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1

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

SciTech Connect

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

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

2005-03-10

2

Peroxisome proliferator-activated receptor ? agonist efatutazone impairs transforming growth factor ?2-induced motility of epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer cells.  

PubMed

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are effective for non-small cell lung cancers (NSCLC) with EGFR-activating mutations. However, most responders develop resistance. Efatutazone, a novel peroxisome proliferator-activated receptor gamma (PPAR?) agonist, is currently under clinical evaluation; it has antiproliferative effects and induces cellular morphological changes and differentiation. The present study investigated the effects of efatutazone in EGFR-TKI-resistant NSCLC cells, while focusing on cell motility. The PC-9-derived NSCLC cell lines PC-9ER and PC-9ZD, resistant to EGFR-TKI due to v-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) amplification-induced phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT) activation and an EGFR T790M mutation, respectively, were used. These cells exhibit enhanced cell motility due to transforming growth factor ? (TGF-?)/Smad2 family member 2 (Smad2) pathway activation. Efatutazone had no growth-inhibitory effect on the tested cells but inhibited the motility of EGFR-TKI-resistant cells in wound closure and transwell assays. Efatutazone plus erlotinib treatment provided greater inhibition of PC-9ER cell migration than efatutazone or erlotinib alone. Efatutazone suppressed increased TGF-?2 secretion from both cell lines (shown by ELISA) and downregulation of TGF-?2 transcription (observed by quantitative RT-PCR). Immunoblot analysis and luciferase assays revealed that efatutazone suppressed Smad2 phosphorylation and its transcriptional activity. These results suggest that efatutazone inhibits cell motility by antagonizing the TGF-?/Smad2 pathway and effectively prevents metastasis in NSCLC patients with acquired resistance to EGFR-TKI regardless of the resistance mechanism. PMID:24698130

Serizawa, Masakuni; Murakami, Haruyasu; Watanabe, Masaru; Takahashi, Toshiaki; Yamamoto, Nobuyuki; Koh, Yasuhiro

2014-06-01

3

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

4

An overview of peroxisome proliferator-induced hepatocarcinogenesis.  

PubMed Central

Peroxisome proliferators are hepatocarcinogens in rats and mice. Chronic administration of these compounds results in the development of altered areas and neoplastic nodules followed by hepatocellular carcinomas. All three types of hepatic lesions do not express gamma-glutamyltranspeptidase, glutathione 8-transferase-P, and alpha-fetoprotein and are resistant to iron accumulation after overload. The mechanism by which nongenotoxic peroxisome proliferators induce hepatic tumors is not well understood. It has been proposed that with continuous administration of peroxisome proliferators, liver cells are subjected to persistent oxidative stress resulting from marked proliferation of peroxisomes and a differential increase in the levels of H2O2 producing (20- to 30-fold) and degrading (2-fold) enzymes. Free oxygen radicals lead to DNA damage (both directly and through lipid peroxidation) and thus may cause initiation and promotion of the carcinogenic process.

Rao, M S; Reddy, J K

1991-01-01

5

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

6

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.

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

7

Peroxisome proliferator-activated receptor ?1 (PPAR-?1) as a major PPAR in a tissue in which estrogen induces peroxisome proliferation  

Microsoft Academic Search

Estradiol administration induces peroxisome proliferation and the production of 3-hydroxy fatty acid pheromones in the uropygial glands of the duck, but not in the goose gland, which does not produce such pheromones. We isolated a peroxisome proliferator-activated receptor (PPAR)?1 cDNA from a duck uropygial gland cDNA library. Northern blots revealed two transcripts, PPAR?1 and ?2, and showed that PPAR? was

Hongwen Ma; Quach Thanh Tam; Pappachan E. Kolattukudy

1998-01-01

8

Peroxisome proliferator-activated receptor? agonists differentially regulate inhibitor of DNA binding expression in rodents and human cells.  

PubMed

Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPAR? activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPAR?. In order to determine whether the fibrate effects were mediated by PPAR?, wild-type mice and PPAR?-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPAR?-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPAR? antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPAR?-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPAR? agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPAR? agonists have different effects in rodents and humans. PMID:22701468

González, María Del Carmen; Corton, J Christopher; Acero, Nuria; Muñoz-Mingarro, Dolores; Quirós, Yolanda; Alvarez-Millán, Juan José; Herrera, Emilio; Bocos, Carlos

2012-01-01

9

Theophylline and Dexamethasone Induce Peroxisome Proliferator-Activated Receptor-? Expression in Human Eosinophils  

Microsoft Academic Search

Eosinophils are major effector cells in allergic diseases including asthma. Peroxisome proliferator-activated receptor-? (PPAR?) is a nuclear receptor that regulates immune reaction. We have previously demonstrated that human eosinophils express PPAR? and that stimulation with a synthetic agonist for PPAR? attenuated the factor-induced eosinophil survival and chemotaxis. However, the modulator of the eosinophil PPAR? expression has not yet been studied.

Atsuko Usami; Shigeharu Ueki; Wataru Ito; Yoshiki Kobayashi; Takahito Chiba; Gulixian Mahemuti; Hajime Oyamada; Yumiko Kamada; Miyoshi Fujita; Hikari Kato; Norihiro Saito; Hiroyuki Kayaba; Junichi Chihara

2006-01-01

10

Peroxisome proliferator-activated receptor gamma1 (PPAR-gamma1) as a major PPAR in a tissue in which estrogen induces peroxisome proliferation.  

PubMed

Estradiol administration induces peroxisome proliferation and the production of 3-hydroxy fatty acid pheromones in the uropygial glands of the duck, but not in the goose gland, which does not produce such pheromones. We isolated a peroxisome proliferator-activated receptor (PPAR)gamma1 cDNA from a duck uropygial gland cDNA library. Northern blots revealed two transcripts, PPAR gamma1 and gamma2, and showed that PPAR gamma was expressed at higher levels than PPAR alpha in the uropygial gland of the duck. Although PPAR gamma2 was expressed in both duck and goose uropygial gland, PPAR gamma1 was expressed only in the duck gland, which responds to estrogen by peroxisome proliferation. In NIH 3T3 transfected cells, PPAR gamma1 was activated by peroxisome proliferators such as Wy-14643, clofibric acid and Ly-171883 causing induction of the target marker gene. By cotransfection with a plasmid containing alpha-cis-retinoic acid receptor RXR alpha, the induction increased up to 9-fold. These results suggest that PPAR gamma1 may be involved in peroxisome proliferation while PPAR gamma2 may be involved in lipid metabolism. PMID:9742961

Ma, H; Tam, Q T; Kolattukudy, P E

1998-09-01

11

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

12

Octreotide inhibits the enterochromaffin-like cell but not peroxisome proliferator-induced hypergastrinemia  

Microsoft Academic Search

The peroxisome proliferator ciprofibrate induces hypergastrinemia and as a consequence, enterochromaffin-like (ECL) cell hyperplasia. The mechanism for the gastrin cell stimulation is unknown. The somatostatin analog octreotide LAR (long-acting release) was used to see if the stimulating effects of ciprofibrate could be attenu- ated. Female Fischer rats were dosed with cipro- fibrate (50 mg\\/kg body weight per day) alone or

I Bakke; A K Sandvik; H L Waldum

2000-01-01

13

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

Microsoft Academic Search

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

Marten Veenhuis; Anneke Douma; Wim Harder; Masako Osumi

1983-01-01

14

Hepatomegaly is an early biomarker for hepatocarcinogenesis induced by peroxisome proliferators.  

PubMed

The relationship between hepatomegaly and the hepatocarcinogenesis associated with by peroxisome proliferators was examined. (1) Male F-344 rats were maintained on diets containing clofibrate, ciprofibrate, nafenopin, gemfibrozil, Wy-14, 643, di(2-ethylhexyl)phthalate (DEHP), or di(2-ethylhexyl)adipate (DEHA) at carcinogenic doses for 1 week. A close correlation between relative liver weights and hepatocarcinogenicity was observed (r = 0.910). (2) Administration of perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), simfibrate, or DL-040, for which hepatocarcinogenicity is not known, resulted in hepatomegaly in all treated groups, this being especially marked in the PFOA case. Therefore, PFOA may have strong hepatocarcinogenic potential. (3) Administration of the antioxidants butylated hydroxyanisole (BHA) or vitamin E (VE) did not affect the hepatomegaly induced by DEHP. These results suggest that the hepatomegaly may be an early biomarker for prediction of the potential hepatocarcinogenicity of peroxisome proliferators. However, this requires further clarification in terms of its relation to the oxidative stress thought to be involved in peroxisome proliferator-induced hepatocarcinogenesis. PMID:1625184

Takagi, A; Sai, K; Umemura, T; Hasegawa, R; Kurokawa, Y

1992-01-01

15

Activation of Peroxisome Proliferator-Activated Receptor   by Substituted Urea-Derived Soluble Epoxide Hydrolase Inhibitors  

Microsoft Academic Search

Soluble epoxide hydrolase (sEH) plays a major role in regulating vascular epoxyeicosatrienoic acid metabolism and function, and substituted urea derivatives that inhibit sEH activity reduce blood pressure in hypertensive rats. We found that substituted urea derivatives containing a dodecanoic acid group, besides effectively inhibiting sEH, increased peroxisome proliferator- activated receptor (PPAR) activity. In PPAR transfected COS-7 cells, treatment with 10

Xiang Fang; Shanming Hu; Takaho Watanabe; Neal L. Weintraub; Gary D. Snyder; Jianrong Yao; Yi Liu; John Y.-J. Shyy; Bruce D. Hammock; Arthur A. Spector

2005-01-01

16

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

17

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

Microsoft Academic Search

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

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

2005-01-01

18

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

19

Oleuropein as an inhibitor of peroxisome proliferator-activated receptor gamma.  

PubMed

Oleuropein, the major phenolic compound found in olive leaves and oil, exerts antioxidant, anti-inflammatory and anti-atherogenic effects and suppresses the adipocyte differentiation in vitro. Herein, we characterized molecular mechanisms underlying the anti-adipogenic effects of oleuropein on 3T3-L1 cells and adipocytes derived from stromal-vascular fraction of dorsolumbar and gonadal fat dissected from mice. We found that oleuropein (>100 ?M) decreased viability of preadipocytes proliferating in vitro and did not exerted any cytotoxic effects in post-confluent cells after induction of differentiation. Oleuropein (>100 ?M) inhibited adipocyte differentiation, suppressed gene expression of peroxisome proliferator-activated receptor ? (PPAR?), CCAAT-/enhancer-binding protein ?, sterol regulatory element-binding transcription factor 1c and fatty acid synthase. Furthermore, we tested ability of oleuropein to regulate of PPAR?-, PPAR?- or PPAR?-/PPAR?-mediated ?-lactamase expression in appropriate reporter gene assays. Oleuropein between 10 and 400 ?M concentrations did not affect activity of PPAR? or PPAR?/?. Contrary, PPAR? activity, either basal or rosiglitazone activated, was inhibited by oleuropein. Our data suggest that oleuropein exerts anti-adipogenic effect through direct inhibition of PPAR? transcriptional activity. PMID:24323842

Svobodova, Michaela; Andreadou, Ioanna; Skaltsounis, Alexios-Leandros; Kopecky, Jan; Flachs, Pavel

2014-01-01

20

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

Microsoft Academic Search

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

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

2006-01-01

21

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.

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

2008-01-01

22

Clofibrate treatment in pigs: Effects on parameters critical with respect to peroxisome proliferator-induced hepatocarcinogenesis in rodents  

PubMed Central

Background In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whether fibrates could also induce liver cancer in species not responsive to peroxisome proliferation. In this study the effect of clofibrate treatment on peroxisome proliferation, production of oxidative stress, gene expression of pro- and anti-apoptotic genes and proto-oncogenes was investigated in the liver of pigs, a non-proliferating species. Results Pigs treated with clofibrate had heavier livers (+16%), higher peroxisome counts (+61%), higher mRNA concentration of acyl-CoA oxidase (+66%), a higher activity of catalase (+41%) but lower concentrations of hydrogen peroxide (-32%) in the liver than control pigs (P < 0.05); concentrations of lipid peroxidation products (thiobarbituric acid-reactive substances, conjugated dienes) and total and reduced glutathione in the liver did not differ between both groups. Clofibrate treated pigs also had higher hepatic mRNA concentrations of bax and the proto-oncogenes c-myc and c-jun and a lower mRNA concentration of bcl-XL than control pigs (P < 0.05). Conclusion The data of this study show that clofibrate treatment induces moderate peroxisome proliferation but does not cause oxidative stress in the liver of pigs. Gene expression analysis indicates that clofibrate treatment did not inhibit but rather stimulated apoptosis in the liver of these animals. It is also shown that clofibrate increases the expression of the proto-oncogenes c-myc and c-jun in the liver, an event which could be critical with respect to carcinogenesis. As the extent of peroxisome proliferation by clofibrate was similar to that observed in humans, the pig can be regarded as a useful model for investigating the effects of peroxisome proliferators on liver function and hepatocarcinogenesis.

Luci, Sebastian; Giemsa, Beatrice; Hause, Gerd; Kluge, Holger; Eder, Klaus

2007-01-01

23

The role of NF-?B in SAA-induced peroxisome proliferator-activated receptor ? activation.  

PubMed

Serum amyloid A (SAA) is an acute phase protein whose expression increases markedly during bacterial infection, tissue damage, and inflammation. The potential beneficial roles of SAA include its involvement in the reverse cholesterol transport and possibly extracellular lipid deposition at sites of inflammation and tissue repair. It is an attractive therapeutic target for the treatment of atherosclerosis. Peroxisome proliferator-activated receptor ? (PPAR?) plays a major regulatory role in adipogenesis, and the expression of genes involved in lipid metabolism. Activation of PPAR? leads to multiple changes in gene expression, some of which are believed to be atherogenic while others are antiatherogenic. In this study, we demonstrated that SAA upregulated COX-2 expression and induced PPAR? activity through NF-?B pathway. The effect of SAA on NF-?B activity is mediated by FPRL-1 and TLR4. PMID:23340376

Li, Hongzhe; Ooi, Shu Qin; Heng, Chew-Kiat

2013-03-01

24

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

PubMed Central

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

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

2013-01-01

25

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

PubMed

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

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

2013-01-01

26

Training-induced mitochondrial adaptation: role of peroxisome proliferator-activated receptor ? coactivator-1?, nuclear factor-?B and ?-blockade.  

PubMed

Interaction of peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) with other cellular signalling pathways plays an important role in training-induced mitochondrial adaptations. The purpose of this study was to examine whether pyrolidine dithiocarbamate (PDTC), a nuclear factor-?B inhibitor and antioxidant, and the ?-adrenergic blocker propranolol would affect the PGC-1?-induced mitochondrial transcription factors, enzymes and proteins involved in energy metabolism and antioxidant defense in response to endurance training. Female Sprague-Dawley rats (aged 8 weeks) were randomly divided into two groups (n = 24), one subjected to 8 weeks of treadmill training and one remaining sedentary. Each group of rats was subdivided in to three groups that were injected (i.p.) daily with PDTC (50 mg (kg body weight)(-1)), propranolol (30 mg kg(-1)) or saline as a control 1 h before the daily exercise session. Sedentary PDTC-treated rats showed 75% higher PGC-1? content (P < 0.01) but lower mitochondrial transcription factor A and phosphorylated cAMP-responsive element binding protein (p-CREB) than control rats. Training increased PGC-1? by 57% (P < 0.01), cytochrome c oxidase 4 by 30% (P < 0.05) and p-CREB by 13% (P < 0.05), whereas the mitochondrial mitofusin-2 level was decreased by 24% (P < 0.01). Treatment with PDTC decreased PGC-1? and p-CREB content by 34 and 53% (P < 0.05), respectively, in trained rats and abolished training effects on cytochrome c oxidase 4 and mitochondrial mitofusin-2. None of the training effects was abolished by propranolol treatment. Mitochondrial superoxide dismutase activity was decreased with PDTC, whereas training-induced glutathione peroxidase activity was unaltered by either drug. The data indicates that nuclear factor-?B-inhibitory and antioxidant properties of PDTC can attenuate PGC-1?-mediated mitochondrial adaptation to endurance training, whereas the ?-adrenergic pathway has little adverse effect. PMID:23104933

Feng, Hong; Kang, Chounghun; Dickman, Jonathan R; Koenig, Ryan; Awoyinka, Iwalola; Zhang, Yong; Ji, Li Li

2013-03-01

27

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

Microsoft Academic Search

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

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

1999-01-01

28

Estrogen-induced production of a peroxisome proliferator-activated receptor (PPAR) ligand in a PPARgamma-expressing tissue.  

PubMed

Peroxisome proliferation has been associated with carcinogenesis in the liver, and estrogen intake has been associated with increased risk of cancer in the hormone target tissues. Estrogen-induced peroxisome proliferation has been observed in an estrogen target tissue, the uropygial gland in the duck. To elucidate the molecular mechanism of this process, we previously isolated the cDNA of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) from the duck uropygial gland and found that its expression was high exclusively in this tissue of duck. However, the nature of the ligand for PPARgamma1 and how estrogen might enhance PPARgamma1-regulated gene expression were not known. Here we demonstrate that estrogen treatment of animals enhanced the metabolism of arachidonic acid in the uropygial gland. Conversion of prostaglandin D2 to a metabolite was induced by estradiol treatment preceding peroxisome proliferation. High performance liquid chromatography and TLC analyses showed that the metabolite behaved chromatographically similar to prostaglandin J2 and Delta12-prostaglandin J2. Gas chromatography/mass spectrometry revealed a striking similarity of the metabolite to Delta12-prostaglandin J2, the only form among the J2 series whose natural occurrence has been detected. Furthermore, this metabolite was able to activate duck PPARgamma1 to the same extent as the same concentrations of Delta12-prostaglandin J2 and 15-deoxy-Delta12, 14-prostaglandin J2, whereas under the same conditions, prostaglandin D2 was not effective. The results suggest that estrogen treatment induced the formation of a prostaglandin D2 metabolite that activated duck PPARgamma1, causing the induction of peroxisome proliferation in the duck uropygial gland. PMID:9804768

Ma, H; Sprecher, H W; Kolattukudy, P E

1998-11-13

29

Fenofibrate, a peroxisome proliferator-activated receptor ? ligand, prevents abnormal liver function induced by a fasting–refeeding process  

SciTech Connect

Highlights: •A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit. •A fasting–refeeding HFD induces liver ballooning injury. •A fasting–refeeding HDF process elicits hepatic triglyceride accumulation. •Fenofibrate, PPAR? ligand, prevents liver damage induced by refeeding HFD. -- Abstract: Fenofibrate, a peroxisome proliferator-activated receptor ? (PPAR?) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determined by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-?B is activated and consequently induces the expression of TNF-?, IL1-?, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-?B target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation.

Lee, Joon No; Dutta, Raghbendra Kumar; Kim, Seul-Gi; Lim, Jae-Young; Kim, Se-Jin; Choe, Seong-Kyu [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of)] [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Yoo, Kyeong-Won [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of) [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Immune-network Pioneer Research Center, Department of Biochemistry, College of Medicine, Dong-A University, Busan (Korea, Republic of); Song, Seung Ryel [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of)] [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Do-Sim [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of) [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Department of Laboratory of Medicine, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); So, Hong-Seob [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of)] [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Raekil, E-mail: rkpark@wku.ac.kr [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of)] [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of)

2013-12-06

30

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

PubMed

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

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

2005-11-01

31

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...

32

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.

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

2011-01-01

33

Hypoxia Up-regulates Expression of Peroxisome Proliferator-activated Receptor ? Angiopoietin-related Gene (PGAR) in Cardiomyocytes: Role of Hypoxia Inducible Factor 1?  

Microsoft Academic Search

A. J. Belanger, H. Lu, T. Date, L. X. Liu, K. A. Vincent, G. Y. Akita, S. H. Cheng, R. J. Gregory and C. Jiang. Hypoxia Up-regulates Expression of Peroxisome Proliferator-activated Receptor ? Angiopoietin-related Gene (PGAR) in Cardiomyocytes: Role of Hypoxia Inducible Factor 1?. Journal of Molecular and Cellular Cardiology (2002)34 , 765–774. Peroxisome proliferator-activated receptors (PPAR), especially the PPAR?

Adam J. Belanger; Hsienwie Lu; Taro Date; Louis X. Liu; Karen A. Vincent; Geoffery Y. Akita; Seng H. Cheng; Richard J. Gregory; Canwen Jiang

2002-01-01

34

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

35

Fenofibrate A peroxisome proliferator activated receptor-? agonist treatment ameliorates Concanavalin A-induced hepatitis in rats.  

PubMed

Peroxisome proliferator-activated receptor-? (PPAR?) is physiologically highly expressed by hepatocytes, where it plays a pivotal anti-inflammatory and metabolic role. The decrease expression and functional activity of PPAR? in hepatocytes during hepatitis C virus infection may contribute to the pathogenesis of the disease in humans. This study aims at evaluating the effects of PPAR? activation with fenofibrate (FF) on liver inflammation, fibrosis and portal pressure (PP) in Concanavalin A (Con A)- induced hepatitis in rats. The rats were randomly divided to 3 groups; control (1 ml saline iv/wk) group, Con A (20mg/kg/iv/wk) group and Con A with FF (100mg/kg/day p.o) group. Blood samples and livers were collected by the end of the first, second, fourth and eighth injections of Con A for biochemical, histopathological and immunohistochemistry studies for ?-smooth muscle actin (? SMA). Measurement of PP was performed by the end of the 8th week. FF group had a significant (P<0.05) decrease of serum alanine and aspartate aminotransferases with significant reduction of hepatic tumor necrosis factor alpha and malondialdehyde levels than Con A group. Histopathological examination revealed that treatment with FF significantly suppressed early inflammation, reduced ? SMA, and apoptosis of hepatocytes induced by Con A, thereby preventing the progression of chronic liver injury and fibrosis. In addition FF group had a significantly lower PP (-89.0%) than Con A group. In conclusion PPAR? activation significantly reduced liver inflammation, fibrosis and PP in Con A model of hepatitis that may represent a new therapeutic strategy for hepatitis and its complications. PMID:24140572

Mohamed, Doaa I; Elmelegy, Ahmed A M; El-Aziz, Lubna F A; Abdel Kawy, Hala S; El-Samad, Abeer A Abd; El-Kharashi, Omnyah A

2013-12-01

36

Fatty aldehyde dehydrogenase is up-regulated by polyunsaturated fatty acid via peroxisome proliferator-activated receptor alpha and suppresses polyunsaturated fatty acid-induced endoplasmic reticulum stress.  

PubMed

Fatty aldehyde dehydrogenase (FALDH; also known as ALDH3A2 or ALDH10) oxidizes medium- or long-chain aliphatic aldehydes. FALDH deficiency in humans is known to be the cause of Sjögren-Larsson syndrome, in which individuals display neurological symptoms and cutaneous abnormality. FALDH-V, a splice isoform of FALDH, is localized in the peroxisome and contributes to the oxidization of pristanal, an intermediate of the alpha-oxidation pathway. FALDH-N, another splice isoform of FALDH, is induced by peroxisomal proliferator-activated receptor alpha ligands, although its activation mechanism has not been clarified. In the present study, we show that transcriptional activation of FALDH is directly regulated by peroxisomal proliferator-activated receptor alpha through a direct repeat-1 site located in the FALDH promoter. In addition, FALDH is efficiently induced by linoleic acid in rat hepatoma Fao cells through transcriptional activation by peroxisomal proliferator-activated receptor alpha. Furthermore, ectopic expression of endoplasmic reticulum-localizing FALDH-N, but not peroxisome-localizing FALDH-V, suppresses endoplasmic reticulum stress caused by linoleic acid in HEK293 cells. These results suggest the autocatalytic nature of the FALDH-N system against endoplasmic reticulum stress that is induced by polyunsaturated fatty acid; polyunsaturated fatty acid binds to peroxisomal proliferator-activated receptor alpha to activate the expression of FALDH-N, which then detoxifies polyunsaturated fatty acid-derived fatty aldehydes and protects cells from endoplasmic reticulum stress. PMID:19860831

Ashibe, Bunichiro; Motojima, Kiyoto

2009-12-01

37

Peroxisome Proliferator-Activated Receptor ? Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect  

PubMed Central

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor ? (PPAR?), leading to the reduction of serum triglyceride levels, the effects of these drugs on NAFLD remain controversial. Clinical studies have reported that PPAR? activation does not improve hepatic steatosis. In the present study, we focused on exploring the effect and mechanism of PPAR? activation on hepatic triglyceride accumulation and hepatic steatosis. Male C57BL/6J mice, Ppar?-null mice and HepG2 cells were treated with fenofibrate, one of the most commonly used fibrate drugs. Both low and high doses of fenofibrate were administered. Hepatic steatosis was detected through oil red O staining and electron microscopy. Notably, in fenofibrate-treated mice, the serum triglyceride levels were reduced and the hepatic triglyceride content was increased in a dose-dependent manner. Oil red O staining of liver sections demonstrated that fenofibrate-fed mice accumulated abundant neutral lipids. Fenofibrate also increased the intracellular triglyceride content in HepG2 cells. The expression of sterol regulatory element-binding protein 1c (SREBP-1c) and the key genes associated with lipogenesis were increased in fenofibrate-treated mouse livers and HepG2 cells in a dose-dependent manner. However, the effect was strongly impaired in Ppar?-null mice treated with fenofibrate. Fenofibrate treatment induced mature SREBP-1c expression via the direct binding of PPAR? to the DR1 motif of the SREBP-1c gene. Taken together, these findings indicate the molecular mechanism by which PPAR? activation increases liver triglyceride accumulation and suggest an adverse effect of fibrates on the pathogenesis of hepatic steatosis.

Yan, Fang; Wang, Qi; Xu, Chao; Cao, Mingfeng; Zhou, Xiaoming; Wang, Tingting; Yu, Chunxiao; Jing, Fei; Chen, Wenbin; Gao, Ling; Zhao, Jiajun

2014-01-01

38

Pathogenesis of calcineurin inhibitor-induced hypertension  

PubMed Central

This article reviews the current understanding of the mechanisms of calcineurin inhibitor–induced hypertension. Already early after the introduction of cyclosporine in the 1980s, vasoconstriction, sympathetic excitation and sodium retention by the kidney had been shown to play a role in this form of hypertension. The vasoconstrictive effects of calcineurin inhibitors are related to interference with the balance of vasoactive substances, including endothelin and nitric oxide. Until recently, the renal site of the sodium-retaining effect of calcineurin inhibitors was unknown. We and others have shown that calcineurin inhibitors increase the activity of the thiazide-sensitive sodium chloride cotransporter through an effect on the kinases WNK and SPAK. Here, we review the pertinent literature on the hypertensinogenic effects of calcineurin inhibitors, including neural, vascular and renal effects, and we propose an integrated model of calcineurin inhibitor–induced hypertension.

Hoorn, Ewout J.; Walsh, Stephen B.; McCormick, James A.; Zietse, Robert; Unwin, Robert J.; Ellison, David H.

2014-01-01

39

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...

40

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

PubMed Central

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

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

2013-01-01

41

Peroxisome proliferator-activated receptor gamma induces apoptosis and inhibits autophagy of human monocyte-derived macrophages via induction of cathepsin L: potential role in atherosclerosis.  

