes both in vitro and in vivo. Our findings define a novel group of PPARgamma ligands and provide a molecular basis for the biological effects of these drugs on adipogenesis and peroxisome activity. PMID:9013583

Lehmann, J M; Lenhard, J M; Oliver, B B; Ringold, G M; Kliewer, S A

1997-02-01

104

Polyunsaturated Fatty Acid Suppression of Hepatic Fatty Acid Synthase and S14 Gene Expression Does Not Require Peroxisome  

E-print Network

Not Require Peroxisome Proliferator-activated Receptor * (Received for publication, March 21, 1996, Maryland 20892 Dietary polyunsaturated fatty acids (PUFA) induce hepatic peroxisomal and microsomal fatty (CYP4A2)), and peroxisomal (acyl-CoA oxidase (AOX)) enzymes. PUFA ingestion in- duced mRNAAOX (2.3-fold

Omiecinski, Curtis

105

Peroxisomal ATP Import Is Essential for Seedling Development in Arabidopsis thaliana[W  

PubMed Central

Several recent proteomic studies of plant peroxisomes indicate that the peroxisomal matrix harbors multiple ATP-dependent enzymes and chaperones. However, it is unknown whether plant peroxisomes are able to produce ATP by substrate-level phosphorylation or whether external ATP fuels the energy-dependent reactions within peroxisomes. The existence of transport proteins that supply plant peroxisomes with energy for fatty acid oxidation and other ATP-dependent processes has not previously been demonstrated. Here, we describe two Arabidopsis thaliana genes that encode peroxisomal adenine nucleotide carriers, PNC1 and PNC2. Both proteins, when fused to enhanced yellow fluorescent protein, are targeted to peroxisomes. Complementation of a yeast mutant deficient in peroxisomal ATP import and in vitro transport assays using recombinant transporter proteins revealed that PNC1 and PNC2 catalyze the counterexchange of ATP with ADP or AMP. Transgenic Arabidopsis lines repressing both PNC genes were generated using ethanol-inducible RNA interference. A detailed analysis of these plants showed that an impaired peroxisomal ATP import inhibits fatty acid breakdown during early seedling growth and other ?-oxidation reactions, such as auxin biosynthesis. We show conclusively that PNC1 and PNC2 are essential for supplying peroxisomes with ATP, indicating that no other ATP generating systems exist inside plant peroxisomes. PMID:19073763

Linka, Nicole; Theodoulou, Frederica L.; Haslam, Richard P.; Linka, Marc; Napier, Jonathan A.; Neuhaus, H. Ekkehard; Weber, Andreas P.M.

2008-01-01

106

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

107

Integrin Inhibitor Suppresses Bevacizumab-Induced Glioma Invasion12  

PubMed Central

Glioblastoma is known to secrete high levels of vascular endothelial growth factor (VEGF), and clinical studies with bevacizumab, a monoclonal antibody to VEGF, have demonstrated convincing therapeutic benefits in glioblastoma patients. However, its induction of invasive proliferation has also been reported. We examined the effects of treatment with cilengitide, an integrin inhibitor, on bevacizumab-induced invasive changes in glioma. U87?EGFR cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor implantation, cilengitide and bevacizumab were administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically. Next, the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis. Bevacizumab treatment led to increased cell invasion in spite of decreased angiogenesis. When the rats were treated with a combination of bevacizumab and cilengitide, the depth of tumor invasion was significantly less than with only bevacizumab. Pathway analysis demonstrated the inhibition of invasion-associated genes such as the integrin-mediated cell adhesion pathway in the combination group. This study showed that the combination of bevacizumab with cilengitide exerted its anti-invasive effect. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma. PMID:24704537

Ishida, Joji; Onishi, Manabu; Kurozumi, Kazuhiko; Ichikawa, Tomotsugu; Fujii, Kentaro; Shimazu, Yosuke; Oka, Tetsuo; Date, Isao

2014-01-01

108

Partial Proteasome Inhibitors Induce Hair Follicle Growth by Stabilizing ?-catenin  

PubMed Central

The activation of tissue stem cells from their quiescent state represents the initial step in the complex process of organ regeneration and tissue repair. While the identity and location of tissue stem cells are becoming known, how key regulators control the balance of activation and quiescence remains mysterious. The vertebrate hair is an ideal model system where hair cycling between growth and resting phases is precisely regulated by morphogen signaling pathways, but how these events are coordinated to promote orderly signaling in a spatial and temporal manner remains unclear. Here, we show that hair cycle timing depends on regulated stability of signaling substrates by the ubiquitin-proteasome system. Topical application of partial proteasomal inhibitors (PaPIs) inhibits epidermal and dermal proteasome activity throughout the hair cycle. PaPIs prevent the destruction of the key anagen signal ?-catenin, resulting in more rapid hair growth and dramati cally shortened telogen. We show that PaPIs induce excess ?-catenin, act similarly to the GSK3? antagonist LiCl, and antagonize Dickopf-related protein-mediated inhibition of anagen. PaPIs thus represent a novel class of hair growth agents that act through transiently modifying the balance of stem cell activation and quiescence pathways. PMID:23963711

Yucel, Gozde; Van Arnam, John; Means, Paula Casey; Huntzicker, Erik; Altindag, Banu; Lara, Maria Fernanda; Yuan, Jenny; Kuo, Calvin; Oro, Anthony E.

2014-01-01

109

PPAR-? Impairment Alters Peroxisome Functionality in Primary Astrocyte Cell Cultures  

PubMed Central

Peroxisomes provide glial cells with protective functions against the harmful effects of H2O2 on neurons and peroxisome impairment results in nervous lesions. Agonists of the ?-subtype of the Peroxisome-Proliferator-Activated-Receptors (PPAR) have been proposed as neuroprotective agents in neurodegenerative disorders. Nevertheless, the role of PPAR-? alterations in pathophysiological mechanisms and the relevance of peroxisome functions in the PPAR-? effects are not yet clear. In a primary cell culture of rat astrocytes, the irreversible PPAR-? antagonist GW9662 concentration-dependently decreased the activity of catalase, the most important antioxidant defense enzyme in peroxisomes. Catalase functionality recovered in a few days and the PPAR-? agonist rosiglitazone promoted reversal of enzymatic damage. The reversible antagonist G3335 reduced both the activity and expression of catalase in a rosiglitazone-prevented manner. G3335 reduced also the glutathione reductase expression, indicating that enzyme involved in glutathione regeneration was compromised. Neither the PPAR-? target gene Acyl-Coenzyme-A-oxidase-1 nor the mitochondrial detoxifying enzyme NADH:ubiquinone-oxidoreductase (NDFUS3) was altered by PPAR-? inhibition. In conclusion, PPAR-? inhibition induced impairment of catalase in astrocytes. A general decrease of the antioxidant defenses of the cell suggests that a PPAR-? hypofunction could participate in neurodegenerative mechanisms through peroxisomal damage. This series of experiments could be a useful model for studying compounds able to restore peroxisome functionality. PMID:24729976

Di Cesare Mannelli, Lorenzo; Zanardelli, Matteo; Micheli, Laura; Ghelardini, Carla

2014-01-01

110

Peroxisomes as Novel Players in Cell Calcium Homeostasis*  

PubMed Central

Ca2+ concentration in peroxisomal matrix ([Ca2+]perox) has been monitored dynamically in mammalian cells expressing variants of Ca2+-sensitive aequorin specifically targeted to peroxisomes. Upon stimulation with agonists that induce Ca2+ release from intracellular stores, peroxisomes transiently take up Ca2+ reaching peak values in the lumen as high as 50–100 ?m, depending on cell types. Also in resting cells, peroxisomes sustain a Ca2+ gradient, [Ca2+]perox being ?20-fold higher than [Ca2+] in the cytosol ([Ca2+]cyt). The properties of Ca2+ traffic across the peroxisomal membrane are different from those reported for other subcellular organelles. The sensitivity of peroxisomal Ca2+ uptake to agents dissipating H+ and Na+ gradients unravels the existence of a complex bioenergetic framework including V-ATPase, Ca2+/H+, and Ca2+/Na+ activities whose components are yet to be identified at a molecular level. The different [Ca2+]perox of resting and stimulated cells suggest that Ca2+ could play an important role in the regulation of peroxisomal metabolism. PMID:18364350

Lasorsa, Francesco Massimo; Pinton, Paolo; Palmieri, Luigi; Scarcia, Pasquale; Rottensteiner, Hanspeter; Rizzuto, Rosario; Palmieri, Ferdinando

2008-01-01

111

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

112

Peroxisome Proliferator-Activated Receptor g1 Expression Is Induced during Cyclic Adenosine Monophosphate-Stimulated Differentiation of Alveolar Type II Pneumonocytes  

Microsoft Academic Search

The primary function of lung alveolar type II cells is to synthesize pulmonary surfactant, a lipoprotein enriched in dipalmitoylphos- phatidylcholine. Because type II pneumonocytes are highly lipogenic, we considered the possible role of the adipogenic nuclear hormone receptor, peroxisome proliferator-activated receptor g (PPARg), in their differentiation from epithelial cell precursors. A degenerate PCR-screening strategy revealed that multiple PPARs, including PPARg,

LAURA F. MICHAEL; MITCHELL A. LAZAR; CAROLE R. MENDELSON

2010-01-01

113

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. PMID:24151469

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

2013-01-01

114

Mode of action framework analysis for receptor-mediated toxicity: the Peroxisome Proliferator-Activated Receptor alpha (PPARa) as a case study  

EPA Science Inventory

Therapeutic hypolipidemic agents and industrial chemicals that cause peroxisome proliferation and induce liver tumors in rodents activate the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa). Research has elucidated the cellular and molecular events by w...

115

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

116

Short Communication The nitric oxide synthase inhibitor l-NAME suppresses androgen-induced  

E-print Network

Short Communication The nitric oxide synthase inhibitor l-NAME suppresses androgen-induced male anesthesia and each implanted with a Silastic tube (Helix Medical, 10 mm long, internal diameter 1.47 mm

Crews, David

117

Different forms of cell death induced by putative BCL2 inhibitors  

Microsoft Academic Search

Several inhibitors of BCL2 proteins have been identified that induce apoptosis in a variety of tumor cells, indicating their potential in cancer therapy. We investigated the specificity of six putative BCL2 inhibitors (obatoclax, gossypol, apogossypol, EM20-25, chelerythrine and ABT-737). Using cells deficient either for Bax\\/Bak or caspase-9, we found that only ABT-737 specifically targeted BCL2 proteins and induced apoptosis by

M Vogler; K Weber; D Dinsdale; I Schmitz; K Schulze-Osthoff; M J S Dyer; G M Cohen

2009-01-01

118

Detrimental Effect of the Proteasome Inhibitor, Bortezomib in Bacterial Superantigen- and Lipopolysaccharide-induced Systemic Inflammation  

Microsoft Academic Search

Bacterial superantigen (BSAg)–induced toxic shock syndrome (TSS) and bacterial lipopolysaccharide (LPS)–induced shock are characterized by severe systemic inflammation. As nuclear factor ?B (NF?B) plays an important role in inflammation and bortezomib, a proteasome inhibitor widely used in cancer chemotherapy, is a potent inhibitor of NF?B activation, we evaluated the therapeutic and prophylactic use of bortezomib in these conditions using murine

Ashenafi Y Tilahun; Jayne E Theuer; Robin Patel; Chella S David; Govindarajan Rajagopalan

2010-01-01

119

Formation of the peroxisome lumen is abolished by loss of Pichia pastoris Pas7p, a zinc-binding integral membrane protein of the peroxisome.  

PubMed Central

We have cloned and sequenced PAS7, a gene required for peroxisome assembly in the yeast Pichia pastoris. The product of this gene, Pas7p, is a member of the C3HC4 superfamily of zinc-binding proteins. Point mutations that alter conserved residues of the C3HC4 motif abolish PAS7 activity and reduce zinc binding, suggesting that Pas7p binds zinc in vivo and that zinc binding is essential for PAS7 function. As with most pas mutants, pas7 cells exhibit a pronounced deficiency in import of peroxisomal matrix proteins that contain either the type 1 peroxisomal targeting signal (PTS1) or the type 2 PTS (PTS2). However, while other yeast and mammalian pas mutants accumulate ovoid, vesicular peroxisomal intermediates, loss of Pas7p leads to accumulation of membrane sheets and vesicles which lack a recognizable lumen. Thus, Pas7p appears to be essential for protein translocation into peroxisomes as well as formation of the lumen of the organelle. Consistent with these data, we find that Pas7p is an integral peroxisomal membrane protein which is entirely resistant to exogenous protease and thus appears to reside completely within the peroxisome. Our observations suggest that the function of Pas7p defines a previously unrecognized step in peroxisome assembly: formation of the peroxisome lumen. Furthermore, because the peroxisomal intermediates in the pas7 delta mutant proliferate in response to peroxisome-inducing environmental conditions, we conclude that Pas7p is not required for peroxisome proliferation. PMID:7565793

Kalish, J E; Theda, C; Morrell, J C; Berg, J M; Gould, S J

1995-01-01

120

Proteasome inhibitors induce apoptosis in growth hormone- and prolactin-secreting rat pituitary tumor cells.  

PubMed

Proteasome inhibitors induce apoptosis in some malignant cells, and we show here that these inhibitors induce apoptosis in rat pituitary MMQ and GH3 tumor cells but not in normal pituitary cells. Three proteasome inhibitors, PSI, MG-132, and lactacystin, but not the calpain inhibitor, ALLM, dose- and time-dependently caused apoptosis in these cells, and 10 microM PSI caused apoptosis in 70% of MMQ cells and in 25% of GH3 cells within 24 h. A lower PSI dose (10 nM) inhibited GH3 cell growth without causing significant apoptosis or affecting prolactin secretion. Primary rat pituitary cells were resistant to both PSI and MG-132 and did not undergo apoptosis. In MMQ cells, DNA synthesis was slowed (approximately 30%) after 6 h of 10 microM PSI treatment and a partial cell cycle block at G2/M was evident after 8 h. Colorimetric caspase substrate assay and Western blotting of caspase substrates showed that caspases 2 and 3 are activated by PSI while caspases 6 and 8 remained inactive. A broad-range caspase inhibitor, caspase inhibitor III, prevented apoptosis induced by PSI. The results show that proteasome inhibitors induce apoptosis in rat pituitary tumor cells by specific caspase activation. This novel group of drugs may potentially be used in treatment of aggressive pituitary tumors, especially as their action appears relative for tumor cells. PMID:12208657

Yu, R; Ren, S-G; Melmed, S

2002-09-01

121

Hypoxia-inducible factor 1 mediates hypoxia-induced cardiomyocyte lipid accumulation by reducing the DNA binding activity of peroxisome proliferator-activated receptor {alpha}/retinoid X receptor  

SciTech Connect

In response to cellular hypoxia, cardiomyocytes adapt to consume less oxygen by shifting ATP production from mitochondrial fatty acid {beta}-oxidation to glycolysis. The transcriptional activation of glucose transporters and glycolytic enzymes by hypoxia is mediated by hypoxia-inducible factor 1 (HIF-1). In this study, we examined whether HIF-1 was involved in the suppression of mitochondrial fatty acid {beta}-oxidation in hypoxic cardiomyocytes. We showed that either hypoxia or adenovirus-mediated expression of a constitutively stable hybrid form (HIF-1{alpha}/VP16) suppressed mitochondrial fatty acid metabolism, as indicated by an accumulation of intracellular neutral lipid. Both treatments also reduced the mRNA levels of muscle carnitine palmitoyltransferase I which catalyzes the rate-limiting step in the mitochondrial import of fatty acids for {beta}-oxidation. Furthermore, adenovirus-mediated expression of HIF-1{alpha}/VP16 in cardiomyocytes under normoxic conditions also mimicked the reduction in the DNA binding activity of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha})/retinoid X receptor (RXR), in the presence or absence of a PPAR{alpha} ligand. These results suggest that HIF-1 may be involved in hypoxia-induced suppression of fatty acid metabolism in cardiomyocytes by reducing the DNA binding activity of PPAR{alpha}/RXR.

Belanger, Adam J.; Luo Zhengyu; Vincent, Karen A.; Akita, Geoffrey Y.; Cheng, Seng H.; Gregory, Richard J. [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States); Jiang Canwen [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States)], E-mail: canwen.jiang@genzyme.com

2007-12-21

122

Evolving models for peroxisome biogenesis.  

PubMed

Significant progress has been made towards our understanding of the mechanism of peroxisome formation, in particular concerning sorting of peroxisomal membrane proteins, matrix protein import and organelle multiplication. Here we evaluate the progress made in recent years. We focus mainly on progress made in yeasts. We indicate the gaps in our knowledge and discuss conflicting models. PMID:24681485

Hettema, Ewald H; Erdmann, Ralf; van der Klei, Ida; Veenhuis, Marten

2014-08-01

123

Ligands for Peroxisome Proliferator-Activated Receptorgamma and Retinoic Acid Receptor Inhibit Growth and Induce Apoptosis of Human Breast Cancer Cells in vitro and in BNX Mice  

Microsoft Academic Search

Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor gamma (PPARgamma ) is expressed in breast cancer cells. Activation of PPARgamma through a synthetic ligand, troglitazone

Elena Elstner; Carsten Muller; Kozo Koshizuka; Elizabeth A. Williamson; Dorothy Park; Hiroya Asou; Peter Shintaku; Jonathan W. Said; David Heber; H. Phillip Koeffler

1998-01-01

124

Peroxisome Proliferator-Activated Receptor Activators Inhibit Thrombin-Induced Endothelin1 Production in Human Vascular Endothelial Cells by Inhibiting the Activator Protein1 Signaling Pathway  

Microsoft Academic Search

Endothelin-1 (ET-1), a 21-amino acid vasoactive peptide mainly produced by vascular endothelial cells, is involved in the regulation of vascular tone and smooth muscle cell proliferation. Peroxisome proliferator-activated receptors (PPARs), key players in lipid and glucose metabolism, have been implicated in metabolic disorders that are predisposing to atherosclerosis. Because of the potential role of ET-1 in vascular disorders such as

Philippe Delerive; Francoise Martin-Nizard; Giulia Chinetti; Francois Trottein; Jean-Charles Fruchart; Jamila Najib; Patrick Duriez; Bart Staels

125

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

2011-02-01

126

Inhibitors of inositol trisphosphate-induced Ca2+ release from isolated platelet membrane vesicles.  

PubMed

Platelet membrane vesicles accumulated Ca2+ in an ATP-dependent fashion, and 25-50% of the accumulated Ca2+ was released by the addition of 10 microM inositol 1,4,5-trisphosphate (IP3). The concentration of IP3 required for half-maximal Ca2+ release was approximately 0.5 microM. The inhibition of IP3-induced Ca2+ release from these membrane vesicles by various agents was examined. Of the plasma membrane Ca2+ channel blockers, cinnarizine and flunarizine were found to be potent inhibitors of IP3-induced Ca2+ release while having no effect on ATP-dependent Ca2+ uptake. The IC50 value for both cinnarizine and flunarizine as inhibitors of IP3-induced Ca2+ release was below 10(-6) M. Nifedipine, verapamil, bepridil, and diltiazem did not significantly inhibit IP3-induced Ca2+ release at the highest concentration tested (50 microM). The "intracellular Ca2+ antagonists" ryanodine, TMB-8 (8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate), dantroline, trifluoperazine and chlorpromazine were not inhibitors of IP3-induced Ca2+ release at 50 microM. The local anesthetics benzocaine and lidocaine weakly inhibited the IP3-induced Ca2+ release with IC50 values of approximately 5 and 50 microM, respectively, whereas other local anesthetics tested were less potent inhibitors. The potent inhibitors described may prove useful as probes of the IP3-induced Ca2+ release channels. PMID:3499904

Seiler, S M; Arnold, A J; Stanton, H C

1987-10-15

127

MAPK inhibitors and pifithrin-alpha block cinnamaldehyde-induced apoptosis in human PLC\\/PRF\\/5 cells  

Microsoft Academic Search

Cinnamaldehyde (Cin) has been shown to be effective in inducing apoptotic cell death in a number of human cancer cells. The aim of this study was to investigate the effect of pifithrin-alpha (PFT?; a specific p53 inhibitor) and mitogen-activated protein kinases (MAPKs) inhibitors [namely SP600125 (a specific JNK inhibitor), SB203580 (a specific p38 inhibitor) and PD98059 (a specific ERK inhibitor)

Shu-Jing Wu; Lean-Teik Ng

2007-01-01

128

Paronychia induced by the epidermal growth factor receptor inhibitor cetuximab.  

PubMed

While the development of epidermal growth factor receptor inhibitors has been hailed as a remarkable triumph in the field of oncology, it has inherited with it a host of cutaneous side-effects that have been increasingly observed in a substantial number of patients in the recent years. One cutaneous manifestation that may inflict significant pain and affect activities of daily living among some of the patients receiving epidermal growth factor receptor inhibitors is paronychia. A case of paronychia associated with the use of cetuximab in the management of KRAS wild-type midrectal adenocarcinoma along with its management has been described. PMID:23161875

Lee, Soo Lin; Tan, Boon Seang; Chan, Lee Chin

2013-09-01

129

INHIBITORS OF HYDROPEROXIDE METABOLISM ENHANCE ASCORBATE-INDUCED CYTOTOXICITY  

PubMed Central

Pharmacological ascorbate, via its oxidation, has been proposed as a pro-drug for the delivery of H2O2 to tumors. Pharmacological ascorbate decreases clonogenic survival of pancreatic cancer cells, which can be reversed by treatment with scavengers of H2O2. The goal of this study was to determine if inhibitors of intracellular hydroperoxide detoxification could enhance the cytotoxic effects of ascorbate. Human pancreatic cancer cells were treated with ascorbate alone or in combination with inhibitors of hydroperoxide removal including the glutathione disulfide reductase inhibitor 1,3 bis (2-chloroethyl)-1-nitrosurea (BCNU), siRNA targeted to glutathione disulfide reductase (siGR), and 2-deoxy-D-glucose (2DG), which inhibits glucose metabolism. Changes in the intracellular concentration of H2O2 were determined by analysis of the rate of aminotriazole-mediated inactivation of endogenous catalase activity. Pharmacological ascorbate increased intracellular H2O2 and depleted intracellular glutathione. When inhibitors of H2O2 metabolism were combined with pharmacological ascorbate the increase in intracellular H2O2 was amplified and cytotoxicity was enhanced. We conclude that inclusion of agents that inhibit cellular peroxide removal produced by pharmacological ascorbate leads to changes in the intracellular redox state resulting in enhanced cytotoxicity. PMID:23205739

Olney, Kristen E.; Du, Juan; van 't Erve, Thomas J.; Witmer, Jordan R.; Sibenaller, Zita A.; Wagner, Brett A.; Buettner, Garry R.; Cullen, Joseph J.

2013-01-01

130

Inhibitors of hydroperoxide metabolism enhance ascorbate-induced cytotoxicity.  

PubMed

Pharmacological ascorbate, via its oxidation, has been proposed as a pro-drug for the delivery of H(2)O(2) to tumors. Pharmacological ascorbate decreases clonogenic survival of pancreatic cancer cells, which can be reversed by treatment with scavengers of H(2)O(2). The goal of this study was to determine if inhibitors of intracellular hydroperoxide detoxification could enhance the cytotoxic effects of ascorbate. Human pancreatic cancer cells were treated with ascorbate alone or in combination with inhibitors of hydroperoxide removal including the glutathione disulfide reductase inhibitor 1,3 bis (2-chloroethyl)-1-nitrosurea (BCNU), siRNA targeted to glutathione disulfide reductase (siGR), and 2-deoxy-D-glucose (2DG), which inhibits glucose metabolism. Changes in the intracellular concentration of H(2)O(2) were determined by analysis of the rate of aminotriazole-mediated inactivation of endogenous catalase activity. Pharmacological ascorbate increased intracellular H(2)O(2) and depleted intracellular glutathione. When inhibitors of H(2)O(2) metabolism were combined with pharmacological ascorbate the increase in intracellular H(2)O(2) was amplified and cytotoxicity was enhanced. We conclude that inclusion of agents that inhibit cellular peroxide removal produced by pharmacological ascorbate leads to changes in the intracellular redox state resulting in enhanced cytotoxicity. PMID:23205739

Olney, K E; Du, J; van 't Erve, T J; Witmer, J R; Sibenaller, Z A; Wagner, B A; Buettner, G R; Cullen, J J

2013-03-01

131

Selective serotonin reuptake inhibitor-induced urinary incontinence  

Microsoft Academic Search

PURPOSE: Irrespective of its cause, urinary incontinence is a medical condition seriously affecting quality of life and is increasingly recognized. In this study, we examined the association between the use of selective serotonin reuptake inhibitors (SSRIs) and urinary incontinence. METHODS: A retrospective follow-up study among starters with an SSRI was performed to estimate the relative and absolute risk for urinary

K. L. L. Movig; H. G. M. Leufkens; S. V. Belitser; A. W. Lenderink; A. C. G. Egberts

2002-01-01

132

Histone deacetylase inhibitor trichostatin A and proteasome inhibitor PS-341 synergistically induce apoptosis in pancreatic cancer cells  

SciTech Connect

Pancreatic cancer is a common and lethal malignancy. Pancreatic cancer cells overexpress multiple anti-apoptotic factors and death receptor decoys, and are strongly resistant to radiation and to 5-fluorouracil (5-FU)- or gemcitabine (Gem)-based chemotherapy regimens. We have found that low-dose proteasome inhibitor PS-341 and histone deacetylase inhibitor trichostatin A (TSA) synergistically induce cytotoxicity in a panel of eight diverse pancreatic cancer cell lines. Combining TSA with PS-341 effectively inactivated NF{kappa}B signaling, downregulated the predominant endogenous anti-apoptotic factor Bcl-XL overexpression, and disrupted MAP kinase pathway. The combined drug regimen effectively inflicted an average of 71.5% apoptotic cell death (55.2-80%) in diverse pancreatic cancer cell lines by activating the intrinsic apoptotic pathway. Conclusion: the TSA/PS-341 regimen may represent a potential novel therapeutic strategy for pancreatic cancer.

Bai Jirong [Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 0221 (United States)]. E-mail: jbai@bidmc.harvard.edu; Demirjian, Aram [Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 0221 (United States); Sui Jianhua [Dana-Farber Cancer Institute, Harvard Medical School, 330 Brookline Avenue, Boston, MA 0221 (United States); Marasco, Wayne [Dana-Farber Cancer Institute, Harvard Medical School, 330 Brookline Avenue, Boston, MA 0221 (United States); Callery, Mark P. [Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 0221 (United States)]. E-mail: mcallery@bidmc.harvard.ede

2006-10-06

133

Use of a Soluble Epoxide Hydrolase Inhibitor in Smoke-Induced Chronic Obstructive Pulmonary Disease  

E-print Network

Use of a Soluble Epoxide Hydrolase Inhibitor in Smoke-Induced Chronic Obstructive Pulmonary Disease Tobacco smoke-induced chronic obstructive pulmonary disease (COPD) is a prolonged inflammatory condition; anti-inflammatory agents; airway obstruction Chronic obstructive pulmonary disease (COPD) is a major

Hammock, Bruce D.

134

Increasing insight into induced plant defense mechanisms using elicitors and inhibitors  

Microsoft Academic Search

One of the strategies that plants employ to defend themselves against herbivore attack is the induced production of carnivore-attracting volatiles. Using elicitors and inhibitors of different steps of the signal-transduction pathways can improve our understanding of the mechanisms underlying induced plant defenses. For instance, we recently showed that application of jasmonic acid, a key hormone in the octadecanoid pathway involved

Maaike Bruinsma; Loon van J. J. A; Marcel Dicke

2010-01-01

135

Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli  

E-print Network

Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli Daniel J Bioinformatics Program, Boston University, Boston, MA, USA 6 These authors contributed equally to this work forks. This immediately results in bacteriostasis and ultimately induces cell death. Here we demonstrate

Collins, James J.

136

Amelioration of antigen induced arthritis in rabbits treated with a secreted viral serine proteinase inhibitor  

Microsoft Academic Search

OBJECTIVE: To evaluate the effects of intraarticular administration of SERP-1 protein, a myxoma virus derived antiinflammatory serine protease inhibitor, in an antigen induced arthritis (AIA) model of chronic inflammation. METHODS: AIA was induced in a single joint of 15 rabbits after intraarticular (i.a.) injection of ovalbumin in animals previously immunized to the same agent administered in complete Freund's adjuvant. A

W. P. Maksymowych; N. Nation; P. Nash; J. Macen; A. Lucas; G. McFadden; A. S. Russell

1996-01-01

137

Peroxisome proliferator–activated receptor ? mediates the adaptive response to fasting  

Microsoft Academic Search

Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor ? (PPAR?) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPAR? may be involved

Sander Kersten; Josiane Seydoux; Jeffrey M. Peters; Frank J. Gonzalez; Béatrice Desvergne; Walter Wahli

1999-01-01

138

5-Lipoxygenase Inhibitors Attenuate TNF-?-Induced Inflammation in Human Synovial Fibroblasts  

PubMed Central

The lipoxygenase isoform of 5-lipoxygenase (5-LOX) is reported to be overexpressed in human rheumatoid arthritis synovial tissue and involved in the progress of inflammatory arthritis. However, the detailed mechanism of how 5-lipoxygenase regulates the inflammatory response in arthritis synovial tissue is still unclear. The aim of this study was to investigate the involvement of lipoxygenase pathways in TNF-?-induced production of cytokines and chemokines. Human synovial fibroblasts from rheumatoid patients were used in this study. 5-LOX inhibitors and shRNA were used to examine the involvement of 5-LOX in TNF-?-induced cytokines and chemokines expression. The signaling pathways were examined by Western Blotting or immunofluorescence staining. The effect of 5-LOX inhibitor on TNF-?-induced chemokine expression and paw edema was also explored in vivo in C57BL/6 mice. Treatment with 5-LOX inhibitors significantly decreased TNF-?-induced pro-inflammatory mediators including interleukin-6 (IL-6) and monocyte chemo-attractant protein-1 (MCP-1) in human synovial fibroblasts. Knockdown of 5-LOX using shRNA exerted similar inhibitory effects. The abrogation of NF-?B activation was involved in the antagonizing effects of these inhibitors. Furthermore, 5-LOX inhibitor decreased TNF-?-induced up-regulation of serum MCP-1 level and paw edema in mouse model. Our results provide the evidence that the administration of 5-LOX inhibitors is able to ameliorate TNF-?-induced cytokine/chemokine release and paw edema, indicating that 5-LOX inhibitors may be developed for therapeutic treatment of inflammatory arthritis. PMID:25229347

Lin, Han-Ching; Lin, Tzu-Hung; Wu, Ming-Yueh; Chiu, Yung-Cheng; Tang, Chih-Hsin; Hour, Mann-Jen; Liou, Houng-Chi; Tu, Huang-Ju; Yang, Rong-Sen; Fu, Wen-Mei

2014-01-01

139

Phosphorylation-dependent Pex11p and Fis1p interaction regulates peroxisome division  

PubMed Central

Peroxisome division is regulated by the conserved peroxin Pex11p. In Saccharomyces cerevisiae (Sc), induction of the phosphoprotein ScPex11p coincides with peroxisome biogenesis. We show that the ScPex11p homologue in Pichia pastoris (PpPex11p) is phosphorylated at serine 173. PpPex11p expression and phosphorylation are induced in oleate and coordinated with peroxisome biogenesis. PpPex11p transits to peroxisomes via the endoplasmic reticulum (ER). PpPex11p is unstable and ER restricted gin pex3? and pex19? cells, which are impaired in peroxisomal membrane protein biogenesis. In oleate medium, the P. pastoris mutants pex11A (constitutively unphosphorylated; S173A) and pex11D (constitutively phosphorylated; S173D) exhibit juxtaposed elongated peroxisomes (JEPs) and hyperdivided forms, respectively, although protein levels remain unchanged. In contrast with ScPex11p, the ER-to-peroxisome translocation in P. pastoris is phosphorylation independent, and the phosphorylation occurs at the peroxisome. We show that PpPex11p interacts with the peroxisome fission machinery via PpFis1p and is regulated by phosphorylation because PpPex11p and PpPex11Dp interact more strongly with PpFis1p than PpPex11Ap. Neither PpPex11p nor PpFis1p is necessary for peroxisome division in methanol medium. We propose a model for the role of PpPex11p in the regulation of peroxisome division through a phosphorylation-dependent interaction with the fission machinery, providing novel insights into peroxisome morphogenesis. PMID:22337771

Joshi, Saurabh; Agrawal, Gaurav; Subramani, Suresh

2012-01-01

140

Elucidating the function of mycorrhizal-induced Kunitz protease inhibitors and characterization of their putative target proteases in Medicago truncatula.  

E-print Network

??Most terrestrial plants live in symbiosis with arbuscular mycorrhizal fungi. In this study, a mycorrhizal-induced gene family of Medicago truncatula encoding putative Kunitz protease inhibitors… (more)

Hirsch, Stefanie S.

2014-01-01

141

The Pichia pastoris PER6 gene product is a peroxisomal integral membrane protein essential for peroxisome biogenesis and has sequence similarity to the Zellweger syndrome protein PAF-1.  

PubMed Central

We report the cloning of PER6, a gene essential for peroxisome biogenesis in the methylotrophic yeast Pichia pastoris. The PER6 sequence predicts that its product Per6p is a 52-kDa polypeptide with the cysteine-rich C3HC4 motif. Per6p has significant overall sequence similarity with the human peroxisome assembly factor PAF-1, a protein that is defective in certain patients suffering from the peroxisomal disorder Zellweger syndrome, and with car1, a protein required for peroxisome biogenesis and caryogamy in the filamentous fungus Podospora anserina. In addition, the C3HC4 motif and two of the three membrane-spanning segments predicted for Per6p align with the C3HC4 motifs and the two membrane-spanning segments predicted for PAF-1 and car1. Like PAF-1, Per6p is a peroxisomal integral membrane protein. In methanol- or oleic acid-induced cells of per6 mutants, morphologically recognizable peroxisomes are absent. Instead, peroxisomal remnants are observed. In addition, peroxisomal matrix proteins are synthesized but located in the cytosol. The similarities between Per6p and PAF-1 in amino acid sequence and biochemical properties, and between mutants defective in their respective genes, suggest that Per6p is the putative yeast homolog of PAF-1. PMID:8628321

Waterham, H R; de Vries, Y; Russel, K A; Xie, W; Veenhuis, M; Cregg, J M

1996-01-01

142

The phosphoinositide-dependent protein kinase 1 inhibitor, UCN-01, induces fragmentation: Possible role of metalloproteinases.  

PubMed

Phosphoinositide-dependent protein kinase 1 (PDK1) is a key enzyme, master regulator of cellular proliferation and metabolism; it is considered a key target for pharmacological intervention. Using membranes obtained from DDT1 MF-2 cells, phospho-PDK1 was identified by Western blotting, as two major protein bands of Mr 58-68kDa. Cell incubation with the PDK1 inhibitor, UCN-01, induced a time- and concentration-dependent decrease in the amount of phospho-PDK1 with a concomitant appearance of a ?42kDa phosphorylated fragment. Knocking down PDK1 diminished the amount of phospho-PDK1 detected in membranes, accompanied by similarly decreased fragment generation. UCN-01-induced fragment generation was also observed in membranes from cells stably expressing a myc-tagged PDK1 construct. Other PDK1 inhibitors were also tested: OSU-03012 induced a clear decrease in phospho-PDK1 and increased the presence of the phosphorylated fragment in membrane preparations; in contrast, GSK2334470 and staurosporine induced only marginal increases in the amount of PDK1 fragment. Galardin and batimastat, two metalloproteinase inhibitors, markedly attenuated inhibitor-induced PDK1 fragment generation. Metalloproteinases 2, 3, and 9 co-immunoprecipitated with myc-PDK1 under baseline conditions and this interaction was stimulated by UCN-01; batimastat also markedly diminished this effect of the PDK1 inhibitor. Our results indicate that a series of protein kinase inhibitors, namely UCN-01 and OSU-03012 and to a lesser extent GSK2334470 and staurosporine induce PDK1 fragmentation and suggest that metalloproteinases could participate in this effect. PMID:25016091

Alcántara-Hernández, Rocío; Hernández-Méndez, Aurelio; Adolfo García-Sáinz, J

2014-10-01

143

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

144

Icatibant in the treatment of Angiotensin-converting enzyme inhibitor-induced angioedema.  