PubMed

Macrophages play a pivotal role in the pathophysiology of atherosclerosis. These cells express cathepsin L (CatL), a cysteine protease that has been implicated in atherogenesis and the associated arterial remodeling. In addition, macrophages highly express peroxisome proliferator-activated receptor (PPAR) ?, a transcription factor that regulates numerous genes important for lipid and lipoprotein metabolism, for glucose homeostasis, and inflammation. Hence, PPAR? might affect macrophage function in the context of chronic inflammation such as atherogenesis. In the present study, we examined the effect of PPAR? activation on the expression of CatL in human monocyte-derived macrophages (HMDM). Activation of PPAR? by the specific agonist GW929 concentration-dependently increased the levels of CatL mRNA and protein in HMDM. By promoter analysis, we identified a functional PPAR response element-like sequence that positively regulates CatL expression. In addition, we found that PPAR?-induced CatL promotes the degradation of Bcl2 without affecting Bax protein levels. Consistently, degradation of Bcl2 could be prevented by a specific CatL inhibitor, confirming the causative role of CatL. PPAR?-induced CatL was found to decrease autophagy through reduction of beclin 1 and LC3 protein levels. The reduction of these proteins involved in autophagic cell death was antagonized either by the CatL inhibitor or by CatL knockdown. In conclusion, our data show that PPAR? can specifically induce CatL, a proatherogenic protease, in HMDM. In turn, CatL inhibits autophagy and induces apoptosis. Thus, the proatherogenic effect of CatL could be neutralized by apoptosis, a beneficial phenomenon, at least in the early stages of atherosclerosis. PMID:21700710

Mahmood, Dler Faieeq Darweesh; Jguirim-Souissi, Imene; Khadija, El-Hadri; Blondeau, Nicolas; Diderot, Vimala; Amrani, Souliman; Slimane, Mohamed-Naceur; Syrovets, Tatiana; Simmet, Thomas; Rouis, Mustapha

2011-08-19

42

Peroxisome Proliferator-activated Receptor ? Induces Apoptosis and Inhibits Autophagy of Human Monocyte-derived Macrophages via Induction of Cathepsin L  

PubMed Central

Macrophages play a pivotal role in the pathophysiology of atherosclerosis. These cells express cathepsin L (CatL), a cysteine protease that has been implicated in atherogenesis and the associated arterial remodeling. In addition, macrophages highly express peroxisome proliferator-activated receptor (PPAR) ?, a transcription factor that regulates numerous genes important for lipid and lipoprotein metabolism, for glucose homeostasis, and inflammation. Hence, PPAR? might affect macrophage function in the context of chronic inflammation such as atherogenesis. In the present study, we examined the effect of PPAR? activation on the expression of CatL in human monocyte-derived macrophages (HMDM). Activation of PPAR? by the specific agonist GW929 concentration-dependently increased the levels of CatL mRNA and protein in HMDM. By promoter analysis, we identified a functional PPAR response element-like sequence that positively regulates CatL expression. In addition, we found that PPAR?-induced CatL promotes the degradation of Bcl2 without affecting Bax protein levels. Consistently, degradation of Bcl2 could be prevented by a specific CatL inhibitor, confirming the causative role of CatL. PPAR?-induced CatL was found to decrease autophagy through reduction of beclin 1 and LC3 protein levels. The reduction of these proteins involved in autophagic cell death was antagonized either by the CatL inhibitor or by CatL knockdown. In conclusion, our data show that PPAR? can specifically induce CatL, a proatherogenic protease, in HMDM. In turn, CatL inhibits autophagy and induces apoptosis. Thus, the proatherogenic effect of CatL could be neutralized by apoptosis, a beneficial phenomenon, at least in the early stages of atherosclerosis.

Mahmood, Dler Faieeq Darweesh; Jguirim-Souissi, Imene; Khadija, El-Hadri; Blondeau, Nicolas; Diderot, Vimala; Amrani, Souliman; Slimane, Mohamed-Naceur; Syrovets, Tatiana; Simmet, Thomas; Rouis, Mustapha

2011-01-01

43

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

PubMed Central

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

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

2011-01-01

44

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

PubMed Central

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

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

2011-01-01

45

Thyroid hormone (T3) inhibits ciprofibrate-induced transcription of genes encoding beta-oxidation enzymes: cross talk between peroxisome proliferator and T3 signaling pathways.  

PubMed Central

Peroxisome proliferators cause rapid and coordinated transcriptional activation of genes encoding peroxisomal beta-oxidation system enzymes by activating peroxisome proliferator-activated receptor (PPAR) isoform(s). Since the thyroid hormone (T3; 3,3',5-triiodothyronine) receptor (TR), another member of the nuclear hormone receptor superfamily, regulates a subset of fatty acid metabolism genes shared with PPAR, we examined the possibility of interplay between peroxisome proliferator and T3 signaling pathways. T3 inhibited ciprofibrate-induced luciferase activity as well as the endogenous peroxisomal beta-oxidation enzymes in transgenic mice carrying a 3.2-kb 5'-flanking region of the rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase gene fused to the coding region of luciferase. Transfection assays in hepatoma H4-II-E-C3 and CV-1 cells indicated that this inhibition is mediated by TR in a ligand-dependent fashion. Gel shift assays revealed that modulation of PPAR action by TR occurs through titration of limiting amounts of retinoid X receptor (RXR) required for PPAR activation. Increasing amounts of RXR partially reversed the inhibition in a reciprocal manner; PPAR also inhibited TR activation. Results with heterodimerization-deficient TR and PPAR mutants further confirmed that interaction between PPAR and TR signaling systems is indirect. These results suggest that a convergence of the peroxisome proliferator and T3 signaling pathways occurs through their common interaction with the heterodimeric partner RXR. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7

Chu, R; Madison, L D; Lin, Y; Kopp, P; Rao, M S; Jameson, J L; Reddy, J K

1995-01-01

46

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

Microsoft Academic Search

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

Yanhong Shi; Michelle Hon; Ronald M. Evans

2002-01-01

47

Agranulocytosis induced by proton pump inhibitors.  

PubMed

We report the first published case of agranulocytosis induced by omeprazole and its recurrence with esomeprazole, the S-isomer form of omeprazole. Interestingly, we found an homozygotous mutation of CYP2C19*17, responsible for the metabolism of proton pump inhibitors. PMID:22240865

Dury, Sandra; Nardi, Julie; Gozalo, Claire; Lebargy, François; Deslee, Gaëtan

2012-01-01

48

Activation of peroxisome proliferator-activated receptor-? coactivator 1? ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury.  

PubMed

Glomerular podocytes are highly specialized epithelial cells whose injury in glomerular diseases causes proteinuria. Since mitochondrial dysfunction is an early event in podocyte injury, we tested whether a major regulator of oxidative metabolism and mitochondrial function, the transcriptional coactivator peroxisome proliferator-activated receptor-? coactivator 1? (PGC-1?), affects podocyte damage. Aldosterone-induced injury decreased PGC-1? expression, and induced mitochondrial and podocyte damage in dose- and time-dependent manners. The suppression of endogenous PGC-1? by RNAi caused podocyte mitochondrial damage and apoptosis while its increase by infection with an adenoviral vector prevented aldosterone-induced mitochondrial malfunction and inhibited injury. Overexpression of the silent mating type information regulation 2 homolog 1, a gene upstream of PGC-1?, prevented aldosterone-induced mitochondrial damage and podocyte injury by upregulating PGC-1? at both the transcriptional and post-translational levels. Resveratrol, a SIRT1 activator, attenuated aldosterone-induced mitochondrial malfunction and podocyte injury in vitro and in aldosterone-infused mice in vivo. Hence, endogenous PGC-1? may be important for maintenance of mitochondrial function in podocytes under normal conditions. Activators of SIRT1, such as resveratol, may be therapeutically useful in glomerular diseases to promote and maintain PGC-1? expression and, consequently, podocyte integrity. PMID:22648295

Yuan, Yanggang; Huang, Songming; Wang, Wenyan; Wang, Yingying; Zhang, Ping; Zhu, Chunhua; Ding, Guixia; Liu, Bicheng; Yang, Tianxin; Zhang, Aihua

2012-10-01

49

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

PubMed

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

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

2013-03-15

50

Differentiation of SWO-38 glioma cells induced by CDA-2 is mediated by peroxisome proliferator-activated receptor gamma.  

PubMed

Glioma remains one of the most lethal human tumors in spite of the progress in radiotherapy, chemotherapy, and surgical techniques. Cell differentiation agent-2 (CDA-2) is an extraction from healthy human urine consisting of primary organic acids and peptides, and it has been demonstrated to inhibit growth and induce differentiation in glioma and other cell lines. However, the mechanism remains unclear. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptors (NHRs) which are involved in cellular differentiation and proliferation. In this study, we investigated if CDA-2 induced differentiation of SWO-38 glioma cells is mediated by PPARgamma. CDA-2 induced differentiation of SWO-38 cells was characterized by typical morphological changes, increased expression of GFAP, inhibition of proliferation and G(0)/G(1) cell cycle arrest. CDA-2 also triggered up-regulation of PPARgamma, GFAP and PTEN protein and a reduction of COX-2 protein. However, the effects of CDA-2 on SWO-38 cells could be partly reversed by GW9662, an irreversible PPARgamma antagonist. Our investigation demonstrated that CDA-2 could be a potential drug for tumor differentiation therapy, and activation of the PPARgamma pathway might be a crucial factor in glioma differentiation induced by CDA-2. PMID:19434372

Lin, Chen Li; Wang, Ming Hua; Qin, Yan Fang; Fang, Mao; Xie, Bin Bin; Zhong, Xue Yun

2009-10-01

51

Protective role of peroxisome proliferator-activated receptor ?/? in acute lung injury induced by prolonged hyperbaric hyperoxia in rats.  

PubMed

Peroxisome proliferator-activated receptor (PPAR)-?/? is a transcription factor that belongs to the PPAR family, but the role of PPAR-?/? in acute lung injury (ALI) induced by hyperbaric oxygen is unknown. In this study we investigated if PPAR-?/? activation protects from hyperoxia-induced ALI in a rat model. ALI was induced by prolonged hyperbaric oxygen (HBO2) (2.3ATA, 100% O2) for 8h. Administration of PPAR-?/? agonist GW0742 (0.3mg/kg, i.p.) at 1 and 6h prior to HBO2 exposure significantly reduced the (1) lung injury, (2) proinflammatory cytokines (TNF-?, IL-1?, IL-6), (3) apoptosis (Bax/Bcl-2, cleaved-caspase-3 and TUNEL), (4) nuclear factor (NF)-?B expression level and DNA binding activity in the nucleus, and (5) extracellular signal-regulated kinase (ERK)1/2 phosphorylation and markedly elevated (6) superoxide dismutase and glutathione peroxidase activities as well as (7) I?B expression. However, administration of the PPAR-?/? antagonist GSK0660 abolished these protective effects. These findings indicate that activation of PPAR-?/? ameliorates hyperoxia-induced ALI in rats by up-regulating antioxidant enzyme activity as well as suppressing inflammation and apoptosis. PMID:24780550

Bao, Xiao-Chen; Fang, Yi-Qun; You, Pu; Zhang, Shi; Ma, Jun

2014-08-01

52

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

Microsoft Academic Search

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

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

1997-01-01

53

Secondary alterations of human hepatocellular peroxisomes.  

PubMed

The morphological and morphometric characteristics of peroxisomes in normal human liver and the peroxisomal alterations in the liver of patients with acquired or congenital non-peroxisomal diseases are reviewed. Secondary peroxisomal changes are observed in steatosis, hepatitis and cirrhosis induced by various agents (viruses, alcohol, drugs, etc.), in cholestasis, in hepatomas, in extra-hepatic cancer with or without liver metastasis, in extrahepatic inflammatory processes, in metabolic disorders affecting metabolism of carbohydrates, lipids and lipoproteins, glycoproteins, amino acids, bilirubin or copper, and in altered thyroid hormone levels. They are recognized as a proliferation of peroxisomes (increased in number and to a lesser extent in surface density and volume density) often accompanied by a minor reduction in size (at most to 68% of the mean diameter in control livers) but very rarely by an increase in mean peroxisomal diameter, and as proliferation-related changes in shape (tails, gastruloid cisternae, funnel-like constrictions, elongation, protrusions) in at least a few of the peroxisomes. These secondary alterations of the peroxisomes are clearly distinguishable from the primary changes in peroxisomes observed in the liver of patients with congenital peroxisomal disorders. PMID:9053551

De Craemer, D

1995-01-01

54

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

PubMed

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

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

2014-01-01

55

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

56

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.

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

2014-01-01

57

Multiple Peroxisomal Enzymatic Deficiency Disorders  

PubMed Central

Biologic, morphologic, and biochemical investigations performed in 2 patients demonstrate multiple peroxisomal deficiencies in the cerebrohepatorenal syndrome of Zellweger (CHRS) and neonatal adrenoleukodystrophy (NALD). Very long chain fatty acids, abnormal bile acids, including bile acid precursors (di- and trihydroxycoprostanoic acids), and C29-dicarboxylic acid accumulated in plasma in both patients. Generalized hyperaminoaciduria was also present. Peroxisomes could not be detected in CHRS liver and kidney; however, in the NALD patient, small and sparse cytoplasmic bodies resembling altered peroxisomes were found in hepatocytes. Hepatocellular and Kupffer cell lysosomes were engorged with ferritin and contained clefts and trilaminar structures believed to represent very long chain fatty acids. Enzymatic deficiencies reflected the peroxisomal defects. Hepatic glycolate oxidase and palmitoyl-CoA oxidase activities were deficient. No particle-bound catalase was found in cultured fibroblasts, and ether glycerolipid (plasmalogen) biosynthesis was markedly reduced. Administration of phenobarbital and clofibrate, an agent that induces peroxisomal proliferation and enzymatic activities, to the NALD patient did not bring about any changes in plasma metabolites, liver peroxisome population, or oxidizing activities. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5

Vamecq, Joseph; Draye, Jean-Pierre; Van Hoof, Francois; Misson, Jean-Paul; Evrard, Philippe; Verellen, Gaston; Eyssen, Hendrik J.; Van Eldere, Johan; Schutgens, Ruud B. H.; Wanders, Ronald J. A.; Roels, Frank; Goldfischer, Sidney L.

1986-01-01

58

Dysferlin Domain-containing Proteins, Pex30p and Pex31p, Localized to Two Compartments, Control the Number and Size of Oleate-induced Peroxisomes in Pichia pastoris  

Microsoft Academic Search

Yarrowia lipolytica Pex23p and Saccharomyces cerevisiae Pex30p, Pex31p, and Pex32p comprise a family of dysferlin domain- containing peroxins. We show that the deletion of their Pichia pastoris homologues, PEX30 and PEX31, does not affect the function or division of methanol-induced peroxisomes but results in fewer and enlarged, functional, oleate- induced peroxisomes. Synthesis of Pex30p is constitutive, whereas that of Pex31p

Mingda Yan; Dorian A. Rachubinski; Saurabh Joshi; Richard A. Rachubinski; Suresh Subramani

2008-01-01

59

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.

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

2012-01-01

60

Involvement of glucocorticoid receptor activation on anti-inflammatory effect induced by peroxisome proliferator-activated receptor ? agonist in mice.  

PubMed

Glucocorticoids are effective anti-inflammatory agents widely used for the treatment of acute and chronic inflammatory diseases. Recent in vitro studies have proposed that glucocorticoid receptor (GR) activation is involved in peroxisome proliferator-activated receptor ? (PPAR?) agonist-induced effects. In this study, to examine the involvement of the GR in PPAR? agonist- and retinoid X receptor (RXR) agonist-mediated anti-inflammatory effects in vivo, we tested the anti-inflammatory effects of dexamethasone (a GR agonist) with pioglitazone (a PPAR? agonist) or 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl)-amino] nicotinic acid (NEt-3IP; an RXR agonist) by using an experimental model of carrageenan-induced inflammation. We also evaluated the effects of a GR antagonist on PPAR? agonist- or RXR agonist-induced anti-inflammatory effects. Results showed that the GR antagonist RU486 reduced the anti-inflammatory effects of GR or PPAR? agonists but not those of the RXR agonist. In addition, combinations of GR and PPAR? agonists or GR and RXR agonists had no effect on carrageenan-induced paw edema. Moreover, the PPAR? antagonist GW9662 and RXR antagonist 6-[N-4-(trifluoromethyl)-benzenesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-amino] nicotinic acid (NS-4TF) had no effect on the anti-inflammatory effect of the GR agonist dexamethasone. Therefore, it is suggested that GR activation in vivo does not play a direct role in PPAR?/RXR heterodimer signaling. In contrast, pioglitazone showed a partial anti-inflammatory effect via GR activation. These data provide evidence for the pro-inflammatory activity of pioglitazone. PMID:24975659

Yamamoto, Atsuki; Kakuta, Hiroki; Sugimoto, Yukio

2014-09-01

61

Rodent Carcinogenicity of Peroxisome Proliferators and Issues on Human Relevance  

Microsoft Academic Search

A variety of substances such as hypolipidemic drugs, phthalate ester plasticizers, pesticides, and industrial solvents have been shown to increase the size and number of peroxisomes in rats and mice. They are grouped under the generic term peroxisome proliferators (PP) because of their unique property of inducing peroxisome proliferation. There are marked species differences in response to PP. Rats and

David Y. Lai

2004-01-01

62

Neuronal apoptosis induced by histone deacetylase inhibitors.  

PubMed

Histone acetylation has a key role in transcriptional activation, whereas deacetylation of histones correlates with the transcriptional repression and silencing of genes. Genetic repression may have an important role in neuronal aging, atrophy and degenerative diseases. Our aim was to study how histone deacetylase inhibitors, trichostatin A (TSA) and sodium butyrate, affect the metabolism of cultured rat cerebellar granule neurons and mouse Neuro-2a neuroblastoma cells. Cultured cells were exposed to 1-3 microM TSA and 1-10 mM butyrate for 1-2 days. Both of these inhibitors induced a prominent neuronal apoptosis characterized by morphological changes as well as by the activation of caspase-3 protease and subsequent cleavage of poly(ADP-ribose) polymerase, one of the caspase-3 targets. Caspase-3 activities reached the highest level on the second day after treatment, higher in the proliferating neuroblastoma cells than in the cerebellar granule neurons. Caspase-3 activation and morphological changes were prevented by cycloheximide treatment. Histone deacetylase inhibitors increased the DNA-binding activities of AP1, CREB and NF-kappaB transcription factors. These observations show that an excessive level of histone acetylation induces a stress response and an apoptotic cell death in neuronal cells. PMID:9795219

Salminen, A; Tapiola, T; Korhonen, P; Suuronen, T

1998-10-30

63

Bacillus Calmette-Guérin induces the expression of peroxisome proliferator-activated receptor gamma in bladder cancer cells.  

PubMed

Bacillus Calmette-Guérin (BCG) is considered to be one of the most effective treatments for superficial and in situ bladder cancer. The exact mechanism of the antitumor activity of BCG is not completely understood. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that is involved in cell growth and differentiation as well as inflammatory processes. PPARgamma is expressed in normal urothelium and a lack of expression was associated with bladder cancer progression. We analyzed whether PPARgamma is involved in the inhibition of bladder cancer cell survival by BCG. PPARgamma expression in murine MB49 and human T24 bladder cancer cells was evaluated employing immunofluorescence and immunohistochemistry techniques. In vitro cell viability and nitric oxide (NO) production was evaluated by using MTS and Griess reagent respectively. Our results show that BCG induced the cytoplasmatic expression of PPARgamma in bladder tumor cells in vitro and in vivo. BADGE, antagonist of this receptor, abrogated in vitro BCG-mediated cell cytotoxicity. Natural agonist 15-deoxy-Delta12,14 prostaglandin J2 (15-d-PGJ2) but not rosiglitazone (RO), a synthetic agonist, induced in vitro inhibition of cell viability of both cancer cell lines and the effect was partially reversed by BADGE. We also determined whether the activation of PPARgamma could inhibit NO production, which is considered a survival factor for bladder tumor cells. Both 15-d-PGJ2 and RO significantly inhibited the NO production in T24 and MB49 cells by PPARgamma-independent pathway since it was not antagonized by BADGE. Thus, our results show that BCG induces functional PPARgamma in bladder tumor cells in vivo and in vitro, being these receptors intrinsically involved in the antitumor activity of BCG. PMID:16391825

Lodillinsky, Catalina; Umerez, María Sol; Jasnis, María Adela; Casabé, Alberto; Sandes, Eduardo; Eiján, Ana María

2006-02-01

64

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

PubMed Central

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

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

1997-01-01

65

Thyroid dysfunctions induced by tyrosine kinase inhibitors.  

PubMed

Introduction: Recently, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anticancer therapy. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do cause significant side effects including fatigue and hypertension. In addition, thyroid dysfunction is a well-known adverse effect of TKI. Areas covered: This review provides a comprehensive assessment of TKI-induced thyroid dysfunctions by sunitinib, sorafenib, pazopanib, imatinib, dasatinib, nilotinib, vandetanib, axitinib, motesanib and tivozanib. Furthermore, the potential mechanisms that result in this toxicity, the clinical impact of thyroid dysfunction in these patients and the controversies regarding treatment with thyroid hormone (TH) therapy are evaluated. Expert opinion: Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and may necessitate treatment. Potential benefits in developing thyroid dysfunction and potential harm in treating it necessitate controlled studies. Finally, if treatment is pursued, appropriate dosing and timing of TH replacement will require prospective clinical evaluation. PMID:24821006

Fallahi, Poupak; Ferrari, Silvia M; Vita, Roberto; Di Domenicantonio, Andrea; Corrado, Alda; Benvenga, Salvatore; Antonelli, Alessandro

2014-06-01

66

Ligands of peroxisome proliferator-activated receptor gamma induce apoptosis in multiple myeloma.  

PubMed

The activation of proliferator-activated receptor gamma (PPAR-gamma) by its natural and synthetic ligands induces apoptosis in several tumor cell lines, including malignant B-lineage cells. We investigated whether treatment with pioglitazone (PGZ), rosiglitazone (RGZ) or 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) inhibited tumor cell growth in five human multiple myeloma cell lines (LP-1, U-266, RPMI-8226-S, OPM-2 and IM-9) and human bone marrow myeloma cells expressing PPAR-gamma protein. MTT assays revealed growth arrest induced by the natural activator of PPAR-gamma 15d-PGJ2 and a lower antiproliferative effect with thiazolidinediones (PGZ and RGZ) in a dose-dependent manner. Induction of apoptosis was indicated by Annexin-V staining. At a dose of 50 microM, 15d-PGJ2 led to a high rate of apoptosis in all cell lines (60-92%). Furthermore, induction of apoptosis in sorted bone marrow plasma cells from myeloma patients was detected. Thiazolidinediones comprise anti-myeloma activity in vitro and should be explored further for the treatment of multiple myeloma. PMID:15514564

Eucker, Jan; Bängeroth, Katharina; Zavrski, Ivana; Krebbel, Holger; Zang, Chuanbing; Heider, Ulrike; Jakob, Christian; Elstner, Elena; Possinger, Kurt; Sezer, Orhan

2004-11-01

67

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

Microsoft Academic Search

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

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

68

Peroxisome Proliferator-Activated Receptor-Alpha Deficiency Protects Aged Mice from Insulin Resistance Induced by High-Fat Diet  

Microsoft Academic Search

Background\\/Aims: Insulin resistance is a central feature of the metabolic syndrome and progressively increases with age, resulting in excessively high incidence of type II diabetes in the elderly population. Peroxisome proliferator-activated receptor-? (PPAR?) is widely expressed in insulin target tissues, including those of the liver, kidney, and muscle, where it mediates expression of genes promoting fatty acid ?-oxidation. The aim

Dae Ryong Cha; Jee Young Han; Dong Ming Su; Yahua Zhang; Xuefeng Fan; Matthew D. Breyer; Youfei Guan

2007-01-01

69

Antagonism of peroxisome proliferator-activated receptor ? prevents high-fat diet-induced obesity in vivo  

Microsoft Academic Search

Peroxisome proliferator-activated receptor ? (PPAR?) has been reported to play an important role to regulate adiposity and insulin sensitivity. It is not clear whether antagonism of PPAR? using a synthetic ligand has significant effects on adipose tissue weight and glucose metabolism in vivo. The aim of this study is to examine the effects of a synthetic PPAR? antagonist (GW9662) on

Ryosuke Nakano; Eiji Kurosaki; Shigeru Yoshida; Masanori Yokono; Akiyoshi Shimaya; Tatsuya Maruyama; Masayuki Shibasaki

2006-01-01

70

Genome-Wide Analysis of Effectors of Peroxisome Biogenesis  

PubMed Central

Peroxisomes are intracellular organelles that house a number of diverse metabolic processes, notably those required for ?-oxidation of fatty acids. Peroxisomes biogenesis can be induced by the presence of peroxisome proliferators, including fatty acids, which activate complex cellular programs that underlie the induction process. Here, we used multi-parameter quantitative phenotype analyses of an arrayed mutant collection of yeast cells induced to proliferate peroxisomes, to establish a comprehensive inventory of genes required for peroxisome induction and function. The assays employed include growth in the presence of fatty acids, and confocal imaging and flow cytometry through the induction process. In addition to the classical phenotypes associated with loss of peroxisomal functions, these studies identified 169 genes required for robust signaling, transcription, normal peroxisomal development and morphologies, and transmission of peroxisomes to daughter cells. These gene products are localized throughout the cell, and many have indirect connections to peroxisome function. By integration with extant data sets, we present a total of 211 genes linked to peroxisome biogenesis and highlight the complex networks through which information flows during peroxisome biogenesis and function.

Saleem, Ramsey A.; Long-O'Donnell, Rose; Dilworth, David J.; Armstrong, Abraham M.; Jamakhandi, Arvind P.; Wan, Yakun; Knijnenburg, Theo A.; Niemisto, Antti; Boyle, John; Rachubinski, Richard A.; Shmulevich, Ilya; Aitchison, John D.

2010-01-01

71

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

PubMed Central

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

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

2008-01-01

72

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

73

FLT3 inhibitor-induced neutrophilic dermatosis.  

PubMed

The FLT3-ITD mutation is associated with poor outcomes in acute myeloid leukemia. Multiple FMS-like tyrosine kinase 3 (FLT3)-inhibitors have been studied in clinical trials. Recently, potent FLT3 inhibition was shown to induce terminal differentiation of FLT3-mutant myeloblasts. In 3 patients who developed characteristic skin nodules on initiation of FLT3-inhibition, we conducted dermatopathologic evaluation of skin samples, as well as FLT3 and NPM1 mutational analysis and fluorescence in situ hybridization. All 3 patients demonstrated characteristically deep dermal and subcutaneous neutrophilic infiltrates without evidence of myeloblasts. Discovery of FLT3-ITD and NPM1 mutations in 2 of the samples, as well as the presence of FLT3-ITD and deletion of 7q in the other, confirmed the ancestry of the differentiated neutrophils as that of the original FLT3-mutant myeloblasts. FLT3 inhibition can lead to clinically distinct dermatoses, which suggests the effect of FLT3 inhibition on myeloid differentiation and a manifestation of a broader "syndrome" associated with this therapy. PMID:23687091

Fathi, Amir T; Le, Long; Hasserjian, Robert P; Sadrzadeh, Hossein; Levis, Mark; Chen, Yi-Bin

2013-07-11

74

Characterization of hepatic mitochondrial injury induced by fatty acid oxidation inhibitors.  

PubMed

Impairment of liver mitochondrial beta-oxidation is an important mechanism of drug-induced liver injury. Four inhibitors of fatty acid oxidation were compared in short-term rat in vivo studies in which the rats were administered one or four doses. The hepatocellular vacuolation represented ultra-structural mitochondrial changes. Urine nuclear magnetic resonance (NMR) spectroscopy revealed that both FOX988 and SDZ51-641 induced a persistent dicarboxylic aciduria, suggesting an inhibition of mitochondrial beta-oxidation and incomplete fatty acid metabolism. Etomoxir caused minimal mitochondrial ultrastructural changes and induced only transient dicarboxylic aciduria. CPI975 served as a negative control, in that there were no significant perturbations to the mitochondrial ultrastructural morphology or in the urine NMR composition; however, compound exposure was confirmed by the up-regulation of liver gene expression compared to vehicle control. The liver gene expression changes that were altered by the compounds were indicative of mitochondria, general and oxidative stress, and peroxisomal enzymes involved in beta-oxidation, suggestive of a compensatory response to the inhibition in the mitochondria. In addition, both FOX988 and SDZ51-641 up-regulated ribosomal genes associated with apoptosis, as well as p53 pathways linked with apoptosis. In summary, metabonomics and liver gene expression provided mechanistic information on mitochondrial dysfunction and impaired fatty acid oxidation to further define the clinical pathology and histopathology findings of hepatotoxicity. PMID:19234235

Vickers, Alison E M

2009-01-01

75

Peroxisomes take shape  

PubMed Central

Peroxisomes carry out various oxidative reactions that are tightly regulated to adapt to the changing needs of the cell and varying external environments. Accordingly, they are remarkably fluid and can change dramatically in abundance, size, shape and content in response to numerous cues. These dynamics are controlled by multiple aspects of peroxisome biogenesis that are coordinately regulated with each other and with other cellular processes. Ongoing studies are deciphering the diverse molecular mechanisms that underlie biogenesis and how they cooperate to dynamically control peroxisome utility. These important challenges should lead to an understanding of peroxisome dynamics that can be capitalized upon for bioengineering and the development of therapies to improve human health.