PubMed

We describe the case of a 75-year-old woman who presented with massive tongue and lip swelling secondary to angiotensin-converting enzyme inhibitor-induced angioedema. An awake fibre-optic intubation was performed because of impending airway obstruction. As there was no improvement in symptoms after 72 hours, the selective bradykinin B2 receptor antagonist icatibant (Firazyr) was administered and the patient's trachea was successfully extubated 36 hours later. To our knowledge this is the first documented case of icatibant being used for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema in the United Kingdom and represents a novel therapeutic option in its management. PMID:25328718

Crooks, Neil H; Patel, Jaimin; Diwakar, Lavanya; Smith, Fang Gao

2014-01-01

145

Icatibant in the Treatment of Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema  

PubMed Central

We describe the case of a 75-year-old woman who presented with massive tongue and lip swelling secondary to angiotensin-converting enzyme inhibitor-induced angioedema. An awake fibre-optic intubation was performed because of impending airway obstruction. As there was no improvement in symptoms after 72 hours, the selective bradykinin B2 receptor antagonist icatibant (Firazyr) was administered and the patient's trachea was successfully extubated 36 hours later. To our knowledge this is the first documented case of icatibant being used for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema in the United Kingdom and represents a novel therapeutic option in its management. PMID:25328718

Crooks, Neil H.; Patel, Jaimin; Diwakar, Lavanya; Smith, Fang Gao

2014-01-01

146

Arsenic toxicity induced endothelial dysfunction and dementia: pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors.  

PubMed

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate & brain GSH levels along with increase in serum & brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. PMID:23921152

Sharma, Bhupesh; Sharma, P M

2013-11-15

147

Location of Inhibitor Binding Sites in the Human Inducible Prostaglandin E Synthase, MPGES1  

PubMed Central

The inducible microsomal prostaglandin E2 synthase 1 (MPGES1) is an integral membrane protein co-expressed with and functionally coupled to cyclooxygenase 2 (COX-2) generating the pro-inflammatory molecule PGE2. The development of effective inhibitors of MPGES1 holds promise as a highly selective route to control inflammation. In this paper we describe the use of backbone amide H/D exchange mass spectrometry to map the binding sites of different types of inhibitors of MPGES1. The results reveal the locations of specific inhibitor binding sites which include the GSH binding site and a hydrophobic cleft in the protein thought to accommodate the prostaglandin H2 substrate. In the absence of three-dimensional crystal structures of the enzyme-bound inhibitors, the results provide clear physical evidence that three pharmacologically active inhibitors bind in a hydrophobic cleft composed of sections of trans-membrane helices Ia, IIb, IIIb and IVb at the interface of subunits in the trimer. In principle, the H/D exchange behavior of the protein can be used as a preliminary guide for optimization of inhibitor efficacy. Finally, a comparison of the structures and H/D exchange behavior of MPGES1 and the related enzyme MGST1 in the presence of glutathione and the inhibitor glutathione sulfonate confirm the unusual observation that two proteins from the same superfamily harbor GSH binding sites in different locations. PMID:21805999

Prage, Edward B.; Pawelzik, Sven-Christian; Busenlehner, Laura S.; Kim, Kwangho; Morgenstern, Ralf; Jakobsson, Per-Johan; Armstrong, Richard N.

2011-01-01

148

VEGFR2 and Src Kinase Inhibitors Suppress Andes Virus-Induced Endothelial Cell Permeability ?  

PubMed Central

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 (IC50s), 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.

2011-01-01

149

Ultrastructural alterations in Trypanosoma (Schizotrypanum) cruzi induced by ? 24(25) sterol methyl transferase inhibitors and their combinations with ketoconazole  

Microsoft Academic Search

We report the ultrastructural alterations induced on the proliferative stages of Trypanosoma cruzi, the causative agent of Chagas' disease, by two ?24(25) sterol methyl transferase (24(25)-SMT) inhibitors, 22,26-azasterol and 24(R,S),25-epiminolanosterol. Both compounds are sterol biosynthesis inhibitors which had previously been shown to be potent growth inhibitors and whose effects are potentiated by the C14a demethylase inhibitor, ketoconazole. Epimastigotes treated with

Julio Vivas; Julio A. Urbina; Wanderley de Souza

1997-01-01

150

Ultrastructural alterations in Trypanosoma (Schizotrypanum) cruzi induced by ? 24(25) sterol methyl transferase inhibitors and their combinations with ketoconazole  

Microsoft Academic Search

We report the ultrastructural alterations induced on the proliferative stages of Trypanosoma cruzi, the causative agent of Chagas' disease, by two ?24(25) sterol methyl transferase (24(25)-SMT) inhibitors, 22,26-azasterol and 24(R,S),25-epiminolanosterol. Both compounds are sterol biosynthesis inhibitors which had previously been shown to be potent growth inhibitors and whose effects are potentiated by the C14a demethylase inhibitor, ketoconazole. Epimastigotes treated with

Julio Vivas; Julio A. Urbina; Wanderley de Souza

1996-01-01

151

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

2013-01-15

152

Na+/H+ exchanger inhibitor augments hyperosmolarity-induced vasoconstriction by enhancing actin polymerization.  

PubMed

Vascular smooth muscle cells (VSMCs) exhibit shrinkage-induced activation of Na(+)/H(+) exchanger isoform 1 (NHE-1) and Na(+), K(+), 2Cl(-) cotransporter (NKCC) under hyperosmotic conditions. To investigate the roles of these ion transporters in vascular smooth muscle force induced by hyperosmotic stress, we tested the effects of 5-(N, N-dimethyl)-amiloride (DMA; NHE inhibitor), cariporide (a selective NHE-1 inhibitor), and bumetanide (NKCC inhibitor) on the contractile response of rat aortic rings to hyperosmolar solutions. NHE inhibitors significantly augmented the maximum force response and contractile sensitivity to hyperosmolar sucrose, NaCl, and glucose in endothelium-denuded rings. Bumetanide elicited a comparatively modest increase in sensitivity. NHE inhibitors blocked the increase in intracellular pH and enhanced the cell volume decrease of cultured VSMCs after exposure to hyperosmolar sucrose. However, DMA had no effect on the increase in cytosolic free Ca(2+) concentration ([Ca(2+)]i) in rat VSMCs and on the increases in phosphorylation of myosin phosphatase target subunit 1 and myosin light chain (MLC) in aortic rings in response to hyperosmolar sucrose. Hyperosmolar sucrose-induced force was significantly attenuated by cytochalasin B in the presence or absence of DMA. Exposure to hyperosmolar sucrose increased the ratio of F- to G-actin; the ratio was further elevated by DMA. These results suggest that the potentiation of hyperosmotic shrinkage by NHE inhibition promotes actin polymerization in VSMCs and augments force production independent of changes in [Ca(2+)]i and MLC phosphorylation. PMID:23872622

Sasahara, Tomoya; Yayama, Katsutoshi; Tahara, Tsuyoshi; Onoe, Hirotaka; Okamoto, Hiroshi

2013-01-01

153

Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity  

Microsoft Academic Search

Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using

P. S. Chen; C.-C. Wang; C. D. Bortner; G.-S. Peng; X. Wu; H. Pang; R.-B. Lu; P.-W. Gean; D.-M. Chuang; J.-S. Hong

2007-01-01

154

Virus-induced gene silencing of jasmonate-induced direct defences, nicotine and trypsin proteinase-inhibitors in Nicotiana attenuata  

Microsoft Academic Search

Research into the molecular basis of plant-insect interactions is hampered by the inability to alter the expression of individual genes in plants growing under natural conditions. The ability of virus-induced gene silencing (VIGS) to silence the expression of two jasmonate-induced genes known to mediate the expression of two potent direct defences (nicotine and proteinase inhibitors) that are produced in differ-

Rainer Saedler; Ian T. Baldwin

2003-01-01

155

Yeast Methylotrophy: Metabolism, Gene Regulation and Peroxisome Homeostasis  

PubMed Central

Eukaryotic methylotrophs, which are able to obtain all the carbon and energy needed for growth from methanol, are restricted to a limited number of yeast species. When these yeasts are grown on methanol as the sole carbon and energy source, the enzymes involved in methanol metabolism are strongly induced, and the membrane-bound organelles, peroxisomes, which contain key enzymes of methanol metabolism, proliferate massively. These features have made methylotrophic yeasts attractive hosts for the production of heterologous proteins and useful model organisms for the study of peroxisome biogenesis and degradation. In this paper, we describe recent insights into the molecular basis of yeast methylotrophy. PMID:21754936

Yurimoto, Hiroya; Oku, Masahide; Sakai, Yasuyoshi

2011-01-01

156

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

157

Inhibition of reaper-induced apoptosis by interaction with inhibitor of apoptosis proteins (IAPs).  

PubMed

IAPs comprise a family of inhibitors of apoptosis found in viruses and animals. In vivo binding studies demonstrated that both baculovirus and Drosophila IAPs physically interact with an apoptosis-inducing protein of Drosophila, Reaper (RPR), through their baculovirus IAP repeat (BIR) region. Expression of IAPs blocked RPR-induced apoptosis and resulted in the accumulation of RPR in punctate perinuclear locations which coincided with IAP localization. When expressed alone, RPR rapidly disappeared from the cells undergoing RPR-induced apoptosis. Expression of P35, a caspase inhibitor, also blocked RPR-induced apoptosis and delayed RPR decline, but RPR remained cytoplasmic in its location. Mutational analysis of RPR demonstrated that caspases were not directly responsible for RPR disappearance. The physical interaction of IAPs with RPR provides a molecular mechanism for IAP inhibition of RPR's apoptotic activity. PMID:9294184

Vucic, D; Kaiser, W J; Harvey, A J; Miller, L K

1997-09-16

158

Functional Interaction between Peroxisome Proliferator-Activated Receptor   and  -Catenin  

Microsoft Academic Search

Studies have demonstrated cross talk between -catenin and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Specifically, activation of PPAR induces the proteasomal degradation of -catenin in cells that express an adenomatous polyposis coli-containing destruction complex. In contrast, oncogenic -catenin is resistant to such degradation and inhibits the expression of PPAR target genes. In the present studies, we demonstrate a functional interaction

Jiajian Liu; Hong Wang; Ying Zuo; Stephen R. Farmer

2006-01-01

159

Import of alcohol oxidase into peroxisomes of Saccharomyces cerevisiae.  

PubMed Central

Saccharomyces cerevisiae is unable to grow on methanol because it lacks the enzymes required for its metabolism. To study the possibility of whether or not the methanol oxidation pathway of Hansenula polymorpha can be transferred to S. cerevisiae, the gene coding for alcohol oxidase, a peroxisomal homo-octameric flavoprotein, was introduced into S. cerevisiae. Transformed cells contain varying amounts of alcohol oxidase depending on the plasmid used. Immunocytochemical experiments indicate that the protein is imported into peroxisomes, whether organelle proliferation is induced or not. Cells lack alcohol oxidase activity however, and only the monomeric, non-functional, form of the protein is found. These findings indicate that the H. polymorpha peroxisomal targeting signal of alcohol oxidase is recognized in S. cerevisiae and protein monomers are imported. Images Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. PMID:2826130

Distel, B; Veenhuis, M; Tabak, H F

1987-01-01

160

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 ...

161

Thyroid Hormone Is an Inhibitor of Estrogen-Induced Degradation of Estrogen Receptor-Protein: Estrogen-  

E-print Network

Thyroid Hormone Is an Inhibitor of Estrogen-Induced Degradation of Estrogen Receptor- Protein in the control of receptor transcriptional activation function. Herein, we report that thyroid hormone can of the pituitary. The stabilization of ER pro- tein by thyroid hormone represents a selective blockade against

Alarid, Elaine T.

162

Reduction of diabetes-induced oxidative stress by phosphodiesterase inhibitors in rats  

Microsoft Academic Search

Increased oxidative stress has been suggested to be involved in the pathogenesis and progression of diabetic tissue damage. The aim of this study was to investigate the effect of different phosphodiesterase inhibitors on lipid peroxidation and total antioxidant capacity (TAC) of plasma in streptozotocin-induced diabetic rats (Rattus norvegicus). Rats became diabetic by a single administration of streptozotocin (STZ, 45 mg\\/kg).

Elham Milani; Shekoufeh Nikfar; Reza Khorasani; Mohammad Jafar Zamani; Mohammad Abdollahi

2005-01-01

163

?-Glucosidase inhibitors prevent diet-induced increases in intestinal sugar transport in diabetic mice  

Microsoft Academic Search

The recommended diet for diabetes mellitus is rich in complex carbohydrates. We have previously shown that high carbohydrate levels in the intestinal lumen induce adaptive increases in sugar absorption which in turn exacerbate postprandial hyperglycemia in diabetic mice. ?-Glucosidase inhibitors (AGIs) hinder digestion of complex carbohydrates and therefore alleviate postprandial glycemic excursions. In this study, we tested the hypothesis that

Donatella M. Casirola; Ronaldo P. Ferraris

2006-01-01

164

Wound-Induced Proteinase Inhibitor in Plant Leaves: A Possible Defense Mechanism against Insects  

Microsoft Academic Search

Wounding of the leaves of potato or tomato plants by adult Colorado potato beetles, or their larvae, induces a rapid accumulation of a proteinase inhibitor throughout the plants' tissues that are exposed to air. This effect of insect damage can be simulated by mechanically wounding the leaves. The transport of a factor out of damaged leaves takes place rapidly after

T. R. Green; C. A. Ryan

1972-01-01

165

Adalimumab Induced Subcutaneous Nodular Sarcoidosis; A Rare Side Effect of Tumor Necrosis Factor-? Inhibitor  

PubMed Central

Adalimumab and other tumor necrosis factor-? inhibitors have been shown in the recent years to successfully treat sarcoidosis refractory to systemic corticosteroids and other agents. However, there have been an increasing number of cases of sarcoidosis paradoxically induced by these agents. It is hypothesized that this is due to the disruption of the fine balance of cytokines involved in granuloma formation. We describe the first case of adalimumab-induced subcutaneous nodular sarcoidosis in a patient with pulmonary sarcoidosis. PMID:25363227

Au, Sonoa; Mirsaeidi, Mehdi; Aronson, Iris K; Sweiss, Nadera J.

2014-01-01

166

Effects of Protein Kinase C Inhibitors on Ethanol-Induced Contractions in Isolated Rat Aorta  

Microsoft Academic Search

The activation of intracellular contractile proteins induces vascular contraction mediated through signal transduction mechanisms. Protein kinase C (PKC) is involved in this signal transduction. The purpose of the present study was designed to investigate the role of PKC on EtOH-, KCl- and phorbol 12, 13-dibutyrate (PDBu)-induced contractions in isolated rat aorta through the use of several different PKC inhibitors. Prior

Teresa Jover; Bella T Altura; Burton M Altura

1999-01-01

167

A neutrophil elastase inhibitor reduces cigarette smoke-induced remodelling of lung vessels  

Microsoft Academic Search

A neutrophil elastase inhibitor reduces cigarette smoke-induced remodelling of lung vessels. J.L. Wright, S.G. Farmer, A. Churg. #ERS Journals Ltd 2003. ABSTRACT: Cigarette smoking produces pulmonary hypertension (PHT) through unknown mechanisms. In animal models acute smoke exposure induces cell proliferation in the small arteries adjacent to the alveolar ducts, and chronic exposure results in muscularisation of these vessels, with changes

J. L. Wright; S. G. Farmer; A. Churg

2003-01-01

168

Adalimumab Induced Subcutaneous Nodular Sarcoidosis; A Rare Side Effect of Tumor Necrosis Factor-? Inhibitor.  

PubMed

Adalimumab and other tumor necrosis factor-? inhibitors have been shown in the recent years to successfully treat sarcoidosis refractory to systemic corticosteroids and other agents.  However, there have been an increasing number of cases of sarcoidosis paradoxically induced by these agents.  It is hypothesized that this is due to the disruption of the fine balance of cytokines involved in granuloma formation. We describe the first case of adalimumab-induced subcutaneous nodular sarcoidosis in a patient with pulmonary sarcoidosis. PMID:25363227

Au, Sonoa; Mirsaeidi, Mehdi; Aronson, Iris K; Sweiss, Nadera J

2014-01-01

169

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

170

Fis1, DLP1, and Pex11p coordinately regulate peroxisome morphogenesis  

SciTech Connect

Dynamin-like protein 1 (DLP1) and Pex11p{beta} function in morphogenesis of peroxisomes. In the present work, we investigated whether Fis1 is involved in fission of peroxisomes. Endogenous Fis1 was morphologically detected in peroxisomes as well as mitochondria in wild-type CHO-K1 and DLP1-defective ZP121 cells. Subcellular fractionation studies also revealed the presence of Fis1 in peroxisomes. Peroxisomal Fis1 showed the same topology, i.e., C-tail anchored membrane protein, as the mitochondrial one. Furthermore, ectopic expression of FIS1 induced peroxisome proliferation in CHO-K1 cells, while the interference of FIS1 RNA resulted in tubulation of peroxisomes, hence reducing the number of peroxisomes. Fis1 interacted with Pex11p{beta}, by direct binding apparently involving the C-terminal region of Pex11p{beta} in the interaction. Pex11p{beta} also interacted with each other, whereas the binding of Pex11p{beta} to DLP1 was not detectable. Moreover, ternary complexes comprising Fis1, Pex11p{beta}, and DLP1 were detected by chemical cross-linking. We also showed that the highly conserved N-terminal domain of Pex11p{beta} was required for the homo-oligomerization of Pex11p{beta} and indispensable for the peroxisome-proliferating activity. Taken together, these findings indicate that Fis1 plays important roles in peroxisome division and maintenance of peroxisome morphology in mammalian cells, possibly in a concerted manner with Pex11p{beta} and DLP1.

Kobayashi, Shinta [Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581 (Japan); Tanaka, Atsushi [Department of Biology, Faculty of Sciences, Kyushu University Graduate School, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan); Fujiki, Yukio [Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581 (Japan) and Department of Biology, Faculty of Sciences, Kyushu University Graduate School, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan) and JST, CREST (Japan)]. E-mail: yfujiscb@mbox.nc.kyushu-u.ac.jp

2007-05-01

171

Proteasome inhibitors induce apoptosis and reduce viral replication in primary effusion lymphoma cells  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Constitutive NF-{kappa}B signaling is essential for the survival and growth of PEL cells. Black-Right-Pointing-Pointer NF-{kappa}B signaling is upregulated by the proteasome-dependent degradation of I{kappa}B{alpha}. Black-Right-Pointing-Pointer Proteasome inhibitors suppress NF-{kappa}B signaling and induce apoptosis in PEL cells through stabilization of I{kappa}B{alpha}. Black-Right-Pointing-Pointer Proteasome inhibitors suppress viral replication in PEL cells during lytic KSHV infection. -- Abstract: Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV). This study provides evidence that proteasomal activity is required for both survival of PEL cells stably harboring the KSHV genome and viral replication of KSHV. We evaluated the cytotoxic effects of proteasome inhibitors on PEL cells. The proteasome inhibitors MG132, lactacystin, and proteasome inhibitor I dramatically inhibited cell proliferation and induced apoptosis of PEL cells through the accumulation of p21 and p27. Furthermore, proteasome inhibitors induced the stabilization of NF-{kappa}B inhibitory molecule (I{kappa}B{alpha}) and suppressed the transcriptional activity of NF-{kappa}B in PEL cells. The NF-{kappa}B specific inhibitor BAY11-7082 also induced apoptosis in PEL cells. The constitutive activation of NF-{kappa}B signaling is essential for the survival and growth of B cell lymphoma cells, including PEL cells. NF-{kappa}B signaling is upregulated by proteasome-dependent degradation of I{kappa}B{alpha}. The suppression of NF-{kappa}B signaling by proteasome inhibitors may contribute to the induction of apoptosis in PEL cells. In addition, proteasome activity is required for KSHV replication in KSHV latently infected PEL cells. MG132 reduced the production of progeny virus from PEL cells at low concentrations, which do not affect PEL cell growth. These findings suggest that proteasome inhibitors may represent a novel strategy for the treatment of KSHV infection and KSHV-associated lymphomas.

Saji, Chiaki [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812 (Japan)] [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812 (Japan); Higashi, Chizuka; Niinaka, Yasufumi [Faculty of Medicine, University of Yamanashi, Chuoh-shi 409-3898 (Japan)] [Faculty of Medicine, University of Yamanashi, Chuoh-shi 409-3898 (Japan); Yamada, Koji [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812 (Japan)] [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812 (Japan); Noguchi, Kohji [Faculty of Pharmacy, Keio University, 1-5-30 Shiba-koen, Minato-ku, Tokyo 105-8512 (Japan)] [Faculty of Pharmacy, Keio University, 1-5-30 Shiba-koen, Minato-ku, Tokyo 105-8512 (Japan); Fujimuro, Masahiro, E-mail: fuji2@mb.kyoto-phu.ac.jp [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan)] [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan)

2011-12-02

172

Mechanism of Action of the Nongenotoxic Peroxisome Proliferators: Role of the Peroxisome Proliferator-  

E-print Network

REVIEW Mechanism of Action of the Nongenotoxic Peroxisome Proliferators: Role of the Peroxisome Proliferator- Activated Receptor Frank J. Gonzalez, Jeffrey M. Peters, Russell C. Cattley Peroxisome, and naturally occurring hormones. As the name implies, peroxisome proliferators cause an increase in the number

Omiecinski, Curtis

173

Peroxisomal and Mitochondrial Fatty Acid -Oxidation in Mice Nullizygous for Both Peroxisome Proliferator-activated  

E-print Network

Peroxisomal and Mitochondrial Fatty Acid -Oxidation in Mice Nullizygous for Both Peroxisome Proliferator-activated Receptor and Peroxisomal Fatty Acyl-CoA Oxidase GENOTYPE CORRELATION WITH FATTY LIVER 20892 Fatty acid -oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also

Omiecinski, Curtis

174

Wound-induced proteinase inhibitors from tomato leaves. II. The cDNA-deduced primary structure of pre-inhibitor II.  

PubMed

A cDNA containing the complete amino acid-coding region of wound-induced tomato Inhibitor II was constructed in the plasmid pUC9. The open reading frame codes for 148 amino acids including a 25-amino acid signal sequence preceding the N-terminal lysine of the mature Inhibitor II. The Inhibitor II sequence exhibits two domains, one domain having a trypsin inhibitory site and the other a chymotrypsin inhibitory site, apparently evolved from a smaller gene by a process of gene duplication and elongation. The amino acid sequence of tomato leaf Inhibitor II exhibits homology with two small proteinase inhibitors isolated from potato tuber and an inhibitor from eggplant. The small potato tuber inhibitors are homologous with 33 amino acids of the N-terminal domain and 19 amino acids from the C-terminal domain. Two identical nucleotide sequences of Inhibitor II cDNA in the 3' noncoding region were present that were also found in an Inhibitor I cDNA. These include an atypical polyadenylation signal, AATAAG, and a 10-base palindromic sequence, CATTATAATG, for which no function is yet known. PMID:3838986

Graham, J S; Pearce, G; Merryweather, J; Titani, K; Ericsson, L H; Ryan, C A

1985-06-10

175

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. PMID:19417144

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

2009-01-01

176

Haemolysis induced by tyrosine crystals: Modifiers and inhibitors.  

PubMed Central

Tyrosine as a solid, but not in solution, caused human erythrocyte haemolysis. Haemolysis was increased with higher tyrosine concentrations and extended incubation times; it was greater at 37degrees than 4degreesC, and decreased by higher erythrocyte concentrations. Titration of phenolic groups on the surface of di-iodotyrosine crystals altered the extent of di-iodotyrosine-induced haemolysis. Haemolysis induced by tyrosine was inhibited by polyethylene glycol (mol.wt. 6000 or 20000) in a competitive fashion; polyoxyethylene/polyoxypropylene non-ionic detergents, polyvinylpyrrolidone (mol.wt. 40000 or 360000), 0.25--1.0M-NaC1, 0.25--1.0 M-KC1 and 0.25 M-NaSCN also inhibited haemolysis. H+-ion donation from the phenolic groups of tyrosine is suggested as part of the mechanism of haemolysis. Non-ionic detergents may inhibit tyrosine-crystal-induced haemolysis by binding the phenolic groups at the surface of the crystal. PMID:9076

Goldsmith, L A

1976-01-01

177

Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha.  

PubMed

Peroxisomes are the exclusive site for the beta-oxidation of very-long-chain fatty acids of more than 20 carbons in length (VLCFAs). Although the bulk of dietary long-chain fatty acids are oxidized in the mitochondria, VLCFAs cannot be catabolized in mitochondria and must be shortened first by peroxisomal beta-oxidation. The regulation of peroxisomal, mitochondrial, and microsomal fatty acid oxidation systems in liver is mediated principally by peroxisome proliferator-activated receptor alpha (PPARalpha). In this study we provide evidence that the liver X receptor (LXR) regulates the expression of the genetic program for peroxisomal beta-oxidation in liver. The genes encoding the three enzymes of the classic peroxisomal beta-oxidation cycle, acyl-coenzyme A (acyl-CoA) oxidase, enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase, are activated by the LXR ligand, T0901317. Accordingly, administration of T0901317 in mice promoted a dose-dependent and greater than 2-fold increase in the rate of peroxisomal beta-oxidation in the liver. The LXR effect is independent of PPARalpha, because T0901317-induced peroxisomal beta-oxidation in the liver of PPARalpha-null mice. Interestingly, T0901317-induced peroxisomal beta-oxidation is dependent on the LXRalpha isoform, but not the LXRbeta isoform. We propose that induction of peroxisomal beta-oxidation by LXR agonists may serve as a counterregulatory mechanism for responding to the hypertriglyceridemia and liver steatosis that is promoted by potent LXR agonists in vivo; however, additional studies are warranted. PMID:16123164

Hu, Tonghuan; Foxworthy, Patricia; Siesky, Angela; Ficorilli, James V; Gao, Hong; Li, Shuyu; Christe, Michael; Ryan, Timothy; Cao, Guoqing; Eacho, Patrick; Michael, M Dodson; Michael, Laura F

2005-12-01

178

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 Central

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

2013-01-01

179

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. PMID:24046747

Peraza-Reyes, Leonardo; Berteaux-Lecellier, Veronique

2013-01-01

180

Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib: preclinical study.  

PubMed

Common adverse effects of angiogenesis inhibition are hypertension and renal injury. To determine the most optimal way to prevent these adverse effects and to explore their interdependency, the following drugs were investigated in unrestrained Wistar Kyoto rats exposed to the angiogenesis inhibitor sunitinib: the dual endothelin receptor antagonist macitentan; the calcium channel blocker amlodipine; the angiotensin-converting enzyme inhibitor captopril; and the phosphodiesterase type 5 inhibitor sildenafil. Mean arterial pressure was monitored telemetrically. After 8 days, rats were euthanized and blood samples and kidneys were collected. In addition, 24-hour urine samples were collected. After sunitinib start, mean arterial pressure increased rapidly by ?30 mm Hg. Coadministration of macitentan or amlodipine largely prevented this rise, whereas captopril or sildenafil did not. Macitentan, captopril, and sildenafil diminished the sunitinib-induced proteinuria and endothelinuria and glomerular intraepithelial protein deposition, whereas amlodipine did not. Changes in proteinuria and endothelinuria were unrelated. We conclude that in our experimental model, dual endothelin receptor antagonism and calcium channel blockade are suitable to prevent angiogenesis inhibition-induced hypertension, whereas dual endothelin receptor antagonism, angiotensin-converting enzyme inhibitor, and phosphodiesterase type 5 inhibition can prevent angiogenesis inhibition-induced proteinuria. Moreover, the variable response of hypertension and renal injury to different antihypertensive agents suggests that these side effects are, at least in part, unrelated. PMID:25185126

Lankhorst, Stephanie; Kappers, Mariëtte H W; van Esch, Joep H M; Smedts, Frank M M; Sleijfer, Stefan; Mathijssen, Ron H J; Baelde, Hans J; Danser, A H Jan; van den Meiracker, Anton H

2014-12-01

181

Paradoxical Reaction to Golimumab: Tumor Necrosis Factor ? Inhibitor Inducing Psoriasis Pustulosa  

PubMed Central

Importance Golimumab is a human monoclonal antibody, used for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Adverse reactions are increasing with this class of medication (tumor necrosis factor ? inhibitors). Observations The authors present a case of a female patient who presented with psoriasis pustulosa after the use of golimumab for rheumatoid arthritis. Conclusions and Relevance Paradoxically, in this case, golimumab, which is used for psoriasis, induced the pustular form of this disease. We are observing an increasing number of patients who develop collateral effects with tumor necrosis factor ? inhibitors, and the understanding of the mechanism of action and how these adverse reactions occur may contribute to avoid these sometimes severe situations. PMID:24348382

Soto Lopes, Marien Siqueira; Trope, Beatriz Moritz; Rochedo Rodriguez, Maria Paula Rua; Grynszpan, Rachel Lima; Cuzzi, Tullia; Ramos-e-Silva, Marcia

2013-01-01

182

UK114, a YjgF/Yer057p/UK114 family protein highly conserved from bacteria to mammals, is localized in rat liver peroxisomes  

SciTech Connect

Mammalian UK114 belongs to a highly conserved family of proteins with unknown functions. Although it is believed that UK114 is a cytosolic or mitochondrial protein there is no detailed study of its intracellular localization. Using analytical subcellular fractionation, electron microscopic colloidal gold technique, and two-dimensional gel electrophoresis of peroxisomal matrix proteins combined with mass spectrometric analysis we show here that a large portion of UK114 is present in rat liver peroxisomes. The peroxisomal UK114 is a soluble matrix protein and it is not inducible by the peroxisomal proliferator clofibrate. The data predict involvement of UK114 in peroxisomal metabolism.

Antonenkov, Vasily D. [Department of Biochemistry, Biocenter Oulu, University of Oulu, Linnanmaa, P.O. Box 3000, FIN-90014 Oulu (Finland)]. E-mail: vasily.antonenkov@oulu.fi; Ohlmeier, Steffen [Department of Biochemistry, Biocenter Oulu, University of Oulu, Linnanmaa, P.O. Box 3000, FIN-90014 Oulu (Finland); Proteomics Core Facility of the Biocenter Oulu, Biocenter Oulu, University of Oulu, Linnanmaa, P.O. Box 3000, FIN-90014 Oulu (Finland); Sormunen, Raija T. [Department of Pathology, Biocenter Oulu, University of Oulu, Linnanmaa, P.O. Box 3000, FIN-90014 Oulu (Finland); Hiltunen, J. Kalervo [Department of Biochemistry, Biocenter Oulu, University of Oulu, Linnanmaa, P.O. Box 3000, FIN-90014 Oulu (Finland)

2007-05-25

183

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. PMID:22721706

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

2013-01-01

184

Wound-induced Accumulation of Trypsin Inhibitor Activities in Plant Leaves  

PubMed Central

Proteinase inhibitor-inducing factor (PIIF)-induced accumulation of trypsin inhibitory activity was assayed in leaves of 23 species of plants representing 10 agriculturally important genera. Inhibitory activity was assayed in extracts from attached leaves or from excised leaves supplied through the cut petioles for 30 minutes with extracts containing the wound hormone PIIF, obtained from either tomato leaves or from the leaves of each plant under study. During subsequent incubation in light for 72 hours, PIIF-induced trypsin inhibitory activity accumulated in significant quantities in 10 of the 23 species. Alfalfa accumulated the highest levels of inhibitory activity (340 ?g trypsin inhibited/ml leaf juice), followed by tobacco, tomato, potato, strawberry, cucumber, squash, clover, broadbean, and grape. It is suggested that the inhibitors might be classed as allelochemics that are present in certain plants and not others in response to environmental pressures during their evolution. PMID:16659868

Walker-Simmons, Mary; Ryan, Clarence A.

1977-01-01

185

Lucanthone Is a Novel Inhibitor of Autophagy That Induces Cathepsin D-mediated Apoptosis*  

PubMed Central

Cellular stress induced by nutrient deprivation, hypoxia, and exposure to many chemotherapeutic agents activates an evolutionarily conserved cell survival pathway termed autophagy. This pathway enables cancer cells to undergo self-digestion to generate ATP and other essential biosynthetic molecules to temporarily avoid cell death. Therefore, disruption of autophagy may sensitize cancer cells to cell death and augment chemotherapy-induced apoptosis. Chloroquine and its analog hydroxychloroquine are the only clinically relevant autophagy inhibitors. Because both of these agents induce ocular toxicity, novel inhibitors of autophagy with a better therapeutic index are needed. Here we demonstrate that the small molecule lucanthone inhibits autophagy, induces lysosomal membrane permeabilization, and possesses significantly more potent activity in breast cancer models compared with chloroquine. Exposure to lucanthone resulted in processing and recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes, but impaired autophagic degradation as revealed by transmission electron microscopy and the accumulation of p62/SQSTM1. Microarray analysis, qRT-PCR, and immunoblotting determined that lucanthone stimulated a large induction in cathepsin D, which correlated with cell death. Accordingly, knockdown of cathepsin D reduced lucanthone-mediated apoptosis. Subsequent studies using p53+/+ and p53?/? HCT116 cells established that lucanthone induced cathepsin D expression and reduced cancer cell viability independently of p53 status. In addition, lucanthone enhanced the anticancer activity of the histone deacetylase inhibitor vorinostat. Collectively, our results demonstrate that lucanthone is a novel autophagic inhibitor that induces apoptosis via cathepsin D accumulation and enhances vorinostat-mediated cell death in breast cancer models. PMID:21148553

Carew, Jennifer S.; Espitia, Claudia M.; Esquivel, Juan A.; Mahalingam, Devalingam; Kelly, Kevin R.; Reddy, Guru; Giles, Francis J.; Nawrocki, Steffan T.

2011-01-01

186

Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis.  

PubMed

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been proposed as a therapeutic target for neurodegenerative diseases because of its anti-inflammatory action in glial cells. However, PPARgamma agonists preventbeta-amyloid (Abeta)-induced neurodegeneration in hippocampal neurons, and PPARgamma is activated by the nerve growth factor (NGF) survival pathway, suggesting a neuroprotective anti-inflammatory independent action. Here we show that the PPARgamma agonist rosiglitazone (RGZ) protects hippocampal and dorsal root ganglion neurons against Abeta-induced mitochondrial damage and NGF deprivation-induced apoptosis, respectively, and promotes PC12 cell survival. In neurons and in PC12 cells RGZ protective effects are associated with increased expression of the Bcl-2 anti-apoptotic protein. NGF-differentiated PC12 neuronal cells constitutively overexpressing PPARgamma are resistant to Abeta-induced apoptosis and morphological changes and show functionally intact mitochondria and no increase in reactive oxygen species when challenged with up to 50 microM H2O2. Conversely, cells expressing a dominant negative mutant of PPARgamma show increased Abeta-induced apoptosis and disruption of neuronal-like morphology and are highly sensitive to oxidative stress-induced impairment of mitochondrial function. Cells overexpressing PPARgamma present a 4- to 5-fold increase in Bcl-2 protein content, whereas in dominant negative PPARgamma-expressing cells, Bcl-2 is barely detected. Bcl-2 knockdown by small interfering RNA in cells overexpressing PPARgamma results in increased sensitivity to Abeta and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPARgamma protective effects. PPARgamma prosurvival action is independent of the signal-regulated MAPK or the Akt prosurvival pathways. Altogether, these data suggest that PPARgamma supports survival in neurons in part through a mechanism involving increased expression of Bcl-2. PMID:17965419

Fuenzalida, Karen; Quintanilla, Rodrigo; Ramos, Patricio; Piderit, Daniela; Fuentealba, Rodrigo A; Martinez, Gabriela; Inestrosa, Nibaldo C; Bronfman, Miguel

2007-12-21

187

Oxaliplatin Neurotoxicity Involves Peroxisome Alterations. PPAR? Agonism as Preventive Pharmacological Approach  

PubMed Central

The development of neuropathic syndromes is an important, dose limiting side effect of anticancer agents like platinum derivates, taxanes and vinca alkaloids. The causes of neurotoxicity are still unclear but the impairment of the oxidative equilibrium is strictly related to pain. Two intracellular organelles, mitochondria and peroxisomes cooperate to the maintaining of the redox cellular state. Whereas a relationship between chemotherapy-dependent mitochondrial alteration and neuropathy has been established, the role of peroxisome is poor explored. In order to study the mechanisms of oxaliplatin-induced neurotoxicity, peroxisomal involvement was evaluated in vitro and in vivo. In primary rat astrocyte cell culture, oxaliplatin (10 µM for 48 h or 1 µM for 5 days) increased the number of peroxisomes, nevertheless expression and functionality of catalase, the most important antioxidant defense enzyme in mammalian peroxisomes, were significantly reduced. Five day incubation with the selective Peroxisome Proliferator Activated Receptor-? (PPAR-?) antagonist G3335 (30 µM) induced a similar peroxisomal impairment suggesting a relationship between PPAR? signaling and oxaliplatin neurotoxicity. The PPAR? agonist rosiglitazone (10 µM) reduced the harmful effects induced both by G3335 and oxaliplatin. In vivo, in a rat model of oxaliplatin induced neuropathy, a repeated treatment with rosiglitazone (3 and 10 mg kg?1 per os) significantly reduced neuropathic pain evoked by noxious (Paw pressure test) and non-noxious (Cold plate test) stimuli. The behavioral effect paralleled with the prevention of catalase impairment induced by oxaliplatin in dorsal root ganglia. In the spinal cord, catalase protection was showed by the lower rosiglitazone dosage without effect on the astrocyte density increase induced by oxaliplatin. Rosiglitazone did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. These results highlight the role of peroxisomes in oxaliplatin-dependent nervous damage and suggest PPAR? stimulation as a candidate to counteract oxaliplatin neurotoxicity. PMID:25036594

Zanardelli, Matteo; Micheli, Laura; Cinci, Lorenzo; Failli, Paola; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo

2014-01-01

188

A Case of Tumor Necrosis Factor-? Inhibitors-induced Pustular Psoriasis  

PubMed Central

Anti-tumor necrosis factor (TNF)-? agents promise better disease control for the treatment of ankylosing spondylitis resistant to classical disease-modifying treatments. Etanercept, a recombinant human TNF receptor fusion protein, is used to treat a variety of TNF-?-mediated diseases by inhibiting the biological activity of TNF-?. We experienced a case of pustular psoriasis in a 32-year-old man during anti-TNF-? therapy with etanercept. He had a history of ankylosing spondylitis for 2 years. Two years after treatment of etanercept, erythematous pustules developed on his palms and soles. He had no previous history of pustular psoriasis. The skin lesion improved as the etanercept therapy was stopped, but pustular skin eruption recurred as adalimumab, a different TNF-? inhibitor, was administered to manage his ankylosing spondylitis. Several TNF-? inhibitors have different molecular structures, but these inhibitors might have a similar potency to induce pustular psoriasis from this case. PMID:20548918

Park, Jae-Jeong

2010-01-01

189

Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632.  

PubMed

Rho-kinase is a main player in the regulation of cytoskeletal events and a promising drug target in the treatment of both vascular and neurological disorders. Here we report the crystal structure of the Rho-kinase catalytic domain in complex with the specific inhibitor Y-27632. Comparison with the structure of PKA bound to this inhibitor revealed a potential induced-fit binding mode that can be accommodated by the phosphate binding loop. This binding mode resembles to that observed in the Rho-kinase-fasudil complex. A structural database search indicated that a pocket underneath the phosphate-binding loop is present that favors binding to a small aromatic ring. Introduction of such a ring group might spawn a new modification scheme of pre-existing protein kinase inhibitors for improved binding capability. PMID:16891330

Yamaguchi, Hiroto; Miwa, Yukiko; Kasa, Miyuki; Kitano, Ken; Amano, Mutsuki; Kaibuchi, Kozo; Hakoshima, Toshio

2006-09-01

190

The ?-lactamase inhibitor avibactam (NXL104) does not induce ampC ?-lactamase in Enterobacter cloacae  

PubMed Central

Induction of ampC ?-lactamase expression can often compromise antibiotic treatment and is triggered by several ?-lactams (such as cefoxitin and imipenem) and by the ?-lactamase inhibitor clavulanic acid. The novel ?-lactamase inhibitor avibactam (NXL104) is a potent inhibitor of both class A and class C enzymes. The potential of avibactam for induction of ampC expression in Enterobacter cloacae was investigated by ampC messenger ribonucleic acid quantitation. Cefoxitin and clavulanic acid were confirmed as ampC inducers, whereas avibactam was found to exert no effect on ampC expression. Thus, avibactam is unlikely to diminish the activity of any partner ?-lactam antibiotic against AmpC-producing organisms. PMID:24348054

Miossec, Christine; Claudon, Monique; Levasseur, Premavathy; Black, Michael T

2013-01-01

191

A novel histone deacetylase inhibitor Chidamide induces apoptosis of human colon cancer cells  

SciTech Connect

Many studies have demonstrated that histone deacetylase (HDAC) inhibitors induce various tumor cells to undergo apoptosis, and such inhibitors have been used in different clinical trials against different human cancers. In this study, we designed and synthesized a novel HDAC inhibitor, Chidamide. We showed that Chidamide was able to increase the acetylation levels of histone H3 and to inhibit the PI3K/Akt and MAPK/Ras signaling pathways, which resulted in arresting colon cancer cells at the G1 phase of the cell cycle and promoting apoptosis. As a result, the proliferation of colon cancer cells was suppressed in vitro. Our data support the potential application of Chidamide as an anticancer agent in treating colon cancer. Future studies are needed to demonstrate its in vivo efficacy.

Liu, Lin [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China)] [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China); Chen, Baoan, E-mail: wenyu811@126.com [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China)] [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China); Qin, Shukui [Chinese PLA Cancer Center, The 81st PLA Hospital, Nanjing 210002, Jiangsu (China)] [Chinese PLA Cancer Center, The 81st PLA Hospital, Nanjing 210002, Jiangsu (China); Li, Suyi; He, Xiangming [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China)] [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China); Qiu, Shaomin; Zhao, Wei; Zhao, Hong [Department of Internal Medicine, Nanjing Municipal Cancer Hospital, Nanjing 210003, Jiangsu (China)] [Department of Internal Medicine, Nanjing Municipal Cancer Hospital, Nanjing 210003, Jiangsu (China)

2010-02-05

192

Comparison of the effects of the ace inhibitors trandolapril and enalapril on phlogogen induced foot pad oedema in the rat  

Microsoft Academic Search

Two angiotensin converting enzyme (ACE) inhibitors, trandolapril and enalapril, were compared for their effects on rat food-pad oedema induced by carrageenin, bradykinin dextran and platelet activating factor (PAF). Trandolapril (0.03–30.0 mg\\/kg, per os) potentiated carrageenin-induced oedemas. Enalapril produced the same effect at 3–10 fold higher doses (0.3–30.0 mg\\/kg per os). Both ACE inhibitors were equiactive in potentiating bradykinin-induced oedema. Neither

S. Jouquey; N. L. Brown; J. Fichelle; M. Worcel

1988-01-01

193

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. PMID:9620867

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

1998-01-01

194

Proteasome inhibitors suppress formation of polyglutamine-induced nuclear inclusions in cultured postmitotic neurons.  

PubMed

At least nine neurodegenerative disorders are caused by expansion of polyglutamine repeats in various genes. This expansion induces the formation of nuclear inclusions (NI) within various cell types. In this study, we developed a model for polyglutamine diseases using primary cultures of sympathetic neurons from the superior cervical ganglia of prenatal rat pups. Transfection with a plasmid encoding 127 glutamine repeats causes NI to develop in approximately 70% of the sympathetic neurons within 6 days. In addition, it causes somatic atrophy and inhibits dendritic growth. The NIs contain ubiquitinated proteins and sequester the molecular chaperone heat shock protein 70 (Hsp70). We found that two specific proteasome inhibitors, lactacystin and CEP1612, suppress thezformation of polyglutamine-induced NI. In addition, lactacystin treatment induced the removal of preexisting NI. Western blotting and immunocytochemistry revealed that lactacystin and CEP1612 strongly induce the expression of Hsp70, whereas less specific proteasome inhibitor such as N-acetyl-Leu-Leu-Norleucinal does not. Coexpression of 127 glutamines with a plasmid encoding wild-type Hsp70 gene resulted in a marked reduction of the percentage of neurons containing NI. In addition, transfection with plasmids encoding mutant Hsp70 blocked the effects of lactacystin. These findings further implicate Hsp70 as a neuroprotective molecule and they suggest the potential utility of certain proteasome inhibitors in the treatment of polyglutamine diseases. PMID:15569248

Kim, Woo-Yang; Horbinski, Craig; Sigurdson, Wade; Higgins, Dennis

2004-12-01

195

Angiotensin converting enzyme (ACE) inhibitor-induced cough and substance P.  

PubMed Central

BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors cause coughing in 5-10% of patients, but the exact mechanisms of this effect are still unclear. In the airways ACE degrades substance P so the cough mechanism may be related to this peptide. METHODS: Nine patients who developed a cough and five patients who did not develop a cough when taking the ACE inhibitor enalapril (2.5 or 5.0 mg/day) for hypertension were enrolled in the study. No subjects had respiratory disease and the respiratory function of all subjects was normal. One month after stopping enalapril, inhalation of hypertonic saline (4%) was performed using an ultrasonic nebuliser for 15-30 minutes to induce sputum. The concentration of substance P in the sputum sample was measured by radioimmunoassay. In four of the nine cases with a cough enalapril was given again for 1-2 weeks and the concentration of substance P in the induced sputum was again measured. RESULTS: One month after stopping enalapril the mean (SE) concentration of substance P in the sputum of the group with a cough was 16.6 (3.0) fmol/ml, significantly higher than that in the subjects without a cough (0.9 (0.5) fmol/ml). All four subjects in the group with a cough who were given a repeat dose of enalapril developed a cough again, but the concentrations of substance P in the induced sputum while taking enalapril (17.9 (3.2) fmol/ml) were similar to the values whilst off enalapril (20.0 (2.5) fmol/ml). CONCLUSIONS: The mechanisms of ACE inhibitor-induced coughing may involve substance P mediated airway priming. However, the final triggering of the ACE inhibitor-induced coughing is unlikely to be due to this peptide. PMID:8711657

Tomaki, M.; Ichinose, M.; Miura, M.; Hirayama, Y.; Kageyama, N.; Yamauchi, H.; Shirato, K.

1996-01-01

196

Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity.  

PubMed

Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. Other histone deacetylase inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson's disease. PMID:17850978

Chen, P S; Wang, C-C; Bortner, C D; Peng, G-S; Wu, X; Pang, H; Lu, R-B; Gean, P-W; Chuang, D-M; Hong, J-S

2007-10-12

197

Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs.  

PubMed

Heat shock protein 90 (Hsp90) is a constitutively expressed molecular chaperone and plays an important role in the folding of client proteins with key regulatory roles in growth, survival, differentiation and metastasis. Because inhibition of Hsp90 degrades multiple oncogenic client proteins, it is considered to be an attractive anticancer therapy, and clinical trials of several Hsp90 inhibitors have been carried out. In the present study, two structurally distinct Hsp90 inhibitors, CH5164840 and CH5449302, were orally administered to beagle dogs to evaluate systemic toxicity. CH5164840 induced symptoms that suggest visual disorder, and ophthalmological observation and electroretinography (ERG) revealed loss of pupillary light reflex and abnormal waveforms, respectively. Histopathological examination showed changes in the photoreceptor cell layer and the outer nuclear layer of retina. On the other hand, while there were no clinical symptoms related to visual disorder, animals treated with CH5449302 showed similar abnormalities of ERG responses and histopathological changes in the photoreceptor cell layer and the outer nuclear layer of retina. The visual symptoms and abnormalities of ERG responses were noted at an earlier stage or lower dose than other toxicities in both compounds. Considering that two structurally distinct Hsp90 inhibitors induced a retinal toxicity in dogs after repeated administration, and that visual disorders were also reported in some clinical trials of Hsp90 inhibitors, it would seem highly likely that Hsp90 inhibition induces retinal toxicity. Also, our study indicated that a detailed ocular examination to evaluate the safety of Hsp90 inhibitors would be useful in both preclinical and clinical studies. PMID:24418710

Kanamaru, Chisako; Yamada, Yuichiro; Hayashi, Shuji; Matsushita, Tomochika; Suda, Atsushi; Nagayasu, Miho; Kimura, Kazuya; Chiba, Shuichi

2014-02-01

198

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. PMID:23626729

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

2013-01-01

199

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

2013-01-01

200

Localization of peroxisomal matrix proteins by photobleaching  

SciTech Connect

The distribution of some enzymes between peroxisomes and cytosol, or a dual localization in both these compartments, can be difficult to reconcile. We have used photobleaching in live cells expressing green fluorescent protein (GFP)-fusion proteins to show that imported bona fide peroxisomal matrix proteins are retained in the peroxisome. The high mobility of the GFP-fusion proteins in the cytosol and absence of peroxisomal escape makes it possible to eliminate the cytosolic fluorescence by photobleaching, to distinguish between exclusively cytosolic proteins and proteins that are also present at low levels in peroxisomes. Using this technique we found that GFP tagged bile acid-CoA:amino acid N-acyltransferase (BAAT) was exclusively localized in the cytosol in HeLa cells. We conclude that the cytosolic localization was due to its carboxyterminal non-consensus peroxisomal targeting signal (-SQL) since mutation of the -SQL to -SKL resulted in BAAT being efficiently imported into peroxisomes.

Buch, Charlotta [Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 57 Huddinge (Sweden) [Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 57 Huddinge (Sweden); Soedertoerns University, Life Sciences, SE-141 89 Huddinge (Sweden); Hunt, Mary C. [Department of Genetics, Microbiology and Toxicology, Stockholm University, Arrhenius Laboratory, Svante Arrhenius vaeg 16F, SE-106 91 Stockholm (Sweden)] [Department of Genetics, Microbiology and Toxicology, Stockholm University, Arrhenius Laboratory, Svante Arrhenius vaeg 16F, SE-106 91 Stockholm (Sweden); Alexson, Stefan E.H. [Karolinska Institutet, Department of Laboratory Medicine, Division of Clinical Chemistry C1-74, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm (Sweden)] [Karolinska Institutet, Department of Laboratory Medicine, Division of Clinical Chemistry C1-74, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm (Sweden); Hallberg, Einar, E-mail: einar.hallberg@sh.se [Soedertoerns University, Life Sciences, SE-141 89 Huddinge (Sweden)] [Soedertoerns University, Life Sciences, SE-141 89 Huddinge (Sweden)

2009-10-16

201

Dipeptidyl Peptidase IV Inhibitor MK-0626 Attenuates Pancreatic Islet Injury in Tacrolimus-Induced Diabetic Rats  

PubMed Central

Background Tacrolimus (TAC)-induced pancreatic islet injury is one of the important causes of new-onset diabetes in transplant recipients. This study was performed to evaluate whether a dipeptidyl peptidase IV (DPP IV) inhibitor is effective in improving TAC-induced diabetes mellitus by reducing pancreatic islet injury. Methods Rats were treated with TAC (1.5 mg/kg, subcutaneously) and the DPP IV inhibitor MK-0626 (10 or 20 mg/kg, oral gavage) for 4 weeks. The effect of MK-0626 on TAC-induced diabetes was evaluated by assessing pancreatic islet function, histopathology. TAC-induced incretin dysfunction was also examined based on active glucagon-like peptide-1 (GLP-1) levels in the serum after glucose loading. The protective effect of MK-0626 was evaluated by measuring markers of oxidative stress, oxidative resistance, and apoptosis. To determine whether enhanced GLP-1 signaling is associated with these protective effects, we measured the expression of the GLP-1 receptor (GLP-1R) and the effect of the GLP-1 analog exendin-4 on cell viability and oxidative stress in isolated islets. Results MK-0626 treatment attenuated TAC-induced pancreatic islet dysfunction and islet morphology. TAC treatment led to a defect in active GLP-1 secretion; however, MK-0626 reversed these effects. TAC treatment increased the level of 8-hydroxy-2?-deoxyguanosine (8-OHdG), the number of apoptotic death, and the level of active caspase-3, and decreased the level of manganese superoxide dismutase and heme oxygenase-1; MK-0626 treatment reversed these changes. MK-0626 treatment restored the expression of GLP-1R, and direct administration of exendin-4 to isolated islets reduced TAC-induced cell death and 8-OHdG expression. Conclusions The DPP IV inhibitor MK-0626wasan effective antidiabetic agent that exerted antioxidative and antiapoptotic effects via enhanced GLP-1 signaling in TAC-induced diabetics. PMID:24959755

Doh, Kyoung Chan; Piao, Shang Guo; Jin, Jian; Heo, Seong Beom; Chung, Byung Ha; Yang, Chul Woo

2014-01-01

202

Sycamore cell wall polysaccharide and a chemically related tomato leaf polysaccharide possess similar proteinase inhibitor-inducing activities  

SciTech Connect

A large pectic polysaccharide, called rhamnogalacturonann I, that is solubilized by a fungal endo-..cap alpha..-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, C.A. (Washington State Univ., Pullman); Bishop, P.; Pearce, G.; Darvill, A.G.; McNeil, M.; Albersheim, P.

1981-09-01

203

Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells  

PubMed Central

Multiple myeloma (MM) is an incurable plasma cell malignancy. The 26S proteasome inhibitor, bortezomib, selectively induces apoptosis in MM cells; however, the nature of its selectivity remains unknown. Here we demonstrate that 5 different MM cell lines display similar patterns of sensitivity to 3 proteasome inhibitors (PIs) but respond differently to specific NF-?B inhibition. We further show that PIs initiate the unfolded protein response (UPR), a signaling pathway activated by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). Consistent with reports that prosurvival/physiologic UPR components are required for B-cell differentiation into antibody-secreting cells, we found that MM cells inherently expressed the ER chaperones GRP78/Bip and GRP94/gp96. However, bortezomib rapidly induced components of the proapoptotic/terminal UPR, including PERK, the ER stress–specific eIF-2? kinase; ATF4, an ER stress–induced transcription factor; and its proapoptotic target, CHOP/GADD153. Consistent with our hypothesis that PIs induce the accumulation of misfolded ER-processed proteins, we found that the amount of immunoglobulin subunits retained within MM cells correlated with their sensitivity to PIs. These findings suggest that MM cells have a lower threshold for PI-induced UPR induction and ER stress–induced apoptosis because they constitutively express ER stress survival factors to function as secretory cells. PMID:16507771

Obeng, Esther A.; Carlson, Louise M.; Gutman, Delia M.; Harrington, William J.; Lee, Kelvin P.; Boise, Lawrence H.

2006-01-01

204

Camptothecin, a specific inhibitor of type I DNA topoisomerase, induces DNA breakage at replication forks  

SciTech Connect

The structure of replicating simian virus 40 minichromosomes, extracted from camptothecin-treated infected cells, was investigated by biochemical and electron microscopic methods. The authors found that camptothecin frequently induced breaks at replication forks close to the replicative growth points. Replication branches were disrupted at about equal frequencies at the leading and the lagging strand sides of the fork. Since camptothecin is known to be a specific inhibitor of type I DNA topoisomerase, the authors suggest that this enzyme is acting very near the replication forks. This conclusion was supported by experiments with aphidicolin, a drug that blocks replicative fork movement, but did not prevent the camptothecin-induced breakage of replication forks. The drug teniposide, and inhibitor of type II DNA topoisomerase, had only minor effects on the structure of these replicative intermediates.

Avemann, K.; Knippers, R.; Koller, T.; Sogo, J.M.

1988-08-01

205

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

2012-07-01

206

Visualizing inducible nitric-oxide synthase in living cells with a heme-binding fluorescent inhibitor  

Microsoft Academic Search

The study of nitric-oxide synthase (NOS) physiology is constrained by the lack of suitable probes to detect NOS in living cells or animals. Here, we characterized a fluorescent inducible NOS (iNOS) inhibitor called PIF (pyrimidine imidazole FITC) and examined its utility for microscopic imaging of iNOS in living cells. PIF binding to iNOS displayed high affinity, isoform selectivity, and heme

Koustubh Panda; Mamta Chawla-Sarkar; Cecile Santos; Thomas Koeck; Serpil C. Erzurum; John F. Parkinson; Dennis J. Stuehr

2005-01-01

207

Interplant communication: airborne methyl jasmonate induces synthesis of proteinase inhibitors in plant leaves.  

PubMed

Inducible defensive responses in plants are known to be activated locally and systemically by signaling molecules that are produced at sites of pathogen or insect attacks, but only one chemical signal, ethylene, is known to travel through the atmosphere to activate plant defensive genes. Methyl jasmonate, a common plant secondary compound, when applied to surfaces of tomato plants, induces the synthesis of defensive proteinase inhibitor proteins in the treated plants and in nearby plants as well. The presence of methyl jasmonate in the atmosphere of chambers containing plants from three species of two families, Solanaceae and Fabaceae, results in the accumulation of proteinase inhibitors in leaves of all three species. When sagebrush, Artemisia tridentata, a plant shown to possess methyl jasmonate in leaf surface structures, is incubated in chambers with tomato plants, proteinase inhibitor accumulation is induced in the tomato leaves, demonstrating that interplant communication can occur from leaves of one species of plant to leaves of another species to activate the expression of defensive genes. PMID:11607107

Farmer, E E; Ryan, C A

1990-10-01

208

Effect of ethylene action inhibitors upon wound-induced gene expression in tomato pericarp  

SciTech Connect

The contribution of wound-ethylene to wound-induced gene expression was investigated in unripe tomato pericarp using inhibitors of ethylene action. Wounded unripe tomato pericarp was treated with 2,5-norbornadiene or silver thiosulfate to inhibit specifically the induction of ethylene-dependent mRNA species. Poly(A){sup +} RNAs isolated from these tissues after 12 hours of wounding were translated in vitro in a rabbit reticulocyte lysate system and ({sup 35}S)methionine-labeled polypeptides were compared to unwounded controls after separation by one and two-dimensional polyacrylamide gel electrophoresis. Results show that mechanical wounding induces a dramatic shift in gene expression (over 50 mRNA species) but expression of less than 15% of these genes is affected by the treatment with ethylene action inhibitors. A selective decrease in mRNAs coding for a 37 kilodalton doublet and 75 kilodalton polypeptides is observed in 2,5-norbornadiene and silver thiosulfate treated wounded pericarp. Levels of hydroxyproline-rich glycoprotein mRNAs induced in wounded tissue were not influenced by inhibitors of ethylene action.

Henstrand, J.M.; Handa, A.K. (Purdue Univ., West Lafayette, IN (USA))

1989-09-01

209

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. PMID:21629798

Escalante, Carmen P.; Zalpour, Ali

2011-01-01

210

Histone Deacetylase Inhibitors Facilitate Dihydroartemisinin-Induced Apoptosis in Liver Cancer In Vitro and In Vivo  

PubMed Central

Liver cancer ranks in prevalence and mortality among top five cancers worldwide. Accumulating interests have been focused in developing new strategies for liver cancer treatment. We have previously showed that dihydroartemisinin (DHA) exhibited antitumor activity towards liver cancer. In this study, we demonstrated that histone deacetylase inhibitors (HDACi) significantly augmented the antineoplastic effect of DHA via increasing apoptosis in vitro and in vivo. Inhibition of ERK phosphorylation contributed to DHA-induced apoptosis, due to the fact that inhibitor of ERK phosphorylation (PD98059) increased DHA-induced apoptosis. Compared with DHA alone, the combined treatment with DHA and HDACi reduced mitochondria membrane potential, released cytochrome c into cytoplasm, increased p53 and Bak, decreased Mcl-1 and p-ERK, activated caspase 3 and PARP, and induced apoptotic cells. Furthermore, we showed that HDACi pretreatment facilitated DHA-induced apoptosis. In Hep G2-xenograft carrying nude mice, the intraperitoneal injection of DHA and SAHA resulted in significant inhibition of xenograft tumors. Results of TUNEL and H&E staining showed more apoptosis induced by combined treatment. Immunohistochemistry data revealed the activation of PARP, and the decrease of Ki-67, p-ERK and Mcl-1. Taken together, our data suggest that the combination of HDACi and DHA offers an antitumor effect on liver cancer, and this combination treatment should be considered as a promising strategy for chemotherapy. PMID:22761917

Zhang, Chris Zhiyi; Pan, Yinghua; Cao, Yun; Lai, Paul B. S.; Liu, Lili; Chen, George Gong; Yun, Jingping

2012-01-01

211

HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: A potential mechanism for protease inhibitor-induced hyperlipidemia  

Microsoft Academic Search

Highly active anti-retroviral therapies, which incorporate HIV protease inhibitors, resolve many AIDS-defining illnesses. However, patients receiving protease inhibitors develop a marked lipodystrophy and hyperlipidemia. Using cultured human and rat hepatoma cells and primary hepatocytes from transgenic mice, we demonstrate that protease inhibitor treatment inhibits proteasomal degradation of nascent apolipoprotein B, the principal protein component of triglyceride and cholesterol-rich plasma lipoproteins.

Jun-Shan Liang; Oliver Distler; David A. Cooper; Haris Jamil; Richard J. Deckelbaum; Henry N. Ginsberg; Stephen L. Sturley

2001-01-01

212

Origin and evolution of the peroxisomal proteome  

PubMed Central

Background Peroxisomes are ubiquitous eukaryotic organelles involved in various oxidative reactions. Their enzymatic content varies between species, but the presence of common protein import and organelle biogenesis systems support a single evolutionary origin. The precise scenario for this origin remains however to be established. The ability of peroxisomes to divide and import proteins post-translationally, just like mitochondria and chloroplasts, supports an endosymbiotic origin. However, this view has been challenged by recent discoveries that mutant, peroxisome-less cells restore peroxisomes upon introduction of the wild-type gene, and that peroxisomes are formed from the Endoplasmic Reticulum. The lack of a peroxisomal genome precludes the use of classical analyses, as those performed with mitochondria or chloroplasts, to settle the debate. We therefore conducted large-scale phylogenetic analyses of the yeast and rat peroxisomal proteomes. Results Our results show that most peroxisomal proteins (39–58%) are of eukaryotic origin, comprising all proteins involved in organelle biogenesis or maintenance. A significant fraction (13–18%), consisting mainly of enzymes, has an alpha-proteobacterial origin and appears to be the result of the recruitment of proteins originally targeted to mitochondria. Consistent with the findings that peroxisomes are formed in the Endoplasmic Reticulum, we find that the most universally conserved Peroxisome biogenesis and maintenance proteins are homologous to proteins from the Endoplasmic Reticulum Assisted Decay pathway. Conclusion Altogether our results indicate that the peroxisome does not have an endosymbiotic origin and that its proteins were recruited from pools existing within the primitive eukaryote. Moreover the reconstruction of primitive peroxisomal proteomes suggests that ontogenetically as well as phylogenetically, peroxisomes stem from the Endoplasmic Reticulum. Reviewers This article was reviewed by Arcady Mushegian, Gáspár Jékely and John Logsdon Open peer review Reviewed by Arcady Mushegian, Gáspar Jékely and John Logsdon. For the full reviews, please go to the Reviewers' comments section. PMID:16556314

Gabaldón, Toni; Snel, Berend; Zimmeren, Frank van; Hemrika, Wieger; Tabak, Henk; Huynen, Martijn A

2006-01-01

213

Pex3-anchored Atg36 tags peroxisomes for degradation in Saccharomyces cerevisiae  

PubMed Central

Peroxisomes undergo rapid, selective autophagic degradation (pexophagy) when the metabolic pathways they contain are no longer required for cellular metabolism. Pex3 is central to the formation of peroxisomes and their segregation because it recruits factors specific for these functions. Here, we describe a novel Saccharomyces cerevisiae protein that interacts with Pex3 at the peroxisomal membrane. We name this protein Atg36 as its absence blocks pexophagy, and its overexpression induces pexophagy. We have isolated pex3 alleles blocked specifically in pexophagy that cannot recruit Atg36 to peroxisomes. Atg36 is recruited to mitochondria if Pex3 is redirected there, where it restores mitophagy in cells lacking the mitophagy receptor Atg32. Furthermore, Atg36 binds Atg8 and the adaptor Atg11 that links receptors for selective types of autophagy to the core autophagy machinery. Atg36 delivers peroxisomes to the preautophagosomal structure before being internalised into the vacuole with peroxisomes. We conclude that Pex3 recruits the pexophagy receptor Atg36. This reinforces the pivotal role played by Pex3 in coordinating the size of the peroxisome pool, and establishes its role in pexophagy in S. cerevisiae. PMID:22643220

Motley, Alison M; Nuttall, James M; Hettema, Ewald H

2012-01-01

214

T0070907, a PPAR ? Inhibitor, Induced G2/M Arrest Enhances the Effect of Radiation in Human Cervical Cancer Cells Through Mitotic Catastrophe.  

PubMed

Overexpression of peroxisome proliferator activator receptor ? (PPAR?) has been implicated in many types of cancer including cervical cancer. Radiation therapy remains the main nonsurgical modality for the treatment of cervical cancer. The present study reports the impact of pharmacological inhibition of PPAR? in enhancing the radiosensitization of cervical cancer cells in vitro. Three cervical cancer cell lines (HeLa, SiHa, and Me180) were treated with a PPAR? inhibitor, T0070907, and/or radiation. The changes in protein, cell cycle, DNA content, apoptosis, and cell survival were analyzed. The PPAR? is differentially expressed in cervical cancer cells with maximum expression in ME180 cells. T0070907 has significantly decreased the tubulin levels in a time-dependent manner in ME180 cells. The decrease in the tubulin levels after T0070907 in ME180 and SiHa cells was associated with significant increase in the cells at the G2/M phase. The changes in the tubulin and G2/M phase were not evident in HeLa cells. T0070907 reduced the protein levels of PPAR?; however, PPAR? silencing had no effect on the ?-tubulin level in ME180 cells suggesting the PPAR?-dependent and -independent actions of T0070907. To ascertain the impact of synergistic effect of T0070907 and radiation, HeLa and ME180 cells were pretreated with T0070907 and subjected to radiation (4 Gy). Annexin V-fluorescein isothiocyanate analysis revealed increased apoptosis in cells treated with radiation and T0070907 when compared to control and individual treatment. In addition, T0070907 pretreatment enhanced radiation-induced tetraploidization reinforcing the additive effect of T0070907. Confocal analysis of tubulin confirmed the onset of mitotic catastrophe in cells treated with T0070907 and radiation. These results strongly suggest the radiosensitizing effects of T0070907 through G2/M arrest and mitotic catastrophe. PMID:24642720

An, Zhengzhe; Muthusami, Sridhar; Yu, Jae-Ran; Park, Woo-Yoon

2014-11-01

215

HSP90 inhibitor CH5164840 induces micronuclei in TK6 cells via an aneugenic mechanism.  

PubMed

Heat-shock protein 90 (HSP90) is a promising druggable target for therapy of conditions including cancer, renal disease, and chronic neurodegenerative diseases. Despite the possible beneficial effects of HSP90 inhibitors, some of these agents present a genotoxicity liability. We have examined the mode of action of micronucleus formation in TK6 cells by a novel and highly specific HSP90 inhibitor, CH5164840, by means of an in vitro micronucleus test with fluorescence in situ hybridization (FISH), ?H2AX staining to detect DNA damage, and microscopic observation of chromosomal alignment in mitotic cells. The percentage of centromere-positive micronuclei induced by CH5164840 (FISH analysis) was significant, but the percentage of centromere-negative ones was not, suggesting that induction of micronuclei was due to a mechanism of aneugenicity rather than DNA reactivity. This conclusion was further supported by the result of co-staining ?H2AX and the apoptosis marker caspase-3; the predominant elevation of apoptotic ?H2AX rather than non-apoptotic ?H2AX indicated little involvement of DNA-reactivity mechanisms. Microscopic observation revealed asymmetric spindle microtubules and chromosomal misalignment of metaphase cells. These data indicated that CH5164840 causes spindle dysfunction that induces micronuclei. The risk/benefit ratio must be considered in the development of HSP90 inhibitors. PMID:25308700

Matsuzaki, Kaori; Harada, Asako; Tanaka, Kenji; Takeiri, Akira; Mishima, Masayuki

2014-10-01

216

Natural Haemozoin Induces Expression and Release of Human Monocyte Tissue Inhibitor of Metalloproteinase-1  

PubMed Central

Recently matrix metalloproteinase-9 (MMP-9) and its endogenous inhibitor (tissue inhibitor of metalloproteinase-1, TIMP-1) have been implicated in complicated malaria. In vivo, mice with cerebral malaria (CM) display high levels of both MMP-9 and TIMP-1, and in human patients TIMP-1 serum levels directly correlate with disease severity. In vitro, natural haemozoin (nHZ, malarial pigment) enhances monocyte MMP-9 expression and release. The present study analyses the effects of nHZ on TIMP-1 regulation in human adherent monocytes. nHZ induced TIMP-1 mRNA expression and protein release, and promoted TNF-?, IL-1?, and MIP-1?/CCL3 production. Blocking antibodies or recombinant cytokines abrogated or mimicked nHZ effects on TIMP-1, respectively. p38 MAPK and NF-?B inhibitors blocked all nHZ effects on TIMP-1 and pro-inflammatory molecules. Still, total gelatinolytic activity was enhanced by nHZ despite TIMP-1 induction. Collectively, these data indicate that nHZ induces inflammation-mediated expression and release of human monocyte TIMP-1 through p38 MAPK- and NF-?B-dependent mechanisms. However, TIMP-1 induction is not sufficient to counterbalance nHZ-dependent MMP-9 enhancement. Future investigation on proteinase-independent functions of TIMP-1 (i.e. cell survival promotion and growth/differentiation inhibition) is needed to clarify the role of TIMP-1 in malaria pathogenesis. PMID:23967215

Polimeni, Manuela; Valente, Elena; Ulliers, Daniela; Opdenakker, Ghislain; Van den Steen, Philippe E.

2013-01-01

217

XIAP inhibitors induce differentiation and impair clonogenic capacity of acute myeloid leukemia stem cells  

PubMed Central

Acute myeloid leukemia (AML) is a neoplasia characterized by the rapid expansion of immature myeloid blasts in the bone marrow, and marked by poor prognosis and frequent relapse. As such, new therapeutic approaches are required for remission induction and prevention of relapse. Due to the higher chemotherapy sensitivity and limited life span of more differentiated AML blasts, differentiation-based therapies are a promising therapeutic approach. Based on public available gene expression profiles, a myeloid-specific differentiation-associated gene expression pattern was defined as the therapeutic target. A XIAP inhibitor (Dequalinium chloride, DQA) was identified in an in silico screening searching for small molecules that induce similar gene expression regulation. Treatment with DQA, similarly to Embelin (another XIAP inhibitor), induced cytotoxicity and differentiation in AML. XIAP inhibition differentially impaired cell viability of the most primitive AML blasts and reduced clonogenic capacity of AML cells, sparing healthy mature blood and hematopoietic stem cells. Taken together, these results suggest that XIAP constitutes a potential target for AML treatment and support the evaluation of XIAP inhibitors in clinical trials. PMID:24952669

Moreno-Martinez, Daniel; Nomdedeu, Meritxell; Lara-Castillo, Maria Carmen; Etxabe, Amaia; Pratcorona, Marta; Tesi, Niccolo; Diaz-Beya, Marina; Rozman, Maria; Montserrat, Emili; Urbano-Ispizua, Alvaro; Esteve, Jordi; Risueno, Ruth M.

2014-01-01

218

Survivin Inhibition Is Critical for Bcl-2 Inhibitor-Induced Apoptosis in Hepatocellular Carcinoma Cells  

PubMed Central

Our study aims to study the therapeutic effects of a novel Bcl-2 inhibitor, ABT-263, on hepatocellular carcinoma (HCC) and to provide primary preclinical data for future clinical trial with ABT-263. In this study we showed that Bcl-xL and survivin were up-regulated in HCC cell lines and human liver cancer tissues. Clinic used ABT-263 single treatment had no apoptotic effects on HCC cells whereas higher doses of ABT-263 did. Interestingly, the combination treatment of ABT-263 with survivin inhibitor YM-155 could result in significant apoptosis in HCC cells. Survivin inhibition through gene silencing significantly enhanced ABT-263 to induce apoptosis in HCC cells. We found that low dose of ABT-263 single treatment resulted in ERK activation and survivin up-regulation, which might be involved in the resistance of HCC cells to ABT-263 since blockade of ERK activation sensitized ABT-263-induced apoptosis. Importantly, ABT-263 and YM-155 combination treatment had no apoptotic effects on normal human hepatocytes. Taken together, these data suggest the combination treatment of Bcl-2 inhibitor and survivin inhibition may have a great potential for liver cancer therapy. PMID:21829603

Zhao, Xiangxuan; Ogunwobi, Olorunseun O.; Liu, Chen

2011-01-01

219

Human uridine phosphorylase-1 inhibitors: a new approach to ameliorate 5-fluorouracil-induced intestinal mucositis.  