Smith, Jennifer J.; Aitchison, John D.

2014-01-01

76

Peroxisome Biogenesis and Function  

PubMed Central

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

Kaur, Navneet; Reumann, Sigrun; Hu, Jianping

2009-01-01

77

The dietary histone deacetylase inhibitor sulforaphane induces human ?-defensin-2 in intestinal epithelial cells  

PubMed Central

Antimicrobial peptides like human ?-defensin-2 (HBD-2) play an important role in the innate immune system protecting the intestinal mucosa against bacterial invasion. The dietary histone deacetylase (HDAC) inhibitors sulforaphane (SFN) and butyrate have received a great deal of attention because of their ability to simultaneously modulate multiple cellular targets involved in cellular protection. In this study the influence of SFN and butyrate on HBD-2 expression as well as the molecular pathways involved in SFN-mediated induction of HBD-2 were scrutinized. Treatment of Caco-2, HT-29 and SW480 cells with SFN led to a time- and dose-dependent upregulation of HBD-2 mRNA expression as determined by semi-quantitative reverse transcription–polymerase chain reaction. Moreover, HBD-2 protein production increased in response to SFN, measured by enzyme-linked immunosorbent assay. Induction of HBD-2 was also observed in response to butyrate. Immunofluorescence analysis revealed that the protein was localized in the cytosol. Coincubation of SFN with a vitamin D receptor (VDR), or an extracellular-regulated kinase 1/2 or a nuclear factor-?B inhibitor all reduced HBD-2 mRNA upregulation. In contrast, transfection of cells with a dominant-negative peroxisome proliferator-activated receptor ? (PPAR?) mutant vector to inhibit PPAR? wild-type action and inhibition of p38 mitogen-activated protein kinase (MAPK) signalling did not affect SFN-mediated upregulation of HBD-2 mRNA. Moreover, SFN induced the expression of VDR, PPAR? and phosphorylated ERK1/2 but did not affect p38 MAPK activation. The data clearly demonstrate for the first time that the dietary HDAC inhibitor SFN is able to induce antimicrobial peptides in colonocytes. In this process HBD-2 expression is regulated via VDR, mitogen-activated protein kinase kinase/extracellular-regulated kinase and nuclear factor-?B signalling.

Schwab, Markus; Reynders, Veerle; Loitsch, Stefan; Steinhilber, Dieter; Schroder, Oliver; Stein, Jurgen

2008-01-01

78

Partial disassembly of peroxisomes  

Microsoft Academic Search

ABSTRACT Rat liver peroxisomes,were,subjected,to a variety of procedures,intended,to partially disassemble,or damage,them; the effects were,analyzed,by recentrifugation into sucrose gradients, enzyme analyses, electron microscopy, and SDS PAGE. Freezing and thawing,or mild sonication released some,matrix proteins and produced,apparently intact peroxisomal,\\

Stefan E. H. Alexson; Yukio Fujiki; Helen Shio; Paul B. Lazarow

1985-01-01

79

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

80

Gluconeogenesis and the peroxisome.  

PubMed

In this article, the capabilities of peroxisomal involvement in the gluconeogenetic processes of vertebrate animals are reviewed in the light of recent findings on peroxisomal metabolism and proliferation. It is demonstrated that the participation of this organelle affords the potential of alternative pathways for the conversion of triacylglycerols to glucose, and for the conversion of amino acids and lactate to carbohydrate. Of interest in this connection, too, is that glyoxylate may act as a key intermediate in the gluconeogenetic functions of peroxisomes in both plants and animals. In addition, a close connection between peroxisomal function and the hormonal control of gluconeogenesis has been described, with these interrelationships extending to the associated phenomena of cellular signalling, gene expression, peroxisomal proliferation, and the function of insulin-like growth factors. The metabolic advantages of some of these alternative pathways for gluconeogenesis have been detailed, and suggestions made for the further testing of their quantitative relativities. PMID:9046033

Masters, C

1997-01-01

81

AtPex14p maintains peroxisomal functions by determining protein targeting to three kinds of plant peroxisomes  

PubMed Central

We previously isolated an Arabidopsis peroxisome-deficient ped2 mutant by its resistance to 2,4-dichlorophenoxybutyric acid. Here, we describe the isolation of a gene responsible for this deficiency, called the PED2 gene, by positional cloning and confirmed its identity by complementation analysis. The amino acid sequence of the predicted protein product is similar to that of human Pex14p, which is a key component of the peroxisomal protein import machinery. Therefore, we decided to call it AtPex14p. Analyses of the ped2 mutant revealed that AtPex14p controls intracellular transport of both peroxisome targeting signal (PTS)1- and PTS2-containing proteins into three different types of peroxisomes, namely glyoxysomes, leaf peroxisomes and unspecialized peroxisomes. Mutation in the PED2 gene results in reduction of enzymes in all of these functionally differentiated peroxisomes. The reduction in these enzymes induces pleiotropic defects, such as fatty acid degradation, photorespiration and the morphology of peroxisomes. These data suggest that the AtPex14p has a common role in maintaining physiological functions of each of these three kinds of plant peroxisomes by determining peroxisomal protein targeting.

Hayashi, Makoto; Nito, Kazumasa; Toriyama-Kato, Kanako; Kondo, Maki; Yamaya, Tomoyuki; Nishimura, Mikio

2000-01-01

82

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation  

PubMed Central

Increased NADP reduced (NADPH) oxidase 4 (Nox4) and reduced expression of the nuclear hormone receptor peroxisome proliferator-activated receptor ? (PPAR?) contribute to hypoxia-induced pulmonary hypertension (PH). To examine the role of Nox4 activity in pulmonary vascular cell proliferation and PH, the current study used a novel Nox4 inhibitor, GKT137831, in hypoxia-exposed human pulmonary artery endothelial or smooth muscle cells (HPAECs or HPASMCs) in vitro and in hypoxia-treated mice in vivo. HPAECs or HPASMCs were exposed to normoxia or hypoxia (1% O2) for 72 hours with or without GKT137831. Cell proliferation and Nox4, PPAR?, and transforming growth factor (TGF)?1 expression were measured. C57Bl/6 mice were exposed to normoxia or hypoxia (10% O2) for 3 weeks with or without GKT137831 treatment during the final 10 days of exposure. Lung PPAR? and TGF-?1 expression, right ventricular hypertrophy (RVH), right ventricular systolic pressure (RVSP), and pulmonary vascular remodeling were measured. GKT137831 attenuated hypoxia-induced H2O2 release, proliferation, and TGF-?1 expression and blunted reductions in PPAR? in HPAECs and HPASMCs in vitro. In vivo GKT137831 inhibited hypoxia-induced increases in TGF-?1 and reductions in PPAR? expression and attenuated RVH and pulmonary artery wall thickness but not increases in RVSP or muscularization of small arterioles. This study shows that Nox4 plays a critical role in modulating proliferative responses of pulmonary vascular wall cells. Targeting Nox4 with GKT137831 provides a novel strategy to attenuate hypoxia-induced alterations in pulmonary vascular wall cells that contribute to vascular remodeling and RVH, key features involved in PH pathogenesis.

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

2012-01-01

83

Utility of a topical peroxisome proliferator-activated receptor-? ligand with glucocorticoids in a hapten-induced murine model with features of atopic dermatitis  

PubMed Central

Although topical glucocorticoids (GCs) display potent anti-inflammatory activity in inflamed skin, they also can exert numerous harmful effects on epidermal structure and function. In contrast, topical applications of ligands of peroxisome proliferator-activated receptor-? (PPAR?) not only reduce inflammation, and also improve cutaneous barrier homeostasis. Therefore, we examined whether sequential topical GCs followed by topical Wy14643 (a ligand of PPAR?) might be more effective than either alone for atopic dermatitis (AD) in a hapten (oxazolone)-induced, murine model with multiple features of AD (Ox-AD). Despite expected anti-inflammatory benefits, topical GC alone induced: i) epidermal thinning; ii) reduced expression of involucrin, loricrin and filaggrin; and iii) allowed outside-to-inside penetration of an epicutaneous tracer. While Wy14643 alone yielded significant therapeutic benefits in mice with mild or moderate Ox-AD, it was less effective in severe Ox-AD. Yet, topical applications of Wy14643 after GC was not only significantly effective comparable to GC alone, but it also prevented GC-induced structural and functional abnormalities in permeability barrier homeostasis. Moreover, rebound flares were largely absent after sequential treatment with GC and Wy14643. Together, these results show that GC and PPAR? ligand therapy together is not only effective but also prevents development of GC-induced side effects, including rebound flares, in murine AD.

Hatano, Yutaka; Elias, Peter M.; Crumrine, Debra; Feingold, Kenneth R.; Katagiri, Kazumoto; Fujiwara, Sakuhei

2011-01-01

84

Peroxisome proliferator-activated receptor ?/? (PPAR?/?) protects against ceramide-induced cellular toxicity in rat brain astrocytes and neurons by activation of ceramide kinase.  

PubMed

Peroxisome proliferator-activated receptors (PPARs) are important members of the nuclear receptor superfamily. Ligands of these nuclear receptors (PPAR?, ?/? and ?) belong to a wide range of lipophilic substances. In spite of the proven neuroprotective efficacy of PPAR?/? in models of neurological diseases, the biology of PPAR?/? in the brain has been much less investigated than that of PPAR? and PPAR?. In the present study, we test the hypothesis that neuroprotection induced by PPAR?/? could rely on the regulation of ceramide metabolism. We found that preincubation of neural cells with the PPAR?/? agonist L-165041 exerts significant protection against ceramide-induced cell death. Most importantly, L-165041 protects against ceramide-induced cell death not only before the insult, but also after the onset of the insult. To identify the mechanism of protection, we show that L-165041 upregulates ceramide kinase (CerK) expression levels in neural cells. Consistent with that, we detected that pharmacological inhibition of CerK reduces the protective effects of L-165041. To further decipher the mechanism of protection, gene knockdown in astrocytes was studied. Knockdown of PPAR?/? and CerK in astrocytes was used to verify that the protective effects of L-165041 are CerK- and PPAR?/?-dependent. We demonstrate that in CerK- or PPAR?/?-knockdown astrocytes, addition of L-165041 has no protective effect. Thus, we conclude that PPAR?/? protects neural cells against ceramide-induced cell death via induction and activation of CerK. PMID:24513118

Aleshin, Stepan; Reiser, Georg

2014-03-01

85

Proteomic Analysis Reveals That the Rab GTPase RabE1c Is Involved in the Degradation of the Peroxisomal Protein Receptor PEX7 (Peroxin 7)*  

PubMed Central

The biogenesis of peroxisomes is mediated by peroxins (PEXs). PEX7 is a cytosolic receptor that imports peroxisomal targeting signal type 2 (PTS2)-containing proteins. Although PEX7 is important for protein transport, the mechanisms that mediate its function are unknown. In this study, we performed proteomic analysis to identify PEX7-binding proteins using transgenic Arabidopsis expressing green fluorescent protein (GFP)-tagged PEX7. Our analysis identified RabE1c, a small GTPase, as a PEX7 binding partner. In vivo analysis revealed that GTP-bound RabE1c binds to PEX7 and that a subset of RabE1c localizes to peroxisomes and interacts with PEX7 on the peroxisome membrane. Unlike endogenous PEX7, which is predominantly localized to the cytosol, GFP-PEX7 accumulates abnormally on the peroxisomal membrane and induces degradation of endogenous PEX7, concomitant with a reduction in import of PTS2-containing proteins and decreased peroxisomal ?-oxidation activity. Thus, GFP-PEX7 on the peroxisomal membrane exerts a dominant negative effect. Mutation of RabE1c restored endogenous PEX7 protein expression and import of PTS2-containing proteins as well as peroxisomal ?-oxidation activity. Treatment with proteasome inhibitors also restored endogenous PEX7 protein levels in GFP-PEX7-expressing seedlings. Based on these findings, we conclude that RabE1c binds PEX7 and facilitates PEX7 degradation in the presence of immobile GFP-PEX7 accumulated at the membrane.

Cui, Songkui; Fukao, Yoichiro; Mano, Shoji; Yamada, Kenji; Hayashi, Makoto; Nishimura, Mikio

2013-01-01

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.

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

2012-01-01

87

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

PubMed Central

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

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

2012-01-01

88

Peroxisome Proliferator-activated Receptor ? Ligands Inhibit Transforming Growth Factor-?-induced, Hyaluronan-dependent, T Cell Adhesion to Orbital Fibroblasts*  

PubMed Central

Thyroid eye disease is characterized by the infiltration of leukocytes and accumulation of hyaluronan (HA) in orbital tissue. Inflamed orbital tissue expands in size due to excessive HA and to the formation of scar tissue (fibrosis) and/or adipose accumulation. Transforming growth factor ? (TGF-?) acts as a key inducer of fibrosis by enhancing extracellular matrix production. Treatment of primary human orbital fibroblasts with TGF-? led to significant increases in both HA synthesis and secretion. TGF-? also strongly induced hyaluronan synthase 1 (HAS1) and HAS2 mRNA levels, which increased 50- and 6-fold, respectively. Remarkably, the addition of the peroxisome proliferator-activated receptor (PPAR?) ligands pioglitazone (Pio) or rosiglitazone (Rosi) to TGF-?-treated orbital fibroblasts attenuated HA synthesis and reduced HAS1 and HAS2 mRNA levels. The attenuation of TGF-? function by Pio and Rosi was independent of PPAR? activity. Furthermore, Pio and Rosi treatment inhibited TGF-?-induced T cell adhesion to orbital fibroblasts. Our findings demonstrate that TGF-? plays an important role in HA synthesis and in the inflammatory response by enhancing or facilitating inflammatory cell infiltration and adhesion to orbital tissue. Pio and Rosi exhibit anti-fibrotic and anti-inflammatory activity and may be useful in treating thyroid eye disease.

Guo, Naxin; Woeller, Collynn F.; Feldon, Steven E.; Phipps, Richard P.

2011-01-01

89

The Peroxisome Proliferator-Activated Receptor (PPAR) ? Agonist Fenofibrate Suppresses Chemically Induced Lung Alveolar Proliferative Lesions in Male Obese Hyperlipidemic Mice  

PubMed Central

Activation of peroxisome proliferator-activated receptor (PPAR) ? disrupts growth-related activities in a variety of human cancers. This study was designed to determine whether fenofibrate, a PPAR? agonist, can suppress 4-nitroquinoline 1-oxide (4-NQO)-induced proliferative lesions in the lung of obese hyperlipidemic mice. Male Tsumura Suzuki Obese Diabetic mice were subcutaneously injected with 4-NQO to induce lung proliferative lesions, including adenocarcinomas. They were then fed a diet containing 0.01% or 0.05% fenofibrate for 29 weeks, starting 1 week after 4-NQO administration. At week 30, the incidence and multiplicity (number of lesions/mouse) of pulmonary proliferative lesions were lower in mice treated with 4-NQO and both doses of fenofibrate compared with those in mice treated with 4-NQO alone. The incidence and multiplicity of lesions were significantly lower in mice treated with 4-NQO and 0.05% fenofibrate compared with those in mice treated with 4-NQO alone (p < 0.05). Both doses of fenofibrate significantly reduced the proliferative activity of the lesions in 4-NQO-treated mice (p < 0.05). Fenofibrate also significantly reduced the serum insulin and insulin-like growth factor (IGF)-1 levels, and decreased the immunohistochemical expression of IGF-1 receptor (IGF-1R), phosphorylated Akt, and phosphorylated Erk1/2 in lung adenocarcinomas. Our results indicate that fenofibrate can prevent the development of 4-NQO-induced proliferative lesions in the lung by modulating the insulin-IGF axis.

Kuno, Toshiya; Hata, Kazuya; Takamatsu, Manabu; Hara, Akira; Hirose, Yoshinobu; Takahashi, Satoru; Imaida, Katsumi; Tanaka, Takuji

2014-01-01

90

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

91

Dysregulation of Claudin-5 in HIV-induced Interstitial Pneumonitis and Lung Vascular Injury. Protective Role of Peroxisome Proliferator-activated Receptor-?.  

PubMed

Rationale: HIV-1-induced interstitial pneumonitis (IP) is a serious complication of HIV-1 infection, characterized by inflammation and cellular infiltration in lungs, often leading to respiratory failure and death. The barrier function of the pulmonary endothelium is caused in part by tight junction (TJ) proteins, such as claudin-5. Peroxisome proliferator-activated receptor (PPAR)-? is expressed in lung tissues and regulates inflammation. We hypothesize that HIV-1 induces vascular lung injury, and HIV-1-mediated damage of the pulmonary endothelium and IP is associated with dysregulation of PPAR-?. Objectives: Investigate the effects of HIV-1 infection on the pulmonary microvasculature and the modulatory effects of the PPAR-? ligands. Methods: Using human lung tissues, we demonstrated down-regulation of claudin-5 (marker of pulmonary barrier integrity), down-regulation of PPAR-? transcription, and expression in lung tissues of HIV-1-infected humans with IP. Measurements and Main Results: Human lung microvascular endothelial cells expressed the TJ proteins claudin-5, ZO-1, and ZO-2; HIV-1 decreased TJ proteins expression and induced nuclear factor-?B promoter activity, which was reversed by PPAR-? agonist. Using two murine HIV/AIDS models, we demonstrated decreased claudin-5 expression and increased macrophage infiltration in the lungs of HIV-1-infected animals. Activation of PPAR-? prevented HIV-1-induced claudin-5 down-regulation and significantly reduced viremia and pulmonary macrophage infiltration. Conclusions: HIV-induced IP is associated with injury to the lung vascular endothelium, with decreased TJ and PPAR-? expression, and increased pulmonary macrophage infiltration. PPAR-? ligands abrogated these effects. Thus, regulation of PPAR-? can be a therapeutic approach against HIV-1-induced vascular damage and IP in infected humans. Removal of Expression of Concern: Issues leading to the previous expression of concern for this article have been resolved after further revisions and editorial review. No further concerns exist. PMID:22345580

Li, Hong; Singh, Sangya; Potula, Raghava; Persidsky, Yuri; Kanmogne, Georgette D

2014-07-01

92

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.

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

2013-01-01

93

No evidence for a role of the peroxisome proliferator-activated receptor gamma (PPARG) and adiponectin (ADIPOQ) genes in antipsychotic-induced weight gain.  

PubMed

Antipsychotics frequently cause changes in glucose metabolism followed by development of weight gain and/or diabetes. Recent findings from our group indicated an influence of glucose-related genes on this serious side effect. With this study, we aimed to extend previous research and performed a comprehensive study on the peroxisome proliferator-activated receptor gamma (PPARG) and the adiponectin (ADIPOQ) genes. In 216 schizophrenic patients receiving antipsychotics for up to 14 weeks, we investigated single-nucleotide polymorphisms in or near PPARG (N=24) and ADIPOQ (N=18). Statistical analysis was done using ANCOVA in SPSS. Haplotype analysis was performed in UNPHASED 3.1.4 and Haploview 4.2. None of the PPARG or ADIPOQ variants showed significant association with antipsychotic-induced weight gain in our combined sample or in a refined subsample of patients of European ancestry treated with clozapine or olanzapine after correction for multiple testing. Similarly, no haplotype association could withstand multiple test correction. Although we could not find a significant influence of ADIPOQ and PPARG on antipsychotic-induced weight gain, our comprehensive examination of these two genes contributes to understanding the biology of this serious side effect. More research on glucose metabolism genes is warranted to elucidate their role in metabolic changes during antipsychotic treatment. PMID:24953421

Brandl, Eva J; Tiwari, Arun K; Zai, Clement C; Chowdhury, Nabilah I; Lieberman, Jeffrey A; Meltzer, Herbert Y; Kennedy, James L; Müller, Daniel J

2014-10-30

94

Involvement of hepatic peroxisome proliferator-activated receptor ?/? in the therapeutic effect of osthole on high-fat and high-sucrose-induced steatohepatitis in rats.  

PubMed

Our previous studies have indicated that osthole may be a dual agonist of peroxisome proliferator-activated receptor (PPAR) ?/? and decrease the hepatic lipid accumulation. But there has been no report about therapeutic effect on steatohepatitis. In the present study, we investigated the action of osthole and its potential mechanisms. The rats with steatohepatitis induced by orally feeding high-fat and high-sucrose emulsion were given osthole 5-20mg/kg for 4weeks. The results showed that after treatment with osthole, the serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride (TG), and free fatty acid (FFA) levels, the hepatic TG, FFA, tumor necrosis factor-?, monocyte chemotactic protein-1, interleukin-6, and interleukin-8 contents, and the hepatic weight and liver index were lowered, especially in the osthole 20mg/kg group. The histological evaluation of liver specimens demonstrated that osthole might improve the hepatic steatosis and inflammation. At the same time, osthole treatment increased the hepatic protein expressions of PPAR?/? and lipoprotein lipase, and decreased the hepatic protein expressions of nuclear factor-?B, sterol regulatory element-binding protein-1c, fatty acid synthase, and diacylglycerol acyltransferase. These findings demonstrate that osthole is effective in treating rat steatohepatitis, and the PPAR?/? may be involved in the osthole-induced modulation of hepatic lipogenic gene expressions and inflammatory cytokine production. PMID:24993341

Zhao, Xi; Xue, Jie; Wang, Xiao-Li; Zhang, Yan; Deng, Min; Xie, Mei-Lin

2014-09-01

95

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

96

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

97

Rosiglitazone Prevents Advanced Glycation End Products-Induced Renal Toxicity Likely through Suppression of Plasminogen Activator Inhibitor1  

Microsoft Academic Search

In the development of diabetic nephropathy, advanced gly- cation end products (AGEs) play a causative role via induction of extracellular matrix (ECM) accumulation. Plasminogen activator inhibitor-1 (PAI-1), as a major inhibitor of plasminogen activator that plays an important role in degrading ECM, was found to significantly increase in renal fibrotic diseases. Activation of peroxisome proliferator-activated receptor (PPAR)-g prevented diabetic nephropathy.

Xiaoyan Yu; Cai Li; Xiaokun Li; Lu Cai

2007-01-01

98

Proteomics of the Peroxisome  

PubMed Central

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

Saleem, RA; Smith, JJ; Aitchison, JD

2007-01-01

99

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

PubMed

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

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

2012-10-01

100

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.

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

2013-01-01

101

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,...

102

Antagonist of peroxisome proliferator-activated receptor {gamma} induces cerebellar amyloid-{beta} levels and motor dysfunction in APP/PS1 transgenic mice  

SciTech Connect

Recent evidences show that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is involved in the modulation of the amyloid-{beta} (A{beta}) cascade causing Alzheimer's disease (AD) and treatment with PPAR{gamma} agonists protects against AD pathology. However, the function of PPAR{gamma} steady-state activity in A{beta} cascade and AD pathology remains unclear. In this study, an antagonist of PPAR{gamma}, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPAR{gamma} activity in cerebellum. The results show that inhibition of PPAR{gamma} significantly induced A{beta} levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellar levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degradation of A{beta}. Since cerebellum is spared from significant A{beta} accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPAR{gamma} steady-state activity in protection of cerebellum against AD pathology.

Du, Jing; Sun, Bing [Protein Science Key Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, School of Medicine, Tsinghua University, Beijing 100084 (China)] [Protein Science Key Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, School of Medicine, Tsinghua University, Beijing 100084 (China); Chen, Kui [Department of Pharmacology, Anhui Medical University, Hefei, Anhui 230032 (China)] [Department of Pharmacology, Anhui Medical University, Hefei, Anhui 230032 (China); Fan, Li [Department of Pharmacology, Anhui Medical University, Hefei, Anhui 230032 (China) [Department of Pharmacology, Anhui Medical University, Hefei, Anhui 230032 (China); Cardiovascular Research, Starr Academic Center, Providence Heart and Vascular Institute, Portland, OR 97225 (United States); Wang, Zhao, E-mail: zwang@tsinghua.edu.cn [Protein Science Key Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, School of Medicine, Tsinghua University, Beijing 100084 (China)] [Protein Science Key Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, School of Medicine, Tsinghua University, Beijing 100084 (China)

2009-07-03

103

FPTIII Mitigates Peroxisome-Mediated Oxidative Stress in Kidneys of Spontaneously Hypertensive Diabetic Rats  

Microsoft Academic Search

Aim: Peroxisomes are known to play a role in cellular oxidative stress during pathogenesis of diabetes and hypertension. We reported earlier that FPTIII (a farnesyl protein transferase inhibitor) attenuates ischemia-reperfusion injury and renal dysfunction in diabetic hypertensive (DH) rats. In this study, we have examined the effect of FPTIII on peroxisomal enzymes in relation to oxidative stress in kidneys of

Gursev S. Dhaunsi; Mariam H. M. Yousif; Ibrahim F. Benter

2010-01-01

104

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.

2012-01-01

105

Angiotensin converting enzyme inhibitor induced cough in Nigerians.  

PubMed

A persistent dry cough is the commonest class of adverse reaction to Angiotensin converting enzyme inhibitors (ACE-I). This ACE-I induced cough appears to exhibit interracial differences being commoner in Chinese subjects as compared to Caucasians. We conducted a cross sectional study of one hundred (100) patients (63 males and 37 females) on ACE-I to determine the prevalence of ACE-induced cough in Nigerians, a Negroid population. Twenty seven patients (27%) had ACE-induced cough and four (4%) had withdrawal of ACE-I therapy on account of cough. The prevalence of ACE-I induced cough was significantly higher amongst females (43%) as compared to males (17%) p < 0.01. The biological basis for the apparent racial and gender differences in ACE-I induced cough requires further study. PMID:11505887

Adigun, A Q; Ajayi, A A

2001-01-01

106

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.

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

2011-01-01

107

Activation of peroxisome proliferator-activated receptor-gamma protects pancreatic beta-cells from cytokine-induced cytotoxicity via NF kappaB pathway.  

PubMed

Diabetes mellitus is characterized by cytokine-induced insulitis and a deficit in beta-cell mass. Ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma) have been shown to have anti-inflammatory effects in various experimental models. We questioned whether activation of endogenous PPAR-gamma by either PPAR-gamma ligands or adenoviral-directed overexpression of PPAR-gamma (Ad-PPAR-gamma) could inhibit cytokine-induced beta-cell death in RINm5F (RIN) cells, a rat insulinoma cell line. Treatment of RIN cells with interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma) induced beta-cell damage through NF kappaB-dependent signaling pathways. Activation of PPAR-gamma by PPAR-gamma ligands or Ad-PPAR-gamma inhibited IL-1 beta and IFN-gamma-stimulated nuclear translocation of the p65 subunit and DNA binding activity. NF kappaB target gene expression and their product formation, namely inducible nitric oxide synthase and cyclooxygenase-2 were decreased by PPAR-gamma activation, as established by real-time PCR, Western blots and measurements of NO and PGE(2). The mechanism by which PPAR-gamma activation inhibited NF kappaB-dependent cell death signals appeared to involve the inhibition of I kappa B alpha degradation, evidenced by inhibition of cytokine-induced NF kappaB-dependent signaling events by Ad-I kappaB alpha (S32A, S36A), non-degradable I kappaB alpha mutant. I kappaB beta mutant, Ad-I kappaB beta (S19A, S23A) was not effective in preventing cytokine toxicity. Furthermore, a protective effect of PPAR-gamma ligands was proved by assaying for normal insulin secreting capacity in response to glucose in isolated rat pancreatic islets. The beta-cell protective function of PPAR-gamma ligands might serve to counteract cytokine-induced beta-cell destruction. PMID:17521952

Kim, Eun-Kyung; Kwon, Kang-Beom; Koo, Bon-Sun; Han, Mi-Jeong; Song, Mi-Young; Song, Eun-Kyung; Han, Myung-Kwan; Park, Jin-Woo; Ryu, Do-Gon; Park, Byung-Hyun

2007-01-01

108

The Yarrowia lipolytica gene PAY2 encodes a 42-kDa peroxisomal integral membrane protein essential for matrix protein import and peroxisome enlargement but not for peroxisome membrane proliferation.  