PubMed

Purpose 5-fluorouracil (5-FU) has been broadly used to treat solid tumors for more than 50 years. One of the major side effects of fluoropyrimidines therapy is oral and intestinal mucositis. Human uridine phosphorylase (hUP) inhibitors have been suggested as modulators of 5-FU toxicity. Therefore, the present study aimed to test the ability of hUP blockers in preventing mucositis induced by 5-FU. Methods We induced intestinal mucositis in Wistar rats with 5-FU, and the intestinal damage was evaluated in presence or absence of two hUP1 inhibitors previously characterized. We examined the loss of weight and diarrhea following the treatment, the villus integrity, uridine levels in plasma, and the neutrophil migration by MPO activity. Results We found that one of the compounds, 6-hydroxy-4-methyl-1H-pyridin-2-one-3-carbonitrile was efficient to promote intestinal mucosa protection and to inhibit the hUP1 enzyme, increasing the uridine levels in the plasma of animals. However, the loss of body weight, diarrhea intensity or neutrophil migration remained unaffected. Conclusion Our results bring support to the hUP1 inhibitor strategy as a novel possibility of prevention and treatment of mucositis during the 5-FU chemotherapy, based on the approach of uridine accumulation in plasma and tissues. PMID:25052233

Renck, Daiana; Santos, André A; Machado, Pablo; Petersen, Guilherme O; Lopes, Tiago G; Santos, Diógenes S; Campos, Maria M; Basso, Luiz A

2014-12-01

220

Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death.  

PubMed

VCP (also known as p97 or Cdc48p in yeast) is an AAA(+) ATPase regulating endoplasmic reticulum-associated degradation. After high-throughput screening, we developed compounds that inhibit VCP via different mechanisms, including covalent modification of an active site cysteine and a new allosteric mechanism. Using photoaffinity labeling, structural analysis and mutagenesis, we mapped the binding site of allosteric inhibitors to a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis. These compounds induced an increased affinity for nucleotides. Interference with nucleotide turnover in individual subunits and distortion of interprotomer communication cooperated to impair VCP enzymatic activity. Chemical expansion of this allosteric class identified NMS-873, the most potent and specific VCP inhibitor described to date, which activated the unfolded protein response, interfered with autophagy and induced cancer cell death. The consistent pattern of cancer cell killing by covalent and allosteric inhibitors provided critical validation of VCP as a cancer target. PMID:23892893

Magnaghi, Paola; D'Alessio, Roberto; Valsasina, Barbara; Avanzi, Nilla; Rizzi, Simona; Asa, Daniela; Gasparri, Fabio; Cozzi, Liviana; Cucchi, Ulisse; Orrenius, Christian; Polucci, Paolo; Ballinari, Dario; Perrera, Claudia; Leone, Antonella; Cervi, Giovanni; Casale, Elena; Xiao, Yang; Wong, Chihunt; Anderson, Daniel J; Galvani, Arturo; Donati, Daniele; O'Brien, Tom; Jackson, Peter K; Isacchi, Antonella

2013-09-01

221

A human autoantibody to peroxisomes.  

PubMed Central

A complement fixing, non-organ specific IgG autoantibody is described in 29 patients. The autoantibody gives a highly characteristic, granular staining of liver cells, proximal kidney tubules and stomach surface epithelium. By studies with various subcellular fractions from rat liver, employing two different techniques (quantitative complement fixation, and absorption combined with indirect immunofluorescence) the autoantibody was shown to react with a peroxisomal antigen. No convincing clinical correlations were found. Images Fig. 1 PMID:3899430

Holm, R; Gaarder, P I; Helgeland, L; Falkenhaug, E I

1985-01-01

222

The Hansenula polymorpha PER1 gene is essential for peroxisome biogenesis and encodes a peroxisomal matrix protein with both carboxy- and amino-terminal targeting signals  

PubMed Central

We describe the cloning of the Hansenula polymorpha PER1 gene and the characterization of the gene and its product, PER1p. The gene was cloned by functional complementation of a per1 mutant of H. polymorpha, which was impaired in the import of peroxisomal matrix proteins (Pim- phenotype). The DNA sequence of PER1 predicts that PER1p is a polypeptide of 650 amino acids with no significant sequence similarity to other known proteins. PER1 expression was low but significant in wild-type H. polymorpha growing on glucose and increased during growth on any one of a number of substrates which induce peroxisome proliferation. PER1p contains both a carboxy- (PTS1) and an amino- terminal (PTS2) peroxisomal targeting signal which both were demonstrated to be capable of directing bacterial beta-lactamase to the organelle. In wild-type H. polymorpha PER1p is a protein of low abundance which was demonstrated to be localized in the peroxisomal matrix. Our results suggest that the import of PER1p into peroxisomes is a prerequisite for the import of additional matrix proteins and we suggest a regulatory function of PER1p on peroxisomal protein support. PMID:7962056

1994-01-01

223

The Prolyl Hydroxylase Inhibitor Dimethyloxalylglycine Enhances Dentin Sialophoshoprotein Expression through VEGF-Induced Runx2 Stabilization  

PubMed Central

Prolyl hydroxylase (PHD) inhibitors are suggested as therapeutic agents for tissue regeneration based on their ability to induce pro-angiogenic responses. In this study, we examined the effect of the PHD inhibitor dimethyloxalylglycine (DMOG) on odontoblast maturation and sought to determine the underlying mechanism using MDPC-23 odontoblast-like cells. DMOG significantly enhanced matrix mineralization, confirmed by alizarin red staining and by measurement of the calcium content. DMOG dose-dependently increased alkaline phosphatase activity and the expressions of dentin sialophosphoprotein (Dspp) and osteocalcin. To determine the underlying events leading to DMOG-induced Dspp expression, we analyzed the effect of DMOG on Runx2. Knockdown of Runx2 using siRNAs decreased Dspp expression and prevented DMOG-induced Dspp expression. DMOG enhanced the transcriptional activity and level of Runx2 protein but not Runx2 transcript, and this enhancement was linked to the inhibitory effects of DMOG on the degradation of Runx2 protein. The vascular endothelial growth factor (VEGF) siRNAs profoundly decreased the Runx2 protein levels and inhibited the DMOG-increased Runx2 protein. Recombinant VEGF protein treatment significantly and dose-dependently increased the transcriptional activity and level of the Runx2 protein but not Runx2 transcript. Dspp expression was also enhanced by VEGF. Last, we examined the involvement of the Erk mitogen-activated protein kinase and Pin1 pathway in VEGF-enhanced Runx2 because this pathway can regulate the stability and activity of the Runx2 protein. VEGF stimulated Erk activation, and the inhibitors of Erk and Pin1 hampered VEGF-enhanced Runx2 protein. Taken together, the results of this study provide evidence that DMOG can enhance Dspp expression through VEGF-induced stabilization of Runx2 protein, and thus, suggest that DMOG can be used as a therapeutic tool for enhancing odontoblast maturation in dental procedures. PMID:25369078

Rahman, Saeed Ur; Lee, Min-Sun; Baek, Jeong-Hwa; Ryoo, Hyun-Mo; Woo, Kyung Mi

2014-01-01

224

Inhibitors of Hypoxia-Inducible Factor 1 Block Breast Cancer Metastastic Niche Formation and Lung Metastasis  

PubMed Central

Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of the hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through induction 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 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.

2012-01-01

225

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. PMID:19882751

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

2010-01-01

226

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. PMID:11742974

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

227

An ER-peroxisome tether exerts peroxisome population control in yeast  

PubMed Central

Eukaryotic cells compartmentalize biochemical reactions into membrane-enclosed organelles that must be faithfully propagated from one cell generation to the next. Transport and retention processes balance the partitioning of organelles between mother and daughter cells. Here we report the identification of an ER-peroxisome tether that links peroxisomes to the ER and ensures peroxisome population control in the yeast Saccharomyces cerevisiae. The tether consists of the peroxisome biogenic protein, Pex3p, and the peroxisome inheritance factor, Inp1p. Inp1p bridges the two compartments by acting as a molecular hinge between ER-bound Pex3p and peroxisomal Pex3p. Asymmetric peroxisome division leads to the formation of Inp1p-containing anchored peroxisomes and Inp1p-deficient mobile peroxisomes that segregate to the bud. While peroxisomes in mother cells are not released from tethering, de novo formation of tethers in the bud assists in the directionality of peroxisome transfer. Peroxisomes are thus stably maintained over generations of cells through their continued interaction with tethers. PMID:23900285

Knoblach, Barbara; Sun, Xuejun; Coquelle, Nicolas; Fagarasanu, Andrei; Poirier, Richard L; Rachubinski, Richard A

2013-01-01

228

Combination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism.  

PubMed

The current paradigm stipulates that inhibition of histone deacetylase (HDAC) 6 is essential for the combinatorial effect of proteasome and HDAC inhibitors for the treatment of cancers. Our study aims to investigate the effect of combining different class I HDAC inhibitors (without HDAC6 action) with a proteasome inhibitor on apoptosis of nasopharyngeal carcinoma (NPC). We found that combination of a proteasome inhibitor, bortezomib, and several class I HDAC inhibitors, including MS-275, apicidin and romidepsin, potently induced killing of NPC cells both in vitro and in vivo. Among the drug pairs, combination of bortezomib and romidepsin (bort/romidepsin) was the most potent and could induce apoptosis at low nanomolar concentrations. The apoptosis of NPC cells was reactive oxygen species (ROS)- and caspase-dependent but was independent of HDAC6 inhibition. Of note, bort/romidepsin might directly suppress the formation of aggresome through the downregulation of c-myc. In addition, two markers of endoplasmic reticulum (ER) stress-induced apoptosis, ATF-4 and CHOP/GADD153, were upregulated, whereas a specific inhibitor of caspase-4 (an initiator of ER stress-induced apoptosis) could suppress the apoptosis. When ROS level in the NPC cells was reduced to the untreated level, ER stress-induced caspase activation was abrogated. Collectively, our data demonstrate a model of synergism between proteasome and class I HDAC inhibitors in the induction of ROS-dependent ER stress-induced apoptosis of NPC cells, independent of HDAC6 inhibition, and provide the rationale to combine the more specific and potent class I HDAC inhibitors with proteasome inhibitors for the treatment of cancers. PMID:24771510

Hui, Kwai Fung; Chiang, Alan K S

2014-12-15

229

Vascular dysfunction induced by hypochlorite is improved by the selective phosphodiesterase-5-inhibitor vardenafil.  

PubMed

Reactive oxygen species, such as hypochlorite induce oxidative stress, which impairs nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling and leads to vascular dysfunction. It has been proposed, that elevated cGMP-levels may contribute to an effective cytoprotection against oxidative stress. We investigated the effects of vardenafil, a selective inhibitor of the cGMP-degrading phosphodiesterase-5 enzyme on vascular dysfunction induced by hypochlorite. In organ bath experiments for isometric tension, we investigated the endothelium-dependent and endothelium-independent vasorelaxation of isolated rat aortic rings using cumulative concentrations of acetylcholine and sodium nitroprusside (SNP). Vascular dysfunction was induced by exposing rings to hypochlorite (100-400 µM). In the treatment groups, rats were pretreated with vardenafil (30 and 300 µg/kg i.v.). Immunohistochemical analysis was performed for the oxidative stress markers nitrotyrosine, poly(ADP-ribose) and for apoptosis inducing factor (AIF). Exposure to hypochlorite resulted in a marked impairment of acetylcholine-induced endothelium-dependent vasorelaxation of aortic rings. Pretreatment with vardenafil led to improved endothelial function as reflected by the higher maximal vasorelaxation (Rmax) to acetylcholine. Regarding endothelium-independent vasorelaxation, hypochlorite exposure led to a left-shift of SNP concentration-response curves in the vardenafil groups without any alterations of the Rmax. In the hypochlorite groups immunohistochemical analysis showed enhanced poly(ADP-ribose)-formation and nuclear translocation of AIF, which were prevented by vardenafil-pretreatment. Our results support the view that cytoprotective effects of PDE-5-inhibitors on the endothelium may underlie the improved endothelial function, however, a slight sensitisation of vascular smooth muscle to NO was also confirmed. PDE-5-inhibition may represent a potential therapy approach for treating vascular dysfunction induced by oxidative stress. PMID:23623933

Radovits, Tamás; Arif, Rawa; Bömicke, Timo; Korkmaz, Sevil; Barnucz, Enik?; Karck, Matthias; Merkely, Béla; Szabó, Gábor

2013-06-15

230

The inborn errors of peroxisomal ?-oxidation: A review  

Microsoft Academic Search

Summary In recent years a growing number of inherited diseases in man have been recognized in which there is an impairment in peroxisomal ß-oxidation. In some diseases this is due to the (virtual) absence of peroxisomes leading to a generalized loss of peroxisomal functions including peroxisomal ß-oxidation. In most inborn errors of peroxisomal ß-oxidation, however, peroxisomes are normally present and

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

1990-01-01

231

Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis.  

PubMed

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer treatment, but some cancer cell types are resistant to TRAIL cytotoxicity. Therefore, overcoming this resistance is necessary for effective TRAIL therapy. Mitochondrial morphology is important for the maintenance of cell function and survival, and is regulated by the delicate balance between fission and fusion. However, the role of mitochondrial morphology dynamics in TRAIL-induced apoptosis is unknown. Here we show that mitochondrial division inhibitor-1 (mdivi-1), an inhibitor of dynamin-related protein1 (Drp1), modulates mitochondrial morphology and TRAIL-induced apoptosis in human cancer cells. mdivi-1 treatment (?12.5 µM) caused dose- and time?dependent cell death in malignant melanoma, lung cancer and osteosarcoma cells, while sparing normal cells. mdivi-1 also sensitized cancer cells to TRAIL-induced apoptosis. This potentiation of apoptosis occurred through a caspase-depependent mechanism including the mitochondrial and endoplasmic reticulum (ER) stress pathways. Mdivi-1 potentiated mitochondrial oxidative stress, a major cause of mitochondrial and ER stresses, as evidenced by increases in mitochondrial reactive oxygen species levels, mitochondrial mass, and cardiolipin oxidation. Live cell fluorescence imaging using MitoTracker Red CMXRos revealed that Mdivi-1 caused substantial mitochondrial hyperfusion. Moreover, silencing of Drp1 expression also caused mitochondrial hyperfusion and sensitized cancer cells to TRAIL-induced apoptosis. Our results suggest that cancer cells are more vulnerable than normal cells to a perturbation in mitochondrial morphology dynamics and that this higher susceptibility can be exploited to selectively kill cancer cells and sensitize to TRAIL. PMID:25174275

Akita, Mamoru; Suzuki-Karasaki, Miki; Fujiwara, Kyoko; Nakagawa, Chinatsu; Soma, Masayoshi; Yoshida, Yukihiro; Ochiai, Toyoko; Tokuhashi, Yasuaki; Suzuki-Karasaki, Yoshihiro

2014-11-01

232

Differential effects of cyclooxygenase inhibitors on intracerebroventricular colchicine-induced dysfunction and oxidative stress in rats.  

PubMed

Alzheimer's disease is a progressive neurological and psychiatric disorder. Oxidative stress and neuroinflammation have been implicated in pathophysiology of Alzheimer's disease. Inflammatory cells, such as astrocytes and microglia, are activated in areas of the brain affected by amyloid plaques and inflammatory mediators including cytokines, chemokines, prostaglandins, oxygen free radicals and reactive nitrogen species may have a crucial role in Alzheimer's disease pathogenesis. Central administration of colchicine, a microtubule-disrupting agent, causes loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation. The present study was aimed to evaluate the effects of cyclooxygenase inhibitors against colchicine-induced cognitive dysfunction and oxidative stress in rats. Following intracerebroventricular (i.c.v.) administration of colchicine (15 microg/5 microl), rats exhibited poor retention of memory in Morris water maze and elevated plus maze task paradigms and oxidative stress in rats. Chronic treatment with naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) daily respectively for a period of 25 days beginning 4 days prior to colchicine injection significantly improved colchicine-induced cognitive impairment. Intracerebroventricular colchicine injection resulted in free radical generation characterized by alterations in oxidative stress markers with a significant increase in malondialdehyde and nitrite levels and depletion of reduced glutathione levels in the brains of rats. It also caused a decrease in acetylcholinesterase activity. Besides, improving cognitive dysfunction, chronic administration of cyclooxygenase inhibitors (naproxen and valdecoxib) significantly reduced elevated malondialdehyde, nitrite levels and restored reduced glutathione levels and acetylcholinesterase activity. The results of the present study indicated that naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) treatment has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress. The present findings further support the potential use of cyclooxygenase inhibitors in treatment of neurodegenerative diseases such as Alzheimer's disease. PMID:17027965

Kumar, Anil; Seghal, Neha; Padi, Satyanaryana Venketeshwara; Naidu, Pattipati Sreenivaslu

2006-12-01

233

Proteases and protease inhibitors in taurocholate-induced acute pancreatitis in rats  

Microsoft Academic Search

Summary  \\u000a Background. Proteases and protease inhibitors have been indicated to play an important role in both human and experimental acute pancreatitis,\\u000a although little is known about them in rats.\\u000a \\u000a \\u000a Methods. Three percent sodium taurocholate was infused into the bilio-pancreatic duct to induce AP, and over 0–72 h we measured lipase,\\u000a amylase, albumin, prekallikrein, factor X, ?-1-macroglobulin, ?-2-antiplasmin, antithrombin III, ?-1-protease

Peter Kruse; Esther Hage; Åke Lasson

1999-01-01

234

Conformational Changes in HIV-1 Reverse Transcriptase Induced by Nonnucleoside Reverse Transcriptase Inhibitor Binding  

PubMed Central

Nonnucleoside reverse transcriptase inhibitors (NNRTI) are a group of small hydrophobic compounds with diverse structures that specifically inhibit HIV-1 reverse transcriptase (RT). NNRTIs interact with HIV-1 RT by binding to a single site on the p66 subunit of the p66/p51 heterodimeric enzyme, termed the NNRTI-binding pocket (NNRTI-BP). This binding interaction results in both short-range and long-range distortions of RT structure. In this article, we review the structural, computational and experimental evidence of the NNRTI-induced conformational changes in HIV-1 RT and relate them to the mechanism by which these compounds inhibit HIV-1 reverse transcription. PMID:15544453

Sluis-Cremer, Nicolas; Temiz, N. Alpay; Bahar, Ivet

2005-01-01

235

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. PMID:22075252

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

236

Proteasome inhibitor MG-132 induces C6 glioma cell apoptosis via oxidative stress  

PubMed Central

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 level was evaluated with the redox-sensitive dye DCFH-DA. Apoptosis was detected using fluorescence and transmission electron microscopy as well as flow cytometry. The expression of apoptosis-related proteins was investigated using Western blot analysis. Results: MG-132 inhibited C6 glioma cell proliferation in a time- and dose-dependent manner (the IC50 value at 24 h was 18.5 ?mol/L). MG-132 (18.5 ?mol/L) suppressed the proteasome activity by about 70% at 3 h. It induced apoptosis via down-regulation of antiapoptotic proteins Bcl-2 and XIAP, up-regulation of pro-apoptotic protein Bax and caspase-3, and production of cleaved C-terminal 85 kDa PARP). It also caused a more than 5-fold increase of reactive oxygen species. Tiron (1 mmol/L) effectively blocked oxidative stress induced by MG-132 (18.5 ?mol/L), attenuated proliferation inhibition and apoptosis in C6 glioma cells, and reversed the expression pattern of apoptosis-related proteins. Conclusion: MG-132 induced apoptosis of C6 glioma cells via the oxidative stress. PMID:21499287

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

2011-01-01

237

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. PMID:8091318

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

238

Cytoprotective effect of selective small-molecule caspase inhibitors against staurosporine-induced apoptosis  

PubMed Central

Caspases are currently known as the central executioners of the apoptotic pathways. Inhibition of apoptosis and promotion of normal cell survival by caspase inhibitors would be a tremendous benefit for reducing the side effects of cancer therapy and for control of neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. The objective of this study was to discover small-molecule caspase inhibitors with which to achieve cytoprotective effect. We completed the high-throughput screening of Bionet’s 37,500-compound library (Key Organics Limited, Camelford, Cornwall, UK) against caspase-1, -3, and -9 and successfully identified 43 initial hit compounds. The 43 hit compounds were further tested for cytoprotective activity against staurosporine-induced cell death in NIH3T3 cells. Nineteen compounds were found to have significant cytoprotective effects in cell viability assays. One of the compounds, RBC1023, was demonstrated to protect NIH3T3 cells from staurosporine-induced caspase-3 cleavage and activation. RBC1023 was also shown to protect against staurosporine-induced impairment of mitochondrial membrane potential. DNA microarray analysis demonstrated that staurosporine treatment induced broad global gene expression alterations, and RBC1023 co-treatment significantly restored these changes, especially of the genes that are related to cell growth and survival signaling such as Egr1, Cdc25c, cdkn3, Rhob, Nek2, and Taok1. Collectively, RBC1023 protects NIH3T3 cells against staurosporine-induced apoptosis via inhibiting caspase activity, restoring mitochondrial membrane potential, and possibly upregulating some cell survival-related gene expressions and pathways. PMID:24920883

Wu, Jianghong; Wang, Yuren; Liang, Shuguang; Ma, Haiching

2014-01-01

239

Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells.  

PubMed

There is an unmet need to develop new, more effective and safe therapies for the aggressive forms of triple negative breast cancers (TNBCs). While up to 20% of women under 50 years of age with TNBC harbor germline mutations in BRCA1, and these tumors are sensitive to treatment with poly(ADP) ribose polymerase inhibitors, a majority of TNBCs lack BRCA1 mutations or loss of expression. Findings presented here demonstrate that by attenuating the levels of DNA damage response and homologous recombination proteins, pan-histone deacetylase inhibitor (HDI) treatment induces 'BRCAness' and sensitizes TNBC cells lacking BRCA1 to lethal effects of PARP inhibitor or cisplatin. Treatment with HDI also induced hyperacetylation of nuclear hsp90. Similar effects were observed following shRNA-mediated depletion of HDAC3, confirming its role as the deacetylase for nuclear HSP90. Furthermore, cotreatment with HDI and ABT-888 induced significantly more DNA strand breaks than either agent alone, and synergistically induced apoptosis of TNBC cells. Notably, co-treatment with HDI and ABT-888 significantly reduced in vivo tumor growth and markedly improved the survival of mice bearing TNBC cell xenografts. These findings support the rationale to interrogate the clinical activity of this novel combination against human TNBC, irrespective of its expression of mutant BRCA1. PMID:25026298

Ha, Kyungsoo; Fiskus, Warren; Choi, Dong Soon; Bhaskara, Srividya; Cerchietti, Leandro; Devaraj, Santhana G T; Shah, Bhavin; Sharma, Sunil; Chang, Jenny C; Melnick, Ari M; Hiebert, Scott; Bhalla, Kapil N

2014-07-30

240

Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage  

PubMed Central

BACKGROUND AND PURPOSE Prevention or disease-modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson's disease models. EXPERIMENTAL APPROACH Mesencephalic neuron–glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured toxicity in dopaminergic neurons, using dopamine uptake assay and morphological analysis and expression of neurotrophic substances by enzyme-linked immunosorbent assay and real-time RT PCR. KEY RESULTS In mesencephalic neuron–glia cultures, SAHA displayed dose- and time-dependent prolongation of the survival and protection against neurotoxin-induced neuronal death of dopaminergic neurons. Mechanistic studies revealed that the neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation. CONCLUSION AND IMPLICATIONS The novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases. PMID:21726209

Chen, SH; Wu, HM; Ossola, B; Schendzielorz, N; Wilson, BC; Chu, CH; Chen, SL; Wang, Q; Zhang, D; Qian, L; Li, X; Hong, JS; Lu, RB

2012-01-01

241

Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation  

SciTech Connect

Research highlights: {yields} Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma}. {yields} GW9662 treatment alone increased RAGE mRNA levels in tubular cells. {yields} Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-{beta} gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression via PPAR{gamma} activation.

Matsui, Takanori [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan)] [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Yamagishi, Sho-ichi, E-mail: shoichi@med.kurume-u.ac.jp [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan)] [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Takeuchi, Masayoshi [Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa (Japan)] [Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa (Japan); Ueda, Seiji; Fukami, Kei; Okuda, Seiya [Department of Medicine, Kurume University School of Medicine, Kurume (Japan)] [Department of Medicine, Kurume University School of Medicine, Kurume (Japan)

2010-07-23

242

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

2013-10-01

243

Imaging of VEGF Receptor Kinase Inhibitor-Induced Antiangiogenic Effects in Drug-Resistant Human Adenocarcinoma Model1  

Microsoft Academic Search

Small molecule vascular endothelial growth factor (VEGF) receptor tyrosinase kinase inhibitors (VEGFR- TKIs) show great promise in inducing antiangiogenic responses in tumors. We investigated whether anti- angiogenic tumor responses induced by an experi- mental VEGFR-TKI (AG013925; Pfizer Global Research and Development) could be reported by magnetic resonance imaging (MRI) during the initial phase of treatment. We used MRI and superparamagnetic

Wilfried Reichardt; Dana Hu-Lowe; Denise Torres; Ralph Weissleder; Alexei Bogdanov Jr

2005-01-01

244

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. PMID:18443198

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

245

Metabolite transport across the peroxisomal membrane  

PubMed Central

In recent years, much progress has been made with respect to the unravelling of the functions of peroxisomes in metabolism, and it is now well established that peroxisomes are indispensable organelles, especially in higher eukaryotes. Peroxisomes catalyse a number of essential metabolic functions including fatty acid ?-oxidation, ether phospholipid biosynthesis, fatty acid ?-oxidation and glyoxylate detoxification. The involvement of peroxisomes in these metabolic pathways necessitates the transport of metabolites in and out of peroxisomes. Recently, considerable progress has been made in the characterization of metabolite transport across the peroxisomal membrane. Peroxisomes posses several specialized transport systems to transport metabolites. This is exemplified by the identification of a specific transporter for adenine nucleotides and several half-ABC (ATP-binding cassette) transporters which may be present as hetero- and homo-dimers. The nature of the substrates handled by the different ABC transporters is less clear. In this review we will describe the current state of knowledge of the permeability properties of the peroxisomal membrane. PMID:17173541

Visser, Wouter F.; van Roermund, Carlo W. T.; Ijlst, Lodewijk; Waterham, Hans R.; Wanders, Ronald J. A.

2006-01-01

246

Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine.  

PubMed

A large body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists may improve some of the pathological features of Parkinson's disease (PD). In the present study, we evaluated the effects of the PPAR-? agonist fenofibrate (100mg/kg) and PPAR-? agonist pioglitazone (30mg/kg) in a rat model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP). Male Wistar rats were pretreated with both drugs for 5 days and received an infusion of MPTP. The experiments were divided into two parts. First, 1, 7, 14, and 21 days after surgery, the animals were submitted to the open field test. On days 21 and 22, the rats were subjected to the forced swim test and two-way active avoidance task. In the second part of the study, 24h after neurotoxin administration, immunohistochemistry was performed to assess tyrosine hydroxylase activity. The levels of dopamine and its metabolites in the striatum were determined using high-performance liquid chromatography, and fluorescence detection was used to assess caspase-3 activation in the substantia nigra pars compacta (SNpc). Both fenofibrate as pioglitazone protected against hypolocomotion, depressive-like behavior, impairment of learning and memory, and dopaminergic neurodegeneration caused by MPTP, with dopaminergic neuron loss of approximately 33%. Fenofibrate and pioglitazone also protected against the increased activation of caspase-3, an effector enzyme of the apoptosis cascade that is considered one of the pathological features of PD. Thus, PPAR agonists may contribute to therapeutic strategies in PD. PMID:25127682

Barbiero, Janaína K; Santiago, Ronise M; Persike, Daniele Suzete; da Silva Fernandes, Maria José; Tonin, Fernanda S; da Cunha, Claudio; Lucio Boschen, Suelen; Lima, Marcelo M S; Vital, Maria A B F

2014-11-01

247

ACE inhibitor or angiotensin II receptor antagonist attenuates diabetic neuropathy in streptozotocin-induced diabetic rats.  

PubMed

ACE inhibition and/or blocking of the angiotensin II receptor are recognized as first-line treatment for nephropathy and cardiovascular disease in diabetic patients. However, little information is available about the potential benefits of these drugs on diabetic neuropathy. We examined vascular and neural activity in streptozotocin-induced diabetic rats that were treated for 12 weeks with enalapril, an ACE inhibitor, or L-158809, an angiotensin II receptor blocker. A prevention protocol (group 1) as well as three intervention protocols (treatment was initiated after 4, 8, or 12 weeks of diabetes [groups 2, 3, and 4, respectively]) were used. Endoneurial blood flow and motor nerve conduction velocity (MNCV) were impaired in all groups of untreated diabetic rats. In group 1, treatment of diabetic rats with enalapril or L-158809 partially prevented the diabetes-induced decrease in endoneurial blood flow and MNCV. In groups 2-4, intervention with enalapril was more effective in reversing the diabetes-induced impairment in endoneurial blood flow and MNCV than L-158809. The superoxide level in the aorta and epineurial arterioles of diabetic rats was increased. Treatment of diabetic rats with enalapril or L-158809 reduced the superoxide level in the aorta in all groups but was less effective in epineurial arterioles. Acetylcholine and calcitonin gene-related peptide (CGRP) cause vasodilation in epineurial arterioles of the sciatic nerve, which was impaired by diabetes. Treatment of diabetic rats (all groups) with enalapril or L-158809 completely prevented/reversed the diabetes-induced impairment in CGRP-mediated vascular relaxation. Treatment with enalapril or L-158809 was also effective in improving impaired acetylcholine-mediated vasodilation, but the efficacy was diminished from groups 1 to 4. These studies suggest that ACE inhibitors and/or angiotensin II receptor blockers may be effective treatments for diabetes and vascular and neural dysfunction. However, the efficacy of these treatments may be dependent on when the treatment is initiated. PMID:16443766

Coppey, Lawrence J; Davidson, Eric P; Rinehart, Thomas W; Gellett, Jill S; Oltman, Christine L; Lund, Donald D; Yorek, Mark A

2006-02-01

248

Glycine transporters type 1 inhibitor promotes brain preconditioning against NMDA-induced excitotoxicity.  

PubMed

Brain preconditioning is a protective mechanism, which can be activated by sub-lethal stimulation of the NMDA receptors (NMDAR) and be used to achieve neuroprotection against stroke and neurodegenerative diseases models. Inhibitors of glycine transporters type 1 modulate glutamatergic neurotransmission through NMDAR, suggesting an alternative therapeutic strategy of brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by NFPS, a GlyT1 inhibitor, against NMDA-induced excitotoxicity in mice hippocampus, as well as to study its neurochemical mechanisms. C57BL/6 mice (male, 10-weeks-old) were preconditioned by intraperitoneal injection of NFPS at doses of 1.25, 2.5 or 5.0 mg/kg, 24 h before intrahippocampal injection of NMDA. Neuronal death was evaluated by fluoro jade C staining and neurochemical parameters were evaluated by gas chromatography-mass spectrometry, scintillation spectrometry and western blot. We observed that NFPS preconditioning reduced neuronal death in CA1 region of hippocampus submitted to NMDA-induced excitotoxicity. The amino acids (glycine and glutamate) uptake and content were increased in hippocampus of animals treated with NFPS 5.0 mg/kg, which were associated to an increased expression of type-2 glycine transporter (GlyT2) and glutamate transporters (EAAT1, EAAT2 and EAAT3). The expression of GlyT1 was reduced in animals treated with NFPS. Interestingly, the preconditioning reduced expression of GluN2B subunits of NMDAR, whereas did not change the expression of GluN1 or GluN2A in all tested doses. Our study suggests that NFPS preconditioning induces resistance against excitotoxicity, which is associated with neurochemical changes and reduction of GluN2B-containing NMDAR expression. PMID:25312280

Cunha Xavier Pinto, Mauro; Lima, Isabel Vieira de Assis; Pessoa da Costa, Flávia Lage; Rosa, Daniela Valadão; Mendes-Goulart, Vânia Aparecida; Resende, Rodrigo Ribeiro; Romano-Silva, Marco Aurélio; Pinheiro de Oliveira, Antônio Carlos; Gomez, Marcus Vinícius; Gomez, Renato Santiago

2015-02-01

249

High-throughput screening identifies inhibitors of DUX4-induced myoblast toxicity  

PubMed Central

Background Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic alterations at the D4Z4 macrosatellite repeat locus on chromosome 4, resulting in inappropriate expression of the DUX4 protein. The DUX4 protein is therefore the primary molecular target for therapeutic intervention. Methods We have developed a high-throughput screen based on the toxicity of DUX4 when overexpressed in C2C12 myoblasts, and identified inhibitors of DUX4-induced toxicity from within a diverse set of 44,000 small, drug-like molecules. A total of 1,280 hits were then subjected to secondary screening for activity against DUX4 expressed by 3T3 fibroblasts, for absence of activity against the tet-on system used to conditionally express DUX4, and for potential effects on cellular proliferation rate. Results This allowed us to define a panel of 52 compounds to use as probes to identify essential pathways of DUX4 activity. We tested these compounds for their ability to protect wild-type cells from other types of cell death-inducing insults. Remarkably, we found that 60% of the DUX4 toxicity inhibitors that we identified also protected cells from tert-butyl hydrogen peroxide, an oxidative stress-inducing compound. Compounds did not protect against death induced by caspase activation, DNA damage, protein misfolding, or ER stress. Encouragingly, many of these compounds are also protective against DUX4 expression in human cells. Conclusion These data suggest that oxidative stress is a dominant pathway through which DUX4-provoked toxicity is mediated in this system, and we speculate that enhancing the oxidative stress response pathway might be clinically beneficial in FSHD. PMID:24484587

2014-01-01

250

Diverse intracellular pathogens activate type III interferon expression from peroxisomes.  

PubMed

Type I interferon responses are considered the primary means by which viral infections are controlled in mammals. Despite this view, several pathogens activate antiviral responses in the absence of type I interferons. The mechanisms controlling type I interferon-independent responses are undefined. We found that RIG-I like receptors (RLRs) induce type III interferon expression in a variety of human cell types, and identified factors that differentially regulate expression of type I and type III interferons. We identified peroxisomes as a primary site of initiation of type III interferon expression, and revealed that the process of intestinal epithelial cell differentiation upregulates peroxisome biogenesis and promotes robust type III interferon responses in human cells. These findings highlight the importance of different intracellular organelles in specific innate immune responses. PMID:24952503

Odendall, Charlotte; Dixit, Evelyn; Stavru, Fabrizia; Bierne, Helene; Franz, Kate M; Durbin, Ann Fiegen; Boulant, Steeve; Gehrke, Lee; Cossart, Pascale; Kagan, Jonathan C

2014-08-01

251

Proteasome Inhibitors MG132 and Lactacystin Hyperphosphorylate HSF1 and Induce hsp70 and hsp27 Expression  

Microsoft Academic Search

MG132 and lactacystin, two 26S proteasome-specific protease inhibitors, can upregulate heat-shock gene transcription without heat shock. In this study, we showed that both of these inhibitors induce hyperphosphorylation and DNA-binding activity of HSF1 in the absence of heat shock (at 37°C). Since trimerization of HSF1 is known to precede the acquisition of HSF1–DNA binding activity, it seems that MG132- and

Dooha Kim; Sun-Hee Kim; Gloria C. Li

1999-01-01

252

Protein-linked DNA Strand Breaks Induced in Mammalian Cells by Camptothecin, an Inhibitor of Topoisomerase I  

Microsoft Academic Search

Camptothecin was recently identified as an inhibitor of mammalian topoisomerase I. Similar to inhibitors of topoisomerase II, Camptothecin produces DNA single-strand breaks (SSB) and DNA-protein cross-links (DPC) in mammalian cells. However, their one-to-one association, ex pected for trapped topoisomerase complexes, has not previously been demonstrated. We have studied camptothecin-induced SSB and DPC in Chinese hamster DC3F cells and their isolated

Joseph M. Covey; Christine Jaxel; Kurt W. Kohn; Yves Pommier

253

Characterization of membrane polypeptides from pea leaf peroxisomes involved in superoxide radical generation.  

PubMed Central

The production of superoxide radicals (O2(-).) and the activities of ferricyanide reductase and cytochrome c reductase were investigated in peroxisomal membranes from pea (Pisum sativum L.) leaves using NADH and NADPH as electron donors. The generation of O2(-). by peroxisomal membranes was also assayed in native polyacrylamide gels using an in situ staining method with NitroBlue Tetrazolium (NBT). When peroxisomal membranes were assayed under native conditions using NADH or NADPH as inducer, two different O2(-).-dependent Formazan Blue bands were detected. Analysis by SDS/PAGE of these bands demonstrated that the NADH-induced NBT reduction band contained several polypeptides (PMP32, PMP61, PMP56 and PMP18, where PMP is peroxisomal membrane polypeptide and the number indicates molecular mass in kDa), while the NADPH-induced band was due exclusively to PMP29. PMP32 and PMP29 were purified by preparative SDS/PAGE and electroelution. Reconstituted PMP29 showed cytochrome c reductase activity and O2(-). production, and used NADPH specifically as electron donor. PMP32, however, had ferricyanide reductase and cytochrome c reductase activities, and was also able to generate O2(-). with NADH as electron donor, whereas NADPH was not effective as an inducer. The reductase activities of, and O2(-). production by, PMP32 were inhibited by quinacrine. Polyclonal antibodies against cucumber monodehydroascorbate reductase (MDHAR) recognized PMP32, and this polypeptide is likely to correspond to the MDHAR reported previously in pea leaf peroxisomal membranes. PMID:9895298

Lopez-Huertas, E; Corpas, F J; Sandalio, L M; Del Rio, L A

1999-01-01

254

Effect of the Angiotensin I Converting Enzyme Inhibitor, MK-421, on Experimentally Induced Drinking  

NASA Technical Reports Server (NTRS)

MK-421, the ethyl ester maleate salt of N-(S)-1-(ethoxycarbonyl)-3-phenyl-propyl- Ala-L-Pro, is an angiotensin I converting enzyme inhibitor. An initial objective was to determine whether MK-421, administered at 0, 2.5, 5.0, 10.0, 20.0 and 40.0 mg/kg, ip to 96 female rats 15 min prior to administration of the beta-adrenergic agonist, isoproterenol (25 microgram/kg, ip), would inhibit the drinking induced by isoproterenol during 2 h after its administration. The water intake induced by isoproterenol was inhibited significantly by 2.5 mg MK-421/kg. When a similar experiment was performed using Angiotensin I (AI) (200 microgram/kg, ip) as the dipsogenic agent, MK-421 (5 mg/kg, ip), administered 15 min prior to AI, inhibited significantly both the dipsogenic and the diuretic effect of AI. However, administration of angiotensin II (AII, 200 microgram/kg, ip) 15 min after MK-421 (5mg/kg) was accompanied by a water intake that did not differ from AII alone. The drink induced by ip administration of 1.0 m NaCl solution (1% of body wt, ip) was not inhibited by administration of MK-421 (5 mg/kg) 15 min prior to allowing access to water while the drink induced by a 24 h dehydration was partially inhibited. Thus, the drinks induced by administraition of either isoproterenol or AI are dependent on formation of AII. That induced by dehydration is partially dependent, while that induced by hypertonic siilinc is independent of the formation of AII.

Fregley, Melvin J.; Fater, Dennis C.; Greenleaf, John E.

1982-01-01

255

Pip2p: a transcriptional regulator of peroxisome proliferation in the yeast Saccharomyces cerevisiae.  

PubMed Central

In Saccharomyces cerevisiae, peroxisomes are the exclusive site for the degradation of fatty acids. Upon growth with the fatty acid oleic acid as sole carbon source, not only are the enzymes of beta-oxidation and catalase A induced, but also the peroxisomal compartment as a whole increases in volume and the number of organelles per cell rises. We previously identified a cis-acting DNA sequence [oleate response element (ORE)] involved in induction of genes encoding peroxisomal proteins. The aim of our investigation was to test whether a single mechanism acting via the ORE coordinates the events necessary for the proliferation of an entire organelle. Here we report the cloning and characterization of the oleate-specific transcriptional activator protein Pip2p (pip: peroxisome induction pathway). Pip2p contains a typical Zn(2)-Cys(6) cluster domain and binds to OREs. A pip2 deletion strain is impaired in growth on oleate as sole carbon source and the induction of beta-oxidation enzymes is abolished. Moreover, only a few, small peroxisomes per cell can be detected. These results indicate that fatty acids activate Pip2p, which in turn activates the transcription of genes encoding beta-oxidation components and acts as the crucial activator of peroxisomes. Images PMID:8670793

Rottensteiner, H; Kal, A J; Filipits, M; Binder, M; Hamilton, B; Tabak, H F; Ruis, H

1996-01-01

256

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

257

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. PMID:22692539

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

258

Inhibition of Chlorine-Induced Lung Injury by the Type 4 Phosphodiesterase Inhibitor Rolipram  

PubMed Central

Chlorine is a highly toxic respiratory irritant that when inhaled causes epithelial cell injury, alveolar-capillary barrier disruption, airway hyperreactivity, inflammation, and pulmonary edema. Chlorine is considered a chemical threat agent, and its release through accidental or intentional means has the potential to result in mass casualties from acute lung injury. The type 4 phosphodiesterase inhibitor rolipram was investigated as a rescue treatment for chlorine-induced lung injury. Rolipram inhibits degradation of the intracellular signaling molecule cyclic AMP. Potential beneficial effects of increased cyclic AMP levels include inhibition of pulmonary edema, inflammation, and airway hyperreactivity. Mice were exposed to chlorine (whole body exposure, 228–270 ppm for 1 h) and were treated with rolipram by intraperitoneal, intranasal, or intramuscular (either aqueous or nanoemulsion formulation) delivery starting 1 h after exposure. Rolipram administered intraperitoneally or intranasally inhibited chlorine-induced pulmonary edema. Minor or no effects were observed on lavage fluid IgM (indicative of plasma protein leakage), KC (Cxcl1, neutrophil chemoattractant), and neutrophils. All routes of administration inhibited chlorine-induced airway hyperreactivity assessed 1 day after exposure. The results of the study suggest that rolipram may be an effective rescue treatment for chlorine-induced lung injury and that both systemic and targeted administration to the respiratory tract were effective routes of delivery. PMID:22763362

Chang, Weiyuan; Chen, Jing; Schlueter, Connie F.; Rando, Roy J.; Pathak, Yashwant V.; Hoyle, Gary W.

2012-01-01

259

Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma  

PubMed Central

Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAFV600E melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAFV600E melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway. PMID:24569374

Ma, Xiao-Hong; Piao, Sheng-Fu; Dey, Souvik; Mcafee, Quentin; Karakousis, Giorgos; Villanueva, Jessie; Hart, Lori S.; Levi, Samuel; Hu, Janice; Zhang, Gao; Lazova, Rossitza; Klump, Vincent; Pawelek, John M.; Xu, Xiaowei; Xu, Wei; Schuchter, Lynn M.; Davies, Michael A.; Herlyn, Meenhard; Winkler, Jeffrey; Koumenis, Constantinos; Amaravadi, Ravi K.

2014-01-01

260

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. PMID:24141285

McKallip, Robert J.; Hagele, Harriet F.; Uchakina, Olga N.

2013-01-01

261

Treatment with the hyaluronic acid synthesis inhibitor 4-methylumbelliferone suppresses SEB-induced lung inflammation.  

PubMed

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. PMID:24141285

McKallip, Robert J; Hagele, Harriet F; Uchakina, Olga N

2013-10-01

262

Inhibitors of the 5-lipoxygenase arachidonic acid pathway induce ATP release and ATP-dependent organic cation transport in macrophages.  

PubMed

We have previously described that arachidonic acid (AA)-5-lipoxygenase (5-LO) metabolism inhibitors such as NDGA and MK886, inhibit cell death by apoptosis, but not by necrosis, induced by extracellular ATP (ATPe) binding to P2X7 receptors in macrophages. ATPe binding to P2X7 also induces large cationic and anionic organic molecules uptake in these cells, a process that involves at least two distinct transport mechanisms: one for cations and another for anions. Here we show that inhibitors of the AA-5-LO pathway do not inhibit P2X7 receptors, as judged by the maintenance of the ATPe-induced uptake of fluorescent anionic dyes. In addition, we describe two new transport phenomena induced by these inhibitors in macrophages: a cation-selective uptake of fluorescent dyes and the release of ATP. The cation uptake requires secreted ATPe, but, differently from the P2X7/ATPe-induced phenomena, it is also present in macrophages derived from mice deficient in the P2X7 gene. Inhibitors of phospholipase A2 and of the AA-cyclooxygenase pathway did not induce the cation uptake. The uptake of non-organic cations was investigated by measuring the free intracellular Ca(2+) concentration ([Ca(2+)]i) by Fura-2 fluorescence. NDGA, but not MK886, induced an increase in [Ca(2+)]i. Chelating Ca(2+) ions in the extracellular medium suppressed the intracellular Ca(2+) signal without interfering in the uptake of cationic dyes. We conclude that inhibitors of the AA-5-LO pathway do not block P2X7 receptors, trigger the release of ATP, and induce an ATP-dependent uptake of organic cations by a Ca(2+)- and P2X7-independent transport mechanism in macrophages. PMID:24743022

da Silva-Souza, Hercules Antônio; Lira, Maria Nathalia de; Costa-Junior, Helio Miranda; da Cruz, Cristiane Monteiro; Vasconcellos, Jorge Silvio Silva; Mendes, Anderson Nogueira; Pimenta-Reis, Gabriela; Alvarez, Cora Lilia; Faccioli, Lucia Helena; Serezani, Carlos Henrique; Schachter, Julieta; Persechini, Pedro Muanis

2014-07-01

263

Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram  

SciTech Connect

Chlorine is a highly toxic respiratory irritant that when inhaled causes epithelial cell injury, alveolar-capillary barrier disruption, airway hyperreactivity, inflammation, and pulmonary edema. Chlorine is considered a chemical threat agent, and its release through accidental or intentional means has the potential to result in mass casualties from acute lung injury. The type 4 phosphodiesterase inhibitor rolipram was investigated as a rescue treatment for chlorine-induced lung injury. Rolipram inhibits degradation of the intracellular signaling molecule cyclic AMP. Potential beneficial effects of increased cyclic AMP levels include inhibition of pulmonary edema, inflammation, and airway hyperreactivity. Mice were exposed to chlorine (whole body exposure, 228–270 ppm for 1 h) and were treated with rolipram by intraperitoneal, intranasal, or intramuscular (either aqueous or nanoemulsion formulation) delivery starting 1 h after exposure. Rolipram administered intraperitoneally or intranasally inhibited chlorine-induced pulmonary edema. Minor or no effects were observed on lavage fluid IgM (indicative of plasma protein leakage), KC (Cxcl1, neutrophil chemoattractant), and neutrophils. All routes of administration inhibited chlorine-induced airway hyperreactivity assessed 1 day after exposure. The results of the study suggest that rolipram may be an effective rescue treatment for chlorine-induced lung injury and that both systemic and targeted administration to the respiratory tract were effective routes of delivery. -- Highlights: ? Chlorine causes lung injury when inhaled and is considered a chemical threat agent. ? Rolipram inhibited chlorine-induced pulmonary edema and airway hyperreactivity. ? Post-exposure rolipram treatments by both systemic and local delivery were effective. ? Rolipram shows promise as a rescue treatment for chlorine-induced lung injury.

Chang, Weiyuan; Chen, Jing; Schlueter, Connie F. [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States)] [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States); Rando, Roy J. [Department of Environmental Health Sciences, School of Public Health and Tropical Medicine, Tulane University Health Sciences Center, New Orleans, LA (United States)] [Department of Environmental Health Sciences, School of Public Health and Tropical Medicine, Tulane University Health Sciences Center, New Orleans, LA (United States); Pathak, Yashwant V. [College of Pharmacy, University of South Florida, Tampa, FL (United States)] [College of Pharmacy, University of South Florida, Tampa, FL (United States); Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States)

2012-09-01

264

Peroxisome proliferator-activated receptors (PPARs)-independent functions of fish oil on glucose and lipid metabolism in diet-induced obese mice  

PubMed Central

Background Fish oil is known to improve lifestyle-related diseases. These effects occur partly via activation of PPARs by the n-3 polyunsaturated fatty acids included abundantly in fish oil. We investigated fish oil functions on glucose and lipid metabolism that are both dependent on and independent of PPARs pathway. Methods Mice were fed a diet containing 30 en% beef tallow (B diet) for twelve weeks to induce obesity. The mice were then divided into two groups which were fed either a B diet or a diet containing 30 en% fish oil (F diet). Each group was further divided into two groups which were administered PPAR? and ? antagonists or vehicle once a day for three weeks. Results The F diet groups showed lower triglyceride levels in plasma and liver than the B diet groups, but PPARs antagonists did not affect the triglyceride levels in either diet groups. The F diet groups also showed improvement of glucose tolerance compared with the B diet groups. However, PPARs antagonists made glucose tolerance worse in the F diet group but improved it in the B diet group. Therefore, by the administration of antagonists, glucose tolerance was inversely regulated between the B and F diets, and hypolipidemic action in the plasma and liver of the F diet group was not affected. Conclusion These results suggest that fish oil decreases lipid levels in plasma and liver via PPARs pathway-independent mechanism, and that glucose tolerance is inversely regulated by PPARs antagonists under diets containing different oils. PMID:20846400

2010-01-01

265

Histone deacetylase inhibitors induce thymidine phosphorylase expression in cultured breast cancer cell lines.  

PubMed

Thymidine phosphorylase (TP) is an enzyme involved in thymidine synthesis and degradation. The expression of this enzyme has been proposed as a predictive factor for the therapeutic benefit of capecitabine, which is a precursor of the drug 5'-fluorouracil. In fact, TP is the rate-limiting enzyme in the activation of capecitabine. Therefore, higher levels of TP are expected to sensitize cancer cells to capecitabine treatment. In the present study, using breast cancer cell lines, we found a correlation between TP mRNA and protein levels, suggesting that compounds able to increase TP gene expression also increase protein levels. Accordingly, we demonstrated that treatment of breast cancer MCF7 and MDA231 cell lines with histone deacetylase inhibitors, tricostatin A and suberoylanilide hydroxamic acid, increased TP both at the mRNA and protein level. The effects of histone deacetylase inhibitors were not found to occur via the cytokine TNF?, a known inducer of TP expression. Our findings suggest a strategy to sensitize breast cancer cells to capecitabine treatment. PMID:21617864

Puppin, Cinzia; Puglisi, Fabio; Pandolfi, Maura; Di Loreto, Carla; Damante, Giuseppe

2011-08-01

266

TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis.  

PubMed

TOPK (T-lymphokine-activated killer cell-originated protein kinase) is highly and frequently transactivated in various cancer tissues, including lung and triple-negative breast cancers, and plays an indispensable role in the mitosis of cancer cells. We report the development of a potent TOPK inhibitor, OTS964 {(R)-9-(4-(1-(dimethylamino)propan-2-yl)phenyl)-8-hydroxy-6-methylthieno[2,3-c]quinolin-4(5H)-one}, which inhibits TOPK kinase activity with high affinity and selectivity. Similar to the knockdown effect of TOPK small interfering RNAs (siRNAs), this inhibitor causes a cytokinesis defect and the subsequent apoptosis of cancer cells in vitro as well as in xenograft models of human lung cancer. Although administration of the free compound induced hematopoietic adverse reactions (leukocytopenia associated with thrombocytosis), the drug delivered in a liposomal formulation effectively caused complete regression of transplanted tumors without showing any adverse reactions in mice. Our results suggest that the inhibition of TOPK activity may be a viable therapeutic option for the treatment of various human cancers. PMID:25338756

Matsuo, Yo; Park, Jae-Hyun; Miyamoto, Takashi; Yamamoto, Shinji; Hisada, Shoji; Alachkar, Houda; Nakamura, Yusuke

2014-10-22

267

Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor  

PubMed Central

There is significant interest in treating cancers by blocking protein synthesis, to which hematological malignancies seem particularly sensitive. The translation elongation inhibitor homoharringtonine (Omacetaxine mepesuccinate) is undergoing clinical trials for chronic myeloid leukemia, whereas the translation initiation inhibitor silvestrol has shown promise in mouse models of cancer. Precisely how these compounds induce cell death is unclear, but reduction in Mcl-1, a labile pro-survival Bcl-2 family member, has been proposed to constitute the critical event. Moreover, the contribution of translation inhibitors to neutropenia and lymphopenia has not been precisely defined. Herein, we demonstrate that primary B cells and neutrophils are highly sensitive to translation inhibitors, which trigger the Bax/Bak-mediated apoptotic pathway. However, contrary to expectations, reduction of Mcl-1 did not significantly enhance cytotoxicity of these compounds, suggesting that it does not have a principal role and cautions that strong correlations do not always signify causality. On the other hand, the killing of T lymphocytes was less dependent on Bax and Bak, indicating that translation inhibitors can also induce cell death via alternative mechanisms. Indeed, loss of clonogenic survival proved to be independent of the Bax/Bak-mediated apoptosis altogether. Our findings warn of potential toxicity as these translation inhibitors are cytotoxic to many differentiated non-cycling cells. PMID:23059828

Lindqvist, L M; Vikstrom, I; Chambers, J M; McArthur, K; Ann Anderson, M; Henley, K J; Happo, L; Cluse, L; Johnstone, R W; Roberts, A W; Kile, B T; Croker, B A; Burns, C J; Rizzacasa, M A; Strasser, A; Huang, DC S

2012-01-01

268

Specificity of protein turnover in tomato leaves. Accumulation of proteinase inhibitors, induced with the wound hormone, PIIF.  

PubMed

Detached tomato leaves, supplied with the proteinase inhibitor inducing factor (PIIF) and incubated with water under constant light, exhibited a specificity of intracellular protein turnover directed toward the selective accumulation of heat-stable proteins having disulfide corss-linkages. Approximately 70% of the accumulated proteins could be accounted for in two proteinase inhibitors rich in disulfide links. The accumulation of proteins containing disulfides was accompanied by a net loss in total leaf protein, mainly of heat-precipitable proteins having free sulfhydryl residues. Relative rates of synthesis of --S--S-- proteins and --SH proteins were assessed by comparing rates of incorporation of isotope into the inhibitor proteins and noninhibitor leaf proteins. Although the inhibitors represented about 12% of total leaf protein after 71 h of induction, only about 2% of total protein synthesis was directed toward inhibitor synthesis during incubation of induced leaves. The marked stability of inhibitors, and other disulfide proteins against degradation in vivo, appeared to be a major factor providing for their selective accumulation. It was concluded that the state of oxidation of protein-bound half-cystine residues may be a principle parameter influencing the susceptibility of leaf proteins to degradation in vivo. PMID:993201

Gustafson, G; Ryan, C A

1976-11-25

269

Treatment of streptozotocin-induced diabetic rats with AVE7688, a vasopeptidase inhibitor: effect on vascular and neural disease.  

PubMed

In epineurial arterioles, acetylcholine-mediated vascular relaxation is mediated by nitric oxide and endothelium-derived hyperpolarizing factor (EDHF), and both mechanisms are impaired by diabetes. The mediator responsible for the effect of EDHF is unknown. In epineurial arterioles, C-type natriuretic peptide (CNP) has properties consistent with EDHF-like activity. Epineurial arterioles express CNP, and exogenous CNP causes a concentration-dependent vascular relaxation. In streptozotocin-induced diabetic rats, CNP-mediated vascular relaxation in epineurial arterioles is decreased. Since CNP may be a regulator of vascular function, a vasopeptidase inhibitor may be an effective treatment for diabetes-induced vascular and neural disease. Vasopeptidase inhibitors inhibit ACE activity and neutral endopeptidase, which degrades natriuretic peptides. Streptozotocin-induced diabetic rats were treated with AVE7688 (450 mg/kg in the diet), a vasopeptidase inhibitor, for 8-10 weeks after 4 weeks of untreated diabetes. Treatment of diabetic rats corrected the diabetes-induced decrease in endoneurial blood flow, significantly improved motor and sensory nerve conduction velocity, prevented the development of hypoalgesia in the hind paw, and reduced superoxide and nitrotyrosine levels in epineurial arterioles. The diabetes-induced decrease in acetylcholine-mediated vascular relaxation by epineurial arterioles was significantly improved with treatment. These studies suggest that vasopeptidase inhibitors may be an effective approach for the treatment of diabetic vascular and neural dysfunction. PMID:17259379

Davidson, Eric P; Kleinschmidt, Travis L; Oltman, Christine L; Lund, Donald D; Yorek, Mark A

2007-02-01

270

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury  

PubMed Central

Cardiac injury is a major complication for oxidative stress-generating anticancer agents exemplified by Adriamycin (ADR). Recently, several histone deacetylase inhibitors (HDACIs) including phenylbutyrate (PBA) have shown promise in the treatment of cancer with little known toxicity to normal tissues. PBA has been shown to protect against oxidative stress in normal tissues. Here, we examined whether PBA might protect heart against ADR toxicity in a mouse model. The mice were i.p. injected with ADR (20 mg/kg). PBA (400 mg/kg/day) was i.p. injected one day before and daily after the ADR injection for two days. We found that PBA significantly decreased the ADR-associated elevation of serum lactase dehydrogenase (LDH) and creatine kinase (CK) activities, and diminished ADR-induced ultrastructual damages of cardiac tissue by more than 70%. Importantly, PBA completely rescued ADR-caused reduction of cardiac functions exemplified by ejection fraction and fraction shortening, and increased cardiac MnSOD protein and activity. Our results reveal a previously unrecognized role of HDACIs in protecting against ADR-induced cardiac injury, and suggest that PBA may exert its cardioprotective effect, in part, by the increase of MnSOD. Thus, combining HDACIs with ADR could add a new mechanism to fight cancer while simultaneously decrease ADR-induced cardiotoxicity. PMID:17512461

Daosukho, Chotiros; Chen, Yumin; Noel, Teresa; Sompol, Pradoldej; Nithipongvanitch, Ramaneeya; Velez, Joyce M.; Oberley, Terry D.; Clair, Daret K. St.

2007-01-01

271

The heat shock protein inhibitor KNK437 induces neurite outgrowth in PC12 cells.  

PubMed

The nervous system is highly sensitive to various environmental stresses, such as ischemia. Stress response mechanisms that result in neuroprotection, including the induction of heat shock proteins (HSP), are not well understood. We examined the effect of KNK437, a compound that inhibits the synthesis of inducible heat shock proteins, on neuronal differentiation in rat pheochromocytoma PC12 cells. KNK437 decreased the expression of HSP70, and induced the neurite outgrowth of PC12 cells in the absence of stress stimulation, although with lower efficacy than nerve growth factor (NGF). Neurite outgrowth stimulated by KNK437 and NGF was blocked by inhibitors of ERK mitogen-activated protein (MAP) kinase, p38 MAP kinase, and glycogen synthase kinase 3beta signaling pathways. NGF, and not KNK437, induced acetylcholine esterase (AChE) activity, a functional differentiation marker, indicating that KNK437 utilizes a mechanism distinct from that of NGF. KNK437 enhanced the activity of low dose NGF treatment on neurite outgrowth induction and ERK phosphorylation in PC12 cells, a finding that identifies KNK437 as a possible nerve regeneration agent. This compound may be a useful tool for the investigation of neuronal differentiation and neuroprotection against environmental stress. PMID:17055158

Koike, Tomoko; Uno, Shigeyuki; Ishizawa, Michiyasu; Takahashi, Hideo; Ikeda, Kazumasa; Yokota, Shinichi; Makishima, Makoto

2006-12-27

272

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. PMID:22586683

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

273

Visualizing inducible nitric-oxide synthase in living cells with a heme-binding fluorescent inhibitor.  

PubMed

The study of nitric-oxide synthase (NOS) physiology is constrained by the lack of suitable probes to detect NOS in living cells or animals. Here, we characterized a fluorescent inducible NOS (iNOS) inhibitor called PIF (pyrimidine imidazole FITC) and examined its utility for microscopic imaging of iNOS in living cells. PIF binding to iNOS displayed high affinity, isoform selectivity, and heme specificity, and was essentially irreversible. PIF was used to successfully image iNOS expressed in RAW264.7 cells, HEK293T cells, human A549 epithelial cells, and freshly obtained human lung epithelium. PIF was used to estimate a half-life for iNOS of 1.8 h in HEK293T cells. Our work reveals that fluorescent probes like PIF will be valuable for studying iNOS cell biology and in understanding the pathophysiology of diseases that involve dysfunctional iNOS expression. PMID:16006534

Panda, Koustubh; Chawla-Sarkar, Mamta; Santos, Cecile; Koeck, Thomas; Erzurum, Serpil C; Parkinson, John F; Stuehr, Dennis J

2005-07-19

274

A mechanism for inducing plant development: the genesis of a specific inhibitor.  

PubMed Central

Parasitic strategies are widely distributed in the plant kingdom and frequently involve coupling parasite organogenesis with cues from the host. In Striga asiatica, for example, the cues that initiate the development of the host attachment organ, the haustorium, originate in the host and trigger the transition from vegetative to parasitic mode in the root meristem. This system therefore offers a unique opportunity to study the signals and mechanisms that control plant cell morphogenesis. Here we establish that the biological activity of structural analogs of the natural inducer displays a marked dependence on redox potential and suggest the existence of a semiquinone intermediate. Building on chemistry that exploits the energetics of such an intermediate, cyclopropyl-p-benzoquinone (CPBQ) is shown to be a specific inhibitor of haustorial development. These data are consistent with a model where haustorial development is initiated by the completion of a redox circuit. Images Fig. 1 Fig. 4 PMID:11607691

Smith, C E; Ruttledge, T; Zeng, Z; O'Malley, R C; Lynn, D G

1996-01-01

275

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

276

HGF induces novel EGFR functions involved in resistance formation to tyrosine kinase inhibitors.  

PubMed

The epidermal growth factor receptor (EGFR) is overexpressed and activated in many human cancers and predicts poor patient prognosis. Targeting the kinase domain with specific EGFR tyrosine kinase inhibitors (TKIs) like gefitinib and erlotinib has been used in anticancer treatments. However, patient response rates in different human cancers were initially low. Only a subgroup of non-small-cell lung cancer (NSCLC) patients harboring EGFR-activating mutations responds to EGFR TKI treatment, but most of these responders relapse and acquire resistance. Recent clinical studies have demonstrated that MET proto-oncogene overexpression correlates with resistance to EGFR TKI treatment. Similarly to MET overexpression, the tumor microenvironment-derived ligand hepatocyte growth factor (HGF) was shown to activate Met and thereby induce short-term resistance to EGFR TKI treatment in gefitinib-sensitive NSCLC cell lines in vitro. However, only little is known about the HGF/Met-induced EGFR TKI resistance mechanism in other human cancer types. Therefore, in order to develop possible new anticancer strategies for diverse human cancers, we screened 12 carcinoma cell lines originating from the breast, kidney, liver and tongue for HGF-induced EGFR tyrosine kinase (TK)-inhibition. In addition, in order to advance our understanding of a TK-inactive EGFR, we used EGFR co-immunoprecipitation, followed by mass spectrometry to identify novel HGF-induced EGFR binding partners, which are potentially involved in tyrosine kinase-independent EGFR signaling mechanisms. Here we show for the first time that HGF-induced EGFR TK-inhibition is a very common mechanism in human cancers, and that the kinase-inactive EGFR directly interacts with and stabilizes several cancer-relevant proteins, including the receptor tyrosine kinases Axl and EphA2, and the CUB domain-containing protein-1. This study has strong implications for the development of new anticancer strategies. PMID:23045285

Gusenbauer, S; Vlaicu, P; Ullrich, A

2013-08-15

277

Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles  

SciTech Connect

Highlights: •Angiotensin converting enzyme (ACE) increases in UVB-irradiated skin. •Administration of an ACE inhibitor improved UVB-induced skin wrinkle. •ACE inhibitor improved UVB-induced epidermal hypertrophy. •ACE inhibitor improved transepidermal water loss in the UVB-irradiated skin. -- Abstract: Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin.

Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio, E-mail: toshio_n@cc.tuat.ac.jp

2013-12-06

278

USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis  

PubMed Central

Neuroblastoma (NB) is a common pediatric cancer and contributes to more than 15% of all pediatric cancer-related deaths. Unlike adult tumors, recurrent somatic mutations in NB, such as tumor protein 53 (p53) mutations, occur with relative paucity. In addition, p53 downstream function is intact in NB cells with wild-type p53, suggesting that reactivation of p53 may be a viable therapeutic strategy for NB treatment. Herein, we report that the ubiquitin-specific protease 7 (USP7) inhibitor, P22077, potently induces apoptosis in NB cells with an intact USP7-HDM2-p53 axis but not in NB cells with mutant p53 or without human homolog of MDM2 (HDM2) expression. In this study, we found that P22077 stabilized p53 by inducing HDM2 protein degradation in NB cells. P22077 also significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) in NB cells with an intact USP7-HDM2-p53 axis. Moreover, P22077 was found to be able to sensitize chemoresistant LA-N-6 NB cells to chemotherapy. In an in vivo orthotopic NB mouse model, P22077 significantly inhibited the xenograft growth of three NB cell lines. Database analysis of NB patients shows that high expression of USP7 significantly predicts poor outcomes. Together, our data strongly suggest that targeting USP7 is a novel concept in the treatment of NB. USP7-specific inhibitors like P22077 may serve not only as a stand-alone therapy but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact USP7-HDM2-p53 axis. PMID:24136231

Fan, Y-H; Cheng, J; Vasudevan, S A; Dou, J; Zhang, H; Patel, R H; Ma, I T; Rojas, Y; Zhao, Y; Yu, Y; Zhang, H; Shohet, J M; Nuchtern, J G; Kim, E S; Yang, J

2013-01-01

279

mTOR inhibitor AZD8055 inhibits proliferation and induces apoptosis in laryngeal carcinoma.  

PubMed

The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, against all class I phosphatidylinositol3-kinase (PI3K) and other members of the PI3K-like kinase family. The study was to determine the effect of AZD8055 on proliferation and apoptosis on Hep-2, a human laryngeal cancer cell line and to investigate the underlying mechanism(s) of action. Hep-2 cells were treated with AZD8055 for 24, 48 or 72 h. MTT was used to determine cell proliferation. Rhodamine 123 and TUNEL staining were used to determine mitochondrial membrane potential and cell apoptosis analyzed by fluorescence-activated cell sorting (FACS). Protein expressions were examined by western blotting. Treatment with AZD8055 inhibited proliferation and induced apoptosis in Hep-2 cells in a dose- and time-dependent manner. During the prolonged treatment with AZD8055, AZD8055 inhibits the mammalian target of rapamycin mTOR. Further experiments showed which signaling cascade p-4EBP1 and substrate EIF4E as well as downstream proteins were down regulated. Furthermore, our study showed that the expression profiles of various BH3-only proteins including Bid, Bad, and Bim, apoptosis regulatory protein cleaved caspase3 was up regulated in a time-dependent manner in Hep-2 cells treated with AZD8055. Thus, in vitro, AZD8055 potently inhibits proliferation and induces apoptosis in head and neck squamous cell carcinoma. PMID:24600487

Zhao, Lijing; Teng, Bo; Wen, Lianji; Feng, Qingjie; Wang, Hebin; Li, Na; Wang, Yafang; Liang, Zuowen

2014-01-01

280

mTOR inhibitor AZD8055 inhibits proliferation and induces apoptosis in laryngeal carcinoma  

PubMed Central

The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, against all class I phosphatidylinositol3-kinase (PI3K) and other members of the PI3K-like kinase family. The study was to determine the effect of AZD8055 on proliferation and apoptosis on Hep-2, a human laryngeal cancer cell line and to investigate the underlying mechanism(s) of action. Hep-2 cells were treated with AZD8055 for 24, 48 or 72 h. MTT was used to determine cell proliferation. Rhodamine 123 and TUNEL staining were used to determine mitochondrial membrane potential and cell apoptosis analyzed by fluorescence-activated cell sorting (FACS). Protein expressions were examined by western blotting. Treatment with AZD8055 inhibited proliferation and induced apoptosis in Hep-2 cells in a dose- and time-dependent manner. During the prolonged treatment with AZD8055, AZD8055 inhibits the mammalian target of rapamycin mTOR. Further experiments showed which signaling cascade p-4EBP1 and substrate EIF4E as well as downstream proteins were down regulated. Furthermore, our study showed that the expression profiles of various BH3-only proteins including Bid, Bad, and Bim, apoptosis regulatory protein cleaved caspase3 was up regulated in a time-dependent manner in Hep-2 cells treated with AZD8055. Thus, in vitro, AZD8055 potently inhibits proliferation and induces apoptosis in head and neck squamous cell carcinoma. PMID:24600487

Zhao, Lijing; Teng, Bo; Wen, Lianji; Feng, Qingjie; Wang, Hebin; Li, Na; Wang, Yafang; Liang, Zuowen

2014-01-01

281

Mitigation and Treatment of Radiation-Induced Thoracic Injury With a Cyclooxygenase-2 Inhibitor, Celecoxib  

SciTech Connect

Purpose: To test whether a cyclooxygenase-2 inhibitor (celecoxib) could reduce mortality resulting from radiation-induced pneumonitis. Methods and Materials: Celecoxib was given to mice twice daily for 40 consecutive days starting on the day of local thoracic irradiation (LTI) or 40 or 80 days later. C3Hf/KamLaw mice were observed for morbidity, and time to death was determined. Results were analyzed using the Cox proportional hazards model. Results: Timing of celecoxib relative to LTI determined efficacy. A significant reduction in time to death was achieved only when celecoxib was started 80 days after LTI, corresponding to the time when pneumonitis is expressed. For these mice the reduction in mortality was quantified as a hazard ratio for mortality of treated vs untreated of 0.36 (95% confidence interval [CI] 0.24-0.53), thus significantly less than 1.0. Correspondingly, the median lethal dose for treated mice (12.9 Gy; 95% CI 12.55-13.25 Gy) was significantly (P=.026) higher than for untreated mice (12.4 Gy; 95% CI 12.2-12.65 Gy). Conclusions: Celecoxib significantly reduced lung toxicity when administered months after LTI when the deleterious effects of radiation were expressed. The schedule-dependent reduction in fatal pneumonitis suggests that celecoxib could be clinically useful by reintroduction of treatment months after completion of radiation therapy. These findings may be important for designing clinical trials using cyclooxygenase-2 inhibitors to treat radiation-induced lung toxicity as a complement to concurrent radiation therapy of lung cancers.

Hunter, Nancy R.; Valdecanas, David [Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)] [Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Liao Zhongxing [Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)] [Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Milas, Luka [Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)] [Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Thames, Howard D. [Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)] [Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mason, Kathy A., E-mail: kmason@mdanderson.org [Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

2013-02-01

282

Selective phosphodiesterase 3 inhibitor olprinone attenuates meconium-induced oxidative lung injury.  