PubMed

PAY genes are required for peroxisome assembly in the yeast Yarrowia lipolytica. Here we show that a mutant strain, pay2, is disrupted for the import of proteins targeted by either peroxisomal targeting signal-1 or -2. Electron microscopy of pay2 cells revealed the presence of small peroxisomal "ghosts," similar to the vesicular structures found in fibroblasts of patients with the human peroxisome assembly disorder, Zellweger syndrome. Functional complementation of pay2 with a plasmid library of Y. lipolytica genomic DNA identified a gene, PAY2, that restores growth of pay2 on oleic acid, import of catalase and multifunctional enzyme into peroxisomes, and formation of wild type peroxisomes. The PAY2 gene encodes Pay2p, a hydrophobic polypeptide of 404 amino acids. An antibody raised against Pay2p recognizes a polypeptide of approximately 42-kDa whose synthesis is induced by growth of Y. lipolytica on oleic acid. Pay2p is a peroxisomal integral membrane protein, as it localizes to carbonate-stripped peroxisomal membranes. Pay2p shows no identity to any known protein. Our results suggest that Pay2p is essential for the activity of the peroxisomal import machinery but does not affect the initial steps of peroxisomal membrane proliferation. PMID:7836411

Eitzen, G A; Aitchison, J D; Szilard, R K; Veenhuis, M; Nuttley, W M; Rachubinski, R A

1995-01-20

109

How Peroxisomes Affect Aflatoxin Biosynthesis in Aspergillus Flavus  

PubMed Central

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

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

2012-01-01

110

How peroxisomes affect aflatoxin biosynthesis in Aspergillus flavus.  

PubMed

In filamentous fungi, peroxisomes are crucial for the primary metabolism and play a pivotal role in the formation of some secondary metabolites. Further, peroxisomes are important site for fatty acids ?-oxidation, the formation of reactive oxygen species and for their scavenging through a complex of antioxidant activities. Oxidative stress is involved in different metabolic events in all organisms and it occurs during oxidative processes within the cell, including peroxisomal ?-oxidation of fatty acids. In Aspergillus flavus, an unbalance towards an hyper-oxidant status into the cell is a prerequisite for the onset of aflatoxin biosynthesis. In our preliminary results, the use of bezafibrate, inducer of both peroxisomal ?-oxidation and peroxisome proliferation in mammals, significantly enhanced the expression of pex11 and foxA and stimulated aflatoxin synthesis in A. flavus. This suggests the existence of a correlation among peroxisome proliferation, fatty acids ?-oxidation and aflatoxin biosynthesis. To investigate this correlation, A. flavus was transformed with a vector containing P33, a gene from Cymbidium ringspot virus able to induce peroxisome proliferation, under the control of the promoter of the Cu,Zn-sod gene of A. flavus. This transcriptional control closely relates the onset of the antioxidant response to ROS increase, with the proliferation of peroxisomes in A. flavus. The AfP33 transformant strain show an up-regulation of lipid metabolism and an higher content of both intracellular ROS and some oxylipins. The combined presence of a higher amount of substrates (fatty acids-derived), an hyper-oxidant cell environment and of hormone-like signals (oxylipins) enhances the synthesis of aflatoxins in the AfP33 strain. The results obtained demonstrated a close link between peroxisome metabolism and aflatoxin synthesis. PMID:23094106

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

2012-01-01

111

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

112

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.

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

2014-01-01

113

AMP-activated protein kinase is required for exercise-induced peroxisome proliferator-activated receptor ? co-activator 1? translocation to subsarcolemmal mitochondria in skeletal muscle  

PubMed Central

In skeletal muscle, mitochondria exist as two subcellular populations known as subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. SS mitochondria preferentially respond to exercise training, suggesting divergent transcriptional control of the mitochondrial genomes. The transcriptional co-activator peroxisome proliferator-activated receptor ? co-activator 1? (PGC-1?) and mitochondrial transcription factor A (Tfam) have been implicated in the direct regulation of the mitochondrial genome in mice, although SS and IMF differences may exist, and the potential signalling events regulating the mitochondrial content of these proteins have not been elucidated. Therefore, we examined the potential for PGC-1? and Tfam to translocate to SS and IMF mitochondria in human subjects, and performed experiments in rodents to identify signalling mechanisms regulating these translocation events. Acute exercise in humans and rats increased PGC-1? content in SS but not IMF mitochondria. Acute exposure to 5-aminoimidazole-4-carboxamide-1-?-ribofuranoside in rats recapitulated the exercise effect of increased PGC-1? protein within SS mitochondria only, suggesting that AMP-activated protein kinase (AMPK) signalling is involved. In addition, rendering AMPK inactive (AMPK kinase dead mice) prevented exercise-induced PGC-1? translocation to SS mitochondria, further suggesting that AMPK plays an integral role in these translocation events. In contrast to the conserved PGC-1? translocation to SS mitochondria across species (humans, rats and mice), acute exercise only increased mitochondrial Tfam in rats. Nevertheless, in rat resting muscle PGC-1? and Tfam co-immunoprecipate with ?-tubulin, suggesting a common cytosolic localization. These data suggest that exercise causes translocation of PGC-1? preferentially to SS mitochondria in an AMPK-dependent manner.

Smith, Brennan K; Mukai, Kazutaka; Lally, James S; Maher, Amy C; Gurd, Brendon J; Heigenhauser, George J F; Spriet, Lawrence L; Holloway, Graham P

2013-01-01

114

Modulation of Receptor Phosphorylation Contributes to Activation of Peroxisome Proliferator Activated Receptor ? by Dehydroepiandrosterone and Other Peroxisome Proliferators  

PubMed Central

Dehydroepiandrosterone (DHEA), a C19 human adrenal steroid, activates peroxisome proliferator-activated receptor ? (PPAR?) in vivo but does not ligand-activate PPAR? in transient transfection experiments. We demonstrate that DHEA regulates PPAR? action by altering both the levels and phosphorylation status of the receptor. Human hepatoma cells (HepG2) were transiently transfected with the expression plasmid encoding PPAR? and a plasmid containing two copies of fatty acyl coenzyme oxidase (FACO) peroxisome-proliferator activated receptor responsive element consensus oligonucleotide in a luciferase reporter gene. Nafenopin treatment increased reporter gene activity in this system, whereas DHEA treatment did not. Okadaic acid significantly decreased nafenopin-induced reporter activity in a concentration-dependent manner. Okadaic acid treatment of primary rat hepatocytes decreased both DHEA- and nafenopin-induced FACO activity in primary rat hepatocytes. DHEA induced both PPAR? mRNA and protein levels, as well as PP2A message in primary rat hepatocytes. Western blot analysis showed that the serines at positions 12 and 21 were rapidly dephosphorylated upon treatment with DHEA and nafenopin. Results using specific protein phosphatase inhibitors suggested that protein phosphatase 2A (PP2A) is responsible for DHEA action, and protein phosphatase 1 might be involved in nafenopin induction. Mutation of serines at position 6, 12, and 21 to an uncharged alanine residue significantly increased transcriptional activity, whereas mutation to negative charged aspartate residues (mimicking receptor phosphorylation) decreased transcriptional activity. DHEA action involves induction of PPAR? mRNA and protein levels as well as increased PPAR? transcriptional activity through decreasing receptor phosphorylation at serines in the AF1 region.

Tamasi, Viola; Miller, Kristy K. Michael; Ripp, Sharon L.; Vila, Ermin; Geoghagen, Thomas E.; Prough, Russell A.

2008-01-01

115

Differentiation of SWO-38 glioma cells induced by CDA-2 is mediated by peroxisome proliferator-activated receptor ?  

Microsoft Academic Search

Glioma remains one of the most lethal human tumors in spite of the progress in radiotherapy, chemotherapy, and surgical techniques.\\u000a Cell differentiation agent-2 (CDA-2) is an extraction from healthy human urine consisting of primary organic acids and peptides,\\u000a and it has been demonstrated to inhibit growth and induce differentiation in glioma and other cell lines. However, the mechanism\\u000a remains unclear.

Chen Li Lin; Ming Hua Wang; Yan Fang Qin; Mao Fang; Bin Bin Xie; Xue Yun Zhong

2009-01-01

116

Consequences of mitochondrial injury induced by pharmaceutical fatty acid oxidation inhibitors is characterized in human and rat liver slices.  

PubMed

Inhibition of liver mitochondrial beta-oxidation by pharmaceuticals may lead to safety concerns including mitochondrial dysfunction, lipid accumulation, inflammation and necrosis. In this study, the consequences of mitochondrial beta-oxidation inhibition by pharmaceuticals is investigated in human and rat liver slices. The fatty acid oxidation inhibitors Etomoxir and CPI975, inhibit the rate limiting mitochondrial beta-oxidation enzyme carnitine palmitoyltransferase I, while FOX988 and SDZ51-641, sequester mitochondrial coenzyme A to inhibit carnitine palmitoyltransferase II. Mitochondrial dysfunction was evident by a significant decrease of liver slice ATP levels and mitochondrial injury was verified by ultrastructural changes in morphology, manifested as enlarged mitochondria, C- or O-shaped mitochondria, and granular or crystalline inclusions. Gene expression changes were evident prior to changes in mitochondrial morphology. Time- and concentration dependent changes in mitochondrial genes linked with respiration and mitochondrial fatty acid beta-oxidation were associated with an up-regulation of peroxisome fatty acid oxidation genes, likely as a compensatory mechanism for the inhibition of the mitochondrial pathways. Gene expression changes preceding the decline of liver slice ATP and GSH levels included an up-regulation of stress response and oxidative stress gene expression, as well as genes linked with transcription, transporters, proliferation, cell matrix and signaling. In association with the decline of liver slice ATP and GSH was increased apoptosis and inflammation. Caspase activity, a functional indicator of apoptosis, was significantly increased as well as an up-regulation of genes linked with apoptosis. The increased gene and protein expression of the pro-inflammatory cytokine IL-8, produced by endothelial cells, is likely in response to the manifestation of oxidative stress and GSH depletion; further amplifying the oxidative stress response induced by the fatty acid oxidation inhibitors and triggering an inflammatory response. In summary, human and rat liver slices exhibited similar effects to the inhibitors of mitochondrial beta-oxidation, and the mitochondrial injury is associated with apoptosis and inflammation in the liver slices. PMID:16545538

Vickers, A E M; Bentley, P; Fisher, R L

2006-10-01

117

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.

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

118

Dual targeting of peroxisomal proteins  

PubMed Central

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

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

2013-01-01

119

Rat preputial sebocyte differentiation involves peroxisome proliferator-activated receptors.  

PubMed

The hallmark of sebaceous epithelial cell (sebocyte) differentiation is the accumulation of fused neutral fat droplets. Very little sebocyte differentiation occurs, however, in primary or organ culture, even upon incubating with androgens, which are required for maturation in vivo. We hypothesized that sebocyte cell culture systems lack activators of the peroxisome proliferator-activated receptors that are involved in adipocyte differentiation. We here report that activation of peroxisome proliferator-activated receptor gamma and alpha by their respective specific ligands, a thiazolidinedione and a fibrate, induced lipid droplet formation in sebocytes but not epidermal cells. Linoleic acid and carbaprostacyclin, both peroxisome proliferator-activated receptor delta and alpha ligand-activators, were more effective but less specific, stimulating lipid formation in both types of cells. Either was more effective than the combination of peroxisome proliferator-activated receptor gamma and alpha activation, suggesting that peroxisome proliferator-activated receptor delta is involved in this lipid formation. Linoleic acid 0.1 mM stimulated significantly more advanced sebocyte maturation than any other treatment, including carbaprostacyclin, which suggests a distinct role of long chain fatty acids in sebocyte differentiation. Peroxisome proliferator-activated receptor gammal mRNA was demonstrated in sebocytes, but not in epidermal cells; it was more strongly expressed in freshly dispersed than in cultured sebocytes. In contrast, peroxisome proliferator-activated receptor delta mRNA was expressed to a similarly high extent before and after culture in both sebocytes and epidermal cells. These findings are compatible with the concepts that peroxisome proliferator-activated receptor gamma1 gene expression plays a unique role in the differentiation of sebocytes, while peroxisome proliferator-activated receptor delta activation and long chain fatty acids finalize sebocyte maturation and are capable of stimulating epidermal lipid formation. These findings have implications for the development of new modalities of treatment for acne vulgaris. PMID:9989800

Rosenfield, R L; Kentsis, A; Deplewski, D; Ciletti, N

1999-02-01

120

Degradation of plant peroxisomes by autophagy.  

PubMed

Peroxisomes play a critical role in many metabolic pathways during the plant life cycle. It has been proposed that the transition between different types of peroxisomes involves the degradation of obsolete peroxisomal enzymes via proteolytic activities in the peroxisome matrix, the cytosol, or the vacuole. Forward and reverse genetic studies recently provided evidence for autophagic degradation of peroxisomes in the vacuole of Arabidopsis seedlings. Here, we briefly review a model of pexophagy, or selective autophagy of peroxisomes, in plant cells. PMID:24782878

Lee, Han Nim; Kim, Jimi; Chung, Taijoon

2014-01-01

121

Degradation of plant peroxisomes by autophagy  

PubMed Central

Peroxisomes play a critical role in many metabolic pathways during the plant life cycle. It has been proposed that the transition between different types of peroxisomes involves the degradation of obsolete peroxisomal enzymes via proteolytic activities in the peroxisome matrix, the cytosol, or the vacuole. Forward and reverse genetic studies recently provided evidence for autophagic degradation of peroxisomes in the vacuole of Arabidopsis seedlings. Here, we briefly review a model of pexophagy, or selective autophagy of peroxisomes, in plant cells.

Lee, Han Nim; Kim, Jimi; Chung, Taijoon

2014-01-01

122

Autophagy induced by farnesyltransferase inhibitors in cancer cells.  

PubMed

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

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

2008-10-01

123

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

124

Effect of Cyclooxygenase and Nitric Oxide Synthase Inhibitors on Streptozotocin-Induced Hyperalgesia in Rats  

Microsoft Academic Search

We examined a possible involvement of cyclooxygenase (COX) and nitric oxide synthase (NOS) products in hyperalgesia occurring during streptozotocin (STZ)-induced diabetes. Indomethacin and celecoxib were used as relatively selective inhibitors of COX-1 and COX-2, respectively. NOS inhibitors included: non-specific inhibitor NG-nitro-L-arginine and L-N6-(1-iminoethyl)lysine preferentially acting on inducible NOS (iNOS) as well as 7-nitroindazole relatively specific inhibitor neuronal NOS (nNOS). The

Magdalena Bujalska; Jan Tatarkiewicz; Anna de Cordé

2008-01-01

125

Combination of Two Cytokine Inhibitors Reduces Nucleus Pulposus-Induced Nerve Injury More Than Using Each Inhibitor Separately  

PubMed Central

Although recent experimental studies indicate that disc-derived cytokines, as for instance TNF, seems to be intimately involved in the pathophysiology of sciatica and low back pain, the clinical studies performed do not provide conclusive data on TNF-inhibition as a useful complement for treatment of such conditions to existing modalities. Based on the fact that TNF is merely one component in a complex network it was assumed that the combination of a TNF-inhibitor and an IL-1?-inhibitor could potentiate the effects in a pig model on nucleus pulposus-induced nerve conduction velocity reduction. The data indicated that combination of two cytokine inhibitors seems to be more efficient in reducing the nucleus pulposus-induced effects on nerve conduction velocity than using each inhibitor separately. This may be considered if future clinical trials for the treatment of sciatica and low back pain using just a single inhibitor may continue to demonstrate inconclusive data.

Olmarker, Kjell

2011-01-01

126

Peroxisome proliferator-activated receptor ? (PPAR?) mediates a Ski oncogene-induced shift from glycolysis to oxidative energy metabolism.  

PubMed

Overexpression of the Ski oncogene induces oncogenic transformation of chicken embryo fibroblasts (CEFs). However, unlike most other oncogene-transformed cells, Ski-transformed CEFs (Ski-CEFs) do not display the classical Warburg effect. On the contrary, Ski transformation reduced lactate production and glucose utilization in CEFs. Compared with CEFs, Ski-CEFs exhibited enhanced TCA cycle activity, fatty acid catabolism through ?-oxidation, glutamate oxidation, oxygen consumption, as well as increased numbers and mass of mitochondria. Interestingly, expression of PPAR?, a key transcription factor that regulates adipogenesis and lipid metabolism, was dramatically elevated at both the mRNA and protein levels in Ski-CEFs. Accordingly, PPAR? target genes that are involved in lipid uptake, transport, and oxidation were also markedly up-regulated by Ski. Knocking down PPAR? in Ski-CEFs by RNA interference reversed the elevated expression of these PPAR? target genes, as well as the shift to oxidative metabolism and the increased mitochondrial biogenesis. Moreover, we found that Ski co-immunoprecipitates with PPAR? and co-activates PPAR?-driven transcription. PMID:21917928

Ye, Fang; Lemieux, Hélène; Hoppel, Charles L; Hanson, Richard W; Hakimi, Parvin; Croniger, Colleen M; Puchowicz, Michelle; Anderson, Vernon E; Fujioka, Hisashi; Stavnezer, Ed

2011-11-18

127

Estradiol induces proliferation of peroxisome-like microbodies and the production of 3-hydroxy fatty acid diesters, the female pheromones, in the uropygial glands of male and female mallards.  

PubMed

During the mating season the female mallards produce sex pheromones, diesters of 3-hydroxy fatty acids, in their uropygial glands. Subcellular fractionation by sucrose and Nycodenz density gradient centrifugations and electron microscopic examination of the fractions showed that diesters of 3-hydroxy acids and the enzymes that catalyze the formation and esterification of the 3-hydroxy fatty acids are located in the catalase-containing fractions, probably peroxisomes, whereas monoester synthesizing activities are located in the endoplasmic reticulum. Fatty acyl-CoA reductase that would provide fatty alcohol needed for the synthesis of monoester and diester waxes was found both in the peroxisomal and endoplasmic reticulum fraction. Upon daily intramuscular injection of estradiol into the females in the nonmating season, the short chain monoester waxes of the uropygial glands were replaced by long chain monoester waxes, and subsequently the monoester waxes were replaced by diester waxes. Injection of thyroxine with estradiol hastened the induction of the compositional changes including diester synthesis. Similar changes, including the synthesis of the female pheromones, were induced in the uropygial glands by the hormone treatment of males that do not normally produce diesters at any time during their life cycle. The structure and composition of the diesters induced by hormone treatment of both males and females were identical to those of the female pheromones produced during their mating season. Electron microscopic examination of diaminobenzidine-treated glands showed that peroxisomes proliferated in the gland of the females in the mating season and in the estradiol-treated males that produce the diesters. PMID:2033066

Bohnet, S; Rogers, L; Sasaki, G; Kolattukudy, P E

1991-05-25

128

Peroxisome metabolism and cellular aging.  

PubMed

The essential role of peroxisomes in fatty acid oxidation, anaplerotic metabolism, and hydrogen peroxide turnover is well established. Recent findings suggest that these and other related biochemical processes governed by the organelle may also play a critical role in regulating cellular aging. The goal of this review is to summarize and integrate into a model the evidence that peroxisome metabolism actually helps define the replicative and chronological age of a eukaryotic cell. In this model, peroxisomal reactive oxygen species (ROS) are seen as altering organelle biogenesis and function, and eliciting changes in the dynamic communication networks that exist between peroxisomes and other cellular compartments. At low levels, peroxisomal ROS activate an anti-aging program in the cell; at concentrations beyond a specific threshold, a pro-aging course is triggered. PMID:21083858

Titorenko, Vladimir I; Terlecky, Stanley R

2011-03-01

129

Peroxisome Metabolism and Cellular Aging  

PubMed Central

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

Titorenko, Vladimir I.; Terlecky, Stanley R.

2010-01-01

130

Efficacy of Icatibant as Treatment for ACE Inhibitor-Induced Angioedema in Adults: A Systematic Review  

Microsoft Academic Search

Background: ACE inhibitor-induced angioedema is a rare, yet potentially fatal, drug side effect. Considering nearly 40 million people are taking ACE inhibitors for their anti-hypertensive and renal-protective benefits, a significant number of patients are at risk for this drug-induced angioedema. This review was performed to evaluate the efficacy of icatibant as treatment for ACE inhibitor-induced angioedema. Strength of evidence was

Jessie A Burr

2011-01-01

131

Effects of vitamin E on peroxisome proliferator-activated receptor ? and nuclear factor-erythroid 2-related factor 2 in hypercholesterolemia-induced atherosclerosis.  

PubMed

Atherosclerosis and associated cardiovascular complications such as stroke and myocardial infarction are major causes of morbidity and mortality. We have previously reported a significant increase in mRNA levels of the scavenger receptor CD36 in aortae of cholesterol-fed rabbits and shown that vitamin E treatment attenuated increased CD36 mRNA expression. In the present study, we further investigated the redox signaling pathways associated with protection against atherogenesis induced by high dietary cholesterol and correlated these with CD36 expression and the effects of vitamin E supplementation in a rabbit model. Male albino rabbits were assigned to either a control group fed with a low vitamin E diet alone or a test group fed with a low vitamin E diet containing 2% cholesterol in the absence or presence of daily intramuscular injections of vitamin E (50mg/kg). To elucidate the mechanisms by which vitamin E supplementation alters the effects of hypercholesterolemia in rabbit aortae, we measured peroxisome proliferator-activated receptor ? (PPAR?), ATP-binding cassette transporter A1 (ABCA1), and matrix metalloproteinase-1 (MMP-1) mRNA levels by quantitative RT-PCR and the expression of MMP-1, nuclear factor-erythroid 2-related factor 2 (Nrf2), and glutathione S-transferase ? (GST?) protein by immunoblotting. The increased MMP-1 and decreased GST? expression observed suggests that a cholesterol-rich diet contributes to the development of atherosclerosis, whereas vitamin E supplementation affords protection by decreasing MMP-1 and increasing PPAR?, GST?, and ABCA1 levels in aortae of rabbits fed a cholesterol-rich diet. Notably, protein expression of Nrf2, the antioxidant transcription factor, was increased in both the cholesterol-fed and the vitamin E-supplemented groups. Although Nrf2 activation can promote CD36-mediated cholesterol uptake by macrophages, the increased induction of Nrf2-mediated antioxidant genes is likely to contribute to decreased lesion progression. Thus, our study demonstrates that Nrf2 can mediate both pro- and antiatherosclerotic effects. PMID:24583459

Bozaykut, Perinur; Karademir, Betul; Yazgan, Burak; Sozen, Erdi; Siow, Richard C M; Mann, Giovanni E; Ozer, Nesrin Kartal

2014-05-01

132

The NADPH oxidase inhibitor apocynin (acetovanillone) induces oxidative stress  

SciTech Connect

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

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

2006-05-01

133

Oligopeptide inhibitors of HIV-induced syncytium formation.  

PubMed

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein is essential for virus entry and the formation of multinucleated giant cells by cell fusion, one of the major virus-induced cytopathic effects. To study the effects of potential fusion inhibitors, a vaccinia virus recombinant expressing the envelope glycoprotein was generated and used to infect HeLa CD4+ cells. Syncytium induction was observed as early as 4 h postinfection and continued until the entire monolayer was fused. The N-terminus of the gp41 subunit of the HIV envelope protein is very hydrophobic, and appears to be involved in virus-induced membrane fusion. We synthesized several oligopeptide analogs of the N-terminal region of gp41 and determined their ability to inhibit HIV-induced cell fusion in CD4+ HeLa cells. A hexapeptide which was identical in amino acid sequence to the N-terminus of gp41 was found to completely inhibit cell fusion, whereas peptides with altered sequences showed reduced inhibitory activity. These peptides had no effect on protein synthesis, processing, or transport to the cell surface, and showed no signs of toxicity to cells even at very high concentrations. These results indicate that oligopeptides which are homologous to the fusion peptide of HIV inhibit virus-induced cytopathology, and should be evaluated further as potential antiviral agents. PMID:2078410

Owens, R J; Tanner, C C; Mulligan, M J; Srinivas, R V; Compans, R W

1990-11-01

134

Inhibitors of Fatty Acid Synthesis Induce PPAR?-Regulated Fatty Acid ?-Oxidative Genes: Synergistic Roles of L-FABP and Glucose  

PubMed Central

While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor-? (PPAR?) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20?mM) but not physiological (6?mM) glucose conferred on both TOFA and C75 the ability to induce PPAR? transcription of the fatty acid ?-oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR? in the context of high glucose at levels similar to those in uncontrolled diabetes.

Huang, Huan; McIntosh, Avery L.; Martin, Gregory G.; Petrescu, Anca D.; Landrock, Kerstin K.; Landrock, Danilo; Kier, Ann B.; Schroeder, Friedhelm

2013-01-01

135

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

136

Di(2-ethylhexyl) Phthalate Induces Apoptosis Through Peroxisome Proliferators-Activated Receptor-Gamma and ERK 1\\/2 Activation in Testis of Sprague-Dawley Rats  

Microsoft Academic Search

Di(2-ethylhexyl) phthalate (DEHP) is a well-known hepatic and reproductive toxicant whose toxicity may be mediated by peroxisome proliferators-activated receptor (PPAR). This study examined the effects of DEHP on the expression of PPAR-regulated genes involved in testicular cells apoptosis. Sprague-Dawley male rats were treated orally with 250, 500, or 750 mg\\/kg\\/d DEHP for 28 d, while control rats were given corn

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

2007-01-01

137

Inhibitor-concentration-induced extreme behaviour in electrochemical parameters  

NASA Astrophysics Data System (ADS)

Changes in electrochemical parameters and inhibition performance with inhibitor concentration were investigated by electrochemical measurements of propargyl derivative inhibitors in acidic solution. It was found that with increasing inhibitor concentrations, double layer capacitances, polarization resistances and inhibiting efficiencies showed extreme behavior at certain inhibitor concentration in sulfuric acid but not in hydrochloric acid medium. Analysis of the changes in desorption and corrosion potentials with inhibitor concentration showed that this extreme phenomenon resulted from inhibitor desorption occurring at around corrosion potential in sulfuric acid solution as the inhibitor concentration reached this certain value.

Wang, Jia

1998-06-01

138

Secretory leukocyte protease inhibitor modulates urethane-induced lung carcinogenesis.  