PubMed

Since inflammation and oxidation play a key role in the pathophysiology of neonatal meconium aspiration syndrome, various anti-inflammatory drugs have been tested in the treatment. This study evaluated whether the phosphodiesterase (PDE) 3 inhibitor olprinone can alleviate meconium-induced inflammation and oxidative lung injury. Oxygen-ventilated rabbits intratracheally received 4 ml/kg of meconium (25 mg/ml) or saline. Thirty minutes after meconium/saline instillation, meconium-instilled animals were treated by intravenous olprinone (0.2 mg/kg) or were left without treatment. All animals were oxygen-ventilated for an additional 5 h. A bronchoalveolar lavage (BAL) of the left lungs was performed and differential leukocyte count in the sediment was estimated. The right lungs were used to determine lung edema by wet/dry weight ratio, as well as to detect oxidative damage to the lungs. In the lung tissue homogenate, total antioxidant status (TAS) was determined. In isolated lung mitochondria, the thiol group content, conjugated dienes, thiobarbituric acid-reactive substances (TBARS), dityrosine, lysine-lipid peroxidation products, and activity of cytochrome c oxidase (COX) were estimated. To evaluate the effects of meconium instillation and olprinone treatment on the systemic level, TBARS and TAS were determined in the blood plasma, as well. Meconium instillation increased the relative numbers of neutrophils and eosinophils in the BAL fluid, increased edema formation and concentrations of oxidation markers, and decreased TAS. Treatment with olprinone reduced the numbers of polymorphonuclears in the BAL fluid, decreased the formation of most oxidation markers in the lungs, reduced lung edema and prevented a decrease in TAS in the lung homogenate compared to non-treated animals. In the blood plasma, olprinone decreased TBARS and increased TAS compared to the non-treated group. Conclusion, the selective PDE3 inhibitor olprinone has shown potent antioxidative and anti-inflammatory effects in the meconium-induced oxidative lung injury. PMID:22387424

Mokra, Daniela; Drgova, Anna; Pullmann, Rudolf; Calkovska, Andrea

2012-06-01

283

Pex11a deficiency is associated with a reduced abundance of functional peroxisomes and aggravated renal interstitial lesions.  

PubMed

Although proteinuria is known to be associated with the deterioration of chronic kidney disease, the molecular basis of this mechanism is not fully understood. We previously found that Pex11a deficiency was associated with a reduction of functional peroxisomes and impaired fatty acid metabolism in hepatocytes and resulted in steatosis. Proximal tubule cells are rich in peroxisomes. We assessed whether Pex11a deficiency might result in the derangement of peroxisome systems in proximal tubule cells and the aggravation of tubulointerstitial lesions in chronic kidney disease. Histological analyses showed that the number of functional peroxisomes in proximal tubule cells was reduced in Pex11a knockout (Pex11a(-/-)) mice. To clarify whether a decrease in the number of tubular peroxisomes might aggravate interstitial lesions, we assessed 2 models in which proximal tubule cells are overloaded with fatty acids (ie, deoxycorticosterone acetate and salt hypertension and the overload of fatty acid-bound albumin). Deoxycorticosterone acetate -salt-treated Pex11a(-/-) mice exhibited greater interstitial lesions than deoxycorticosterone acetate-salt-treated wild-type mice in terms of tubular lipid accumulation, blood pressure, urinary albumin, urinary N-acetyl-?-d-glucosaminidase, urinary 8-iso-prostane, and the histological evaluation of fibrosis and inflammation. An overload of fatty acid-bound albumin also resulted in more severe tubulointerstitial lesions in Pex11a(-/-) mice than in wild-type mice. Fenofibrate, a peroxisome proliferator-activated receptor-? agonist, restored the abundance of peroxisomes and reduced the tubulointerstitial lesions induced by deoxycorticosterone acetate-salt hypertension. In conclusion, our results indicate that proximal tubule peroxisomes play an important role in proteinuria-induced interstitial lesions. The activation of tubular peroxisomes might be an excellent therapeutic strategy against chronic kidney disease. PMID:25113963

Weng, Huachun; Ji, Xu; Endo, Kosuke; Iwai, Naoharu

2014-11-01

284

Guggulsterone sensitizes glioblastoma cells to Sonic hedgehog inhibitor SANT-1 induced apoptosis in a Ras/NF?B dependent manner.  

PubMed

Since Shh pathway effector, Gli1, is overexpressed in gliomas, we investigated the effect of novel Shh inhibitor SANT-1 on glioma cell viability. Though SANT-1 failed to induce apoptosis, it reduced proliferation of glioma stem-like cells. Apart from canonical Shh cascade, Gli1 is also induced by non-canonical pathways including NF?B. Therefore, a combinatorial strategy with Ras/NF?B inhibitor, Guggulsterone, was employed to enhance effectiveness of SANT-1. Guggulsterone inhibited Ras and NF?B activity and sensitized cells to SANT-1 induced apoptosis via intrinsic apoptotic mechanism. Inhibition of either Ras or NF?B activity was sufficient to sensitize cells to SANT-1. Guggulsterone induced ERK activation also contributed to Caspase-9 activation. Since SANT-1 and Guggulsterone differentially target stem-like and non-stem glioma cells respectively, this combination warrants investigation as an effective anti-glioma therapy. PMID:23548480

Dixit, Deobrat; Ghildiyal, Ruchi; Anto, Nikhil Ponnor; Ghosh, Sourav; Sharma, Vivek; Sen, Ellora

2013-08-19

285

Microporation is an efficient method for siRNA-induced knockdown of PEX5 in HepG2 cells: evaluation of the transfection efficiency, the PEX5 mRNA and protein levels and induction of peroxisomal deficiency.  

PubMed

The pathomechanism of peroxisomal biogenesis disorders (PBDs), a group of inherited autosomal recessive diseases with mutations of peroxin (PEX) genes, is not yet fully understood. Therefore, several knockout models, e.g., the PEX5 knockout mouse, have been generated exhibiting a complete loss of peroxisomal function. In this study, we wanted to knockdown PEX5 using the siRNA technology (1) to mimic milder forms of PBDs in which the mutated peroxin has some residual function and (2) to analyze the cellular consequences of a reduction of the PEX5 protein without adaption during the development as it is the case in a knockout animal. First, we tried to optimize the transfection of the hepatoma cell line HepG2 with PEX5 siRNA using different commercially available liposomal and non-liposomal transfection reagents (Lipofectamine(®) 2000, FuGENE 6, HiPerFect(®), INTERFERin™, RiboJuice™) as well as microporation using the Neon™ Transfection system. Microporation was found to be superior to the transfection reagents with respect to the transfection efficiency (100 vs. 0-70 %), to the reduction of PEX5 mRNA (by 90 vs. 0-50 %) and PEX5 protein levels (by 70 vs. 0-50 %). Interestingly, we detected that a part of the cleaved PEX5 mRNA still existed as 3' fragment (15 %) 24 h after microporation. Using microporation, we further analyzed whether the reduced PEX5 protein level impaired peroxisomal function. We indeed detected a reduced targeting of SKL-tagged proteins into peroxisomes as well as an increased oxidative stress as found in PBD patients and respective knockout mouse models. Knockdown of the PEX5 protein and functional consequences were at a maximum 48 h after microporation. Thereafter, the PEX5 protein was resynthesized, which may allow the temporal analysis of the loss as well as the reconstitution of peroxisomes in the future. In conclusion, we propose microporation as an efficient and reproducible method to transfect HepG2 cells with PEX5 siRNA. We succeeded to transiently knockdown PEX5 mRNA and its protein level leading to functional consequences similar as observed in peroxisome deficiencies. PMID:25224142

Ahlemeyer, Barbara; Vogt, Julia-Franziska; Michel, Vera; Hahn-Kohlberger, Petra; Baumgart-Vogt, Eveline

2014-11-01

286

Effect of a novel 5-lipoxygenase activating protein inhibitor, BAYx 1005, on asthma induced by cold dry air  

Microsoft Academic Search

BACKGROUND: Leukotrienes have been implicated in the mediation of airway obstruction induced by hyperventilation of cold dry air in asthmatic subjects. The effect of a novel inhibitor of 5-lipoxygenase activating protein, BAYx 1005, on the bronchospastic response to cold dry air hyperventilation was investigated in asthmatic patients. METHODS: After a screening cold dry air hyperventilation challenge to document cold air

A. R. Fischer; M. A. Rosenberg; M. Roth; M. Loper; S. Jungerwirth; E. Israel

1997-01-01

287

Effects of phospholipase a2 inhibitors on diethyl maleate?induced lipid peroxidation and cellular injury in isolated rat hepatocytes  

Microsoft Academic Search

Isolated hepatocytes provide a suitable system for investigation of various aspects of the mechanism of a toxic response. The mechanism by which most chemicals induce hepatotoxicity is still not known. Evidence that phospholipases may play a role in cellular Injury has been reported. In the present study the effects of reported inhibitors of phospholipase A2 (quinacrine, chlorpromazine, dexamethasone, and dibutyryl

Neill H. Stacey; Curtis D. Klaassen

1982-01-01

288

A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib  

Microsoft Academic Search

Summary Bortezomib therapy has proven successful for the treatment of relapsed and\\/or refractory multiple myeloma (MM); how- ever, prolonged treatment is associated with toxicity and development of drug resistance. Here, we show that the novel proteasome inhibitor NPI-0052 induces apoptosis in MM cells resistant to conventional and Bortezomib therapies. NPI- 0052 is distinct from Bortezomib in its chemical structure, effects

Dharminder Chauhan; Laurence Catley; Guilan Li; Klaus Podar; Teru Hideshima; Mugdha Velankar; Constantine Mitsiades; Nicolas Mitsiades; Hiroshi Yasui; Anthony Letai; Huib Ovaa; Celia Berkers; Benjamin Nicholson; Ta-Hsiang Chao; Saskia T. C. Neuteboom; Paul Richardson; Michael A. Palladino; Kenneth C. Anderson

2005-01-01

289

Abscisic Acid is Involved in the Wound-Induced Expression of the Proteinase Inhibitor II Gene in Potato and Tomato  

Microsoft Academic Search

Plants respond to wounding or pathogen attack by a variety of biochemical reactions, involving in some instances gene activation in tissues far apart from the actual site of wounding or pathogen invasion. One of the best analyzed examples for such a systemic reaction is the wound-induced expression of proteinase inhibitor genes in tomato and potato leaves. Local wounding of potato

Hugo Pena-Cortes; Jose J. Sanchez-Serrano; Rudiger Mertens; Lothar Willmitzer; Salome Prat

1989-01-01

290

Molecular characterization and phylogenetic studies of a wound-inducible proteinase inhibitor I gene in Lycopersicon species.  

PubMed

A gene coding for proteinase inhibitor I, whose expression is induced in tomato leaves (Lycopersicon esculentum L. var. Bonny Best) in response to wounding or insect attacks, was isolated from a genomic library and characterized. The nucleotide sequence revealed that the gene is complete and encodes the sequence of an inhibitor I cDNA that was previously isolated from a cDNA library prepared from wound-induced mRNA from tomato leaves. This gene is located 13.1 kilobase pairs (kbp) upstream from an inhibitor II gene. The wound-inducible gene is interrupted by two intervening sequences of 445 and 404 bp, situated within the codons of amino acids 17 and 47, respectively, of the open reading frame. In addition to the presence of putative regulatory sequences, TATAAA and CCACT, two copies of an imperfect direct repeat approximately 100 bp long were identified in the 5'-flanking region. Phylogenetic comparisons of wound-inducible inhibitor I genes within the genomes of various Lycopersicon species revealed that the repeat is found in seven ancestral species of tomato. PMID:3463966

Lee, J S; Brown, W E; Graham, J S; Pearce, G; Fox, E A; Dreher, T W; Ahern, K G; Pearson, G D; Ryan, C A

1986-10-01

291

Curcumin prevents HIV protease inhibitor ritonavir-induced vascular injury and superoxide anion production in porcine coronary arteries  

Microsoft Academic Search

Introduction: HIV protease inhibitor ritonavir (RTV) may induce vascular dysfunction through oxidative stress. The objective of this study was to determine whether a dietary antioxidant curcumin could prevent coronary arteries from RTV-induced injury.Methods: Porcine coronary arteries were incubated with RTV and\\/or curcumin for 24 hours. Vasomotor function was studied with a myograph tension system in response to thromboxane A2 analogue

Changyi J. Chen; Hong Chai; Shaoyu Yan; Peter Lin; Alan Lumsden; Qizhi Yao

2004-01-01

292

Berberine Inhibits HIV Protease Inhibitor-Induced Inflammatory Response by Modulating ER Stress Signaling Pathways in Murine Macrophages  

Microsoft Academic Search

BackgroundHIV protease inhibitor (PI)-induced inflammatory response plays an important role in HIV PI-associated dyslipidemia and cardiovascular complications. This study examined the effect of berberine, a traditional herb medicine, on HIV PI-induced inflammatory response and further investigated the underlying cellular\\/molecular mechanisms in macrophages.Methodology and Principal FindingsCultured mouse J774A.1 macrophages and primary mouse macrophages were used in this study. The expression of

Weibin Zha; Guang Liang; Jian Xiao; Elaine J. Studer; Phillip B. Hylemon; Pandak William M; Guangji Wang; Xiaokun Li; Huiping Zhou; Yuan Luo

2010-01-01

293

Marchantin M: a novel inhibitor of proteasome induces autophagic cell death in prostate cancer cells  

PubMed Central

We previously reported that marchantin M (Mar) is an active agent to induce apoptosis in human prostate cancer (PCa), but the molecular mechanisms of action remain largely unknown. Here, we demonstrate that Mar potently inhibited chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing activities of 20S proteasome both in in vitro and intracellular systems and significantly induced the accumulation of polyubiquitinated proteins in PCa cells. The computational modeling analysis suggested that Mar non-covalently bound to active sites of proteasome ?5 and ?1 subunits, resulting in a non-competitive inhibition. Proteasome inhibition by Mar subsequently resulted in endoplasmic reticulum (ER) stress, as evidenced by elevated glucose-regulated protein 78 and CHOP, increased phospho-eukaryotic translation initiation factor 2? (eIF2?), splicing of X-box-binding protein-1 and dilation of the ER. However, Mar-mediated cell death was not completely impaired by a pan inhibitor of caspases. Further studies revealed that the Mar-induced cell death was greatly associated with the activation of autophagy, as indicated by the significant induction of microtubule-associated protein-1 light chain-3 beta (LC3B) expression and conversion. Electron microscopic and green fluorescent protein-tagged LC3B analyses further demonstrated the ability of autophagy induction by Mar. Time kinetic studies revealed that Mar induced a rapid and highly sustained processing of LC3B in treated cells and simultaneously decreased the expression of p62/SQSTM1. Pharmacological blockade or knockdown of LC3B and Atg5 attenuated Mar-mediated cell death. The autophagic response triggered by Mar required the activation of RNA-dependent protein kinase-like ER kinase/eIF2? and suppression of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin axis via preventing activation and expression of Akt. Our results identified a novel mechanism for the cytotoxic effect of Mar, which strengthens it as a potential agent in cancer chemotherapy. PMID:23928700

Jiang, H; Sun, J; Xu, Q; Liu, Y; Wei, J; Young, C Y F; Yuan, H; Lou, H

2013-01-01

294

Ceramide stimulates ABCA12 expression via peroxisome proliferator-activated receptor {delta} in human keratinocytes.  

PubMed

ABCA12 (ATP binding cassette transporter, family 12) is a cellular membrane transporter that facilitates the delivery of glucosylceramides to epidermal lamellar bodies in keratinocytes, a process that is critical for permeability barrier formation. Following secretion of lamellar bodies into the stratum corneum, glucosylceramides are metabolized to ceramides, which comprise approximately 50% of the lipid in stratum corneum. Gene mutations of ABCA12 underlie harlequin ichthyosis, a devastating skin disorder characterized by abnormal lamellar bodies and a severe barrier abnormality. Recently we reported that peroxisome proliferator-activated receptor (PPAR) and liver X receptor activators increase ABCA12 expression in human keratinocytes. Here we demonstrate that ceramide (C(2)-Cer and C(6)-Cer), but not C(8)-glucosylceramides, sphingosine, or ceramide 1-phosphate, increases ABCA12 mRNA expression in a dose- and time-dependent manner. Inhibitors of glucosylceramide synthase, sphingomyelin synthase, and ceramidase and small interfering RNA knockdown of human alkaline ceramidase, which all increase endogenous ceramide levels, also increased ABCA12 mRNA levels. Moreover, simultaneous treatment with C(6)-Cer and each of these same inhibitors additively increased ABCA12 expression, indicating that ceramide is an important inducer of ABCA12 expression and that the conversion of ceramide to other sphingolipids or metabolites is not required. Finally, both exogenous and endogenous ceramides preferentially stimulate PPARdelta expression (but not other PPARs or liver X receptors), whereas PPARdelta knockdown by siRNA transfection specifically diminished the ceramide-induced increase in ABCA12 mRNA levels, indicating that PPARdelta is a mediator of the ceramide effect. Together, these results show that ceramide, an important lipid component of epidermis, up-regulates ABCA12 expression via the PPARdelta-mediated signaling pathway, providing a substrate-driven, feed-forward mechanism for regulating this key lipid transporter. PMID:19429679

Jiang, Yan J; Uchida, Yoshikazu; Lu, Biao; Kim, Peggy; Mao, Cungui; Akiyama, Masashi; Elias, Peter M; Holleran, Walter M; Grunfeld, Carl; Feingold, Kenneth R

2009-07-10

295

Peroxisomal alterations in Alzheimer’s disease  

Microsoft Academic Search

In Alzheimer’s disease (AD), lipid alterations are present early during disease progression. As some of these alterations\\u000a point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based,\\u000a longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere,\\u000a the patients were grouped into three cohorts of increasing severity (stages

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

296

A conserved tripeptide sorts proteins to peroxisomes  

Microsoft Academic Search

The firefly luciferase protein contains a peroxisomal targeting signal at its extreme COOH ter- minus (Gould et al., 1987). Site-directed mutagenesis of the luciferase gene reveals that this peroxisomal tar- geting signal consists of the COOH-terminal three amino acids of the protein, serine-lysine-leucine. When this tripeptide is appended to the COOH termi- nus of a cytosolic protein (chloramphenicol acetyltransferase), it

Stephen J. Gould; Gilbert-Andre Keller; Nancy Hosken; Jack Wilkinson; Suresh Subramani

1989-01-01

297

Peroxisome Proliferator-Activated Receptor Activators Target Human Endothelial Cells to Inhibit Leukocyte-Endothelial Cell Interaction  

Microsoft Academic Search

Abstract—An early event in acute and,chronic inflammation,and associated diseases such as atherosclerosis and rheumatoid arthritis is the induced expression of specific adhesion molecules on the surface of endothelial cells (ECs), which subsequently bind leukocytes. Peroxisome proliferator?activated receptors (PPARs), members of the nuclear receptor superfamily of transcription factors, are activated by fatty acid metabolites, peroxisome proliferators, and thiazolidinediones and are now,recognized,as

Simon M. Jackson; Farhad Parhami; Xiao-Ping Xi; Judith A. Berliner; Willa A. Hsueh; Ronald E. Law; Linda L. Demer

2010-01-01

298

Host peroxisomal properties are not restored to normal after treatment of visceral leishmaniasis with sodium antimony gluconate  

Microsoft Academic Search

Reason for post-kala-azar dermal leishmaniasis (PKDL) is yet to be established. Earlier it was observed that morphology and biochemical properties of host peroxisomes were impaired during Leishmania infection. As peroxisome is known to be involved in various metabolic pathways to monitor normal function of the host cells, it is essential that Leishmania-induced dysfunction of this organelle should totally be repaired

Shreedhara Gupta; Bikramjit Raychaudhury; Salil C. Datta

2009-01-01

299

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

300

Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function.  

PubMed

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. PMID:20139070

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

2010-04-23

301

Combination of oxidative stress and FOXM1 inhibitors induces apoptosis in cancer cells and inhibits xenograft tumor growth.  

PubMed

Tumor cells accumulate high level of reactive oxygen species (ROS) because they are metabolically more active than normal cells. Elevated ROS levels increase tumorigenecity but also render cancer cells more vulnerable to oxidative stress than normal cells. The oncogenic transcription factor Forkhead Box M1 (FOXM1), which is overexpressed in a wide range of human cancers, was reported to protect cancer cells from the adverse effects of oxidative stress by up regulating the expression of scavenger enzymes. We therefore hypothesized that the combination of FOXM1 ablation and ROS inducers could selectively eradicate cancer cells. We show that RNA interference-mediated knockdown of FOXM1 further elevates intracellular ROS levels and increases sensitivity of cancer cells to ROS-mediated cell death after treatment with ROS inducers. We also demonstrate that the combination of ROS inducers with FOXM1/proteasome inhibitors induces robust apoptosis in different human cancer cells. In addition, we show evidence that FOXM1/proteasome inhibitor bortezomib in combination with the ROS inducer ?-phenylethyl isothiocyanate efficiently inhibits the growth of breast tumor xenografts in nude mice. We conclude that the combination of ROS inducers and FOXM1 inhibitors could be used as a therapeutic strategy to selectively eliminate cancer cells. PMID:23665201

Halasi, Marianna; Pandit, Bulbul; Wang, Ming; Nogueira, Veronique; Hay, Nissim; Gartel, Andrei L

2013-07-01

302

Pexophagy: The Selective Degradation of Peroxisomes  

PubMed Central

Peroxisomes are single-membrane-bounded organelles present in the majority of eukaryotic cells. Despite the existence of great diversity among different species, cell types, and under different environmental conditions, peroxisomes contain enzymes involved in ?-oxidation of fatty acids and the generation, as well as detoxification, of hydrogen peroxide. The exigency of all eukaryotic cells to quickly adapt to different environmental factors requires the ability to precisely and efficiently control peroxisome number and functionality. Peroxisome homeostasis is achieved by the counterbalance between organelle biogenesis and degradation. The selective degradation of superfluous or damaged peroxisomes is facilitated by several tightly regulated pathways. The most prominent peroxisome degradation system uses components of the general autophagy core machinery and is therefore referred to as “pexophagy.” In this paper we focus on recent developments in pexophagy and provide an overview of current knowledge and future challenges in the field. We compare different modes of pexophagy and mention shared and distinct features of pexophagy in yeast model systems, mammalian cells, and other organisms. PMID:22536249

Till, Andreas; Lakhani, Ronak; Burnett, Sarah F.; Subramani, Suresh

2012-01-01

303

The NADPH oxidase inhibitor apocynin induces nitric oxide synthesis via oxidative stress  

SciTech Connect

We have recently shown that apocynin elicits an oxidative stress in N11 mouse glial cells and other cell types. Here we report that apocynin increased the accumulation of nitrite, the stable derivative of nitric oxide (NO), in the extracellular medium of N11 cell cultures, and the NO synthase (NOS) activity in cell lysates. The increased synthesis of NO was associated with increased expression of inducible NOS (iNOS) mRNA, increased nuclear translocation of the redox-sensitive transcription factor NF-{kappa}B and decreased intracellular level of its inhibitor IkB{alpha}. These effects, accompanied by increased production of H{sub 2}O{sub 2}, were very similar to those observed after incubation with bacterial lipopolysaccharide (LPS) and were inhibited by catalase. These results suggest that apocynin, similarly to LPS, induces increased NO synthesis by eliciting a generation of reactive oxygen species (ROS), which in turn causes NF-{kappa}B activation and increased expression of iNOS. Therefore, the increased bioavailability of NO reported in the literature after in vivo or in vitro treatments with apocynin might depend, at least partly, on the drug-elicited induction of iNOS, and not only on the inhibition of NADPH oxidase and the subsequent decreased scavenging of NO by oxidase-derived ROS, as it is often supposed.

Riganti, Chiara [Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, Via Santena 5/bis, 10126 Torino (Italy)], E-mail: chiara.riganti@unito.it; Costamagna, Costanzo; Doublier, Sophie; Miraglia, Erica; Polimeni, Manuela; Bosia, Amalia; Ghigo, Dario [Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, Via Santena 5/bis, 10126 Torino (Italy)

2008-05-01

304

CT-2576, an inhibitor of phospholipid signaling, suppresses constitutive and induced expression of human immunodeficiency virus.  

PubMed Central

Viruses such as human immunodeficiency virus (HIV) require cellular activation for expression. Cellular activation in lymphoid cells is associated with augmented accumulation of certain phosphatidic acid (PA) species derived from the hydrolysis of glycan phosphatidylinositol (GPI). This suggests that activation of a phospholipid pathway may play a role in initiation of viral replication. To test this hypothesis, we examined the effect of tat gene expression on the production of cellular PA species, as the Tat protein is essential for HIV expression and has been implicated in activating the expression of multiple host cellular genes. Expression of tat increased the expression of PA. We then tested whether synthetic inhibitors of PA metabolism would inhibit activation of the HIV long terminal repeat by Tat and tumor necrosis factor alpha (TNF-alpha). CT-2576 suppressed both PA generation induced by Tat and HIV long terminal repeat-directed gene expression in response to Tat or TNF-alpha at a posttranscriptional step. CT-2576 also inhibited constitutive as well as TNF-alpha- and interleukin 6-induced expression of HIV p24 antigen in chronically infected U1 cells and in peripheral blood lymphocytes acutely infected with a clinical isolate of HIV. Pharmacological inhibition of synthesis of selected PA species may therefore provide a therapeutic approach to suppression of HIV replication. Images Fig. 1 Fig. 3 Fig. 5 PMID:7761405

Leung, D W; Peterson, P K; Weeks, R; Gekker, G; Chao, C C; Kaplan, A H; Balantac, N; Tompkins, C; Underiner, G E; Bursten, S

1995-01-01

305

Panhistone deacetylase inhibitors inhibit proinflammatory signaling pathways to ameliorate interleukin-18-induced cardiac hypertrophy  

PubMed Central

We investigated the genome-wide consequences of pan-histone deacetylase inhibitors (HDACIs) trichostatin A (TSA) and m-carboxycinnamic acid bis-hydroxamide (CBHA) in the hearts of BALB/c mice eliciting hypertrophy in response to interleukin-18 (IL-18). Both TSA and CBHA profoundly altered cardiac chromatin structure that occurred concomitantly with normalization of IL-18-induced gene expression and amelioration of cardiac hypertrophy. The hearts of mice exposed to IL-18 +/? TSA or CBHA elicited distinct gene expression profiles. Of 184 genes that were differentially regulated by IL-18 and TSA, 33 were regulated in an opposite manner. The hearts of mice treated with IL-18 and/or CBHA elicited 147 differentially expressed genes (DEGs), a third of which were oppositely regulated by IL-18 and CBHA. Ingenuity Pathways and Kyoto Encyclopedia of Genes and Genomes analyses of DEGs showed that IL-18 impinged on TNF-?- and IFN?-specific gene networks relegated to controlling immunity and inflammation, cardiac metabolism and energetics, and cell proliferation and apoptosis. These TNF-?- and IFN?-specific gene networks, extensively connected with PI3K, MAPK, and NF-?B signaling pathways, were oppositely regulated by IL-18 and pan-HDACIs. Evidently, both TSA and CBHA caused a two- to fourfold induction of phosphatase and tensin homolog expression to counteract IL-18-induced proinflammatory signaling and cardiac hypertrophy. PMID:21954451

Majumdar, Gipsy; Rooney, Robert J.; Johnson, I. Maria

2011-01-01

306

Involvement of the endoplasmic reticulum in peroxisome formation.  

PubMed

The traditional view holds that peroxisomes are autonomous organelles multiplying by growth and division. More recently, new observations have challenged this concept. Herein, we present evidence supporting the involvement of the endoplasmic reticulum (ER) in peroxisome formation by electron microscopy, immunocytochemistry and three-dimensional image reconstruction of peroxisomes and associated compartments in mouse dendritic cells. We found the peroxisomal membrane protein Pex13p and the ATP-binding cassette transporter protein PMP70 present in specialized subdomains of the ER that were continuous with a peroxisomal reticulum from which mature peroxisomes arose. The matrix proteins catalase and thiolase were only detectable in the reticula and peroxisomes. Our results suggest the existence of a maturation pathway from the ER to peroxisomes and implicate the ER as a major source from which the peroxisomal membrane is derived. PMID:12857873

Geuze, Hans J; Murk, Jean Luc; Stroobants, An K; Griffith, Janice M; Kleijmeer, Monique J; Koster, Abraham J; Verkleij, Arie J; Distel, Ben; Tabak, Henk F

2003-07-01

307

The Cytoskeleton and the Peroxisomal-Targeted SNOWY COTYLEDON3 Protein Are Required for Chloroplast Development in Arabidopsis[W  

PubMed Central

Here, we describe the snowy cotyledon3 (sco3-1) mutation, which impairs chloroplast and etioplast development in Arabidopsis thaliana seedlings. SCO3 is a member of a largely uncharacterized protein family unique to the plant kingdom. The sco3-1 mutation alters chloroplast morphology and development, reduces chlorophyll accumulation, impairs thylakoid formation and photosynthesis in seedlings, and results in photoinhibition under extreme CO2 concentrations in mature leaves. There are no readily apparent changes to chloroplast biology, such as transcription or assembly that explain the disruption to chloroplast biogenesis. Indeed, SCO3 is actually targeted to another organelle, specifically to the periphery of peroxisomes. However, impaired chloroplast development cannot be attributed to perturbed peroxisomal metabolic processes involving germination, fatty acid ?-oxidation or photorespiration, though there are so far undescribed changes in low and high CO2 sensitivity in seedlings and young true leaves. Many of the chloroplasts are bilobed, and some have persistent membranous extensions that encircle other cellular components. Significantly, there are changes to the cytoskeleton in sco3-1, and microtubule inhibitors have similar effects on chloroplast biogenesis as sco3-1 does. The localization of SCO3 to the periphery of the peroxisomes was shown to be dependent on a functional microtubule cytoskeleton. Therefore, the microtubule and peroxisome-associated SCO3 protein is required for chloroplast development, and sco3-1, along with microtubule inhibitors, demonstrates an unexpected role for the cytoskeleton and peroxisomes in chloroplast biogenesis. PMID:20978221

Albrecht, Veronica; Simkova, Klara; Carrie, Chris; Delannoy, Etienne; Giraud, Estelle; Whelan, Jim; Small, Ian David; Apel, Klaus; Badger, Murray R.; Pogson, Barry James

2010-01-01

308

Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection.  

PubMed

Animal cells harbour multiple innate effector mechanisms that inhibit virus replication. For the pathogenic retrovirus human immunodeficiency virus type 1 (HIV-1), these include widely expressed restriction factors, such as APOBEC3 proteins, TRIM5-?, BST2 (refs 4, 5) and SAMHD1 (refs 6, 7), as well as additional factors that are stimulated by type 1 interferon (IFN). Here we use both ectopic expression and gene-silencing experiments to define the human dynamin-like, IFN-induced myxovirus resistance 2 (MX2, also known as MXB) protein as a potent inhibitor of HIV-1 infection and as a key effector of IFN-?-mediated resistance to HIV-1 infection. MX2 suppresses infection by all HIV-1 strains tested, has equivalent or reduced effects on divergent simian immunodeficiency viruses, and does not inhibit other retroviruses such as murine leukaemia virus. The Capsid region of the viral Gag protein dictates susceptibility to MX2, and the block to infection occurs at a late post-entry step, with both the nuclear accumulation and chromosomal integration of nascent viral complementary DNA suppressed. Finally, human MX1 (also known as MXA), a closely related protein that has long been recognized as a broadly acting inhibitor of RNA and DNA viruses, including the orthomyxovirus influenza A virus, does not affect HIV-1, whereas MX2 is ineffective against influenza virus. MX2 is therefore a cell-autonomous, anti-HIV-1 resistance factor whose purposeful mobilization may represent a new therapeutic approach for the treatment of HIV/AIDS. PMID:24048477

Goujon, Caroline; Moncorgé, Olivier; Bauby, Hélène; Doyle, Tomas; Ward, Christopher C; Schaller, Torsten; Hué, Stéphane; Barclay, Wendy S; Schulz, Reiner; Malim, Michael H

2013-10-24

309

Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection  

PubMed Central

Animal cells harbour multiple innate effector mechanisms that inhibit virus replication. For the pathogenic retrovirus human immunodeficiency virus type-1 (HIV-1), these include widely expressed restriction factors1 such as APOBEC3 proteins2, TRIM5?3, tetherin/BST24,5 and SAMHD16,7, as well as additional factors that are stimulated by type-1 interferon (IFN)8,9,10,11,12,13,14. Here, we employ both ectopic expression and gene silencing experiments to define the human dynamin-like, IFN-induced guanosine triphosphatase (GTPase), myxovirus resistance 2 (MX2 or MxB) protein, as a potent inhibitor of HIV-1 infection and as a major effector of IFN?-mediated resistance to HIV-1 infection. MX2 suppresses infection by all HIV-1 strains tested, has similar to modest effects on divergent simian immunodeficiency viruses (SIVs), and does not inhibit other retroviruses such as murine leukaemia virus (MLV). The capsid (CA) region of the viral Gag protein dictates susceptibility to MX2, and the block to infection occurs at a late post-entry step with the nuclear accumulation and chromosomal integration of nascent viral cDNA both being suppressed. Finally, human MX1 (or MxA), a closely related protein that has long been recognised as a broadly acting inhibitor of RNA/DNA viruses, including the orthomyxovirus influenza A virus15,16, does not affect HIV-1,whereas MX2 is ineffective against influenza virus. MX2 is therefore a cell-autonomous, anti-HIV-1 resistance factor whose purposeful mobilisation may represent a new therapeutic approach for the treatment of HIV/AIDS. PMID:24048477

Goujon, Caroline; Moncorge, Olivier; Bauby, Helene; Doyle, Tomas; Ward, Christopher C.; Schaller, Torsten; Hue, Stephane; Barclay, Wendy S.; Schulz, Reiner; Malim, Michael H.

2013-01-01

310

Short-term cardiovascular effects of selective phosphodiesterase 3 inhibitor olprinone versus non-selective phosphodiesterase inhibitor aminophylline in a meconium-induced acute lung injury.  

PubMed

Various anti-inflammatory drugs have been used for treatment of neonatal meconium aspiration syndrome (MAS). As their adverse effects are poorly described, this study compared effects of selective phosphodiesterase (PDE) 3 inhibitor olprinone and non-selective PDE inhibitor aminophylline on cardiovascular parameters in animal model of MAS. Oxygen-ventilated rabbits were intratracheally instilled 4 mL/kg of meconium (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were intravenously given olprinone (0.2 mg/kg) at a single dose at 0.5 h after meconium instillation, or aminophylline (2.0 mg/kg) at two doses at 0.5 and 2.5 h after meconium instillation, or were left without treatment. Cardiovascular changes were evaluated within 5 min of administration and 5 min after finishing the administration. Furthermore, respiratory and cardiovascular parameters were measured within 5 hours following treatment delivery. Oxidation markers (thiobarbituric acid-reactive substances (TBARS), and total antioxidant status) and markers of cardiovascular injury (aldosterone, gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT)) were determined in the plasma. Meconium instillation induced acute lung injury associated with oxidative stress, elevated aldosterone, and slightly increased GGT and AST levels. Both aminophylline and olprinone improved lung functions and reduced oxidation stress. However, the PDE inhibitors acutely increased blood pressure and heart rate, whereas heart rate variability remained higher till the end of experiment and correlated well with markers of cardiovascular injury. Considering that systemic administration of olprinone and aminophylline was accompanied by acute cardiovascular changes in the meconium-instilled animals, use of PDE inhibitors in the newborns with MAS should be carefully monitored. PMID:24388890

Mokra, D; Tonhajzerova, I; Pistekova, H; Visnovcova, Z; Mokry, J; Drgova, A; Repcakova, M; Calkovska, A

2013-12-01

311

The Candida boidinii peroxisomal membrane protein Pmp30 has a role in peroxisomal proliferation and is functionally homologous to Pmp27 from Saccharomyces cerevisiae.  