PubMed

Secretory leukocyte protease inhibitor (SLPI), 11.7 kDa serine protease inhibitor, is produced primarily in the respiratory tract, but it is often elevated in lung, head/neck and ovarian cancers. SLPI expression in relation to cancer progression, metastasis and invasion has been studied extensively in non-small cell lung cancer. However, the role of SLPI during the early stages of carcinogenesis remains unknown. We hypothesized that SLPI is required from the initiation and promotion to the progression of lung carcinogenesis. A skin allograft model using SLPI-knockout (SLPI-KO) mice and short hairpin RNA-treated cells was used to demonstrate that SLPI expression in tumor cells is crucial for tumor formation. Moreover, lung tumorigenesis induced by urethane, a chemical lung carcinogen, was significantly suppressed in SLPI-KO mice in association with decreased nuclear factor-kappaB (NF-?B) activity. SLPI deficiency also resulted in decreased cell numbers and decreased production of inflammatory cytokines in bronchoalveolar lavage fluids. The suppression of NF-?B activation in SLPI-KO mice was associated with lower expression of NF-?B-related survival genes and DNA repair genes. Our findings demonstrate that SLPI plays an important role from the initial stages of lung carcinogenesis to the progression of lung cancer in an NF-?B-dependent manner. PMID:24282288

Jan Treda, Cezary; Fukuhara, Tatsuro; Suzuki, Takuji; Nakamura, Akira; Zaini, Jamal; Kikuchi, Toshiaki; Ebina, Masahito; Nukiwa, Toshihiro

2014-04-01

139

The peroxisome: still a mysterious organelle  

PubMed Central

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

Fahimi, H. Dariush

2008-01-01

140

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

141

Aromatase inhibitors-induced bone loss in early breast cancer  

PubMed Central

Women with breast cancer have an increased prevalence and incidence of fractures. This increased risk of fracture has become most evident following the use of aromatase inhibitors (AIs) as standard adjuvant therapy. AI-induced bone loss occurs at more than twice the rate of physiologic postmenopausal bone loss. Moreover, peripheral quantitative computed tomography data indicate that effects of AIs on bone strength and on cortical bone have been substantially underestimated by dual-energy X-ray absorptiometry. All AIs have been associated with an increased fracture risk. The incidence of fractures is at least 33–43% higher in AI-treated patients than in tamoxifen-treated patients, and this increase in fracture risk is maintained at least for the duration of AI therapy. Over the last few years, clinical trials have established the effectiveness of bisphosphonates and denosumab to preserve and even increase bone mineral density (BMD) during adjuvant AIs. Most data have been obtained with zoledronic acid administered twice a year, which effectively maintains or increases BMD in women receiving AIs. In addition, zoledronic acid has been shown to delay disease recurrence and maybe prolong survival in women with hormone-responsive tumors, thereby providing an adjuvant antitumor benefit besides preserving BMD. It is likely that a combined fracture risk assessment will more accurately identify women with breast cancer who require bone protective therapy. The FRAX tool probably underestimates the net increase in fracture risk due to AI therapy. Recent guidelines for the prevention of AI-induced bone loss have adequately considered the presence of several established clinical risk factors for fractures, in addition to BMD, when selecting patients to be treated with inhibitors of bone resorption.

Body, Jean-Jacques

2012-01-01

142

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

143

Peroxisomal Catalase in the Methylotrophic Yeast Candida boidinii: Transport Efficiency and Metabolic Significance  

PubMed Central

In this study we cloned CTA1, the gene encoding peroxisomal catalase, from the methylotrophic yeast Candida boidinii and studied targeting of the gene product, Cta1p, into peroxisomes by using green fluorescent protein (GFP) fusion proteins. A strain from which CTA1 was deleted (cta1? strain) showed marked growth inhibition when it was grown on the peroxisome-inducing carbon sources methanol, oleate, and d-alanine, indicating that peroxisomal catalase plays an important nonspecific role in peroxisomal metabolism. Cta1p carries a peroxisomal targeting signal type 1 (PTS1) motif, -NKF, in its carboxyl terminus. Using GFP fusion proteins, we found that (i) Cta1p is transported to peroxisomes via its PTS1 motif, -NKF; (ii) peroxisomal localization is necessary for Cta1p to function physiologically; and (iii) Cta1p is bimodally distributed between the cytosol and peroxisomes in methanol-grown cells but is localized exclusively in peroxisomes in oleate- and d-alanine-grown cells. In contrast, the fusion protein GFP-AKL (GFP fused to another typical PTS1 sequence, -AKL), in the context of CbPmp20 and d-amino acid oxidase, was found to localize exclusively in peroxisomes. A yeast two-hybrid system analysis suggested that the low transport efficiency of the -NKF sequence is due to a level of interaction between the -NKF sequence and the PTS1 receptor that is lower than the level of interaction with the AKL sequence. Furthermore, GFP-Cta1p?nkf coexpressed with Cta1p was successfully localized in peroxisomes, suggesting that the oligomer was formed prior to peroxisome import and that it is not necessary for all four subunits to possess a PTS motif. Since the main physiological function of catalase is degradation of H2O2, suboptimal efficiency of catalase import may confer an evolutionary advantage. We suggest that the PTS1 sequence, which is found in peroxisomal catalases, has evolved in such a way as to give a higher priority for peroxisomal transport to peroxisomal enzymes other than to catalases (e.g., oxidases), which require a higher level of peroxisomal transport efficiency.

Horiguchi, Hirofumi; Yurimoto, Hiroya; Goh, Toh-Kheng; Nakagawa, Tomoyuki; Kato, Nobuo; Sakai, Yasuyoshi

2001-01-01

144

Targeting Neurite Growth Inhibitors to Induce CNS Regeneration  

Microsoft Academic Search

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

Abba J. Kastin; Weihong Pan

2005-01-01

145

The role of peroxisomes in the integration of metabolism and evolutionary diversity of photosynthetic organisms.  

PubMed

The peroxisome is a metabolic compartment serving for the rapid oxidation of substrates, a process that is not coupled to energy conservation. In plants and algae, peroxisomes connect biosynthetic and oxidative metabolic routes and compartmentalize potentially lethal steps of metabolism such as the formation of reactive oxygen species and glyoxylate, thus preventing poisoning of the cell and futile recycling. Peroxisomes exhibit properties resembling inside-out vesicles and possess special systems for the import of specific proteins, which form multi-enzyme complexes (metabolons) linking numerous reactions to flavin-dependent oxidation, coupled to the decomposition of hydrogen peroxide by catalase. Hydrogen peroxide and superoxide originating in peroxisomes are important mediators in signal transduction pathways, particularly those involving salicylic acid. By contributing to the synthesis of oxalate, formate and other organic acids, peroxisomes regulate major fluxes of primary and secondary metabolism. The evolutionary diversity of algae has led to the presence of a wide range of enzymes in the peroxisomes that are only similar to higher plants in their direct predecessors, the Charophyceae. The appearance of seed plants was connected to the acquirement by storage tissues, of a peroxisomal fatty acid oxidation function linked to the glyoxylate cycle, which is induced during seed germination and maturation. Rearrangement of the peroxisomal photorespiratory function between different tissues of higher plants led to the appearance of different types of photosynthetic metabolism. The peroxisome may therefore have played a key role in the evolutionary formation of metabolic networks, via establishing interconnections between different metabolic compartments. PMID:12127583

Igamberdiev, Abir U; Lea, Peter J

2002-08-01

146

Peroxisome proliferation in liver of rats fed oxidized frying oil.  

PubMed

Oxidized frying oil (OFO) activates peroxisome proliferator-activated receptor a (PPAR alpha) in vitro and in vivo. As most PPARalpha activators are also peroxisome proliferators (PP), this study was aimed at exploring whether OFO induces peroxisome proliferation in the liver of rats. Four groups of male weanling Sprague-Dawley rats were fed the following diets for 6 wk: a basal diet containing 5 g/100 g fresh soybean oil (LSB), high-fat diets containing 20 g/100 g of fresh soybean oil (HSB as a control). OFO (HO) or fish oil (HF, as a positive control). Hepatomegaly and peroxisome proliferation in the liver of the HO group of rats were higher than those of the HF group. In addition, the acyl-CoA oxidase (ACO) activity, as well as cytochrome P450 4A (CYP4A) protein content in the livers of the HO group were 6 fold those of the HSB group, but were 2.5 fold in those of the HF group. These results indicated that dietary OFO induced typical responses to PPARalpha signaling. Moreover. as a dietary source, the OFO prepared under our frying conditions appears to be a more potent peroxisome proliferator than fish oil. PMID:16392708

Chao, Pei-Min; Yang, Mei-Fang; Tseng, Yu-Na; Chang, Ko-Ming; Lu, Kuo-Shyan; Huang, Ching-Jang

2005-10-01

147

Proteasome inhibitors induce p53-independent apoptosis in human cancer cells.  

PubMed

Proteasome inhibitors are used against human cancer, but their mechanisms of action are not entirely understood. For example, the role of the tumor suppressor p53 is controversial. We reevaluated the role of p53 in proteasome inhibitor-induced apoptosis by using isogenic human cancer cell lines with different p53 status. We found that well-known proteasome inhibitors such as MG132 and bortezomib, as well as the recently discovered proteasome inhibitor thiostrepton, induced p53-independent apoptosis in human cancer cell lines that correlated with p53-independent induction of proapoptotic Noxa but not Puma protein. In addition, these drugs inhibited growth of several cancer cell lines independently of p53 status. Notably, thiostrepton induced more potent apoptosis in HepG2 cells with p53 knockdown than in parental cells with wild-type p53. Our data confirm that proteasome inhibitors generally induce p53-independent apoptosis in human cancer cells. PMID:21224072

Pandit, Bulbul; Gartel, Andrei L

2011-01-01

148

Mechanisms of peroxisome proliferation by perfluorooctanoic acid and endogenous fatty acids.  

PubMed

1. The effects of endogenous fatty acids and perfluorooctanoic acid (PFOA) and its analogs on peroxisomal acyl CoA oxidase (ACO) and microsomal laurate hydroxylase (LH) activities were evaluated in primary cultures of rat hepatocytes and activation of peroxisome proliferator-activated receptor alpha (PPARalpha) in CV-1 cells. The rank order for the stimulation of ACO activity in hepatocytes for selected compounds was PFOA > octanoic acid>octanedioic acid, perfluorooctanol (inactive). Increases in ACO activity by PFOA, like those of ciprofibrate, were associated with a marked increase in peroxisome number and cytosolic occupancy volume. Maximal effects of ciprofibrate and PFOA on the stimulation of ACO activity were not additive, suggesting that these two compounds share a common pathway of peroxisome proliferation. 2. Saturated monocarboxylic acids of C4 to C18 chain length were inactive, and, among dicarboxylic acids, only small elevations (40-45%) in ACO activity were observed with the long-chain C12 and C16 dioic acids. Of the C18 fatty acids tested, only oleic and linoleic acids, at 1 mM, produced a two- to three-fold elevation in ACO and LH activities. In comparison with endogenous fatty acids, PFOA was more potent and exhibited a different time course and greater magnitude of stimulation of ACO and LH activities in cultured hepatocytes. 3. Addition of mitochondrial beta-oxidation inhibitors (3-mercaptopropionic and 2-bromooctanoic acids) did not alter ACO activity in the presence of octanoic acid or octanedioic acid; nor did they modify the stimulation of ACO activity by PFOA. The carnitine palmitoyltransferase I inhibitor 2-bromopalmitic acid produced a 2.5-fold increase in ACO stimulatory activity and reduced both ciprofibrate- and PFOA-mediated stimulations of ACO activity. 4. Cycloheximide treatment reduced PFOA- and ciprofibrate-induced ACO activities; however, the response to oleic acid was not blocked and increased slightly. 5. In rat and human PPARalpha transactivation assays, the rank order of activation was ciprofibrate > PFOA > oleic acid > or = octanoic acid > octanedioic acid or perfluorooctanol (inactive). PFOA, ciprofibrate and oleic acid were activators of rPPARalpha at concentrations that correlated favorably with the changes in ACO activity in cell culture. Octanoic acid did not increase ACO activity and was a weak activator of PPARalpha. 6. Our findings suggest that fatty acids such as oleic acid (endogenous fatty acids) and PFOA (a stable fatty acid) act through more than one pathway to increase ACO activity in rat hepatocytes. We conclude that the potent effects of PFOA are primarily mediated by a mechanism that includes the activation of liver PPARalpha. PMID:9688458

Intrasuksri, U; Rangwala, S M; O'Brien, M; Noonan, D J; Feller, D R

1998-08-01

149

Partial proteasome inhibitors induce hair follicle growth by stabilizing ?-catenin.  

PubMed

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 dramatically 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

150

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.

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

151

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.

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

2014-01-01

152

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.

Yurimoto, Hiroya; Oku, Masahide; Sakai, Yasuyoshi

2011-01-01

153

Promotion of organophosphate induced delayed polyneuropathy by certain esterase inhibitors.  

PubMed

Certain esterase inhibitors elicit or intensify the clinical expression of various insults to axons. This phenomenon was called promotion of axonopathies because these chemicals are not additive neurotoxicants nor do they interfere with the pharmacokinetics. Characterization of promotion was carried out by using organophosphate induced delayed polyneuropathy (OPIDP) as a model. The search for a physiological explanation of promotion has the following background: (1) Promotion expresses clinically the biochemical lesions which are otherwise well compensated (such as 30/40% neuropathy target esterase (NTE) inhibition by neuropathic organophosphates). (2) Promotion is not specific because axonopathies of different origin are affected. (3) Promoters are effective when given several days before the neuropathic insult. (4) Promotion is less effective in young animals as compared with adults. (5) Promotion occurs when axons, but not necessarily the cell body, are targeted by promoters. (6) Repeated dosing with a promoter failed to produce axonopathy. Based on this evidence it is suggested that promotion might interfere with a mechanism(s) of compensation and/or repair of long axons. The target of promotion of axonopathies is thought to be similar or linked to NTE which is defined as the phenyl valerate esterase activity (PVE) in nervous tissues resistant to paraoxon and sensitive to mipafox (40 and 50 microM, pH 8.0, 20 min, respectively). Mipafox (50 microM) resistant PVEs include some activity sensitive to the promoter phenylmethane sulfonylfluoride (PMSF) but no correlation was found between its inhibition and promotion. A complete titration curve of paraoxon-resistant PVEs by mipafox (0-1 mM) dissected, besides NTE (I50 about 10 microM), another PVE with an I50 of approximately 200 microM. This enzyme was present in hen brain, spinal cord and peripheral nerve, corresponding to about 10, 20 and 30% of NTE activity, respectively, and was sensitive both in vitro and in vivo to promoters and much less so to neuropathic NTE inhibitors. By means of chromatography, other workers have identified in soluble extracts of peripheral nerves two forms of mipafox-sensitive PVEs with different molecular weights and different sensitivity to mipafox. These might correspond to NTE and to the other enzyme. Inhibition in vivo of the latter also correlated with promotion. PMID:10421491

Lotti, M; Moretto, A

1999-05-14

154

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

155

Successful Treatment of Epidermal Growth Factor Receptor Inhibitor-Induced Periungual Inflammation with Adapalene  

PubMed Central

Epidermal growth factor receptor (EGFR) inhibitors are increasingly used for cancer treatment, but commonly carry dermatologic side effects. Periungual inflammation is a particularly painful condition that additionally worsens quality of life. In this paper, we report 3 cases of successful treatment of periungual inflammation induced by 3 different EGFR inhibitors (gefitinib, erlotinib, and cetuximab) with topically applied adapalene.

Hachisuka, Junichi; Doi, Kazuko; Moroi, Yoichi; Furue, Masutaka

2011-01-01

156

Successful treatment of epidermal growth factor receptor inhibitor-induced periungual inflammation with adapalene.  

PubMed

Epidermal growth factor receptor (EGFR) inhibitors are increasingly used for cancer treatment, but commonly carry dermatologic side effects. Periungual inflammation is a particularly painful condition that additionally worsens quality of life. In this paper, we report 3 cases of successful treatment of periungual inflammation induced by 3 different EGFR inhibitors (gefitinib, erlotinib, and cetuximab) with topically applied adapalene. PMID:21743808

Hachisuka, Junichi; Doi, Kazuko; Moroi, Yoichi; Furue, Masutaka

2011-05-01

157

Peroxisomes and sexual development in fungi.  

PubMed

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, Véronique

2013-01-01

158

Peroxisomes and sexual development in fungi  

PubMed Central

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

Peraza-Reyes, Leonardo; Berteaux-Lecellier, Veronique

2013-01-01

159

Proteasome inhibitors induce apoptosis of prostate cancer cells by inducing nuclear translocation of IkappaBalpha.  

PubMed

Proteasome inhibitors are known to suppress the proteasome-mediated degradation of IkappaBalpha in stimulated cells. This results in the cytoplasmic retention of NFkappaB and its reduced nuclear transcriptional activity. In this study, we show that in the metastatic prostate cancer cells, the proteasome inhibitors exhibit a novel, previously unrecognized effect: they increase the cellular levels of IkappaBalpha, which then translocates to the nucleus, associates with the nuclear p65 NFkappaB, thus inhibiting the constitutive NFkappaB DNA binding activity and inducing apoptosis. The proteasome inhibition-induced nuclear translocation of IkappaBalpha is dependent on de novo protein synthesis, occurs also in other cell types, and does not require IkappaBalpha phosphorylation on Ser-32. Since NFkappaB activity is constitutively increased in many human cancers as well as in inflammatory disorders, the proteasome inhibition-induced nuclear translocation of IkappaBalpha could thus provide a new therapeutic strategy aimed at the specific inhibition of NFkappaB activity by the nuclear IkappaBalpha. PMID:18468507

Vu, Hai-Yen; Juvekar, Ashish; Ghosh, Chandra; Ramaswami, Sitharam; Le, Dung Hong; Vancurova, Ivana

2008-07-15

160

Combined Treatment With Peroxisome Proliferator-Activated Receptor (PPAR) Gamma Ligands and Gamma Radiation Induces Apoptosis by PPAR?-Independent Up-Regulation of Reactive Oxygen Species-Induced Deoxyribonucleic Acid Damage Signals in Non-Small Cell Lung Cancer Cells  

SciTech Connect

Purpose: To investigate possible radiosensitizing activities of the well-known peroxisome proliferator-activated receptor (PPAR)? ligand ciglitazone and novel PPAR? ligands CAY10415 and CAY10506 in non-small cell lung cancer (NSCLC) cells. Methods and Materials: Radiosensitivity was assessed using a clonogenic cell survival assay. To investigate the mechanism underlying PPAR? ligand-induced radiosensitization, the subdiploid cellular DNA fraction was analyzed by flow cytometry. Activation of the caspase pathway by combined PPAR? ligands and ?-radiation treatment was detected by immunoblot analysis. Reactive oxygen species (ROS) were measured using 2,7-dichlorodihydrofluorescein diacetate and flow cytometry. Results: The 3 PPAR? ligands induced cell death and ROS generation in a PPAR?-independent manner, enhanced ?-radiation–induced apoptosis and caspase-3–mediated poly (ADP-ribose) polymerase (PARP) cleavage in vitro. The combined PPAR? ligand/?-radiation treatment triggered caspase-8 activation, and this initiator caspase played an important role in the combination-induced apoptosis. Peroxisome proliferator-activated receptor-? ligands may enhance the ?-radiation-induced DNA damage response, possibly by increasing ?-H2AX expression. Moreover, the combination treatment significantly increased ROS generation, and the ROS scavenger N-acetylcysteine inhibited the combined treatment-induced ROS generation and apoptotic cell death. Conclusions: Taken together, these results indicated that the combined treatment of PPAR? ligands and ?-radiation synergistically induced DNA damage and apoptosis, which was regulated by ROS.

Han, Eun Jong; Im, Chang-Nim; Park, Seon Hwa [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)] [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Moon, Eun-Yi [Department of Bioscience and Biotechnology, Sejong University, Seoul (Korea, Republic of)] [Department of Bioscience and Biotechnology, Sejong University, Seoul (Korea, Republic of); Hong, Sung Hee, E-mail: gobrian@kcch.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

2013-04-01

161

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

162

Evaluation of aspirin metabolites as inhibitors of hypoxia-inducible factor hydroxylases.  

PubMed

Known and potential aspirin metabolites were evaluated as inhibitors of oxygen-sensing hypoxia-inducible transcription factor (HIF) hydroxylases; some of the metabolites were found to stabilise HIF-alpha in cells. PMID:19048166

Lienard, Benoit M; Conejo-García, Ana; Stolze, Ineke; Loenarz, Christoph; Oldham, Neil J; Ratcliffe, Peter J; Schofield, Christopher J

2008-12-21

163

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

National Technical Information Service (NTIS)

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

P. G. Canonico W. Rill E. Ayala

1977-01-01

164

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

PubMed

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

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

2007-09-01

165

The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment.  

PubMed

The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA was up-regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARbeta/delta agonists in rat and human hepatoma cell lines and by PPARgamma and PPARbeta/delta agonists in mouse and human adipocytes. Transactivation, chromatin immunoprecipitation, and gel shift experiments identified a functional PPAR response element within intron 3 of the FIAF gene. At the protein level, in human and mouse blood plasma, FIAF was found to be present both as the native protein and in a truncated form. Differentiation of mouse 3T3-L1 adipocytes was associated with the production of truncated FIAF, whereas in human white adipose tissue and SGBS adipocytes, only native FIAF could be detected. Interestingly, truncated FIAF was produced by human liver. Treatment with fenofibrate, a potent PPARalpha agonist, markedly increased plasma levels of truncated FIAF, but not native FIAF, in humans. Levels of both truncated and native FIAF showed marked interindividual variation but were not associated with body mass index and were not influenced by prolonged semistarvation. Together, these data suggest that FIAF, similar to other adipocytokines such as adiponectin, may partially exert its function via a truncated form. PMID:15190076

Mandard, Stéphane; Zandbergen, Fokko; Tan, Nguan Soon; Escher, Pascal; Patsouris, David; Koenig, Wolfgang; Kleemann, Robert; Bakker, Arjen; Veenman, Frank; Wahli, Walter; Müller, Michael; Kersten, Sander

2004-08-13

166

Histone Deacetylase Inhibitors: Inducers of Differentiation or Apoptosis of Transformed Cells  

Microsoft Academic Search

Histone deacetylase (HDAC) inhibitors have been shown to be potent inducers of growth arrest, differentiation, and\\/or apoptotic cell death of transformed cells in vitro and in vivo. One class of HDAC inhibitors, hydroxamic acid-based hy- brid polar compounds (HPCs), induce differentiation at mi- cromolar or lower concentrations. Studies (x-ray crystallo- graphic) showed that the catalytic site of HDAC has a

Paul A. Marks; Victoria M. Richon; Richard A. Rifkind

167

The cyclin-dependent kinase inhibitor p21 is required for TGF-?1–induced podocyte apoptosis  

Microsoft Academic Search

The cyclin-dependent kinase inhibitor p21 is required for TGF-?1–induced podocyte apoptosis.BackgroundReduced podocyte number is a critical determinant in the development of glomerulosclerosis. Transforming growth factor-?1 (TGF-?1) induces podocyte apoptosis, but the cell cycle events are not known. The cyclin-dependent kinase (CDK) inhibitor p21 increases in podocytes in diseases where TGF-? increases. Accordingly, we studied the role of p21 in podocyte

TAKEHIKO WADA; JEFFREY W PIPPIN; YOSHIO TERADA; STUART J SHANKLAND

2005-01-01

168

The Dipeptidyl Peptidase-4 Inhibitor Des-Fluoro-Sitagliptin Regulates Brown Adipose Tissue Uncoupling Protein Levels in Mice with Diet-Induced Obesity  

PubMed Central

Objective Dipeptidyl peptidase (DPP)-4 is responsible for the degradation of several peptides that contain an alanine or proline at the penultimate position or position P1. DPP-4 inhibitors (DPP-4is) have protective effects against type-2 diabetes and several metabolic disorders. Methods In the present study, we examined the effects of des-fluoro-sitagliptin (DFS), a DDP-4i, on body adiposity and levels of peroxisome proliferator-activated receptor (PPAR)-?, PPAR-? coactivator-1 (PGC-1), and uncoupling proteins (UCPs) in mice with diet-induced obesity. Results Treatment with DFS dose-dependently decreased the weight of white adipose tissue and serum levels of glucose, compared with controls, without influencing food intake (P<0.05). Additionally, DFS treatment increased the levels of PPAR-?, PGC-1, and UCPs in brown adipose tissue (BAT), and of PPAR-? and UCP3 in skeletal muscle (P<0.05). Furthermore, the effects on BAT PGC-1 and muscle PPAR-? levels were attenuated by treatment with the glucagon-like peptide 1 (GLP-1) antagonist exendin (9–39). Interestingly, hypothalamic levels of proopiomelanocortin (POMC) were increased by DFS treatment and the effects of DFS on PPAR-?, PGC-1, and UCP levels were attenuated in melanocortin (MC)-4 receptor-deficient mice. Conclusions In conclusion, high-dose DFS appeared to regulate body adiposity and UCPs in mice with diet-induced obesity, at least partly through a GLP-1 and/or MC-4 pathway.

Shimasaki, Takanobu; Masaki, Takayuki; Mitsutomi, Kimihiko; Ueno, Daisuke; Gotoh, Koro; Chiba, Seiichi; Kakuma, Tetsuya; Yoshimatsu, Hironobu

2013-01-01

169

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

170

Dipeptidyl peptidase IV inhibitor lowers PPAR? agonist-induced body weight gain by affecting food intake, fat mass, and beige/brown fat but not fluid retention.  

PubMed

Peroxisome proliferator-activated receptor-? (PPAR?) agonists like pioglitazone (PGZ) are effective antidiabetic drugs, but they induce fluid retention and body weight (BW) gain. Dipeptidyl peptidase IV (DPP IV) inhibitors are antidiabetic drugs that enhance renal Na(+) and fluid excretion. Therefore, we examined whether the DPP IV inhibitor alogliptin (ALG) ameliorates PGZ-induced BW gain. Male Sv129 mice were treated with vehicle (repelleted diet), PGZ (220 mg/kg diet), ALG (300 mg/kg diet), or a combination of PGZ and ALG (PGZ + ALG) for 14 days. PGZ + ALG prevented the increase in BW observed with PGZ but did not attenuate the increase in body fluid content determined by bioimpedance spectroscopy (BIS). BIS revealed that ALG alone had no effect on fat mass (FM) but enhanced the FM-lowering effect of PGZ; MRI analysis confirmed the latter and showed reductions in visceral and inguinal subcutaneous (sc) white adipose tissue (WAT). ALG but not PGZ decreased food intake and plasma free fatty acid concentrations. Conversely, PGZ but not ALG increased mRNA expression of thermogenesis mediator uncoupling protein 1 in epididymal WAT. Adding ALG to PGZ treatment increased the abundance of multilocular cell islets in sc WAT, and PGZ + ALG increased the expression of brown-fat-like "beige" cell marker TMEM26 in sc WAT and interscapular brown adipose tissue and increased rectal temperature vs. vehicle. In summary, DPP IV inhibition did not attenuate PPAR? agonist-induced fluid retention but prevented BW gain by reducing FM. This involved ALG inhibition of food intake and was associated with food intake-independent synergistic effects of PPAR? agonism and DPP-IV inhibition on beige/brown fat cells and thermogenesis. PMID:24347054

Masuda, Takahiro; Fu, Yiling; Eguchi, Akiko; Czogalla, Jan; Rose, Michael A; Kuczkowski, Alexander; Gerasimova, Maria; Feldstein, Ariel E; Scadeng, Miriam; Vallon, Volker

2014-02-15

171

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

172

Recent advances in peroxisomal matrix protein import  

PubMed Central

Peroxisomes are essential organelles responsible for many metabolic reactions, such as the oxidation of very long chain and branched fatty acids, D-amino acids and polyamines, as well as the production and turnover of hydrogen peroxide. They comprise a class of organelles called microbodies, including glycosomes, glyoxysomes and Woronin bodies. Dysfunction of human peroxisomes causes severe and often fatal peroxisome biogenesis disorders (PBDs). Peroxisomal matrix protein import is mediated by receptors that shuttle between the cytosol and peroxisomal matrix using ubiquitination/deubiquitination reactions and ATP hydrolysis for receptor recycling. We focus on the machinery involved in the peroxisomal matrix protein import cycle, highlighting recent advances in peroxisomal matrix protein import, cargo release and receptor recycling/degradation.

Liu, Xueqian; Ma, Changle; Subramani, Suresh

2012-01-01

173

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.

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

2014-01-01

174

Salicylic Acid Inhibits Synthesis of Proteinase Inhibitors in Tomato Leaves Induced by Systemin and Jasmonic Acid.  

PubMed Central

Salicylic acid (SA) and acetylsalicylic acid (ASA), previously shown to inhibit proteinase inhibitor synthesis induced by wounding, oligouronides (H.M. Doherty, R.R. Selvendran, D.J. Bowles [1988] Physiol Mol Plant Pathol 33: 377-384), and linolenic acid (H. Pena-Cortes, T. Albrecht, S. Prat, E.W. Weiler, L. Willmitzer [1993] Planta 191: 123-128), are shown here to be potent inhibitors of systemin-induced and jasmonic acid (JA)-induced synthesis of proteinase inhibitor mRNAs and proteins. The inhibition by SA and ASA of proteinase inhibitor synthesis induced by systemin and JA, as well as by wounding and oligosaccharide elicitors, provides further evidence that both oligosaccharide and polypeptide inducer molecules utilize the octadecanoid pathway to signal the activation of proteinase inhibitor genes. Tomato (Lycopersicon esculentum) leaves were pulse labeled with [35S]methionine, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the inhibitory effects of SA are shown to be specific for the synthesis of a small number of JA-inducible proteins that includes the proteinase inhibitors. Previous results have shown that SA inhibits the conversion of 13S-hydroperoxy linolenic acid to 12-oxo-phytodienoic acid, thereby inhibiting the signaling pathway by blocking synthesis of JA. Here we report that the inhibition of synthesis of proteinase inhibitor proteins and mRNAs by SA in both light and darkness also occurs at a step in the signal transduction pathway, after JA synthesis but preceding transcription of the inhibitor genes.

Doares, S. H.; Narvaez-Vasquez, J.; Conconi, A.; Ryan, C. A.

1995-01-01

175

Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death  

SciTech Connect

Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway is associated with the neoplastic phenotype of a large number of human tumor cells. Although specific blockade of the ERK pathway by treating such tumor cells with potent mitogen-activated protein kinase/ERK kinase (MEK) inhibitors completely suppresses their proliferation, it by itself shows only a modest effect on the induction of apoptotic cell death. However, these MEK inhibitors markedly enhance the efficacy of histone deacetylase (HDAC) inhibitors to induce apoptotic cell death: such an enhanced cell death is observed only in tumor cells in which the ERK pathway is constitutively activated. Co-administration of MEK inhibitor markedly sensitizes tumor cells to HDAC inhibitor-induced generation of reactive oxygen species, which appears to mediate the enhanced cell death induced by the combination of these agents. These results suggest that the combination of MEK inhibitors and HDAC inhibitors provides an efficient chemotherapeutic strategy for the treatment of tumor cells in which the ERK pathway is constitutively activated.

Ozaki, Kei-ichi [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521 (Japan); Minoda, Ai [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521 (Japan); Kishikawa, Futaba [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521 (Japan); Kohno, Michiaki [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521 (Japan)]. E-mail: kohnom@net.nagasaki-u.ac.jp

2006-01-27

176

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

Microsoft Academic Search

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

M. L. Haasch

1996-01-01

177

Involvement of carnitine acyltransferases in peroxisomal fatty acid metabolism by the yeast Pichia guilliermondii.  

PubMed Central

This article provides information about peroxisomal fatty acid metabolism in the yeast Pichia guilliermondii. The existence of inducible mitochondrial carnitine palmitoyltransferase and peroxisomal carnitine octanoyl-transferase activities was demonstrated after culture of this yeast in a medium containing methyl oleate. The subcellular sites and induction patterns were studied. The inhibition of carnitine octanoyl- and palmitoyl-transferases by chlorpromazine to a large extent prevented the otherwise observed metabolism-dependent inactivation of thiolase by 2-bromofatty acids in vivo. We concluded that the metabolism of long- and medium-chain fatty acids in the peroxisome of this yeast involved carnitine intermediates.

Pagot, Y; Belin, J M

1996-01-01

178

Prostaglandin synthetase inhibitors antagonize hypothermia induced by sedative hypnotics  

Microsoft Academic Search

Previous studies in our laboratory have demonstrated that inhibition of prostaglandin biosynthesis through pretreatment with aspirin and other prostaglandin synthetase inhibitors (PGSI) significantly reduces CNS sensitivity to a hypnotic dose of ethanol. Indomethacin, a potent PGSI, was administered to male LS, SS, and HS\\/Ibg mice (65±10 days of age) 15 min prior to administration of a hypnotic dose of ethanol

Frank R. George; Stanley J. Jackson; Allan C. Collins

1981-01-01

179

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.

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

180

The effect of combined regulation of the expression of peroxisome proliferator-activated receptor-? and calcitonin gene-related peptide on alcohol-induced adipogenic differentiation of bone marrow mesenchymal stem cells.  

PubMed

Studies have shown that alcohol can upregulate the expression of peroxisome proliferator-activated receptor-? (PPAR?) gene in bone marrow mesenchymal stem cells (BMSCs). High expression of PPAR? can promote adipogenic differentiation of BMSCs, and reduce their osteogenic differentiation. Abnormal proliferation of adipocytes and fatty accumulation in osteocytes can result in high intraosseous pressure and disturbance of blood circulation in the femoral head, which induces osteonecrosis of the femoral head (ONFH). Downregulation of PPAR? is efficient in inhibiting adipogenesis and maintaining osteogenesis of BMSCs, which might potentially reduce the incidence of ONFH. Calcitonin gene-related peptide (CGRP) is a neuropeptide gene which has been closely associated with bone regeneration. In this study, we aimed to observe the effect of combined regulation of the expression of PPAR? and CGRP genes on alcohol-induced adipogenic differentiation of BMSCs. Our results demonstrated that simultaneous downregulation of PPAR? and upregulation of CGRP was efficient in suppressing adipogenic differentiation of BMSCs and promoting their osteogenic differentiation. These findings might enlighten a novel approach for the prevention of ONFH. PMID:24633961

Li, Jinfeng; Wang, Yisheng; Li, Yuebai; Sun, Junkui; Zhao, Guoqiang

2014-07-01

181

The exportomer: the peroxisomal receptor export machinery.  

PubMed

Peroxisomes constitute a dynamic compartment of almost all eukaryotic cells. Depending on environmental changes and cellular demands peroxisomes can acquire diverse metabolic roles. The compartmentalization of peroxisomal matrix enzymes is a prerequisite to carry out their physiologic function. The matrix proteins are synthesized on free ribosomes in the cytosol and are ferried to the peroxisomal membrane by specific soluble receptors. Subsequent to cargo release into the peroxisomal matrix, the receptors are exported back to the cytosol to facilitate further rounds of matrix protein import. This dislocation step is accomplished by a remarkable machinery, which comprises enzymes required for the ubiquitination as well as the ATP-dependent extraction of the receptor from the membrane. Interestingly, receptor ubiquitination and dislocation are the only known energy-dependent steps in the peroxisomal matrix protein import process. The current view is that the export machinery of the receptors might function as molecular motor not only in the dislocation of the receptors but also in the import step of peroxisomal matrix protein by coupling ATP-dependent removal of the peroxisomal import receptor with cargo translocation into the organelle. In this review we will focus on the architecture and function of the peroxisomal receptor export machinery, the peroxisomal exportomer. PMID:22983384

Platta, Harald W; Hagen, Stefanie; Erdmann, Ralf

2013-04-01

182

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

183

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

PubMed Central

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

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

2013-01-01

184

PeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease  

PubMed Central

Peroxisomes are essential organelles of eukaryotic origin, ubiquitously distributed in cells and organisms, playing key roles in lipid and antioxidant metabolism. Loss or malfunction of peroxisomes causes more than 20 fatal inherited conditions. We have created a peroxisomal database () that includes the complete peroxisomal proteome of Homo sapiens and Saccharomyces cerevisiae, by gathering, updating and integrating the available genetic and functional information on peroxisomal genes. PeroxisomeDB is structured in interrelated sections ‘Genes’, ‘Functions’, ‘Metabolic pathways’ and ‘Diseases’, that include hyperlinks to selected features of NCBI, ENSEMBL and UCSC databases. We have designed graphical depictions of the main peroxisomal metabolic routes and have included updated flow charts for diagnosis. Precomputed BLAST, PSI-BLAST, multiple sequence alignment (MUSCLE) and phylogenetic trees are provided to assist in direct multispecies comparison to study evolutionary conserved functions and pathways. Highlights of the PeroxisomeDB include new tools developed for facilitating (i) identification of novel peroxisomal proteins, by means of identifying proteins carrying peroxisome targeting signal (PTS) motifs, (ii) detection of peroxisomes in silico, particularly useful for screening the deluge of newly sequenced genomes. PeroxisomeDB should contribute to the systematic characterization of the peroxisomal proteome and facilitate system biology approaches on the organelle.

Schluter, Agatha; Fourcade, Stephane; Domenech-Estevez, Enric; Gabaldon, Toni; Huerta-Cepas, Jaime; Berthommier, Guillaume; Ripp, Raymond; Wanders, Ronald J. A.; Poch, Olivier; Pujol, Aurora

2007-01-01

185

PeroxisomeDB 2.0: an integrative view of the global peroxisomal metabolome  

PubMed Central

Peroxisomes are essential organelles that play a key role in redox signalling and lipid homeostasis. They contain a highly diverse enzymatic network among different species, mirroring the varied metabolic needs of the organisms. The previous PeroxisomeDB version organized the peroxisomal proteome of humans and Saccharomyces cerevisiae based on genetic and functional information into metabolic categories with a special focus on peroxisomal disease. The new release (http://www.peroxisomeDB.org) adds peroxisomal proteins from 35 newly sequenced eukaryotic genomes including fungi, yeasts, plants and lower eukaryotes. We searched these genomes for a core ensemble of 139 peroxisomal protein families and identified 2706 putative peroxisomal protein homologs. Approximately 37% of the identified homologs contained putative peroxisome targeting signals (PTS). To help develop understanding of the evolutionary relationships among peroxisomal proteins, the new database includes phylogenetic trees for 2386 of the peroxisomal proteins. Additional new features are provided, such as a tool to capture kinetic information from Brenda, CheBI and Sabio-RK databases and more than 1400 selected bibliographic references. PeroxisomeDB 2.0 is a freely available, highly interactive functional genomics platform that offers an extensive view on the peroxisomal metabolome across lineages, thus facilitating comparative genomics and systems analysis of the organelle.

Schluter, Agatha; Real-Chicharro, Alejandro; Gabaldon, Toni; Sanchez-Jimenez, Francisca; Pujol, Aurora

2010-01-01

186

A Sulfhydryl Reagent Modulates Systemic Signaling for Wound-Induced and Systemin-Induced Proteinase Inhibitor Synthesis.  

PubMed Central

The sulfhydryl group reagent p-chloromecuribenzene sulfonic acid (PCMBS), an established inhibitor of active apoplastic phloem loading of sucrose in several plant species, is shown to be a powerful inhibitor of wound-induced and systemin-induced activation of proteinase inhibitor synthesis and accumulation in leaves of tomato plants (Lycopersicon esculentum cv Castlemart). PCMBS, supplied to young tomato plants through their cut stems, blocks accumulation of proteinase inhibitors in leaves in response to wounding. The application of systemin directly to fresh wounds enhances systemic accumulation of proteinase inhibitors to levels higher than wounding alone. Placed on fresh wounds, PCMBS severely inhibits systemic induction of proteinase inhibitors, in both the presence and absence of exogenous systemin. PCMBS inhibition can be reversed by cysteine, dithiothreitol, and glutathione. Radiolabeled systemin placed on fresh wounds is readily transported from the wounded leaves to upper leaves. However, in the presence of PCMBS, radiolabeled systemin is not transported away from wound sites. Induction of proteinase inhibitor I synthesis by oligouronides (degree of polymerization [almost equal to] 20), linolenic acid, or methyl jasmonate was not inhibited by PCMBS. The cumulative data support a possible role for sulfhydryl groups in mediating the translocation of systemin from wound sites to distal receptor sites in tomato plants and further support a role for systemin as a systemic wound signal.

Narvaez-Vasquez, J.; Orozco-Cardenas, M. L.; Ryan, C. A.

1994-01-01

187

Mitochondria are targets for peroxisome-derived oxidative stress in cultured mammalian cells.  

PubMed

Many cellular processes are driven by spatially and temporally regulated redox-dependent signaling events. Although mounting evidence indicates that organelles such as the endoplasmic reticulum and mitochondria can function as signaling platforms for oxidative stress-regulated pathways, little is known about the role of peroxisomes in these processes. In this study, we employ targeted variants of the genetically encoded photosensitizer KillerRed to gain a better insight into the interplay between peroxisomes and cellular oxidative stress. We show that the phototoxic effects of peroxisomal KillerRed induce mitochondria-mediated cell death and that this process can be counteracted by targeted overexpression of a select set of antioxidant enzymes, including peroxisomal glutathione S-transferase kappa 1, superoxide dismutase 1, and mitochondrial catalase. We also present evidence that peroxisomal disease cell lines deficient in plasmalogen biosynthesis or peroxisome assembly are more sensitive to KillerRed-induced oxidative stress than control cells. Collectively, these findings confirm and extend previous observations suggesting that disturbances in peroxisomal redox control and metabolism can sensitize cells to oxidative stress. In addition, they lend strong support to the ideas that peroxisomes and mitochondria share a redox-sensitive relationship and that the redox communication between these organelles is not only mediated by diffusion of reactive oxygen species from one compartment to the other. Finally, these findings indicate that mitochondria may act as dynamic receivers, integrators, and transmitters of peroxisome-derived mediators of oxidative stress, and this may have profound implications for our views on cellular aging and age-related diseases. PMID:23988789

Wang, Bo; Van Veldhoven, Paul P; Brees, Chantal; Rubio, Noemí; Nordgren, Marcus; Apanasets, Oksana; Kunze, Markus; Baes, Myriam; Agostinis, Patrizia; Fransen, Marc

2013-12-01

188

Hepatotoxic reactions induced by beta-lactamase inhibitors.  

PubMed

Since amoxicillin/clavulanate was first introduced in the UK in 1981, beta-lactamase inhibitors are used increasingly worldwide. Two more drugs of this class are currently available, sulbactam and tazobactam. Meanwhile, adverse drug reactions associated with amoxicillin/clavulanate occurring late after the end of therapy have been repeatedly published. In many cases, a cholestatic hepatitis was diagnosed that was most likely caused by the clavulanic acid component of the combination. Symptoms were mostly mild and reversible, whereas a number of cases showing a protracted, even fatal course of the disease have been documented. This article summarizes and analyzes all relevant studies and case reports dealing with hepatotoxicity caused by beta-lactamase inhibitors. The description of a typical case from our own patient population illustrates the clinical challenge associated with this adverse drug reaction. PMID:11772541

Berg, P; Hahn, E G

2001-12-17

189

Protection against HIV-envelope-induced neuronal cell destruction by HIV attachment inhibitors  

Microsoft Academic Search

We demonstrate that HIV attachment inhibitors (AIs) prevent HIV envelope-induced destruction of two neuronal cell lines (SH-SY5Y\\u000a and BE(2)-M17) at low nanomolar concentrations. The fusion inhibitor enfuvirtide and the CCR5 inhibitors UK427,857 and TAK779\\u000a do not display protection activity, suggesting the involvement of Env\\/cell interaction site(s) distinct from the sites involved\\u000a in the viral entry process. We surmise that by

Sharon Zhang; Louis Alexander; Tao Wang; Michele Agler; Nannon Zhou; Hua Fang; John Kadow; Paul Clapham; Pin-Fang Lin

2010-01-01

190

Mechanisms of Myocyte Cytotoxicity Induced by the Multikinase Inhibitor Sorafenib  

Microsoft Academic Search

The use of the anticancer multikinase inhibitor sorafenib is associated with cardiac ischemia or infarction and an increase\\u000a in hypertension. We investigated various mechanisms that might be responsible for its cardiotoxicity in a neonatal rat myocyte\\u000a model. As measured by lactate dehydrogenase release, sorafenib treatment of myocytes caused dose-dependent damage at therapeutically\\u000a relevant concentrations. It had been hypothesized that inhibition

Brian B. Hasinoff; Daywin Patel

2010-01-01

191

Severe oligohydramnios induced by cyclooxygenase-2 inhibitor nimesulide  

Microsoft Academic Search

Background: Cyclooxygenase-2 inhibitors might have fewer adverse fetal effects than conventional nonsteroidal anti-inflammatory drugs that inhibit both isoforms of the enzyme. Although cyclooxygenase-2 is expressed in fetal kidneys, there are no reports of adverse effects in human pregnancy.Case: A 27-year-old woman, gravida 2, para 0, with a twin pregnancy at 24 weeks’ gestation had placement of a cervical cerclage. Nimesulide

Robert P Holmes; Peter R Stone

2000-01-01

192

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

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

1985-01-01

193

Thyromimetic mode of action of peroxisome proliferators: activation of 'malic' enzyme gene transcription.  

PubMed Central

Peroxisome proliferators induce thyroid-hormone-dependent liver activities, e.g. 'malic' enzyme, mitochondrial glycerol-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, S14[Hertz, Aurbach, Hashimoto and Bar-Tana (1991) Biochem. J. 274, 745-751]. Here we report that the thyromimetic effect of peroxisome proliferators with respect to 'malic' enzyme result from transcriptional activation of the 'malic' enzyme gene, mediated by binding of the peroxisome proliferator activated receptor (PPAR alpha)/retinoid X receptor (RXR alpha) heterodimer to a 5'-flanking enhancer of the 'malic' enzyme promoter. The enhancer involved is distinct from the thyroid hormone response element of the 'malic' enzyme promoter and is partly homologous with that which mediates transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisome proliferators. Hence transcriptional activation of thyroid-hormone-dependent liver genes by xenobiotic or endogenous amphipathic carboxylates collectively defined as peroxisome proliferators is mediated by a transduction pathway similar to that involved in transcriptional activation of peroxisomal beta-oxidative genes and distinct from that which mediates thyroid hormone action.

Hertz, R; Nikodem, V; Ben-Ishai, A; Berman, I; Bar-Tana, J

1996-01-01

194

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

PubMed

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

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

2013-08-01

195

The anandamide transport inhibitor AM404 reduces the rewarding effects of nicotine and nicotine-induced dopamine elevations in the nucleus accumbens shell in rats  

PubMed Central

BACKGROUND AND PURPOSE The fatty acid amide hydrolase inhibitor URB597 can reverse the abuse-related behavioural and neurochemical effects of nicotine in rats. Fatty acid amide hydrolase inhibitors block the degradation (and thereby magnify and prolong the actions) of the endocannabinoid anandamide (AEA), and also the non-cannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). OEA and PEA are endogenous ligands for peroxisome proliferator-activated receptors alpha (PPAR-?). Since recent evidence indicates that PPAR-? can modulate nicotine reward, it is unclear whether AEA plays a role in the effects of URB597 on nicotine reward. EXPERIMENTAL APPROACH A way to selectively increase endogenous levels of AEA without altering OEA or PEA levels is to inhibit AEA uptake into cells by administering the AEA transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404). To clarify AEA's role in nicotine reward, we investigated the effect of AM404 on conditioned place preference (CPP), reinstatement of abolished CPP, locomotor suppression and anxiolysis in an open field, and dopamine elevations in the nucleus accumbens shell induced by nicotine in Sprague-Dawley rats. KEY RESULTS AM404 prevented the development of nicotine-induced CPP and impeded nicotine-induced reinstatement of the abolished CPP. Furthermore, AM404 reduced nicotine-induced increases in dopamine levels in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. AM404 did not alter the locomotor suppressive or anxiolytic effect of nicotine. CONCLUSIONS AND IMPLICATIONS These findings suggest that AEA transport inhibition can counteract the addictive effects of nicotine and that AEA transport may serve as a new target for development of medications for treatment of tobacco dependence. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7

Scherma, Maria; Justinova, Zuzana; Zanettini, Claudio; Panlilio, Leigh V; Mascia, Paola; Fadda, Paola; Fratta, Walter; Makriyannis, Alexandros; Vadivel, Subramanian K; Gamaleddin, Islam; Le Foll, Bernard; Goldberg, Steven R

2012-01-01

196

Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness  

Microsoft Academic Search

BACKGROUND: Peroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD) has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat

Karina Meidtner; Hermann Schwarzenbacher; Maren Scharfe; Simone Severitt; Helmut Blöcker; Ruedi Fries

2009-01-01

197

Peroxisome biogenesis in the yeast Yarrowia lipolytica.  

PubMed

Extensive peroxisome proliferation during growth on oleic acid, combined with the availability of excellent genetic tools, makes the dimorphic yeast, Yarrowia lipolytica, a powerful model system to study the molecular mechanisms involved in peroxisome biogenesis. A combined genetic, biochemical, and morphological approach has revealed that the endoplasmic reticulum (ER) plays an essential role in the assembly of functional peroxisomes in this yeast. The trafficking of some membrane proteins to the peroxisomes occurs via the ER, results in their glycosylation in the ER lumen, does not involve transit through the Golgi, and requires the products of the SEC238, SRP54, PEX1, and PEX6 genes. The authors' data suggest a model for protein import into peroxisomes via two subpopulations of ER-derived vesicles that are distinct from secretory vesicles. A kinetic analysis of the trafficking of peroxisomal proteins in vivo has demonstrated that membrane and matrix proteins are initially targeted to multiple vesicular precursors that represent intermediates in the assembly pathway of peroxisomes. The authors have also recently identified a novel cytosolic chaperone, Pex20p, that assists in the oligomerization of thiolase in the cytosol and promotes its targeting to the peroxisome. These data provide the first evidence that a chaperone-assisted folding and oligomerization of thiolase in the cytosol is required for the import of this protein into the peroxisomal matrix. PMID:11330048

Titorenko, V I; Smith, J J; Szilard, R K; Rachubinski, R A

2000-01-01

198

Presence of thiamine pyrophosphate in mammalian peroxisomes  

PubMed Central

Background Thiamine pyrophosphate (TPP) is a cofactor for 2-hydroxyacyl-CoA lyase 1 (HACL1), a peroxisomal enzyme essential for the ?-oxidation of phytanic acid and 2-hydroxy straight chain fatty acids. So far, HACL1 is the only known peroxisomal TPP-dependent enzyme in mammals. Little is known about the transport of metabolites and cofactors across the peroxisomal membrane and no peroxisomal thiamine or TPP carrier has been identified in mammals yet. This study was undertaken to get a better insight into these issues and to shed light on the role of TPP in peroxisomal metabolism. Results Because of the crucial role of the cofactor TPP, we reanalyzed its subcellular localization in rat liver. In addition to the known mitochondrial and cytosolic pools, we demonstrated, for the first time, that peroxisomes contain TPP (177 ± 2 pmol/mg protein). Subsequently, we verified whether TPP could be synthesized from its precursor thiamine, in situ, by a peroxisomal thiamine pyrophosphokinase (TPK). However, TPK activity was exclusively recovered in the cytosol. Conclusion Our results clearly indicate that mammalian peroxisomes do contain TPP but that no pyrophosphorylation of thiamine occurs in these organelles, implying that thiamine must enter the peroxisome already pyrophosphorylated. Consequently, TPP entry may depend on a specific transport system or, in a bound form, on HACL1 translocation.

Fraccascia, Patrizia; Sniekers, Mieke; Casteels, Minne; Van Veldhoven, Paul P

2007-01-01

199

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.  

PubMed

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 (LW) by 1.6%, 13.4% and 42.5%, respectively, and in the ratio of LW to body weight by 8.8%, 16.7% and 40.2%, respectively, in male rats. These effects were less pronounced in females. SOW selectively increased liver mass in male rats but Sudan red staining was not different, which indicates that hepatic lipid accumulation was similar in both genders. However, SOW even at the highest dosage did not influence serum ALT and AST activities in male or female rats. Moreover, SOW was found to activate PPAR-alpha in human hepatoma-derived HepG2 cells, as evidenced by the upregulation of PPAR-alpha and acyl-CoA oxidase mRNA expression. Thus, SOW-dependent PPAR-alpha activation may precede the development of the gender difference in hepatic hypertrophy; this process may be influenced by sex hormone status. PMID:18397819

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

2008-06-01

200

Glycoprotein IIb\\/IIIa inhibitor-induced thrombocytopenia  

Microsoft Academic Search

Summary  Thrombocyte glycoprotein IIb\\/IIIa inhibitors prevent fibrinogen binding and thereby thrombocyte aggregation. The inhibition\\u000a of thrombocyte activation at the damaged coronary plaque is the target of the new therapeutic strategies in treating acute\\u000a coronary syndrome. This reduces the ischemic complications associated with the non-STelevation myocardial infarction (NSTEMI)\\u000a and percutaneous coronary intervention (PCI).\\u000a \\u000a Thrombocytopenia is a known complication of glycoprotein (GP) IIb\\/IIIa

Samir M. Said; Judit Hahn; Eberhard Schleyer; Marc Müller; Georg Martin Fiedler; Michael Buerke; Roland Prondzinsky

2007-01-01

201

Proton pump inhibitor-induced hypomagnesemia: A new challenge  

PubMed Central

Proton pump inhibitors (PPIs) are commonly used in clinical practice for the prevention and treatment of peptic ulcer, gastritis, esophagitis and gastroesophageal reflux. Hypomagnesemia has recently been recognized as a side effect of PPIs. Low magnesium levels may cause symptoms from several systems, some of which being potentially serious, such as tetany, seizures and arrhythmias. It seems that PPIs affect the gastrointestinal absorption of magnesium. Clinicians should be vigilant in order to timely consider and prevent or reverse hypomagnesemia in patients who take PPIs, especially if they are prone to this electrolyte disorder.

Florentin, Matilda; Elisaf, Moses S

2012-01-01

202

Proteins and enzymes of the peroxisomal membrane in mammals.  

PubMed

Proteins of the peroxisomal membrane can be schematically divided into two groups, one being made up of more or less characterized proteins with generally unknown functions and the other consisting of enzyme activities of which the corresponding proteins have not been characterized. In the present report, these proteins and enzymes are described with the addition of unpublished results regarding their induction by peroxisome proliferators at the post-transcriptional level. Integral membrane proteins (IMPs) can be isolated using an alkaline solution of sodium carbonate. A dozen of preponderant IMPs can be seen on sodium dodecyl sulfate polyacrylamide gel electrophoresis, and the major band corresponds to a 70 kDa IMP, of which the corresponding rat cDNA is known. Some IMPs have been characterized by immunoblot analysis. Recently, a cDNA has been cloned for a peroxisome assembly factor (35 kDa IMP). Functions have also been proposed for some IMPs but are not yet firmly settled. Some IMPs (450/520, 70 and 26 kDa) are strongly induced by peroxisome proliferators. Our results extend to cipro- and fenofibrate the observation that the 70 kDa IMP mRNA level is strongly increased in di(2-ethylhexyl)phtalate-treated rats. All the enzyme activities associated with the peroxisomal membrane are involved in lipid metabolism: activation of substrates (fatty acids), ether lipid biosynthesis, and formation of precursors (fatty alcohols). It is believed that the same long-chain acyl-CoA synthetase occurs in the peroxisome as well as in the outer mitochondrial membrane and the endoplasmic reticulum. However, two highly homologous but different cDNAs encoding rat liver and brain long-chain acyl-CoA synthetases have been isolated recently. Evidence has been accumulated for a distinct synthetase that specifically activates very-long chain fatty acids. The first two steps of ether lipid biosynthesis require dihydroxyacetone-phosphate (DHAP) acyltransferase and alkyl-DHAP synthetase, the active sites of which are located on the inner surface of the membrane. In contrast, the catalytic site of the acyl/alkyl-DHAP reductase, which generates sn-1-alkyl-glycerol-3-phosphate, is located on the outer surface. Long-chain fatty alcohols, which are obligate precursors of ether lipids and wax esters, are biosynthetized by the reduction of the corresponding acyl-CoAs via the action of an acyl-CoA reductase. Peroxisome proliferators do not appear to stimulate these enzyme activities specifically. However, we report that feno- and ciprofibrate treatments increase six-fold the palmitoyl-CoA synthetase mRNA level in the rat liver. PMID:8518748

Causeret, C; Bentejac, M; Bugaut, M

1993-01-01

203

Dual targeting of yeast catalase A to peroxisomes and mitochondria.  