PubMed Central

The mechanism of peroxisome proliferation is poorly understood. Candida boidinii is a methylotrophic yeast that undergoes rapid and massive peroxisome proliferation and serves as a good model system for this process. Pmp30A and Pmp30B (formerly designated Pmp31 and Pmp32, respectively) are two closely related proteins in a polyploid strain of this yeast that are strongly induced by diverse peroxisome proliferators such as methanol, oleate, and D-alanine. The function of these proteins is not understood. To study this issue, we used a recently described haploid strain (S2) of C. boidinii that can be manipulated genetically. We now report that strain S2 contains a single PMP30 gene very similar in sequence (greater than 93% identity at the DNA level) to PMP30A and PMP30B. When PMP30 was disrupted, cell growth on methanol was greatly inhibited, and cells grown in both methanol and oleate had fewer, larger, and more spherical peroxisomes than wild-type cells. A similar phenotype was recently described for Saccharomyces cerevisiae cultured on oleate in which PMP27, which encodes a protein of related sequence that is important for peroxisome proliferation, was disrupted. To determine whether Pmp27 is a functional homolog of Pmp30, gentle complementation was performed. PMP30A was expressed in the PMP27 disruptant of S. cerevisiae, and PMP27 was expressed in the PMP30 disruptant of C. boidinii S2. Complementation, in terms of both cell growth and organelle size, shape, and number, was successful in both directions, although reversion to a wild-type phenotype was only partial for the PMP30 disruptant. We conclude that these proteins are functional homologs and that both Pmp30 and Pmp27 have a direct role in proliferation and organelle size rather than a role in a specific peroxisomal metabolic pathway of substrate utilization. PMID:7592467

Sakai, Y; Marshall, P A; Saiganji, A; Takabe, K; Saiki, H; Kato, N; Goodman, J M

1995-01-01

312

CDK-4 inhibitor P276 sensitizes Pancreatic Cancer cells to Gemcitabine induced Apoptosis  

PubMed Central

Despite advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. It is a rapidly invasive, metastatic tumor that is resistant to standard therapies. The phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine (Gem) is the mainstay treatment for metastatic pancreatic cancer. P276 is a novel CDK inhibitor that induces G2/M arrest and inhibits tumor growth in vivo models. Here, we determined that P276 sensitizes pancreatic cancer cells to Gem induced apoptosis, a mechanism mediated through inhibition of Akt-mTOR signaling. In vitro, the combination of P276 and Gem resulted in a dose- and time-dependent inhibition of proliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induced apoptosis, as seen by activated caspase 3 and increased Bax/Bcl2 ratio. Gene profiling studies demonstrated that this combination downregulated Akt-mTOR signaling pathway, which was confirmed by western blot analyses. There was also a downregulation of vascular endothelial growth factor (VEGF) and interleukin-8 expression suggesting effects on angiogenesis pathway. In vivo, intraperitoneal administration of the P276-Gem combination significantly suppressed the growth of pancreatic cancer tumor xenografts. There was a reduction in CD31 positive blood vessels, and reduced VEGF expression, again suggesting an effect on angiogenesis. Taken together, these data suggest that P276-Gem combination is a novel potent therapeutic agent that can target the Akt-mTOR signaling pathway to inhibit both tumor growth and angiogenesis. PMID:22532602

Subramaniam, Dharmalingam; Periyasamy, Giridharan; Ponnurangam, Sivapriya; Chakrabarti, Debarshi; Sugumar, Aravind; Padigaru, Muralidhara; Weir, Scott J.; Balakrishnan, Arun; Sharma, Somesh; Anant, Shrikant

2012-01-01

313

HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses  

PubMed Central

The identification of recurrent somatic mutations in genes encoding epigenetic enzymes has provided a strong rationale for the development of compounds that target the epigenome for the treatment of cancer. This notion is supported by biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases to promoter regions through association with oncogenic fusion proteins such as PML-RAR? and AML1-ETO. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis; however, it remains unclear why tumor cells are more sensitive to HDACi-induced cell death than normal cells. Herein, we assessed the biological and molecular responses of isogenic normal and transformed cells to the FDA-approved HDACi vorinostat and romidepsin. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time-course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor-cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance, indicating that specific and selective engagement of the intrinsic apoptotic pathway underlies the tumor-cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and implicates specific molecules and pathways in the tumor-selective cytotoxic activity of these compounds. PMID:23449455

Bolden, J E; Shi, W; Jankowski, K; Kan, C-Y; Cluse, L; Martin, B P; MacKenzie, K L; Smyth, G K; Johnstone, R W

2013-01-01

314

Plasminogen Activator Inhibitor-1 Regulates LPS Induced Inflammation in Rat Macrophages through Autophagy Activation  

PubMed Central

Background. The mechanisms by which plasminogen activator inhibitor-1 (PAI-1) regulates inflammation, especially in acute respiratory distress syndrome (ARDS), are largely unknown. Objective. To assess the relationship between PAI-1 and autophagy in inflammatory reactions induced by LPS in rat NR8383 cells. Methods. ELISA was used to assess the amounts of TNF-?, IL-1?, and PAI-1 in cell culture supernatants; TLR4, MyD88, PAI-1, LC3, Beclin1, and mTOR protein and mRNA levels were determined by western blot and quantitative RT-PCR, respectively; western blot was used to determine NF-?B protein levels. To further evaluate the role of PAI-1, the PAI-1 gene was downregulated and overexpressed using the siRNA transfection technology and the pCDH-PAI-1, respectively. Finally, the GFP Positive Expression Rate Method was used to determine the rate of GFP-LC3 positive NR8383 cells. Results. In LPS-induced NR8383 cells, TNF-?, IL-1?, and PAI-1 expression levels increased remarkably. Upon PAI-1 knockdown, TNF-?, IL-1?, PAI-1, TLR4, MyD88, NF-?B, LC3, and Beclin1 levels were decreased, while mTOR increased. Conversely, overexpression of PAI-1 resulted in increased amounts of TNF-?, IL-1?, PAI-1, TLR4, MyD88, NF-?B, LC3, and Beclin1. However, no significant change was observed in mTOR expression. Conclusions. In NR8383 cells, PAI-1 contributes in the regulation of LPS-induced inflammation, likely by promoting autophagy. PMID:25133205

Wang, Zhong-Hui; Ren, Wei-Ying; Zhu, Lei; Hu, Li-Juan

2014-01-01

315

Peroxisome Proliferator-Activated Receptors (PPAR) and the Mitochondrial Aldehyde Dehydrogenase  

E-print Network

Peroxisome Proliferator-Activated Receptors (PPAR) and the Mitochondrial Aldehyde Dehydrogenase) and -5 (DR-5) element. Because DR-1 elements are preferred binding sites for peroxisome proliferator Receptor, Liver, Peroxisome Proliferator, Aldehyde Dehydrogenase. THE PEROXISOME proliferator

Omiecinski, Curtis

316

Plant autophagy is responsible for peroxisomal transition and plays an important role in the maintenance of peroxisomal quality.  

PubMed

In photosynthetic cells, a large amount of hydrogen peroxide is produced in peroxisomes through photorespiration, which is a metabolic pathway related to photosynthesis. Hydrogen peroxide, a reactive oxygen species, oxidizes peroxisomal proteins and membrane lipids, resulting in a decrease in peroxisomal quality. We demonstrate that the autophagic system is responsible for the elimination of oxidized peroxisomes in plant. We isolated Arabidopsis mutants that accumulated oxidized peroxisomes, which formed large aggregates. We revealed that these mutants were defective in autophagy-related (ATG) genes and that the aggregated peroxisomes were selectively targeted by the autophagic machinery. These findings suggest that autophagy plays an important role in the quality control of peroxisomes by the selective degradation of oxidized peroxisomes. In addition, the results suggest that autophagy is also responsible for the functional transition of glyoxysomes to leaf peroxisomes. PMID:24732712

Shibata, Michitaro; Oikawa, Kazusato; Yoshimoto, Kohki; Goto-Yamada, Shino; Mano, Shoji; Yamada, Kenji; Kondo, Maki; Hayashi, Makoto; Sakamoto, Wataru; Ohsumi, Yoshinori; Nishimura, Mikio

2014-05-01

317

HSP90 Inhibitors, Geldanamycin and Radicicol, Enhance Fisetin-Induced Cytotoxicity via Induction of Apoptosis in Human Colonic Cancer Cells.  

PubMed

We revealed the cytotoxic effect of the flavonoid, fisetin (FIS), on human COLO205 colon cancer cells in the presence and absence of the HSP90 inhibitors, geldanamycin (GA) and radicicol (RAD). Compared to FIS treatment alone of COLO205 cells, GA and RAD significantly enhanced FIS-induced cytotoxicity, increased expression of cleaved caspase-3 and the PAPR protein, and produced a greater density of DNA ladder formation. GA and RAD also reduced the MMPs with induction of caspase-9 protein cleavage in FIS-treated COLO205 cells. Increased caspase-3 and -9 activities were detected in COLO205 cells treated with FIS+GA or FIS+RAD, and the intensity of DNA ladder formation induced by FIS+GA was reduced by adding the caspase-3 inhibitor, DEVD-FMK. A decrease in Bcl-2 but not Bcl-XL or Bax protein by FIS+GA or FIS+RAD was identified in COLO205 cells by Western blotting. A reduction in p53 protein with increased ubiquitin-tagged proteins was observed in COLO205 cells treated with FIS+GA or FIS+RAD. Furthermore, GA and RAD reduced the stability of the p53 protein in COLO205 cells under FIS stimulation. The evidence supports HSP90 inhibitors possibly sensitizing human colon cancer cells to FIS-induced apoptosis, and treating colon cancer by combining HSP90 inhibitors with FIS deserves further in vivo study. PMID:23840275

Wu, Ming-Shun; Lien, Gi-Shih; Shen, Shing-Chuan; Yang, Liang-Yo; Chen, Yen-Chou

2013-01-01

318

Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886.  

PubMed

A series of potent and selective inhibitors of the inducible microsomal PGE2 synthase (mPGES-1) has been developed based on the indole FLAP inhibitor MK-886. Compounds 23 and 30 inhibit mPGES-1 with potencies in the low nanomolar range and with selectivities of at least 100-fold compared to their inhibition of mPGES-2, thromboxane synthase and binding affinity to FLAP. They also block the production of PGE2 in cell based assays but with a decreased potency and more limited selectivity compared to the enzyme assays. PMID:15953724

Riendeau, Denis; Aspiotis, Renee; Ethier, Diane; Gareau, Yves; Grimm, Erich L; Guay, Jocelyne; Guiral, Sébastien; Juteau, Hélène; Mancini, Joseph A; Méthot, Nathalie; Rubin, Joel; Friesen, Richard W

2005-07-15

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

2011-10-01

320

Reduced peroxisomal citrate synthase activity increases substrate availability for polyhydroxyalkanoate biosynthesis in plant peroxisomes.  

PubMed

Polyhydroxyalkanoates (PHAs) are bacterial carbon storage polymers used as renewable, biodegradable plastics. PHA production in plants may be a way to reduce industrial PHA production costs. We recently demonstrated a promising level of peroxisomal PHA production in the high biomass crop species sugarcane. However, further production strategies are needed to boost PHA accumulation closer to commercial targets. Through exogenous fatty acid feeding of Arabidopsis thaliana plants that contain peroxisome-targeted PhaA, PhaB and PhaC enzymes from Cupriavidus necator, we show here that the availability of substrates derived from the ?-oxidation cycle limits peroxisomal polyhydroxybutyrate (PHB) biosynthesis. Knockdown of peroxisomal citrate synthase activity using artificial microRNA increased PHB production levels approximately threefold. This work demonstrates that reduction of peroxisomal citrate synthase activity may be a valid metabolic engineering strategy for increasing PHA production in other plant species. PMID:24944109

Tilbrook, Kimberley; Poirier, Yves; Gebbie, Leigh; Schenk, Peer M; McQualter, Richard B; Brumbley, Stevens M

2014-10-01

321

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 PMID:540103

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

1979-01-01

322

Developmental Roles of D-bifunctional Protein-A Zebrafish Model of Peroxisome Dysfunction  

PubMed Central

The peroxisome is an intracellular organelle that responds dynamically to environmental changes. Various model organisms have been used to study the roles of peroxisomal proteins in maintaining cellular homeostasis. By taking advantage of the zebrafish model whose early stage of embryogenesis is dependent on yolk components, we examined the developmental roles of the D-bifunctional protein (Dbp), an essential enzyme in the peroxisomal ?-oxidation. The knockdown of dbp in zebrafish phenocopied clinical manifestations of its deficiency in human, including defective craniofacial morphogenesis, growth retardation, and abnormal neuronal development. Overexpression of murine Dbp rescued the morphological phenotypes induced by dbp knockdown, indicative of conserved roles of Dbp during zebrafish and mammalian development. Knockdown of dbp impaired normal development of blood, blood vessels, and most strikingly, endoderm-derived organs including the liver and pancreas - a phenotype not reported elsewhere in connection with peroxisome dysfunction. Taken together, our results demonstrate for the first time that zebrafish might be a useful model animal to study the role of peroxisomes during vertebrate development. PMID:24552713

Kim, Yong-Il; Bhandari, Sushil; Lee, Joon No; Yoo, Kyeong-Won; Kim, Se-Jin; Oh, Gi-Su; Kim, Hyung-Jin; Cho, Meyoung; Kwak, Jong-Young; So, Hong-Seob; Park, Raekil; Choe, Seong-Kyu

2014-01-01

323

The Hansenula polymorpha PER8 gene encodes a novel peroxisomal integral membrane protein involved in proliferation  

PubMed Central

We previously described the isolation of mutants of the methylotrophic yeast Hansenula polymorpha that are defective in peroxisome biogenesis. Here, we describe the characterization of one of these mutants, per8, and the cloning of the PER8 gene. In either methanol or methylamine medium, conditions that normally induce the organelles, per8 cells contain no peroxisome-like structures and peroxisomal enzymes are located in the cytosol. The sequence of PER8 predicts that its product (Per8p) is a novel polypeptide of 34 kD, and antibodies against Per8p recognize a protein of 31 kD. Analysis of the primary sequence of Per8p revealed a 39-amino-acid cysteine-rich segment with similarity to the C3HC4 family of zinc-finger motifs. Overexpression of PER8 results in a markedly enhanced increase in peroxisome numbers. We show that Per8p is an integral membrane protein of the peroxisome and that it is concentrated in the membranes of newly formed organelles. We propose that Per8p is a component of the molecular machinery that controls the proliferation of this organelle. PMID:7844145

1995-01-01

324

IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome  

E-print Network

to be determined. We show here that IL-4 inhibits receptor activator of NF- B ligand-induced osteoclast, this inhibitory effect can be mimicked by both natural as well as synthetic peroxisome proliferator- activated receptor 1 (PPAR 1) ligands and can be blocked by the irreversible PPAR antagonist GW 9662. These findings

Pike, J. Wesley

325

Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor ?  

Microsoft Academic Search

Peroxisome proliferator activated receptor (PPAR) ? is an orphan member of the nuclear hormone receptor superfamily and is expressed at high levels specifically in adipose tissue. Recent data suggest that this factor is a central regulator of adipocyte gene expression and differentiation. Fibroblastic cell lines that express PPAR? ectopically can be induced to differentiate into fat cells by a variety

Peter Tontonoz; Erding Hu; Bruce M Spiegelman

1995-01-01

326

IDENTIFICATION OF EARLY MOLECULAR EVENTS AFTER PEROXISOME PROLIFERATOR EXPOSURE IN THE RODENT LIVER  

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 a(PPARa). Development of PP induced hepatocarcinogenesis in mouse liver is known to be dependent on PPARa but do...

327

An Upstream Region of the Enoyl-Coenzyme A Hydratase\\/3-Hydroxyacyl-Coenzyme A Dehydrogenase Gene Directs Luciferase Expression in Liver in Response to Peroxisome Proliferators in Transgenic Mice  

Microsoft Academic Search

Peroxisomeproliferators,which are structurallydiversenonmutagenic agents, induce hepatocarcinogenesis in rats and mice. Exposure to these xenobiotics leads to a rapid and coordinated transcriptional activation of the genes for the peroxisomal fl-oxidation enzyme system pathway in the liver. We have previously identified a peroxisome proliferator-responsive element in the 5'-flanking region of the rat peroxisomal hydratase\\/dehy drogenase (PBE) gene, the second enzyme in the

Keith Alvares; Chungyang Fan; Soheil S. Dadras; Anjana V. Yeldandi; Richard A. Rachubinski; John P. Capone; M. Sambasiva Rao; Janardan K. Reddy

328

Sustained Low-Dose Treatment with the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells  

PubMed Central

Histone deacetylase inhibitors (HDACi) were identified nearly four decades ago based on their ability to induce cellular differentiation. However, the clinical development of these compounds as cancer therapies has focused on their capacity to induce apoptosis in hematologic and lymphoid malignancies, often in combination with conventional cytotoxic agents. In many cases, HDACi doses necessary to induce these effects result in significant toxicity. Since osteosarcoma cells express markers of terminal osteoblast differentiation in response to DNA methyltransferase inhibitors, we reasoned that the epigenetic reprogramming capacity of HDACi might be exploited for therapeutic benefit. Here, we show that continuous exposure of osteosarcoma cells to low concentrations of HDACi LBH589 (Panobinostat) over a three-week period induces terminal osteoblast differentiation and irreversible senescence without inducing cell death. Remarkably, transcriptional profiling revealed that HDACi therapy initiated gene signatures characteristic of chondrocyte and adipocyte lineages in addition to marked upregulation of mature osteoblast markers. In a mouse xenograft model, continuous low dose treatment with LBH589 induced a sustained cytostatic response accompanied by induction of mature osteoblast gene expression. These data suggest that the remarkable capacity of osteosarcoma cells to differentiate in response to HDACi therapy could be exploited for therapeutic benefit without inducing systemic toxicity. PMID:23533324

Cain, Jason E.; McCaw, Andrew; Jayasekara, W. Samantha N.; Rossello, Fernando J.; Marini, Kieren D.; Irving, Aaron T.; Kansara, Maya; Thomas, David M.; Ashley, David M.; Watkins, D. Neil

2013-01-01

329

A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response.  

PubMed

When a cell encounters external stressors, such as lack of nutrients, elevated temperatures, changes in pH or other stressful environments, a key set of evolutionarily conserved proteins, the heat shock proteins (hsps), become overexpressed. Hsps are classified into six major families with the hsp90 family being the best understood; an increase in cell stress leads to increased levels of hsp90, which leads to cellular protection. A hallmark of hsp90 inhibitors is that they induce a cell rescue mechanism, the heat shock response. We define the unique molecular profile of a compound (SM145) that regulates hormone receptor protein levels through hsp90 inhibition without inducing the heat shock response. Modulation of the binding event between heat shock protein 90 and the immunophilins/homologs using SM145, leads to a decrease in hormone receptor protein levels. Unlike N-terminal hsp90 inhibitors, this hsp90 inhibitor does not induce a heat shock response. This work is proof of principle that controlling hormone receptor expression can occur by inhibiting hsp90 without inducing pro-survival protein heat shock protein 70 (hsp70) or other proteins associated with the heat shock response. Innovatively, we show that blocking the heat shock response, in addition to hsp90, is key to regulating hsp90-associated pathways. PMID:24360559

McConnell, Jeanette R; Alexander, Leslie A; McAlpine, Shelli R

2014-01-15

330

Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects  

PubMed Central

Background: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. Methods: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. Results: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ?20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. Conclusion: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes. PMID:24084768

Henry, N L; Chan, H-P; Dantzer, J; Goswami, C P; Li, L; Skaar, T C; Rae, J M; Desta, Z; Khouri, N; Pinsky, R; Oesterreich, S; Zhou, C; Hadjiiski, L; Philips, S; Robarge, J; Nguyen, A T; Storniolo, A M; Flockhart, D A; Hayes, D F; Helvie, M A; Stearns, V

2013-01-01

331

Plasminogen Activator Inhibitor-1 Is Involved in Streptozotocin-Induced Bone Loss in Female Mice  

PubMed Central

In diabetic patients, the risk of fracture is high because of impaired bone formation. However, the details of the mechanisms in the development of diabetic osteoporosis remain unclear. In the current study, we investigated the role of plasminogen activator inhibitor (PAI)-1 in the pathogenesis of type 1 diabetic osteoporosis by using PAI-1–deficient mice. Quantitative computed tomography analysis showed that PAI-1 deficiency protected against streptozotocin-induced bone loss in female mice but not in male mice. PAI-1 deficiency blunted the changes in the levels of Runx2, osterix, and alkaline phosphatase in tibia as well as serum osteocalcin levels suppressed by the diabetic state in female mice only. Furthermore, the osteoclast levels in tibia, suppressed in diabetes, were also blunted by PAI-1 deficiency in female mice. Streptozotocin markedly elevated the levels of PAI-1 mRNA in liver in female mice only. In vitro study demonstrated that treatment with active PAI-1 suppressed the levels of osteogenic genes and mineralization in primary osteoblasts from female mouse calvaria. In conclusion, the current study indicates that PAI-1 is involved in the pathogenesis of type 1 diabetic osteoporosis in females. The expression of PAI-1 in the liver and the sensitivity of bone cells to PAI-1 may be an underlying mechanism. PMID:23715621

Tamura, Yukinori; Kawao, Naoyuki; Okada, Kiyotaka; Yano, Masato; Okumoto, Katsumi; Matsuo, Osamu; Kaji, Hiroshi

2013-01-01

332

Phosphodiesterase-3 inhibitor (cilostazol) attenuates oxidative stress-induced mitochondrial dysfunction in the heart  

PubMed Central

Background Cilostazol is a type 3 phosphodiesterase inhibitor which has been previously demonstrated to prevent the occurrence of tachyarrhythmia and improve defibrillation efficacy. However, the mechanism for this beneficial effect is still unclear. Since cardiac mitochondria have been shown to play a crucial role in fatal cardiac arrhythmias and that oxidative stress is one of the main contributors to arrhythmia generation, we tested the effects of cilostazol on cardiac mitochondria under severe oxidative stress. Methods Mitochondria were isolated from rat hearts and treated with H2O2 to induce oxidative stress. Cilostazol, at various concentrations, was used to study its protective effects. Pharmacological interventions, including a mitochondrial permeability transition pore (mPTP) blocker, cyclosporine A (CsA), and an inner membrane anion channel (IMAC) blocker, 4?-chlorodiazepam (CDP), were used to investigate the mechanistic role of cilostazol on cardiac mitochondria. Cardiac mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential change and mitochondrial swelling were determined as indicators of cardiac mitochondrial function. Results Cilostazol preserved cardiac mitochondrial function when exposed to oxidative stress by preventing mitochondrial depolarization, mitochondrial swelling, and decreasing ROS production. Conclusions Our findings suggest that cardioprotective effects of cilostazol reported previously could be due to its prevention of cardiac mitochondrial dysfunction caused by severe oxidative stress. PMID:25009566

Chattipakorn, Siriporn C.; Thummasorn, Savitree; Sanit, Jantira; Chattipakorn, Nipon

2014-01-01

333

Hsp90 chaperone inhibitor 17-AAG attenuates A?-induced synaptic toxicity and memory impairment.  

PubMed

The excessive accumulation of soluble amyloid peptides (A?) plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in synaptic dysfunction. The role of the two major chaperone proteins, Hsp70 and Hsp90, in clearing misfolded protein aggregates has been established. Despite their abundant presence in synapses, the role of these chaperones in synapses remains elusive. Here, we report that Hsp90 inhibition by 17-AAG elicited not only a heat shock-like response but also upregulated presynaptic and postsynaptic proteins, such as synapsin I, synaptophysin, and PSD95 in neurons. 17-AAG treatment enhanced high-frequency stimulation-evoked LTP and protected neurons from synaptic damage induced by soluble A?. In AD transgenic mice, the daily administration of 17-AAG over 7 d resulted in a marked increase in PSD95 expression in hippocampi. 17-AAG treatments in wild-type C57BL/6 mice challenged by soluble A? significantly improved contextual fear memory. Further, we demonstrate that 17-AAG activated synaptic protein expression via transcriptional mechanisms through the heat shock transcription factor HSF1. Together, our findings identify a novel function of Hsp90 inhibition in regulating synaptic plasticity, in addition to the known neuroprotective effects of the chaperones against A? and tau toxicity, thus further supporting the potential of Hsp90 inhibitors in treating neurodegenerative diseases. PMID:24523537

Chen, Yaomin; Wang, Bin; Liu, Dan; Li, Jing Jing; Xue, Yueqiang; Sakata, Kazuko; Zhu, Ling-qiang; Heldt, Scott A; Xu, Huaxi; Liao, Francesca-Fang

2014-02-12

334

Effects of EGFR Inhibitor on Helicobacter pylori Induced Gastric Epithelial Pathology in Vivo  

PubMed Central

Helicobacter pylori transactivates the Epidermal Growth Factor Receptor (EGFR) and predisposes to gastric cancer development in humans and animal models. To examine the importance of EGFR signalling to gastric pathology, this study investigated whether treatment of Mongolian gerbils with a selective EGFR tyrosine kinase inhibitor, EKB-569, altered gastric pathology in chronic H. pylori infection. Gerbils were infected with H. pylori and six weeks later received either EKB-569-supplemented, or control diet, for 32 weeks prior to sacrifice. EKB-569-treated H. pylori-infected gerbils had no difference in H. pylori colonisation or inflammation scores compared to infected animals on control diet, but showed significantly less corpus atrophy, mucous metaplasia and submucosal glandular herniations along with markedly reduced antral and corpus epithelial proliferation to apoptosis ratios. EKB-569-treated infected gerbils had significantly decreased abundance of Cox-2, Adam17 and Egfr gastric transcripts relative to infected animals on control diet. EGFR inhibition by EKB-569 therefore reduced the severity of pre-neoplastic gastric pathology in chronically H. pylori-infected gerbils. EKB-569 increased gastric epithelial apoptosis in H. pylori-infected gerbils which counteracted some of the consequences of increased gastric epithelial cell proliferation. Similar chemopreventative strategies may be useful in humans who are at high risk of developing H. pylori- induced gastric adenocarcinoma.

Crabtree, Jean E.; Jeremy, Anthony H.T.; Duval, Cedric; Dixon, Michael F.; Danjo, Kazuma; Carr, Ian M.; Pritchard, D. Mark; Robinson, Philip A.

2013-01-01

335

Hsp90 Chaperone Inhibitor 17-AAG Attenuates A?-Induced Synaptic Toxicity and Memory Impairment  

PubMed Central

The excessive accumulation of soluble amyloid peptides (A?) plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in synaptic dysfunction. The role of the two major chaperone proteins, Hsp70 and Hsp90, in clearing misfolded protein aggregates has been established. Despite their abundant presence in synapses, the role of these chaperones in synapses remains elusive. Here, we report that Hsp90 inhibition by 17-AAG elicited not only a heat shock-like response but also upregulated presynaptic and postsynaptic proteins, such as synapsin I, synaptophysin, and PSD95 in neurons. 17-AAG treatment enhanced high-frequency stimulation-evoked LTP and protected neurons from synaptic damage induced by soluble A?. In AD transgenic mice, the daily administration of 17-AAG over 7 d resulted in a marked increase in PSD95 expression in hippocampi. 17-AAG treatments in wild-type C57BL/6 mice challenged by soluble A? significantly improved contextual fear memory. Further, we demonstrate that 17-AAG activated synaptic protein expression via transcriptional mechanisms through the heat shock transcription factor HSF1. Together, our findings identify a novel function of Hsp90 inhibition in regulating synaptic plasticity, in addition to the known neuroprotective effects of the chaperones against A? and tau toxicity, thus further supporting the potential of Hsp90 inhibitors in treating neurodegenerative diseases. PMID:24523537

Chen, Yaomin; Wang, Bin; Liu, Dan; Li, Jing Jing; Xue, Yueqiang; Sakata, Kazuko; Zhu, Ling-qiang; Heldt, Scott A.; Xu, Huaxi

2014-01-01

336

Cystathionine-gamma-lyase inhibitor attenuates acute lung injury induced by acute pancreatitis in rats  

PubMed Central

Introduction Acute pancreatitis (AP) is known to induce injuries to extrapancreatic organs. Because respiratory dysfunction is the main cause of death in patients with severe AP, acute pancreatitis-associated lung injury (APALI) is a great challenge for clinicians. This study aimed to investigate the potential role of hydrogen sulfide (H2S) in the pathogenesis of APALI. Material and methods Fifty-four SD rats were randomly divided into three groups: the AP group of rats that received injection of sodium deoxycholate into the common bile duct, the control group that underwent a sham operation, and the treatment group made by intraperitoneal injection of propargylglycine (PAG), an inhibitor of cystathionine-?-lyase (CSE), into rats with AP. Histopathology of the lung was examined and the expression of CSE and TNF-? mRNA in lung tissue was detected by real-time polymerase chain reaction. The H2S level in the serum was detected spectrophotometrically. Results The serum concentration of H2S and CSE and TNF-? expression in the lung were increased in AP rats modeled after 3 h and 6 h than in control rats (p < 0.05). Intraperitoneal injection of PAG could reduce the serum concentration of H2S, reduce CSE and TNF-? expression, and alleviate the lung pathology (p < 0.05). Conclusions Taken together, our findings suggest that the H2S/CSE system is crucially involved in the pathological process of APALI and represents a novel target for the therapy of APALI.

Qu, Zhen; Wu, Bao-Qiang; Duan, Yun-Fei; Sun, Zhen-Di; Luo, Guang-Hua

2014-01-01

337

A possible antineoplastic potential of selective, irreversible proteasome inhibitor, carfilzomib on chemically induced hepatocarcinogenesis in rats.  

PubMed

The antineoplastic effect of carfilzomib (CFZ) against chemically induced hepatocarcinogenesis was studied. A total of 60 male Wistar albino rats were divided into six groups with 10 animals in each group. Rats in group 1 (control group) were given dimethylsulphoxide (DMSO) (0.4 mL/kg i.p) twice a week for 3 weeks from week 8 to week 10. Animals in groups 2 and 3 were given CFZ (2 and 4 mg/kg i.p) twice a week from week 8 to week 10, respectively. Rats in group 4 were given diethylnitrosamine (DENA) at a dose of 0.01% in drinking water for 10 weeks and received a DMSO (0.4 mL/kg i.p) twice a week from week 8 to week 10. Animals in groups 5 and 6 were given DENA at a dose of 0.01% in drinking water for 10 weeks and treated with CFZ (2 and 4 mg/kg i.p) twice a week from week 8 to week 10, respectively. CFZ succeeded in suppressing the elevated serum tumor marker ?-fetoprotein and carcinoembryonic antigen. The antineoplastic effect of CFZ was also accompanied by normalization of elevated hepatic tissue growth factors, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1, and augmentation of hepatic endostatin and metallothionein. A histopathological examination of liver samples treated with CFZ after DENA intoxication correlated with the biochemical observation. Treatment with CFZ confers an antineoplastic activity against chemically induced hepatocarcinogenesis. These findings suggest that CFZ plays a pivotal role in the treatment of hepatocarcinogenesis. PMID:24861196

Mansour, Mahmoud A; Aljoufi, Mohammed A; Al-Hosaini, Khaled; Al-Rikabi, Ammar C; Nagi, Mahmoud N

2014-09-01

338

Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.  

PubMed

Exogenous cannabinoids are structurally and pharmacologically diverse compounds that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compounds to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clinical care and drug interactions. In vitro data were identified that characterize cytochrome P-450 (CYP-450) enzymes as potential significant contributors to the primary metabolism of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metabolism of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metabolism. Clinical pharmacogenetic data further support CYP2C9 as a significant contributor to THC metabolism, and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis extract further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis extract with omeprazole suggests a less significant role of CYP2C19 in CBD metabolism. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metabolism, although the role of cannabinoids specifically in eliciting this effect is questionable. PMID:24160757

Stout, Stephen M; Cimino, Nina M

2014-02-01

339

Mechanisms of G1 cell cycle arrest and apoptosis in myeloma cells induced by hybrid-compound histone deacetylase inhibitor  

SciTech Connect

Highlights: •Novel histone deacetylase inhibitor Ky-2, remarkably inhibits myeloma cell growth. •Ky-2 demonstrates no cytotoxicity against normal lymphocytic cells. •Ky-2 induces cell cycle arrest through the cell cycle-associated proteins. •Ky-2 induces Bcl-2-inhibitable apoptosis through a caspase-dependent cascade. -- Abstract: Objectives: Histone deacetylase (HDAC) inhibitors are new therapeutic agents, used to treat various types of malignant cancers. In the present study, we investigated the effects of Ky-2, a hybrid-compound HDAC inhibitor, on the growth of mouse myeloma cells. Materials and methods: Myeloma cells, HS-72, P3U1, and mouse normal cells were used in this study. Effect of HDAC inhibitors on cell viability was determined by WST-assay and trypan blue assay. Cell cycle was analyzed using flow cytometer. The expression of cell cycle regulatory and the apoptosis associated proteins were examined by Western blot analysis. Hoechst’s staining was used to detect apoptotic cells. Results: Our findings showed that Ky-2 decreased the levels of HDACs, while it enhanced acetylation of histone H3. Myeloma cell proliferation was inhibited by Ky-2 treatment. Interestingly, Ky-2 had no cytotoxic effects on mouse normal cells. Ky-2 treatment induced G1-phase cell cycle arrest and accumulation of a sub-G1 phase population, while Western blotting analysis revealed that expressions of the cell cycle-associated proteins were up-regulated. Also, Ky-2 enhanced the cleavage of caspase-9 and -3 in myeloma cells, followed by DNA fragmentation. In addition, Ky-2 was not found to induce apoptosis in bcl-2 overexpressing myeloma cells. Conclusion: These findings suggest that Ky-2 induces apoptosis via a caspase-dependent cascade and Bcl-2-inhibitable mechanism in myeloma cells.

Fujii, Seiko [Division of Infections and Molecular Biology, Kyushu Dental University (Japan) [Division of Infections and Molecular Biology, Kyushu Dental University (Japan); Division of Maxillofacial Surgery, Kyushu Dental University (Japan); Okinaga, Toshinori; Ariyoshi, Wataru [Division of Infections and Molecular Biology, Kyushu Dental University (Japan) [Division of Infections and Molecular Biology, Kyushu Dental University (Japan); Oral Biology Research Center, Kyushu Dental University (Japan); Takahashi, Osamu; Iwanaga, Kenjiro [Division of Maxillofacial Surgery, Kyushu Dental University (Japan)] [Division of Maxillofacial Surgery, Kyushu Dental University (Japan); Nishino, Norikazu [Oral Biology Research Center, Kyushu Dental University (Japan)] [Oral Biology Research Center, Kyushu Dental University (Japan); Tominaga, Kazuhiro [Division of Maxillofacial Surgery, Kyushu Dental University (Japan)] [Division of Maxillofacial Surgery, Kyushu Dental University (Japan); Nishihara, Tatsuji, E-mail: tatsujin@kyu-dent.ac.jp [Division of Infections and Molecular Biology, Kyushu Dental University (Japan) [Division of Infections and Molecular Biology, Kyushu Dental University (Japan); Oral Biology Research Center, Kyushu Dental University (Japan)

2013-05-10

340

Peroxin Puzzles and Folded Freight: Peroxisomal Protein Import in Review  

NASA Astrophysics Data System (ADS)

Peroxisomes are organelles that perform a variety of functions, including the metabolism of hydrogen peroxide and the oxidation of fatty acids. Peroxisomes do not possess organellar DNA; all peroxisomal matrix proteins are posttranslationally translocated into the organelle. The mechanism of peroxisomal protein translocation has been the subject of vigorous research in the past decade. Many of the proteins (peroxins, abbreviated Pex) that play critical roles in peroxisome biogenesis have been identified through functional complementation of yeast strains and of Chinese hamster ovary cell lines that are defective in peroxisome biogenesis. Researchers are now turning towards biochemical and genetic analyses of these peroxins to define their roles in peroxisome biogenesis and to discover interacting protein partners. Evidence suggests that some of the interacting partners include molecular chaperones. Several current models for peroxisomal protein import are presented.

Crookes, Wendy J.; Olsen, Laura J.

341

Going against the flow: a case for peroxisomal protein export.  

PubMed

Peroxisomes play a crucial role in regulating cellular metabolism, providing compartments where metabolic pathways can be contained and controlled. Their importance is underlined by the developmental brain disorders caused by peroxisome malfunction, while disturbances in peroxisome function also contribute to ageing. As peroxisomes do not contain DNA, they rely on an active transport system to obtain the full quota of proteins required for function. Organelle protein transport however, is rarely a one-way process and exciting recent data have demonstrated that peroxisomes can selectively export membrane and matrix proteins to fulfil specific functions. This review will summarise the current knowledge on peroxisomal membrane and matrix protein export, discussing the mechanisms underlying export as well as the role of peroxisomal protein export in peroxisomal and cellular function. PMID:24742913

Williams, Chris

2014-07-01

342

A critical role of the C-terminal segment for allosteric inhibitor-induced aberrant multimerization of HIV-1 integrase.  