PubMed Central

Yeast catalase A (Cta1p) contains two peroxisomal targeting signals (SSNSKF) localized at its C-terminus and within the N-terminal third of the protein, which both can target foreign proteins to peroxisomes. In the present study we demonstrated that Cta1p can also enter mitochondria, although the enzyme lacks a classical mitochondrial import sequence. Cta1p co-targeting was studied in a catalase A null mutant after growth on different carbon sources, and expression of a Cta1p-GFP (green fluorescent protein)-fusion protein or a Cta1p derivative containing either a c-Myc epitope (Cta1p(myc)) or a SKF-extended tag (Cta1p(myc-SKF)). Peroxisomal and mitochondrial co-import of catalase A were tested qualitatively by fluorescence microscopy and functional complementation of a Delta cta1 null mutation, and quantitatively by subcellular fractionation followed by Western blot analysis and enzyme activity assays. Efficient Cta1p import into peroxisomes was observed when cells were cultivated under peroxisome-inducing conditions (i.e. growth on oleate), whereas significant co-import of Cta1p-GFP into mitochondria occurred when cells were grown under respiratory conditions that favour oxygen stress and ROS (reactive oxygen species) accumulation within this organelle. In particular, when cells were grown on the non-fermentable carbon source raffinose, respiration is maximally enhanced, and catalase A was efficiently targeted to the mitochondrial matrix where it presumably functions as scavenger of H2O2 and mitochondrial-derived ROS.

Petrova, Ventsislava Y; Drescher, Diane; Kujumdzieva, Anna V; Schmitt, Manfred J

2004-01-01

204

Genes Are Often Sheltered from the Global Histone Hyperacetylation Induced by HDAC Inhibitors  

PubMed Central

Histone deacetylase inhibitors (HDACi) are increasingly used as therapeutic agents, but the mechanisms by which they alter cell behaviour remain unclear. Here we use microarray expression analysis to show that only a small proportion of genes (?9%) have altered transcript levels after treating HL60 cells with different HDACi (valproic acid, Trichostatin A, suberoylanilide hydroxamic acid). Different gene populations respond to each inhibitor, with as many genes down- as up-regulated. Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated. Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi.

O'Neill, Laura P.; Turner, Bryan M.; Nightingale, Karl P.

2012-01-01

205

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

206

Localization of the Tomato Bushy Stunt Virus Replication Protein p33 Reveals a Peroxisome-to-Endoplasmic Reticulum Sorting PathwayW?  

PubMed Central

Tomato bushy stunt virus (TBSV), a positive-strand RNA virus, causes extensive inward vesiculations of the peroxisomal boundary membrane and formation of peroxisomal multivesicular bodies (pMVBs). Although pMVBs are known to contain protein components of the viral membrane-bound RNA replication complex, the mechanisms of protein targeting to peroxisomal membranes and participation in pMVB biogenesis are not well understood. We show that the TBSV 33-kD replication protein (p33), expressed on its own, targets initially from the cytosol to peroxisomes, causing their progressive aggregation and eventually the formation of peroxisomal ghosts. These altered peroxisomes are distinct from pMVBs; they lack internal vesicles and are surrounded by novel cytosolic vesicles that contain p33 and appear to be derived from evaginations of the peroxisomal boundary membrane. Concomitant with these changes in peroxisomes, p33 and resident peroxisomal membrane proteins are relocalized to the peroxisomal endoplasmic reticulum (pER) subdomain. This sorting of p33 is disrupted by the coexpression of a dominant-negative mutant of ADP-ribosylation factor1, implicating coatomer in vesicle formation at peroxisomes. Mutational analysis of p33 revealed that its intracellular sorting is also mediated by several targeting signals, including three peroxisomal targeting elements that function cooperatively, plus a pER targeting signal resembling an Arg-based motif responsible for vesicle-mediated retrieval of escaped ER membrane proteins from the Golgi. These results provide insight into virus-induced intracellular rearrangements and reveal a peroxisome-to-pER sorting pathway, raising new mechanistic questions regarding the biogenesis of peroxisomes in plants.

McCartney, Andrew W.; Greenwood, John S.; Fabian, Marc R.; White, K. Andrew; Mullen, Robert T.

2005-01-01

207

Peroxisome proliferator-activated receptors: insight into multiple cellular functions  

Microsoft Academic Search

Peroxisome proliferator-activated receptors, PPARs, (NR1C) are nuclear hormone receptors implicated in energy homeostasis. Upon activation, these ligand-inducible transcription factors stimulate gene expression by binding to the promoter of target genes. The different structural domains of PPARs are presented in terms of activation mechanisms, namely ligand binding, phosphorylation, and cofactor interaction. The specificity of ligands, such as fatty acids, eicosanoids, fibrates

Pascal Escher; Walter Wahli

2000-01-01

208

Oedematogenic activity induced by Kunitz-type inhibitors from Dimorphandra mollis seeds.  

PubMed

Proteinase inhibitors from plants represent a form of storage protein or may be involved in plant defense mechanisms against pests and diseases. In this study, we have investigated the oedematogenic activity of DMTI (20 kDa) and DMTI-II (23 kDa), two serine proteinases inhibitors isolated from Dimorphandra mollis (Leguminosae-Mimosoideae) seeds, belonging to the Kunitz family. Paw oedema was induced in male Wistar rats, and measured before and selected times after injection of the proteinase inhibitors. Injection of DMTI-II (3-100 microg/paw) induced a dose-dependent rat paw oedema of rapid onset and short duration, whereas DMTI (3-100 microg/paw) caused a discrete response. The histamine/5-HT receptor antagonist cyproheptadine (2 mg/kg) markedly reduced the DMTI-II-induced oedema. The bradykinin B2 receptor antagonist JE 049 (0.6 mg/kg), the tachykinin NK1 receptor antagonist SR140333 (100 microg/kg) or the NK2 receptor antagonist SR48968 (1 mg/kg) all significantly reduced the DMTI-II-induced oedema. Depletion of sensory neuropeptides by capsaicin also resulted in a significant reduction of oedema formation. In rat isolated peritoneal mast cells, DMTI-II failed to directly release histamine. In conclusion, the proteinase inhibitor DMTI-II induces rat paw oedema by triggering the formation of different inflammatory mediators and pathways, where mast cells and sensory fibers seem to play a pivotal role. PMID:16386283

Mello, Gláucia C; Desouza, Ivani A; Marangoni, Sérgio; Novello, José C; Antunes, Edson; Macedo, Maria Lígia R

2006-02-01

209

nNOS inhibitors attenuate methamphetamine-induced dopaminergic neurotoxicity but not hyperthermia in mice.  

PubMed

Methamphetamine (METH)-induced dopaminergic neurotoxicity is associated with hyperthermia. We investigated the effect of several neuronal nitric oxide synthase (nNOS) inhibitors on METH-induced hyperthermia and striatal dopaminergic neurotoxicity. Administration of METH (5 mg/kg; q. 3 h x 3) to Swiss Webster mice produced marked hyperthermia and 50-60% depletion of striatal dopaminergic markers 72 h after METH administration. Pretreatment with the nNOS inhibitors S-methylthiocitrulline (SMTC; 10 mg/kg) or 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg) before each METH injection did not affect the persistent hyperthermia produced by METH, but afforded protection against the depletion of dopaminergic markers. A low dose (25 mg/kg) of the nNOS inhibitor 7-nitroindazole (7-NI) did not affect METH-induced hyperthermia, but a high dose (50 mg/kg) produced significant hypothermia. These findings indicate that low dose of selective nNOS inhibitors protect against METH-induced neurotoxicity with no effect on body temperature and support the hypothesis that nitric oxide (NO) and peroxynitrite have a major role in METH-induced dopaminergic neurotoxicity. PMID:11006970

Itzhak, Y; Martin, J L; Ail, S F

2000-09-11

210

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

PubMed

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

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

2011-03-01

211

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

PubMed Central

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

Hansen, Joel D.; Hannapel, David J.

1992-01-01

212

Effects of inhibitors of radiation-induced potentially lethal damage repair on chemotherapy in murine tumors  

SciTech Connect

Enhancement of various antitumor drugs effects by inhibitors of radiation-induced potentially lethal damage (PLD) repair was studied in three murine tumors (EMT-6, RIF-1 and SQ-1). In EMT-6 tumors, PLD repair inhibitors, 3'-deoxyguanosine (3'dG) and 7904 (a derivative of 3'-deoxyadenosine) showed a marked enhancement of tumor growth inhibition by anticancerous drugs (FT-207 (a derivative of 5-FU), bleomycin, Ara-C, ACNU). However, the effects of mitomycin-C and vincristine were not potentiated by the inhibitors. In SQ-1 carcinomas, another repair inhibitor, ara-A (1-..beta..-D-arabinofuranosyladenine) (32 mg/kg) potentiated the effect of ACNU. In RIF-1 sarcomas, in which a low PLD repair function has been reported after ionizing radiation exposure, the potentiation was not so marked as in EMT-6 or SQ-1 tumors. Thus, as a possibility, the potentiation by inhibitors of radiation-induced PLD repair might be a result of the inhibition of chemical-induced PLD repair. The study of this field may contribute to the improvement of cancer treatment not only by radiotherapy but also by chemotherapy.

Nakatsugawa, S.; Sugahara, T.

1982-09-01

213

Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats  

PubMed Central

Objective: To examine modulations caused by cyclooxygenase-2 (COX-2) inhibitors on altered microenvironments and overbalanced neurotransmitters in pilocarpine-induced epileptic status rats and to investigate possible mechanisms. Methods: Celecoxib (a COX-2 inhibitor) was administered 45 min prior to pilocarpine administration. The effects of COX-2 inhibitors on mIPSCs (miniature GABAergic inhibitory postsynaptic currents) of CA3 pyramidal cells in the hippocampus were recorded. Expressions of COX-2, c-Fos, newly generated neurons, and activated microgliosis were analyzed by immunohistochemistry, and expressions of ?-subunit of ?-amino butyric acid (GABAA) receptors and mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activity were detected by Western blotting. Results: Pretreatment with celecoxib showed protection against pilocarpine-induced seizures. Celecoxib prevented microglia activation in the hilus and inhibited the abnormal neurogenesis and astrogliosis in the hippocampus by inhibiting MAPK/ERK activity and c-Fos transcription. Celecoxib also up-regulated the expression of GABAA receptors. NS-398 (N-2-cyclohexyloxy-4-nitrophenyl-methanesulfonamide), another COX-2 inhibitor, enhanced the frequency and decay time of mIPSCs. Conclusion: The COX-2 inhibitor celecoxib decreased neuronal excitability and prevented epileptogenesis in pilocarpine-induced status epilepticus rats. Celecoxib regulates synaptic reorganization by inhibiting astrogliosis and ectopic neurogenesis by attenuating MAPK/ERK signal activity, mediated by a GABAergic mechanism.

Zhang, Hai-ju; Sun, Ruo-peng; Lei, Ge-fei; Yang, Lu; Liu, Chun-xi

2008-01-01

214

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

PubMed Central

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

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

2011-01-01

215

Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.  

PubMed

Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted. PMID:24689876

Nakagawa, Takayuki; Matsushima, Tomohiro; Kawano, Satoshi; Nakazawa, Youya; Kato, Yu; Adachi, Yusuke; Abe, Takanori; Semba, Taro; Yokoi, Akira; Matsui, Junji; Tsuruoka, Akihiko; Funahashi, Yasuhiro

2014-06-01

216

Arginine improves peroxisome functioning in cells from patients with a mild peroxisome biogenesis disorder  

PubMed Central

Background Zellweger spectrum disorders (ZSDs) are multisystem genetic disorders caused by a lack of functional peroxisomes, due to mutations in one of the PEX genes, encoding proteins involved in peroxisome biogenesis. The phenotypic spectrum of ZSDs ranges from an early lethal form to much milder presentations. In cultured skin fibroblasts from mildly affected patients, peroxisome biogenesis can be partially impaired which results in a mosaic catalase immunofluorescence pattern. This peroxisomal mosaicism has been described for specific missense mutations in various PEX genes. In cell lines displaying peroxisomal mosaicism, peroxisome biogenesis can be improved when these are cultured at 30°C. This suggests that these missense mutations affect the folding and/or stability of the encoded protein. We have studied if the function of mutant PEX1, PEX6 and PEX12 can be improved by promoting protein folding using the chemical chaperone arginine. Methods Fibroblasts from three PEX1 patients, one PEX6 and one PEX12 patient were cultured in the presence of different concentrations of arginine. To determine the effect on peroxisome biogenesis we studied the following parameters: number of peroxisome-positive cells, levels of PEX1 protein and processed thiolase, and the capacity to ?-oxidize very long chain fatty acids and pristanic acid. Results Peroxisome biogenesis and function in fibroblasts with mild missense mutations in PEX1, 6 and 12 can be improved by arginine. Conclusion Arginine may be an interesting compound to promote peroxisome function in patients with a mild peroxisome biogenesis disorder.

2013-01-01

217

Novel peroxisome clustering mutants and peroxisome biogenesis mutants of Saccharomyces cerevisiae  

PubMed Central

The goal of this research is to identify and characterize the protein machinery that functions in the intracellular translocation and assembly of peroxisomal proteins in Saccharomyces cerevisiae. Several genes encoding proteins that are essential for this process have been identified previously by Kunau and collaborators, but the mutant collection was incomplete. We have devised a positive selection procedure that identifies new mutants lacking peroxisomes or peroxisomal function. Immunofluorescence procedures for yeast were simplified so that these mutants could be rapidly and efficiently screened for those in which peroxisome biogenesis is impaired. With these tools, we have identified four complementation groups of peroxisome biogenesis mutants, and one group that appears to express reduced amounts of peroxisomal proteins. Two of our mutants lack recognizable peroxisomes, although they might contain peroxisomal membrane ghosts like those found in Zellweger syndrome. Two are selectively defective in packaging peroxisomal proteins and moreover show striking intracellular clustering of the peroxisomes. The distribution of mutants among complementation groups implies that the collection of peroxisome biogenesis mutants is still incomplete. With the procedures described, it should prove straightforward to isolate mutants from additional complementation groups.

1993-01-01

218

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma.  

PubMed

The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi. PMID:24979794

Bhadury, Joydeep; Nilsson, Lisa M; Veppil Muralidharan, Somsundar; Green, Lydia C; Li, Zhoulei; Gesner, Emily M; Hansen, Henrik C; Keller, Ulrich B; McLure, Kevin G; Nilsson, Jonas A

2014-07-01

219

Anti-inflammatory and anti-hyperalgesic effect of all-trans retinoic acid in carrageenan-induced paw edema in Wistar rats: Involvement of peroxisome proliferator-activated receptor-?/? receptors  

PubMed Central

Objective: In this study, we investigated the role of peroxisome proliferator-activated receptors (PPAR)-?/? receptors in carrageenan-induced inflammation and in the anti-inflammatory effects of all-trans retinoic acid (ATRA). Materials and Methods: The ?-carrageenan (0.1 ml of 1% w/v) was injected into intra-plantar (i.pl.) region of the hind paw to produce acute inflammation. Paw volume was measured by using the mercury plethysmography. Further, mechanical and thermal hyperalgesia (TH) were assessed by using the dynamic plantar aesthesiometer and plantar test apparatus, respectively. In addition, markers of oxido-nitrosative stress were assessed spectrophotometrically in the hind paw tissue 5 h post-carrageenan. Results: An i.pl injection of carrageenan has produced a marked mechanical hyperalgesia (MH) and TH in ipsilateral paw, which was associated with significant elevated oxido-nitrosative stress. Treatment with ATRA (5 mg/kg/p.o/4 days) and GW0742, a selective PPAR-?/? receptor agonist (0.1 mg/kg/i.p/4 days), significantly decreased the paw volume, mechanical and TH as compared to vehicle control. Administration of GSK0660, selective PPAR-?/? receptor antagonist, at a dose of (0.3 mg/kg/i.p/4 days), did not produce a significant effect on carrageenan-induced paw edema, MH and TH. However, co-administration of GSK0660 (0.3 mg/kg/i.p/4 days) along with both ATRA (5 mg/kg/p.o/4 days) and GW0742 (0.1 mg/kg/i.p/4 days), significantly reverse the decreased paw edema, MH, and TH. These observed ameliorative effects on inflammatory pain symptoms are correlated with the extent of reduction of oxido-nitrosative stress. Conclusion: From above findings, it can be concluded that ATRA exerts anti-inflammatory and anti-hyperalgesic effect, possibly through activation of PPAR-?/? and subsequent reduction of oxido-nitrosative stress.

Gill, Navneet; Bijjem, Krishna Reddy V.; Sharma, Pyare L.

2013-01-01

220

Transfer of metabolites across the peroxisomal membrane.  

PubMed

Peroxisomes perform a large variety of metabolic functions that require a constant flow of metabolites across the membranes of these organelles. Over the last few years it has become clear that the transport machinery of the peroxisomal membrane is a unique biological entity since it includes nonselective channels conducting small solutes side by side with transporters for 'bulky' solutes such as ATP. Electrophysiological experiments revealed several channel-forming activities in preparations of plant, mammalian, and yeast peroxisomes and in glycosomes of Trypanosoma brucei. The properties of the first discovered peroxisomal membrane channel - mammalian Pxmp2 protein - have also been characterized. The channels are apparently involved in the formation of peroxisomal shuttle systems and in the transmembrane transfer of various water-soluble metabolites including products of peroxisomal ?-oxidation. These products are processed by a large set of peroxisomal enzymes including carnitine acyltransferases, enzymes involved in the synthesis of ketone bodies, thioesterases, and others. This review discusses recent data pertaining to solute permeability and metabolite transport systems in peroxisomal membranes and also addresses mechanisms responsible for the transfer of ATP and cofactors such as an ATP transporter and nudix hydrolases. PMID:22206997

Antonenkov, Vasily D; Hiltunen, J Kalervo

2012-09-01

221

A newly discovered function of peroxisomes  

PubMed Central

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

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

2012-01-01

222

Hybrids of oxoisoaporphine-tacrine congeners: Novel acetylcholinesterase and acetylcholinesterase-induced ?-amyloid aggregation inhibitors  

Microsoft Academic Search

A series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced ?-amyloid (A?) aggregation. The new hybrids consist of a unit of 1-azabenzanthrone and a tacrine or its congener, connected through an oligomethylene linker containing an amine group at variable position. These hybrids exhibit high

Huang Tang; Li-Zhen Zhao; Hao-Tao Zhao; Shi-Liang Huang; Shu-Ming Zhong; Jiang-Ke Qin; Zhen-Feng Chen; Zhi-Shu Huang; Hong Liang

2011-01-01

223

Inhibitors of Protein Phosphatases 1 and 2A Block Sugar-Inducible Gene Expression in Plants  

Microsoft Academic Search

Genes coding for two major proteins of the tuberous root of sweet potato (Ipomoea batatas), namely, sporamin and &amylase, are inducible in leaves and petioles when they are supplied with high concentrations of sucrose or other metabolizable sugars, such as glucose and fructose, and the accumulation of a large amount of starch accompanies this induction. Three inhibitors of protein phosphatases

Shin Takeda; Shoji Mano; Masa-aki Ohto; Kenzo Nakamura

1994-01-01

224

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 ...

225

Proteasome inhibitors induce nucleolar aggregation of proteasome target proteins and polyadenylated RNA by altering ubiquitin availability  

Microsoft Academic Search

The ubiquitin–proteasome pathway is essential for most cellular processes, including protein quality control, cell cycle, transcription, signaling, protein transport, DNA repair and stress responses. Hampered proteasome activity leads to the accumulation of polyubiquitylated proteins, endoplastic reticulum (ER) stress and even cell death. The ability of chemical proteasome inhibitors (PIs) to induce apoptosis is utilized in cancer therapy. During PI treatment,

L Latonen; H M Moore; B Bai; S Jäämaa; M Laiho

2011-01-01

226

Role of p53 in cdk Inhibitor VMY-1-103-Induced Apoptosis in Prostate Cancer.  

National Technical Information Service (NTIS)

Cyclin-dependent kinase inhibitor VMY-1-103 induces a G2/M cell cycle arrest and apoptosis in prostate cancer cell lines. Cancer cell lines, including prostate cancer, show a differential sensitivity to VMY-1-103 that correlates with p53 status. In additi...

L. Ringer

2012-01-01

227

Role of p53 in cdk Inhibitor VMY-1-103-induced Apoptosis in Prostate Cancer.  

National Technical Information Service (NTIS)

Cyclin-dependent kinase inhibitor VMY-1-103 induces a G2/M cell cycle arrest and apoptosis in prostate cancer cell lines. Cancer cell lines, including prostate cancer, show a differential sensitivity to VMY-1-103 that correlates with p53 status. In additi...

L. Ringer

2013-01-01

228

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

229

A Novel and Selective Poly (ADP-Ribose) Polymerase Inhibitor Ameliorates Chemotherapy-Induced Painful Neuropathy  

PubMed Central

Background Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice. Results An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment. Conclusion Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.

Ta, Lauren E.; Schmelzer, James D.; Bieber, Allan J.; Loprinzi, Charles L.; Sieck, Gary C.; Brederson, Jill D.; Low, Philip A.; Windebank, Anthony J.

2013-01-01

230

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

231

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

PubMed

The ability of macroencapsulated Saccharomyces cerevisiae CBS8066 to withstand readily and not readily in situ convertible lignocellulose-derived inhibitors was investigated in anaerobic batch cultivations. It was shown that encapsulation increased the tolerance against readily convertible furan aldehyde inhibitors and to dilute acid spruce hydrolysate, but not to organic acid inhibitors that cannot be metabolized anaerobically. Gene expression analysis showed that the protective effect arising from the encapsulation is evident also on the transcriptome level, as the expression of the stress-related genes YAP1, ATR1 and FLR1 was induced upon encapsulation. The transcript levels were increased due to encapsulation already in the medium without added inhibitors, indicating that the cells sensed low stress level arising from the encapsulation itself. We present a model, where the stress response is induced by nutrient limitation, that this helps the cells to cope with the increased stress added by a toxic medium, and that superficial cells in the capsules degrade convertible inhibitors, alleviating the inhibition for the cells deeper in the capsule. PMID:23109889

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

2012-01-01

232

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

PubMed Central

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

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

2012-01-01

233

Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4.  

PubMed

Human cytochrome P450 (CYP) 3A4 is the most abundant hepatic and intestinal phase I enzyme that metabolizes approximately 50% marketed drugs. The crystal structure of bound and unbound CYP3A4 has been recently constructed, and a small active site and a peripheral binding site are identified. A recent study indicates that CYP3A4 undergoes dramatic conformational changes upon binding to ketoconazole or erythromycin with a differential but substantial (>80%) increase in the active site volume, providing a structural basis for ligand promiscuity of CYP3A4. A number of important drugs have been identified as substrates, inducers and/or inhibitors of CYP3A4. The ability of drugs to act as inducers, inhibitors, or substrates for CYP3A is predictive of whether concurrent administration of these compounds with a known CYP3A substrate might lead to altered drug disposition, efficacy or toxicity. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein (P-gp). To date, the identified clinically important CYP3A4 inhibitors mainly include macrolide antibiotics (e.g., clarithromycin, and erythromycin), anti-HIV agents (e.g., ritonavir and delavirdine), antidepressants (e.g. fluoxetine and fluvoxamine), calcium channel blockers (e.g. verapamil and diltiazem), steroids and their modulators (e.g., gestodene and mifepristone), and several herbal and dietary components. Many of these drugs are also mechanism-based inhibitors of CYP3A4, which involves formation of reactive metabolites, binding to CYP3A4 and irreversible enzyme inactivation. A small number of drugs such as rifampin, phenytoin and ritonavir are identified as inducers of CYP3A4. The orphan nuclear receptor, pregnane X receptor (PXR), have been found to play a critical role in the induction of CYP3A4. The inhibition or induction of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs and the patients. The study of interactions of newly synthesized compounds with CYP3A4 has been incorporated into drug development and detection of possible CYP3A4 inhibitors and inducers during the early stages of drug development is critical in preventing potential drug-drug interactions and side effects. Clinicians are encouraged to have a sound knowledge on drugs that behave as substrates, inhibitors or inducers of CYP3A4, and take proper cautions and close monitoring for potential drug interactions when using drugs that are CYP3A4 inhibitors or inducers. PMID:18473749

Zhou, Shu-Feng

2008-05-01

234

The interaction between Helminthosporium carbonum and maize: Induced resistance and the role of an inhibitor  

SciTech Connect

Helminthosporium carbonum race 1 produces large, necrotic lesions on susceptible leaves of maize, whereas race 2 causes small, chlorotic flecks. Resistance to race 1 on susceptible leaves was induced when race 2 was inoculated for at least 10 h prior to a challenge inoculation with the pathogen and was manifest as a decrease in the number of appressoria and reduced penetration by race 1 conidia. Induced resistance was prevented or reversed when HC-toxin was added to challenge race 1 inoculum. The basis for protection appears to be a volatile, inhibitory compound produced by the host. This inhibitor was always associated with treatments that resulted in resistance, whereas no inhibitory activity was detected in diffusates from susceptible reactions. The appearance of inhibitor in diffusates coincided with the appearance of protection on the leaf. In addition to race 2 of H. carbonum, other fungi (H. victoriae, H. turcicum, and Alternaria) also induced production of the inhibitor as well as resistance to race 1. The inhibitor prevented the germination of conidia of all fungi tested. The growth of two phytopathogenic bacteria was also completely inhibited. Incorporation of {sup 3}H-leucine and {sup 14}C-uridine into protein and RNA, respectively, by conidia of H. carbonum was prevented within 15 min of exposure to inhibitor. In addition, respiration of conidia in inhibitor was reduced within 90 min to just 25% of the rate of conidia germinated in water. However, inhibitory activity of the diffusates was readily reversed when conidia were rinsed with water or when organic or amino acids were added to inhibited conidia. The addition of sodium acetate to race 2 and race 1 inocula resulted in lesion enlargement and also nullified inhibitory activity in vitro.

Cantone, F.A.

1989-01-01

235

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

PubMed Central

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

1988-01-01

236

Protein tyrosine phosphatase inhibitors in Fc gamma RI-induced myeloid oxidant signaling.  

PubMed

Fc-receptor stimulation in myeloid cells results in increased oxygen consumption, termed the respiratory burst, which is coupled to a rapid and transient increase in tyrosine phosphorylation of cellular proteins. In a previous paper in this journal we showed that the protein tyrosine phosphatase (PTPase) inhibitors sodium orthovanadate and phenylarsine oxide (PAO) block the Fc gamma RI-induced respiratory burst in interferon-gamma-differentiated U937 cells (U937IF) while augmenting the Fc gamma RI-induced tyrosine phosphorylation of cellular proteins. Herein we examine the effects of PTPase inhibitors on specific molecules involved in Fc gamma RI signaling. We show that orthovanadate and PAO augmented the Fc gamma RI-induced tyrosine phosphorylation of the adaptor protein CBL. CBL interactions with other phosphoproteins, among them SHC and CRKL, were also augmented in response to pretreatment with the PTPase inhibitors. SHC was tyrosine phosphorylated in response to Fc gamma RI stimulation of U937IF cells and bound to the SH2 domain of GRB2 in a stimulation-dependent manner. In fusion protein pull-down experiments the interaction of SHC with the SH2 domain of GRB2 was increased in PTPase inhibitor pretreated U937IF cells in response to Fc gamma RI stimulation. Our data support the hypothesis that a tyrosine dephosphorylation event is required for effective transmission of the Fc gamma RI signal to result in activation of the myeloid respiratory burst response. PMID:9434624

Erdreich-Epstein, A; Liu, M; Liu, Y; Durden, D L

1997-12-15

237

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.

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

2013-01-01

238

Indole/triazole conjugates are selective inhibitors and inducers of bacterial biofilms †  

PubMed Central

Herein is described a method of accessing indole/triazole and benzothiophene/triazole analogues that selectively promote or inhibit biofilm formation by Gram-positive and Gram-negative bacteria. Structure/function studies revealed that the addition of a bromine atom at the 2-position of the indole/triazole scaffold altered activity against both Gram-negative and Gram-positive bacteria and could transform a biofilm inhibitor into a biofilm inducer. Isosteric replacement of the indole core by a benzothiophene significantly impaired anti-biofilm activity. A competition assay exposing Escherichia coli to the most potent biofilm inducer and an inhibitor of E. coli biofilm formation was performed. The inducer exhibited the ability to mute the effect of the anti-biofilm compound for this targeted bacterial population.