PubMed

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising class of antiretroviral agents for clinical development. Although ALLINIs promote aberrant IN multimerization and inhibit IN interaction with its cellular cofactor LEDGF/p75 with comparable potencies in vitro, their primary mechanism of action in infected cells is through inducing aberrant multimerization of IN. Crystal structures have shown that ALLINIs bind at the IN catalytic core domain dimer interface and bridge two interacting subunits. However, how these interactions promote higher-order protein multimerization is not clear. Here, we used mass spectrometry-based protein footprinting to monitor surface topology changes in full-length WT and the drug-resistant A128T mutant INs in the presence of ALLINI-2. These experiments have identified protein-protein interactions that extend beyond the direct inhibitor binding site and which lead to aberrant multimerization of WT but not A128T IN. Specifically, we demonstrate that C-terminal residues Lys-264 and Lys-266 play an important role in the inhibitor induced aberrant multimerization of the WT protein. Our findings provide structural clues for exploiting IN multimerization as a new, attractive therapeutic target and are expected to facilitate development of improved inhibitors. PMID:25118283

Shkriabai, Nikoloz; Dharmarajan, Venkatasubramanian; Slaughter, Alison; Kessl, Jacques J; Larue, Ross C; Feng, Lei; Fuchs, James R; Griffin, Patrick R; Kvaratskhelia, Mamuka

2014-09-19

343

Chitosans and pectic polysaccharides both induce the accumulation of the antifungal phytoalexin pisatin in pea pods and antinutrient proteinase inhibitors in tomato leaves.  

PubMed

The Proteinase Inhibitor Inducing Factor, PIIF, a pectic polysaccharide that induces synthesis and accumulation of proteinase inhibitor proteins in tomato and potato leaves, is an effective elicitor of the phytoalexin pisatin in pea pod tissues. The levels of pisatin induced by PIIF, and the time course of elicitation, are similar to those induced by chitosans, beta-1,4 glucosamine polymers, which are potent elicitors of pisatin in pea pods. Similarly, the chitosans, found in both insect and fungal cell walls, are the most potent inducers yet found of proteinase inhibitor accumulation in excised tomato cotyledons. The similarity in the induction of synthesis of proteinase inhibitors in tomato cotyledons and of pisatin in pea pods by pectic polysaccharides and chitosans suggests that the two polysaccharide types may be triggering a similar fundamental system present in pea and tomato plants that regulates the expression of genes for natural protection systems. PMID:6838509

Walker-Simmons, M; Hadwiger, L; Ryan, C A

1983-01-14

344

Chicago sky blue 6B, a vesicular glutamate transporters inhibitor, attenuates methamphetamine-induced hyperactivity and behavioral sensitization in mice.  

PubMed

Several lines of evidence demonstrate that glutamatergic system plays an important role in drug addiction. The present study was designed to investigate the effects of Chicago sky blue 6B (CSB6B), a vesicular glutamate transporters (VGLUTs) inhibitor, on methamphetamine (METH)-induced behaviors in mice. Mice were induced behavioral sensitization to METH by subcutaneous injection of 1mg/kg METH once daily for 7 days and then challenged with 1mg/kg METH in 14th day. Intracerebroventricular administration of CSB6B (7.5?g) 2.5h prior to METH was to observe its effects on METH -induced behavioral sensitization. Our results showed that the expressions of behavioral sensitization were significantly attenuated by intracerebroventricular administration of CSB6B 2.5h prior to METH either during the development period or before methamphetamine challenge in mice, while CSB6B itself had no effect on locomotor activity. Meanwhile, pretreatment of CSB6B also attenuated hyperactivity caused by a single injection of METH in mice. These results demonstrated that CSB6B, a VGLUTs inhibitor, attenuated acute METH-induced hyperactivity and chronic METH-induced behavioral sensitization, which indicated that VGLUTs were involved in the effect of chronic METH-induced behavioral sensitization and may be a new target against the addiction of METH. PMID:23159705

He, Zongsheng; Yan, Lingdi; Yong, Zheng; Dong, Zhaoqi; Dong, Huajin; Gong, Zehui

2013-02-15

345

Molecular characterization of a wound-inducible inhibitor I gene from potato and the processing of its mRNA and protein  

Microsoft Academic Search

Genomic blotting of restriction fragments of Russet Burbank DNA indicated that at least 6 copies of Inhibitor I are present in the tetraploid potato genome. A library of potato genes in bacteriophage ? was screened for the presence of Inhibitor I genes using a wound-inducible tomato Inhibitor I cDNA as a hybridization probe. One phage with an insert of 13.1

Thomas E. Cleveland; Robert W. Thornburg; Clarence A. Ryan

1987-01-01

346

Organic cadmium complexes as proteasome inhibitors and apoptosis inducers in human breast cancer cells  

PubMed Central

Although cadmium (Cd) is a widespread environmental contaminant and human carcinogen, our studies indicate an organic Cd complex to be a potent inhibitor of proteasomal chymotrypsin-like (CT-like) activity, further capable of inducing apoptosis in a cancer cell-specific manner. It has been reported that the ligands indole-3-butyric acid (L1) and indole-3-propionic acid (L2) have cancer-fighting effects when tested in a rat carcinoma model. In addition, 3, 5-diaminobenzoic acid o-vanillin Schiff bases (L3) have high antimicrobial activity and a large number of Schiff base complexes have been reported to have proteasome-inhibitory activity. We therefore hypothesized that synthetic forms of Cd in combination with L1, L2 and L3 may have proteasome-inhibitory and apoptosis-inducing activities, which would be cancer cell-specific. To test this hypothesis, we have synthesized three novel Cd-containing complexes: [Cd2(C12H12O2N)4(H2O)2]·2H2O (Cd1), [Cd2(C11H10O2N)4(H2O)2]·2H2O (Cd2) and [Cd(C7H4N2O2)(C8H6O2)2]·2H2O (Cd3), by using these three ligands. We sought out to characterize and assess the proteasome-inhibitory and anti-proliferative properties of these three Cd complexes in human breast cancer cells. Cd1, Cd2 and Cd3 were found to effectively inhibit the chymotrypsin-like activity of purified 20S proteasome with IC50 values of 2.6, 3.0 and 3.3 ?M, respectively. Moreover, inhibition of cancer cell proliferation also correlated with this effect. As a result of proteasomal shutdown, the accumulation of ubiquitinated proteins and the proteasome target I?B-? protein as well as induction of apoptosis were observed. To account for the cancer specificity of this effect, immortalized, non-tumorigenic breast MCF10A cells were used under the same experimental conditions. Our results indicate that MCF10A cells are much less sensitive to the Cd1, Cd2 and Cd3 complexes when compared to MDA MB 231 breast cancer cells. Therefore, our study suggests that these Cd organic complexes are capable of inhibiting tumor cellular proteasome activity and consequently induce cancer cell-specific apoptotic death. PMID:23499788

Zhang, Zhen; Bi, Caifeng; Buac, Daniela; Fan, Yuhua; Zhang, Xia; Zuo, Jian; Zhang, Pengfei; Zhang, Nan; Dong, Lili; Dou, Q. Ping

2013-01-01

347

Ubiquitin in the peroxisomal protein import pathway.  

PubMed

PEX5 is the shuttling receptor for newly synthesized peroxisomal matrix proteins. Alone, or with the help of an adaptor protein, this receptor binds peroxisomal matrix proteins in the cytosol and transports them to the peroxisomal membrane docking/translocation module (DTM). The interaction between cargo-loaded PEX5 and the DTM ultimately results in its insertion into the DTM with the concomitant translocation of the cargo protein across the organelle membrane. PEX5 is not consumed in this event; rather it is dislocated back into the cytosol so that it can promote additional rounds of protein transportation. Remarkably, the data collected in recent years indicate that dislocation is preceded by monoubiquitination of PEX5 at a conserved cysteine residue. This mandatory modification is not the only type of ubiquitination occurring at the DTM. Indeed, several findings suggest that defective receptors jamming the DTM are polyubiquitinated and targeted to the proteasome for degradation. PMID:23954799

Francisco, Tânia; Rodrigues, Tony A; Pinto, Manuel P; Carvalho, Andreia F; Azevedo, Jorge E; Grou, Cláudia P

2014-03-01

348

Enhanced susceptibility of cyclin kinase inhibitor p21 knockout mice to high fat diet induced atherosclerosis  

Microsoft Academic Search

Cyclin kinase inhibitor p21 is one of the most potent inhibitors of aortic smooth muscle cell proliferation, a key mediator of atherosclerosis. This study tests if p2l deficiency will result in severe atherosclerosis in a mouse model. p21-\\/- and strain matched wild type mice were fed with high fat diet for 21 weeks. Analysis for biochemical parameters (cholesterol, triglycerides) in

Ashwani K Khanna

2009-01-01

349

Secretory Leukocyte Protease Inhibitor: A Macrophage Product Induced by and Antagonistic to Bacterial Lipopolysaccharide  

Microsoft Academic Search

To explore regulation of potentially lethal responses to bacterial lipopolysaccharide (LPS), we used differential display under LPS-free conditions to compare macrophage cell lines from two strains of mice congenic for a locus affecting LPS sensitivity. LPS- hyporesponsive cells, primary macrophages, and polymorphonuclear leukocytes transcribed secretory leukocyte protease inhibitor (SLPI), a known epithelial cell-derived inhibitor of leukocyte serine proteases. Transfection of

Fen-yu Jin; Carl Nathan; Danuta Radzioch; Aihao Ding

1997-01-01

350

Long-term efficacy and safety of mycophenolate mofetil in liver transplant recipients with calcineurin inhibitor-induced renal dysfunction  

Microsoft Academic Search

Long-term survival after orthotopic liver transplantation (OLT) is mainly influenced by adverse events caused by immunosuppression. Several studies have shown the efficacy of mycophenolate mofetil (MMF) in improving calcineurin inhibitor (CI)-induced nephrotoxicity with concomitant reduction or withdrawal of CI. In this prospective study we assessed the long-term effect and safety of MMF. Thirty-two OLT recipients with significant renal impairment due

Robert O. Koch; Ivo W. Graziadei; Frank Schulz; Karin Nachbaur; Alfred Königsrainer; Raimund Margreiter; Wolfgang Vogel

2004-01-01

351

Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis.  

PubMed

Mammalian target of rapamycin (mTOR) inhibitors curtail cap-dependent translation. However, they can also induce post-translational modifications of proteins. We assessed both effects to understand the mechanism by which mTOR inhibitors like rapamycin sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Sensitization was achieved in multiple myeloma cells irrespective of their PTEN or p53 status, enhanced by activation of AKT, and associated with stimulation of both intrinsic and extrinsic pathways of apoptosis. The sensitizing effect was not due to post-translational modifications of the RAFTK kinase, Jun kinase, p38 mitogen-activated protein kinase, or BAD. Sensitization was also not associated with a rapamycin-mediated increase in glucocorticoid receptor reporter expression. However, when cap-dependent translation was prevented by transfection with a mutant 4E-BP1 construct, which is resistant to mTOR-induced phosphorylation, cells responded to dexamethasone with enhanced apoptosis, mirroring the effect of coexposure to rapamycin. Thus, sensitization is mediated by inhibition of cap-dependent translation. A high-throughput screening for translational efficiency identified several antiapoptotic proteins whose translation was inhibited by rapamycin. Immunoblot assay confirmed rapamycin-induced down-regulated expressions of XIAP, CIAP1, HSP-27, and BAG-3, which may play a role in the sensitization to apoptosis. Studies in a xenograft model showed synergistic in vivo antimyeloma effects when dexamethasone was combined with the mTOR inhibitor CCI-779. Synergistic effects were associated with an enhanced multiple myeloma cell apoptosis in vivo. This study supports the strategy of combining dexamethasone with mTOR inhibitors in multiple myeloma and identifies a mechanism by which the synergistic effect is achieved. PMID:16489035

Yan, Huajun; Frost, Patrick; Shi, Yijiang; Hoang, Bao; Sharma, Sanjai; Fisher, Myrna; Gera, Joseph; Lichtenstein, Alan

2006-02-15

352

Effects of the Oral, Direct Factor Xa Inhibitor Rivaroxaban on Platelet-Induced Thrombin Generation and Prothrombinase Activity  

Microsoft Academic Search

Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in advanced development. This study was undertaken to investigate its effects on thrombin generation. In this placebo-controlled, randomized, crossover study, 12 healthy subjects received rivaroxaban (single 5- or 30-mg dose) or placebo. Thrombin generation was investigated by measuring the endogenous thrombin potential and prothrombinase-induced clotting time. Maximal effect of rivaroxaban

Jochen Graff; Nils von Hentig; Frank Misselwitz; Dagmar Kubitza; Michael Becka; Hans-Klaus Breddin; Sebastian Harder

2007-01-01

353

Changes of endothelin in streptozotocin-induced diabetic rats: effects of an angiotensin converting enzyme inhibitor, enalapril maleate  

Microsoft Academic Search

Endothelin-1 (ET-1) concentrations are increased in patients with diabetes mellitus, particularly those with diabetic retinopathy, or essential hypertension. We hypothesized that ET-1 might participate in the develop- ment and progression of diabetic microangiopathy. In this study, the effects of the angiotensin converting enzyme (ACE) inhibitor, enalapril maleate, on diabetic angiopathy were examined in streptozotocin (STZ)-induced diabetic (STZ-DM) rats by monitoring

Y Itoh; S Imamura; K Yamamoto; Y Ono; M Nagata; T Kobayashi; T Kato; M Tomita; A Nakai; M Itoh; A Nagasaka

2002-01-01

354

Effects of serine protease inhibitors on accumulation of polymorphonuclear leukocytes in the lung induced by acute pancreatitis in rats  

Microsoft Academic Search

The administration of a high-dose of a serine protease inhibitor is recommended in patients complicated by multiple organ\\u000a failure (MOF), including adult respiratory distress syndrome (ARDS), induced by acute pancreatitis. The accumulation of polymorphonuclear\\u000a leukocytes (PMN) in affected organs is considered to be one of the causative factors of MOF. Adhesion to endothelial cells\\u000a (EC), via adhesion molecules, and the

Yoshiaki Okumura; Hisayuki Inoue; Yoshihide Fujiyama; Tadao Bamba

1995-01-01

355

Stationary spots and stationary arcs induced by advection in a one-activator, two-inhibitor reactive system.  

PubMed

This paper studies the spatiotemporal dynamics of a reaction-diffusion-advection system corresponding to an extension of the Oregonator model, which includes two inhibitors instead of one. We show that when the reaction-diffusion, two-dimensional problem displays stationary patterns the addition of a plug flow can induce the emergence of new types of stationary structures. These patterns take the form of spots or arcs, the size and the spacing of which can be controlled by the flow. PMID:25273209

Berenstein, Igal; Bullara, Domenico; De Decker, Yannick

2014-09-01

356

Deficiency in thrombin-activatable fibrinolysis inhibitor (TAFI) protected mice from ferric chloride-induced vena cava thrombosis  

Microsoft Academic Search

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma carboxypeptidase that renders a fibrin-containing thrombus\\u000a less sensitive to lysis. Since the role of TAFI in thrombus formation is still controversial in mice, our present study was\\u000a designed to evaluate mice deficient in TAFI (TAFI?\\/?) on FeCl3-induced vena cava and carotid artery thrombosis. Parallel studies were carried out in wild-type mice using a

Xinkang Wang; Patricia L. Smith; Mei-Yin Hsu; Joseph A. Tamasi; Eileen Bird; William A. Schumacher

2007-01-01

357

Isolation of hypoxia-inducible factor 1 (HIF-1) inhibitors from frankincense using a molecularly imprinted polymer  

Microsoft Academic Search

Summary  Hypoxia-Inducible Factor 1 (HIF-1), a transcriptional activator, is highly involved in the pathology of cancer. Inhibition\\u000a of HIF-1 retards tumor growth and enhances treatment efficiency when used in combination with chemo- or radiation therapy.\\u000a The recent validation of HIF-1 as an important drug target in cancer treatment has stimulated efforts to identify and isolate\\u000a natural or synthetic HIF-1 inhibitors. In

Achillia Lakka; Ilias Mylonis; Sophia Bonanou; George Simos; Andreas Tsakalof

358

Therapeutic and cost effectiveness of proton pump inhibitor regimens for idiopathic or drug-induced peptic ulcer complication  

Microsoft Academic Search

Peptic ulcer (PU) disease has a high rate of occurrence and recurrence in Korean and the selection of drug for treatment is\\u000a diverse. In this study, the therapeutical effectiveness of regimens including proton pump inhibitors (PPI) was compared with\\u000a the single PPI therapy. The clinical data were collected from 1,658 patients having idiopathic or drug-induced PU complication\\u000a from a Medical

Doo Hyun Nam; So Young Park; Jong Min Park; Sung Chull Kim

2011-01-01

359

Peroxisome proliferator-activated receptors for hypertension.  

PubMed

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes (?, ?, ?, and ?). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPAR? and PPAR? agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPAR? agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin II receptor blockers, should be studied. This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases. PMID:25228953

Usuda, Daisuke; Kanda, Tsugiyasu

2014-08-26

360

Peroxisome proliferator-activated receptors for hypertension  

PubMed Central

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes (?, ?, ?, and ?). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPAR? and PPAR? agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPAR? agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin II receptor blockers, should be studied. This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases.

Usuda, Daisuke; Kanda, Tsugiyasu

2014-01-01

361

INFLAMMATORY BOWEL DISEASE Peroxisome proliferator activated receptor c in  

E-print Network

INFLAMMATORY BOWEL DISEASE Peroxisome proliferator activated receptor c in colonic epithelial cells . . . . . . . . . . . . . . . . . . . . . . . Gut 2006;55:1104­1113. doi: 10.1136/gut.2005.081745 Introduction: Peroxisome proliferator activated and an aberrant immune response to enteric flora, leading to intestinal inflammation. The role of peroxisome

Omiecinski, Curtis

362

PEX5 and Ubiquitin Dynamics on Mammalian Peroxisome Membranes  

E-print Network

PEX5 and Ubiquitin Dynamics on Mammalian Peroxisome Membranes Aidan I. Brown1 , Peter K. Kim2 Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada Abstract Peroxisomes docking with the peroxisomal membrane, ubiquitination, and export back into the cytosol followed

Rutenberg, Andrew

363

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

E-print Network

Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system? Grant B. Mc Received 21 February 2003 Abstract One of the many functions of liver peroxisomes is the b-oxidation of long-chain fatty acids. It is essential for the continuation of peroxisomal b-oxidation that a redox

McClelland, Grant B.

364

Peroxisomal Membrane Ghosts in Zellweger Syndrome--Aberrant Organelle Assembly  

Microsoft Academic Search

Peroxisomes are apparently missing in Zellweger syndrome; nevertheless, some of the integral membrane proteins of the organelle are present. Their distribution was studied by immunofluorescence microscopy. In control fibroblasts, peroxisomes appeared as small dots. In Zellweger fibroblasts, the peroxisomal membrane proteins were located in unusual empty membrane structures of larger size. These results suggest that the primary defect in this

M. J. Santos; T. Imanaka; H. Shio; G. M. Small; P. B. Lazarow

1988-01-01

365

Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats  

PubMed Central

We have recently reported that the endogenous mGlu2/3 agonist N-acetylaspartylglutamate (NAAG) and the N-acetylated-?-linked-acidic dipepetidase (NAALADase, a NAAG degradation enzyme) inhibitor 2-PMPA significantly inhibit cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior by attenuating cocaine-enhanced extracellular dopamine and glutamate in the nucleus accumbens. However, the poor oral bioavailability of NAAG and 2-PMPA limits their practical use in humans. In the present study, we investigated the effects of the orally active NAALADase inhibitor GPI-5693 and its enantiomers on cocaine-taking and cocaine-seeking behaviors. We found that oral administration of GPI-5693 (15, 30, 60 mg/kg, p.o.) did not significantly alter intravenous cocaine self-administration under fixed-ratio (FR2) reinforcement, but significantly inhibited cocaine-induced reinstatement of the extinguished drug-seeking behavior. This inhibition was blocked by pretreatment with LY341495, a selective mGlu2/3 receptor antagonist. Pretreatment with the same doses (15, 30, 60 mg/kg, p.o.) of GPI-16476 or GPI-16477, two enantiomers of GPI-5693, also inhibited cocaine-induced reinstatement similar to GPI-5693. In contrast, GPI-5693 altered neither oral sucrose self-administration nor sucrose-triggered reinstatement of sucrose-seeking behavior. These data suggest that orally effective NAAG peptidase inhibitors deserve further study as potential agents for the treatment of cocaine addiction. PMID:19887067

Peng, Xiao-Qing; Li, Jie; Gardner, Eliot L.; Ashby, Charles R.; Xi, Zheng-Xiong

2010-01-01

366

Biological and chemical inhibitors of NF-kappaB sensitize SiHa cells to cisplatin-induced apoptosis.  

PubMed

Cisplatin, a chemotherapeutic agent, is known to induce apoptosis of cancer cells. We examined the role of NF-kappaB during cisplatin-induced apoptosis in two human cervical cancer cell lines, HeLa and SiHa, known to differ in their response to cisplatin treatment. We found that SiHa cells were relatively more resistant than HeLa cells to the cytotoxic effects induced by cisplatin as measured by MTT assays. HeLa cells were more sensitive to the apoptotic effects induced by cisplatin as shown by increases in annexin staining, DNA fragmentation, and loss of mitochondrial membrane potential. Similarly the activities of caspases 3, 8, and 9 and cleavage of PARP induced by cisplatin were more in HeLa than SiHa cells. Cisplatin induced NF-kappaB DNA binding activity in HeLa and SiHa cells but not in primary cervical cells and the active DNA binding complex in SiHa cells consists of p50 and RelA heterodimers. However, when NF-kappaB DNA binding activity was blocked by chemical (curcumin, PDTC, or salicylic acid) or biological inhibitors (NIK-KM or IKK-beta DN), the cell viability was less in SiHa cells with cisplatin treatment, but these effects were not observed in HeLa cells. Similarly upon treatment with cisplatin SiHa cells had more activation of caspases compared to that seen in HeLa cells under conditions of NF-kappaB inhibition by biological or chemical inhibitors. These results suggest that NF-kappaB may contribute to the resistance of human cervical cancer cells to cisplatin and highlight the potential use of combination therapy involving cisplatin and NF-kappaB inhibitors. PMID:16044419

Venkatraman, Manickam; Anto, Ruby John; Nair, Asha; Varghese, Merina; Karunagaran, Devarajan

2005-09-01

367

Very large peroxisomes in distinct peroxisomal disorders (rhizomelic chondrodysplasia punctata and acyl-CoA oxidase deficiency): novel data  

Microsoft Academic Search

Summary We report very large hepatic peroxisomes (d-circle >1 ?m) in a patient with rhizomelic chondrodysplasia punctata and a patient with acyl-CoA oxidase deficiency. The effects of peroxisomal enlargement on the enzymatic activity are discussed. As increase in peroxisomal size is also reported in at least 12 other patients with peroxisomal disorders, we propose, a relationship between the enlargement of

D. De Craemer; M. J. Zweens; S. Lyonnet; R. J. A. Wanders; B. T. Poll-The; R. B. H. Schutgens; J. J. J. Waelkens; J. M. Saudubray; F. Roels

1991-01-01

368

Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKC?-dependent downregulation of AKT and XIAP expressions  

Microsoft Academic Search

In this study we examined the effects of proteasome inhibitors on cell apoptosis in TRAIL-resistant glioma cells and glioma stem cells (GSCs). Treatment with proteasome inhibitors and TRAIL induced apoptosis in all the resistant glioma cells and GSCs, but not in astrocytes and neural progenitor cells. Since PKC? has been implicated in the resistance of glioma cells to TRAIL, we

Sarit Kahana; Susan Finniss; Simona Cazacu; Cunli Xiang; Hae-Kyung Lee; Shlomit Brodie; Ronald S. Goldstein; Vered Roitman; Shimon Slavin; Tom Mikkelsen; Chaya Brodie

2011-01-01

369

The ATRA-induced differentiation of medulloblastoma cells is enhanced with LOX/COX inhibitors: an analysis of gene expression  

PubMed Central

Background A detailed analysis of the expression of 440 cancer-related genes was performed after the combined treatment of medulloblastoma cells with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). The combinations of retinoids and celecoxib as a COX-2 inhibitor were reported to be effective in some regimens of metronomic therapy of relapsed solid tumors with poor prognosis. Our previous findings on neuroblastoma cells using expression profiling showed that LOX/COX inhibitors have the capability of enhancing the differentiating action of ATRA. Presented study focused on the continuation of our previous work to confirm the possibility of enhancing ATRA-induced cell differentiation in these cell lines via the application of LOX/COX inhibitors. This study provides more detailed information concerning the mechanisms of the enhancement of the ATRA-induced differentiation of medulloblastoma cells. Methods The Daoy and D283 Med medulloblastoma cell lines were chosen for this study. Caffeic acid (an inhibitor of 5-LOX) and celecoxib (an inhibitor on COX-2) were used in combined treatment with ATRA. The expression profiling was performed using Human Cancer Oligo GEArray membranes, and the most promising results were verified using RT-PCR. Results The expression profiling of the selected cancer-related genes clearly confirmed that the differentiating effects of ATRA should be enhanced via its combined administration with caffeic acid or celecoxib. This effect was detected in both cell lines. An increased expression of the genes that encoded the proteins participating in induced differentiation and cytoskeleton remodeling was detected in both cell lines in a concentration-dependent manner. This effect was also observed for the CDKN1A gene encoding the p21 protein, which is an important regulator of the cell cycle, and for the genes encoding proteins that are associated with proteasome activity. Furthermore, our results showed that D283 Med cells are significantly more sensitive to treatment with ATRA alone than Daoy cells. Conclusions The obtained results on medulloblastoma cell lines are in accordance with our previous findings on neuroblastoma cells and confirm our hypothesis concerning the common mechanism of the enhancement of ATRA-induced cell differentiation in various types of pediatric solid tumors. PMID:24959102

2014-01-01

370

Proton-pump inhibitor as palliative care for chemotherapy-induced gastroesophageal reflux disease in pancreatic cancer patients.  

PubMed

Relief of adverse events induced by chemotherapy is an important issue for patients, especially those with a poor prognosis, such as with pancreatic cancer. There are no reports of the relationship between gastroesophageal reflux disease (GERD) and chemotherapy, so we investigated the incidence of chemotherapy-induced GERD in patients undergoing treatment with gemcitabine or S-1 for pancreatic cancer and the effect of sodium rabeprazole (RPZ), a proton-pump inhibitor. GERD was diagnosed in 40% of the patients according to the Frequency Scale for Symptoms of GERD score, and RBZ therapy significantly improved their symptoms. PMID:20636150

Uwagawa, Tadashi; Misawa, Takeyuki; Iida, Tomonori; Sakamoto, Taro; Gocho, Takeshi; Wakiyama, Shigeki; Hirohara, Shoichi; Yanaga, Katsuhiko

2010-07-01

371

Poly(ADP-ribose) polymerase inhibitors counteract diabetes- and hypoxia-induced retinal vascular endothelial growth factor overexpression.  

PubMed

We hypothesize that poly(ADP-ribose) polymerase (PARP) activation is an important mechanism in the oxidative stress-related development of diabetic retinopathy. In the experiments reported here, we evaluated if: a) PARP activation is present in the retina in short-term diabetes; and b) PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, counteract diabetes- and hypoxia-induced retinal VEGF formation. In vivo studies were performed in control and streptozotocin-diabetic rats treated with/without 3-aminobenzamide or 1,5-isoquinolinediol (30 and 3 mg/kg per day, intraperitoneally, for 2 weeks after 2 weeks of diabetes). In vitro studies were performed in human retinal pigment epithelial cells exposed to normoxia or hypoxia with/without 3-aminobenzamide and 1,5-isoquinolinediol at 200 and 2 micro M. Retinal immunostaining for poly(ADP-ribose) was increased and NAD concentration reduced in diabetic rats, and both variables were corrected by PARP inhibitors. Retinal VEGF protein (ELISA, immunohistochemistry), but not mRNA (ribonuclease protection assay) abundance, was increased in diabetic rats, and this increase was corrected by both 3-aminobenzamide and 1,5-isoquinolinediol. PARP inhibitors did not affect retinal glucose, sorbitol pathway intermediates or lipid peroxidation in diabetic rats. Hypoxia caused a several-fold increase in both VEGF-mRNA and protein in retinal pigment epithelial cells. VEGF mRNA overexpression was only slighly blunted by PARP inhibitors whereas VEGF protein was corrected. In conclusion, PARP is involved in diabetes- and hypoxia-induced VEGF production at post-transcriptional level, downstream from the sorbitol pathway activation and oxidative stress. The results justify studies of PARP inhibitors in models of retinopathy of prematurity and diabetic retinopathy. PMID:15202016

Obrosova, Irina G; Minchenko, Alexander G; Frank, Robert N; Seigel, Gail M; Zsengeller, Zsuzsanna; Pacher, Pál; Stevens, Martin J; Szabó, Csaba

2004-07-01

372

Lapatinib-induced NF-kappaB activation sensitizes triple-negative breast cancer cells to proteasome inhibitors  

PubMed Central

Introduction Triple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. Methods Triple-negative breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the molecular mechanisms of action. Results Our data showed that nuclear factor (NF)-?B activation was elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive activation of NF-?B involved Src family kinase (SFK)-dependent p65 and I?B? phosphorylations, and rendered these cells more vulnerable to NF-?B inhibition by p65 small hairpin RNA. Lapatinib but not other EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-?B, and thus augment the anti-tumor activity of proteasome inhibitors. Conclusions These findings suggest that combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients. PMID:24216290

2013-01-01

373

The Proteome of Human Liver Peroxisomes: Identification of Five New Peroxisomal Constituents by a Label-Free Quantitative Proteomics Survey  

PubMed Central

The peroxisome is a key organelle of low abundance that fulfils various functions essential for human cell metabolism. Severe genetic diseases in humans are caused by defects in peroxisome biogenesis or deficiencies in the function of single peroxisomal proteins. To improve our knowledge of this important cellular structure, we studied for the first time human liver peroxisomes by quantitative proteomics. Peroxisomes were isolated by differential and Nycodenz density gradient centrifugation. A label-free quantitative study of 314 proteins across the density gradient was accomplished using high resolution mass spectrometry. By pairing statistical data evaluation, cDNA cloning and in vivo colocalization studies, we report the association of five new proteins with human liver peroxisomes. Among these, isochorismatase domain containing 1 protein points to the existence of a new metabolic pathway and hydroxysteroid dehydrogenase like 2 protein is likely involved in the transport or ?-oxidation of fatty acids in human peroxisomes. The detection of alcohol dehydrogenase 1A suggests the presence of an alternative alcohol-oxidizing system in hepatic peroxisomes. In addition, lactate dehydrogenase A and malate dehydrogenase 1 partially associate with human liver peroxisomes and enzyme activity profiles support the idea that NAD+ becomes regenerated during fatty acid ?-oxidation by alternative shuttling processes in human peroxisomes involving lactate dehydrogenase and/or malate dehydrogenase. Taken together, our data represent a valuable resource for future studies of peroxisome biochemistry that will advance research of human peroxisomes in health and disease. PMID:23460848

Ofman, Rob; Bunse, Christian; Pawlas, Magdalena; Hayen, Heiko; Eisenacher, Martin; Stephan, Christian; Meyer, Helmut E.; Waterham, Hans R.; Erdmann, Ralf; Wanders, Ronald J.; Warscheid, Bettina

2013-01-01

374

Prefoldin Plays a Role as a Clearance Factor in Preventing Proteasome Inhibitor-induced Protein Aggregation*  

PubMed Central

Prefoldin is a molecular chaperone composed of six subunits, PFD1–6, and prevents misfolding of newly synthesized nascent polypeptides. Although it is predicted that prefoldin, like other chaperones, modulates protein aggregation, the precise function of prefoldin against protein aggregation under physiological conditions has never been elucidated. In this study, we first established an anti-prefoldin monoclonal antibody that recognizes the prefoldin complex but not its subunits. Using this antibody, it was found that prefoldin was localized in the cytoplasm with dots in co-localization with polyubiquitinated proteins and that the number and strength of dots were increased in cells that had been treated with lactacystin, a proteasome inhibitor, and thapsigargin, an inducer of endoplasmic reticulum stress. Knockdown of prefoldin increased the level of SDS-insoluble ubiquitinated protein and reduced cell viability in lactacystin and thapsigargin-treated cells. Opposite results were obtained in prefoldin-overexpressed cells. It has been reported that mice harboring a missense mutation L110R of MM-1?/PFD5 exhibit neurodegeneration in the cerebellum. Although the prefoldin complex containing L110R MM-1? was properly formed in vitro and in cells derived from L110R MM-1? mice, the levels of ubiquitinated proteins and cytotoxicity were higher in L110R MM-1? cells than in wild-type cells under normal conditions and were increased by lactacystin and thapsigargin treatment, and growth of L110R MM-1? cells was attenuated. Furthermore, the polyubiquitinated protein aggregation level was increased in the brains of L110R MM-1? mice. These results suggest that prefoldin plays a role in quality control against protein aggregation and that dysfunction of prefoldin is one of the causes of neurodegenerative diseases. PMID:23946485

Abe, Akira; Takahashi-Niki, Kazuko; Takekoshi, Yuka; Shimizu, Takashi; Kitaura, Hirotake; Maita, Hiroshi; Iguchi-Ariga, Sanae M. M.; Ariga, Hiroyoshi

2013-01-01

375

Identification of novel plant peroxisomal targeting signals by a combination of machine learning methods and in vivo subcellular targeting analyses.  

PubMed

In the postgenomic era, accurate prediction tools are essential for identification of the proteomes of cell organelles. Prediction methods have been developed for peroxisome-targeted proteins in animals and fungi but are missing specifically for plants. For development of a predictor for plant proteins carrying peroxisome targeting signals type 1 (PTS1), we assembled more than 2500 homologous plant sequences, mainly from EST databases. We applied a discriminative machine learning approach to derive two different prediction methods, both of which showed high prediction accuracy and recognized specific targeting-enhancing patterns in the regions upstream of the PTS1 tripeptides. Upon application of these methods to the Arabidopsis thaliana genome, 392 gene models were predicted to be peroxisome targeted. These predictions were extensively tested in vivo, resulting in a high experimental verification rate of Arabidopsis proteins previously not known to be peroxisomal. The prediction methods were able to correctly infer novel PTS1 tripeptides, which even included novel residues. Twenty-three newly predicted PTS1 tripeptides were experimentally confirmed, and a high variability of the plant PTS1 motif was discovered. These prediction methods 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. PMID:21487095

Lingner, Thomas; Kataya, Amr R; Antonicelli, Gerardo E; Benichou, Aline; Nilssen, Kjersti; Chen, Xiong-Yan; Siemsen, Tanja; Morgenstern, Burkhard; Meinicke, Peter; Reumann, Sigrun

2011-04-01

376

Vitamin D attenuates nucleoside reverse transcriptase inhibitor induced human skeletal muscle mitochondria DNA depletion  

PubMed Central

Objective To evaluate the impact of the active metabolite of vitamin D, 1?,25-dihydroxycholecalciferol (1,25D3), on nucleoside reverse transcriptase inhibitor (NRTI) induced mitochondrial DNA (mtDNA) depletion in human skeletal muscle myoblasts and myotubes. Design mtDNA was quantified in human skeletal muscle myoblasts and myotubes following 1,25D3 and NRTI treatment using real-time PCR. Methods Human skeletal muscle myoblasts and myotubes were treated with didanosine (ddI), stavudine (d4T), zidovudine (ZDV), lamivudine (3TC) and abacavir (ABC) alone or in combination either in the presence or absence of 1,25D3 for 5 days. Cells were harvested, DNA extracted and mtDNA quantified. Results ddI and ddI-d4T significantly decreased both myoblast and myotube mtDNA in the absence of 1,25D3 compared with untreated controls (P ? 0.029). In addition, the ZDV-3TC combination resulted in a 47% decrease in myotube mtDNA (P = 0.005). 1,25D3 increased myotube mtDNA levels in ddI, ZDV, 3TC, ABC, ddI-d4T, d4T-3TC, ZDV-3TC, ZDV-ABC and ZDV-3TC-ABC-containing regimens and myoblast mtDNA levels in ddI, d4T, ZDV, 3TC, ddI-d4T, ZDV-3TC and ZDV-ABC-containing regimens. Of note, 1,25D3 protected against myotube mtDNA depletion following ZDV-3TC treatment, rendering them similar to 1,25D3 untreated controls (P = 0.62), and increased both myotube and myoblast mtDNA two to three-fold in ddI-containing regimens (P < 0.05). Conclusion 1,25D3 confers a protective effect against NRTI-induced