Minvielle, Marine J.; Bunders, Cynthia A.; Melander, Christian

2013-01-01

239

High-fat diet-induced reduction of peroxisome proliferator-activated receptor-? coactivator-1? messenger RNA levels and oxidative capacity in the soleus muscle of rats with metabolic syndrome.  

PubMed

Animal models of type 2 diabetes exhibit reduced peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) messenger RNA (mRNA) levels, which are associated with decreased oxidative capacity, in skeletal muscles. In contrast, animal models with metabolic syndrome show normal PGC-1? mRNA levels. We hypothesized that a high-fat diet decreases PGC-1? mRNA levels in skeletal muscles of rats with metabolic syndrome, reducing muscle oxidative capacity and accelerating metabolic syndrome or inducing type 2 diabetes. We examined mRNA levels and fiber profiles in the soleus muscles of rats with metabolic syndrome (SHR/NDmcr-cp [cp/cp]; CP) fed a high-fat diet. Five-week-old CP rats were assigned to a sedentary group (CP-N) that was fed a standard diet (15.1 kJ/g, 23.6% protein, 5.3% fat, and 54.4% carbohydrates) or a sedentary group (CP-H) that was fed a high-fat diet (21.6 kJ/g, 23.6% protein, 34.9% fat, and 25.9% carbohydrates) and were housed for 10 weeks. Body weight, energy intake, and systolic blood pressure were higher in the CP-H group than in the CP-N group. Nonfasting glucose, triglyceride, total cholesterol, and leptin levels were higher in the CP-H group than in the CP-N group. There was no difference in insulin levels between the CP-N and CP-H groups. Muscle PGC-1? mRNA levels and succinate dehydrogenase activity were lower in the CP-H group than in the CP-N group. We concluded that a high-fat diet reduces PGC-1? mRNA levels and oxidative capacity in skeletal muscles and accelerates metabolic syndrome. PMID:22348463

Nagatomo, Fumiko; Fujino, Hidemi; Kondo, Hiroyo; Takeda, Isao; Tsuda, Kinsuke; Ishihara, Akihiko

2012-02-01

240

PEX11 family members are membrane elongation factors that coordinate peroxisome proliferation and maintenance.  

PubMed

Dynamic changes of membrane structure are intrinsic to organelle morphogenesis and homeostasis. Ectopic expression of proteins of the PEX11 family from yeast, plant or human lead to the formation of juxtaposed elongated peroxisomes (JEPs),which is evocative of an evolutionary conserved function of these proteins in membrane tubulation. Microscopic examinations reveal that JEPs are composed of independent elongated peroxisomes with heterogeneous distribution of matrix proteins. We established the homo- and heterodimerization properties of the human PEX11 proteins and their interaction with the fission factor hFis1, which is known to recruit the GTPase DRP1 to the peroxisomal membrane. We show that excess of hFis1 but not of DRP1 is sufficient to fragment JEPs into normal round-shaped organelles, and illustrate the requirement of microtubules for JEP formation. Our results demonstrate that PEX11-induced JEPs represent intermediates in the process of peroxisome membrane proliferation and that hFis1 is the limiting factor for progression. Hence, we propose a model for a conserved role of PEX11 proteins in peroxisome maintenance through peroxisome polarization, membrane elongation and segregation. PMID:20826455

Koch, Johannes; Pranjic, Kornelija; Huber, Anja; Ellinger, Adolf; Hartig, Andreas; Kragler, Friedrich; Brocard, Cécile

2010-10-01

241

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

PubMed

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

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

2002-09-16

242

[Cyclooxygenase inhibitors in some dietary vegetables inhibit platelet aggregation function induced by arachidonic acid].  

PubMed

The study was purposed to investigate whether the cyclooxygenase inhibitors from some dietary vegetables can inhibit platelet aggregation function by the arachidonic acid (AA). The vegetable juice was mixed with platelet rich plasma (PRP), and asprin was used as positive control. The maximum ratio of platelet aggregation induced by AA was measured on the aggregometer; heme and cyclooxygenase-1 (COX(1)) or cyclooxygenase-2 (COX(2)) were added to test tubes containing COX reaction buffer, the mixture was vortex-mixed and exposed to aspirin or vegetable juice, followed by addition of AA and then hydrochloric acid (1 mol/L) was added to stop the COX reaction, followed by chemical reduction with stannous chloride solution. The concentration of COX inhibitors was detected by the enzyme immunoassay kit; vegetable juice (aspirin as positive control) was mixed with whole blood, which was followed by the addition of AA, and then the reaction was stopped by adding indomethacin, centrifuged, then the supernatant was collected, and the plasma thromboxane B(2) (TXB(2)) was measured by radioimmunoassay. The results showed that spinach juice, garlic bolt juice, blanched garlic leave juice and Chinese leek juice could inhibit by 80% human platelet aggregation induced by AA. 4 kinds of vegetables were all found a certain amount of cyclooxygenase inhibitors, which COX(1) and COX(2) inhibitor concentrations of spinach were higher than that of aspirin; 4 vegetable juice could significantly reduce the human plasma concentrations of TXB(2) induced by AA (p < 0.05). It is concluded that 4 kinds of raw vegetables containing cyclooxygenase inhibitors inhibit the production of TXA(2) and thus hinder platelet aggregation. Raw spinach, garlic bolt, blanched garlic and chinese leek inhibit significantly AA-induced human platelet aggregation in vitro. 4 kinds of vegetables may have a good potential perspective of anti-platelet aggregation therapy or prevention of thrombosis. PMID:22040984

Wang, Xin-Hua; Shao, Dong-Hua; Liang, Guo-Wei; Zhang, Ru; Xin, Qin; Zhang, Tao; Cao, Qing-Yun

2011-10-01

243

Peroxisomal acyl-CoA synthetases  

PubMed Central

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

Watkins, Paul A.; Ellis, Jessica M.

2012-01-01

244

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

245

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.

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

2013-01-01

246

The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats.  

PubMed

It was previously shown that sustained fever can be induced in rats by central injection of endothelin-1 (ET-1). This peptide appears to participate in the mechanism(s) of LPS-induced fever, which is reduced by pretreatments with ET(B) receptor antagonists. In this study, we compared the effects of a nonselective cyclooxygenase (COX) inhibitor, indomethacin, with those of two selective COX-2 inhibitors, celecoxib and lumiracoxib, on ET-1-induced fever in rats. Fever induced in conscious animals by ET-1 (1 pmol icv) or LPS (5 mug/kg iv) was prevented by pretreatments with celecoxib (5 and 10 mg/kg) or lumiracoxib (5 mg/kg) given by oral gavage 1 h before stimuli. Lower doses of celecoxib had partial (2.5 mg/kg) or no effect (1 mg/kg). Indomethacin (2 mg/kg ip) partially inhibited fever induced by LPS but had no effect on ET-1-induced fever. The levels of PGE(2) and PGF(2alpha) in the cerebrospinal fluid (CSF) of pentobarbital sodium-anesthetized rats were significantly increased 3 h after the injection of LPS or ET-1. The latter increase was abolished by celecoxib at all tested doses and by indomethacin. In conclusion, selective COX-2 inhibitors were able to prevent ET-1-induced fever, indicating a role for COX-2 in this phenomenon. However, the fact that reduced CSF PG levels obtained with indomethacin and a low dose of celecoxib are not accompanied by changes in fever induced by ET-1, along with the lack of inhibitory effects of indomethacin on ET-1 fever, suggests that the latter might also involve COX-2-independent mechanisms. PMID:15539607

Fabricio, Aline S C; Veiga, Fabiane H; Cristofoletti, Rodrigo; Navarra, Pierluigi; Souza, Gloria E P

2005-03-01

247

Lpx1p is a peroxisomal lipase required for normal peroxisome morphology.  

PubMed

Lpx1p (systematic name: Yor084wp) is a peroxisomal protein from Saccharomyces cerevisiae with a peroxisomal targeting signal type 1 (PTS1) and a lipase motif. Using mass spectrometry, we have identified Lpx1p as present in peroxisomes, and show that Lpx1p import is dependent on the PTS1 receptor Pex5p. We provide evidence that Lpx1p is piggyback-transported into peroxisomes. We have expressed the Lpx1p protein in Escherichia coli, and show that the enzyme exerts acyl hydrolase and phospholipase A activity in vitro. However, the protein is not required for wild-type-like steady-state function of peroxisomes, which might be indicative of a metabolic rather than a biogenetic role. Interestingly, peroxisomes in deletion mutants of LPX1 have an aberrant morphology characterized by intraperoxisomal vesicles or invaginations. PMID:18199283

Thoms, Sven; Debelyy, Mykhaylo O; Nau, Katja; Meyer, Helmut E; Erdmann, Ralf

2008-02-01

248

Arabidopsis LON2 Is Necessary for Peroxisomal Function and Sustained Matrix Protein Import1[C][W][OA  

PubMed Central

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

Lingard, Matthew J.; Bartel, Bonnie

2009-01-01

249

Hepatic peroxisomes in isolated hyperpipecolic acidaemia: evidence supporting its classification as a single peroxisomal enzyme deficiency  

Microsoft Academic Search

Hyperpipecolic acidaemia is still regarded as a peroxisomal assembly deficiency. The enzyme responsible for the accumulation\\u000a of pipecolic acid is located in the peroxisomes in man. We studied the appearance and alterations of peroxisomes in liver\\u000a biopsy material from three unrelated children suffering from isolated hyperpipecolic acidaemia, in which only the metabolism\\u000a of pipecolic acid is disturbed, using light and

I. Kerckaert; B. T. Poll-The; M. Espeel; M. Duran; A. B. C. Roeleveld; R. J. A. Wanders; F. Roels

2000-01-01

250

Uptake inhibitors but not substrates induce protease resistance in extracellular loop two of the dopamine transporter.  

PubMed

Changes in protease sensitivity of extracellular loop two (EL2) of the dopamine transporter (DAT) during inhibitor and substrate binding were examined using trypsin proteolysis and epitope-specific immunoblotting. In control rat striatal membranes, proteolysis of DAT in a restricted region of EL2 was produced by 0.001 to 10 microg/ml trypsin. However, in the presence of the dopamine uptake blockers [2-(diphenylmethoxyl) ethyl]-4-(3phenylpropyl) piperazine (GBR 12909), mazindol, 2beta-carbomethoxy-3beta-(4-flourophenyl)tropane (beta-CFT), nomifensine, benztropine, or (-)-cocaine, 100- to 1000-fold higher concentrations of trypsin were required to produce comparable levels of proteolysis. Protease resistance induced by ligands was correlated with their affinity for DAT binding, was not observed with Zn2+, (+)-cocaine, or inhibitors of norepinephrine or serotonin transporters, and was not caused by altered catalytic activity of trypsin. Together, these results support the hypothesis that the interaction of uptake inhibitors with DAT induces a protease-resistant conformation in EL2. In contrast, binding of substrates did not induce protease resistance in EL2, suggesting that substrates and inhibitors interact with DAT differently during binding. To assess the effects of EL2 proteolysis on DAT function, the binding and transport properties of trypsin-digested DAT were assayed with [3H]CFT and [3H]dopamine. Digestion decreased the Bmax for binding and the Vmax for uptake in amounts that were proportional to the extent of proteolysis, indicating that the structural integrity of EL2 is required for maintenance of both DAT binding and transport functions. Together this data provides novel information about inhibitor and substrate interactions at EL2, possibly relating the protease resistant DAT conformation to a mechanism of transport inhibition. PMID:14978248

Gaffaney, Jon D; Vaughan, Roxanne A

2004-03-01

251

Inhibitor of cyclooxygenase-2 induces cell-cycle arrest in the epithelial cancer cell line via up-regulation of cyclin dependent kinase inhibitor p21.  

PubMed

Cyclooxygenase-2 is the rate-limiting enzyme in synthesis of prostaglandins and other eicosanoids. Prior reports have shown that inhibition of cyclooxygenase-2 activity, either by selective inhibitors or by antisense oligonucleotide, results in suppression of growth of squamous cell carcinoma cell lines which express high cyclooxygenase-2 levels, such as NA, a cell line established from a squamous cell carcinoma of the tongue. To investigate the mechanisms by which cyclooxygenase-2 inhibitors suppressed growth of these cells, the effects of NS-398, the selective cyclooxygenase-2 inhibitor, on cell-cycle distribution were examined. NS-398 induced G0/G1 cell-cycle arrest in NA cells which expressed cyclooxygenase-2. G0/G1 arrest induced by NS-398 was accompanied by up-regulation of cyclin-dependent kinase inhibitor p21, but not by up-regulation of the other cyclin-dependent kinase inhibitors. Transfection with p21 antisense oligonucleotide inhibited cell-cycle arrest induced by NS-398. Accumulation in G0/G1 was also observed in NA cells transfected with cyclooxygenase-2 antisense oligonucleotide. On the other hand, NS-398-treated NA cells showed a loss of plasma membrane asymmetry, a marker of early events in apoptosis. However, NS-398 did not induce other morphological and biochemical changes related to apoptotic cell death. These results suggest that cyclooxygenase-2 inhibitor induces G0/G1 cell-cycle arrest in NA cells by up-regulation of p21. Our results also suggest that NS-398 is not sufficient to complete the whole process of apoptosis in NA cells, although it induces an early event in apoptosis. PMID:11953864

Toyoshima, T; Kamijo, R; Takizawa, K; Sumitani, K; Ito, D; Nagumo, M

2002-04-01

252

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.

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

2014-01-01

253

Nitric oxide synthase inhibitor aminoguanidine potentiates iminodipropionitrile-induced neurotoxicity in rats.  

PubMed

This investigation was undertaken to study the effect of nitric oxide synthase inhibitor, aminoguanidine on iminodipropionitrile (IDPN)-induced neurobehavioral and vestibular toxicity in rats. The dyskinetic syndrome was produced in male Wistar rats by i.p. injections of IDPN (100 mg/kg) for 6 days. Aminoguanidine was administered orally in the doses of 50, 150 and 300 mg/kg, 60 min before IDPN in three different groups. Control rats received vehicle only, whereas another group was treated with 300 mg/kg of aminoguanidine alone (without IDPN). Our results showed that aminoguanidine significantly and dose dependently exacerbated the incidence and intensity of IDPN-induced dyskinetic head movements. Aminoguanidine potentiated IDPN-induced loss of air righting reflex. The histopathological examination of inner ear showed aggravation of IDPN-induced degeneration of sensory hair cells in the crista ampullaris by aminoguanidine. These results suggest the role of nitric oxide in IDPN-induced neurobehavioral and vestibular toxicity. PMID:10586972

Tariq, M; Khan, H A; Al Deeb, S; Al Moutaery, K

1999-11-26

254

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

255

A Novel IB Kinase Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice  

Microsoft Academic Search

Rationale: IB kinase- is a critical regulator in the activation of nuclear factor- B( NF-B), a transcription factor related to the ex- pression and regulation of proinflammatory cytokines. Objective: To evaluate if inhibition of IB kinase- ameliorates pneu- monitis and pulmonary fibrosis. Methods:We examinedwhether anovel IB kinase-inhibitor, IMD- 0354, attenuates bleomycin-induced pulmonary fibrosis in mice. Measurements and Main Results: Administration

Mami Inayama; Yasuhiko Nishioka; Momoyo Azuma; Susumu Muto; Yoshinori Aono; Hideki Makino; Kenji Tani; Hisanori Uehara; Keisuke Izumi; Akiko Itai; Saburo Sone

2006-01-01

256

Inhibition of Akt\\/PKB by a COX2 Inhibitor Induces Apoptosis in Gastric Cancer Cells  

Microsoft Academic Search

Background\\/Aim: Inhibition of cyclooxygenase-2 has been proposed to be a potential mechanism for the chemoprevention of gastrointestinal tumors by nonsteroidal anti-inflammatory drugs. This study investigates the mechanisms by which the cyclooxygenase-2 inhibitor SC236 induces apoptosis of gastric cancer cell lines and its downstream signaling pathway. Methods: Two gastric cancer cell lines, AGS and MKN28, were treated with SC236 and assessed

Xiao Ming Fan; Xiao Hua Jiang; Qing Gu; Yick Pang Ching; Hua He; Harry H. X. Xia; Marie Chia Mi Lin; Annie O. O. Chan; Man Fung Yuen; Hsiang-Fu Kung; Benjamin Chun-Yu Wong

2006-01-01

257

Influence of various prostaglandin synthesis inhibitors on DMH-induced rat colon cancer  

Microsoft Academic Search

To evaluate the influence of inhibitors of prostaglandin synthesis on the incidence of DMH-induced colon cancer, 90 male Sprague-Dawley\\u000a rats were randomly assigned to: 1) indomethacin 20 mg per liter drinking water, 2) meclofenamate 50 mg per liter drinking\\u000a water, or 3) normal drinking water (control group). Dimethylhydrazine was given by weekly subcutaneous injections (20 mg\\/kg\\u000a body weight) during the

U. Metzger; J. Meier; G. Uhlschmid; H. Weihe

1984-01-01

258

ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies1  

Microsoft Academic Search

ACE genotype and ACE induced renoprotection in chronic proteinuric nephropathies.BackgroundWhether angiotensin-converting enzyme (ACE) gene polymorphism affects disease progression and response to ACE inhibitor therapy in nondiabetic proteinuric nephropathies is not clearly established.MethodsThe relationship between insertion\\/deletion (I\\/D) genotypes and proteinuria, rate of glomerular filtration rate decline (?GFR)—centrally evaluated by repeated measures of iohexol plasma clearance—and incidence of end-stage renal disease (ESRD)

Annalisa Perna; Piero Ruggenenti; Alessandra Testa; Belinda Spoto; Roberto Benini; Valerio Misefari; Giuseppe Remuzzi; Carmine Zoccali

2000-01-01

259

Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide  

Microsoft Academic Search

ObjectiveTo investigate if rifampicin is both an inducer and an inhibitor of repaglinide metabolism, it was determined whether the timing of rifampicin co-administration influences the pharmacokinetics of repaglinide.MethodsMale volunteers ( n=12) participated in a randomised, two-period, crossover trial evaluating the effect of multiple doses of 600 mg rifampicin once daily for 7 days on repaglinide metabolism. Subjects were, after baseline measurements of

TanjaBusk Bidstrup; Nicolaj Stilling; Per Damkier; Birgitte Scharling; MikaelSøndergård Thomsen; Kim Brøsen

2004-01-01

260

Effects of mitogen-activated protein kinase inhibitors or phosphodiesterase inhibitors on interleukin-1-induced cytokines production in synovium-derived cells.  

PubMed

The effects of mitogen-activated protein (MAP) kinase inhibitors or phosphodiesterase (PDE) inhibitors on interleukin (IL)-1-induced cytokines production in synovium-derived cells were investigated. Human synoviocyte (HS) or synovial sarcoma (SW982) stimulated by IL-1beta (100 ng/ml) produced various cytokines including IL-6, IL-8, GROalpha, VEGF, basic FGF and tumor necrosis factor alpha (TNFalpha) in vitro. SB202190 or SB203580, an inhibitor of p38 MAP kinase, inhibited all cytokines production in both cells. PD98059, an inhibitor of MAP kinase kinase (MEK), inhibited IL-6, IL-8 and basic FGF production in HS and all cytokines production except basic FGF in SW982. However, many of its effects were weaker than those of SB202190 or SB203580. Quazinone, an inhibitor of cyclic GMP-inhibited PDE, scarcely affected cytokines production in both cells. Rolipram or R0201724, an inhibitor of cyclic AMP-specific PDE, inhibited IL-8 and basic FGF production in HS and TNFalpha production in SW982, however, it enhanced the other cytokines production in SW982. These results suggest that the activation of MAP kinase cascade may be important for IL-1-induced cytokines production in synovium-derived cells. On the other hand, the role of cyclic AMP may be dependent on cell and cytokine types. PMID:10424432

Tsuji, F; Oki, K; Senda, T; Horiuchi, M; Mita, S

1999-06-01

261

Antidepressant-like effect induced by systemic and intra-hippocampal administration of DNA methylation inhibitors  

PubMed Central

BACKGROUND AND PURPOSE Epigenetic modifications are thought to play an important role in the neurobiology of depression. Antidepressant treatment induces histone acetylation in the hippocampus, which is associated with transcriptional activation, whereas stress increases DNA methylation, which is associated with transcriptional repression. Because the specific involvement of DNA methylation in the regulation of depressive-like behaviours is not yet known, we have investigated the effects induced by systemic or intra-hippocampal administration of inhibitors of DNA methyltransferase (DNMT) in rats submitted to a range of behavioural tests. EXPERIMENTAL APPROACH Rats received i.p. injections of 5-aza-2-deoxycytidine (5-azaD, 0.1–0.8 mg·kg?1), 5-azacytidine (5-azaC, 0.4–3.2 mg·kg?1), imipramine (15 mg·kg?1) or vehicle and were submitted to the forced swimming test (FST) or open field test (OFT). Other groups of rats received intra-hippocampal injection of DNMT inhibitors. KEY RESULTS Systemic administration of DNMT inhibitors induced a dose-dependent antidepressant-like effect, which was followed by decreased DNA methylation and increased brain-derived neurotrophic factor (BDNF) levels in the hippocampus. Hippocampal inhibition of DNA methylation induced similar behavioural effects. No treatment induced any locomotor effects in the OFT. Antidepressant-like effects of 5-azaD were confirmed in mice submitted to the FST or the tail suspension test. CONCLUSIONS AND IMPLICATIONS Systemic, as well as hippocampal, inhibition of DNA methylation induced antidepressant-like effects. These effects could be associated with increased hippocampal expression of BDNF. Our data give further support to the hypothesis that DNA methylation is an important epigenetic mechanism involved in the development of depressive-like behaviours.

Sales, Amanda J; Biojone, Caroline; Terceti, Mateus S; Guimaraes, Francisco S; Gomes, Marcus VM; Joca, Samia RL

2011-01-01

262

Betulin, betulinic acid and butein are inhibitors of acetaldehyde-induced activation of liver stellate cells.  

PubMed

Liver fibrosis has been reported to be inhibited in vivo by oleanolic and ursolic acids; however, the activity of other triterpenes like betulin and betulinic acid has not been examined. Butein has also been reported to prevent and partly reverse liver fibrosis in vivo, although its mechanism of action is poorly understood. Therefore, the aim of this study was to determine the antifibrotic potential of butein, betulin, and betulinic acid and examine their mechanisms of action in vitro. This study was conducted in rat stellate cells (HSCs) that were treated with acetaldehyde, which is the most reactive product of ethanol metabolism. Butein, betulin, and betulinic acid were preincubated with rat HSCs at non-toxic concentrations. Treatment effects were measured in regard to acetaldehyde-induced toxicity and cell migration, and several markers of HSC activation were evaluated, including smooth muscle ?-actin (?-SMA) and procollagen I expression. In addition, changes in the release of reactive oxygen species (ROS) and cytokines such as tumor necrosis factor-? (TNF-?) and tumor growth factor-?1 (TGF-?1) and changes in the production of metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were determined. In vitro, HSCs were protected against acetaldehyde-induced toxicity by betulin but not by betulinic acid and butein. However, butein, betulin, and betulinic acid inhibited the production of ROS by HSCs treated with acetaldehyde and inhibited their migration. Butein also inhibited acetaldehyde-induced TGF-?1 production. Butein, betulin, and betulinic acid down-regulated acetaldehyde-induced production of TIMP-1 and TIMP-2. Betulin decreased the acetaldehyde-induced activity of MMP-2, but butein and betulinic acid did not. The results indicated that butein, betulin, and betulinic acid inhibited the acetaldehyde-induced activation of HSCs. Each drug functioned in a different manner, whereby some were acting as either antioxidants or inhibitors of TIMPs expression and butein additionally acted as an inhibitor of TGF-? production. PMID:22180353

Szuster-Ciesielska, Agnieszka; Plewka, Krzysztof; Kandefer-Szersze?, Martyna

2011-01-01

263

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

264

Targeted Fluorescent Probes in Peroxisome Function  

Microsoft Academic Search

Fluorescent peptides form a new generation of analytical tools for visualizing intracellular processes and molecular interactions at the level of single cells. The peptide-based reporters combine the sensitivity of fluorescence detection with the information specificity of amino acid sequences. Recently we have succeeded in targeting a fluorescent heptapeptide (acetyl-CKGGAKL) carrying a peroxisomal targeting signal (PTS1) to peroxisomes in intact cells.

Tobias B. Dansen; Eward H. W. Pap; Ronald J. A. Wanders; Karel W. A. Wirtz

2001-01-01

265

Attenuation of Doxorubicin-induced Cardiotoxicity by Tadalafil: A Long Acting Phosphodiesterase-5 Inhibitor  

PubMed Central

Doxorubicin (DOX) is a broad spectrum antineoplastic drug widely used in the treatment of several hematogenous and solid human malignancies. Despite its excellent clinical efficacy as a chemotherapeutic agent, its therapeutic usage has been restricted due to its cardiotoxicity. Phosphodiesterase-5 (PDE-5) inhibitors or erectile dysfunction drugs including sildenafil, have been shown to have powerful cardioprotective effect against injuries under a variety of experimental situations including ischemia/reperfusion injury, myocardial infarction and DOX-induced cardiomyopathy. We studied the effect of – tadalafil, a long acting PDE-5 inhibitor in preventing damage in the heart with DOX treatment. Our results showed that tadalafil improved left ventricular function and survival by attenuating DOX-induced apoptosis and cardiac oxidative stress without interfering with the anti-tumor efficacy of DOX in both in vitro and in vivo tumor models. Herein, we present an overview of our study, and consider the potential mechanisms by which tadalafil, at therapeutically relevant concentrations mediate beneficial cardioprotective effects in DOX cardiotoxicity. Based on our current and previously published studies, we propose that the class of PDE-5 inhibitors can represent a novel approach which can be exploited for achieving therapeutic benefit in the treatment of DOX-induced cardiotoxicity in patients.

Koka, Saisudha; Kukreja, Rakesh C.

2011-01-01

266

Spautin-1, a novel autophagy inhibitor, enhances imatinib-induced apoptosis in chronic myeloid leukemia.  

PubMed

Imatinib mesylate (IM), a targeted competitive inhibitor of the BCR-ABL tyrosine kinase, has revolutionized the clinical treatment of chronic myeloid leukemia (CML). However, resistance and intolerance are still a challenge in the treatment of CML. Autophagy has been proposed to play a role in IM resistance. To investigate the anti-leukemic activity of specific and potent autophagy inhibitor-1 (spautin-1) in CML, we detected its synergistic effect with IM in K562 and CML cells. Our results showed that spautin-1 markedly inhibited IM-induced autophagy in CML cells by downregulating Beclin-1. Spautin-1 enhanced IM-induced CML cell apoptosis by reducing the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2. We further demonstrated that the pro-apoptotic activity of spautin-1 was associated with activation of GSK3?, an important downstream effector of PI3K/AKT. The findings indicate that the autophagy inhibitor spautin-1 enhances IM-induced apoptosis by inactivating PI3K/AKT and activating downstream GSK3?, leading to downregulation of Mcl-1 and Bcl-2, which represents a promising approach to improve the efficacy of IM in the treatment of patients with CML. PMID:24585095

Shao, Shan; Li, Su; Qin, Youwen; Wang, Xiaorui; Yang, Yining; Bai, Haitao; Zhou, Lili; Zhao, Chuxian; Wang, Chun

2014-05-01

267

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

268

Effect of Ethylene Action Inhibitors upon Wound-Induced Gene Expression in Tomato Pericarp 1  

PubMed Central

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)+ RNAs isolated from these tissues after 12 hours of wounding were translated in vitro in a rabbit reticulocyte lysate system and [35S]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. Images Figure 2 Figure 3 Figure 4

Henstrand, John M.; Handa, Avtar K.

1989-01-01

269

A quantitative evaluation of the effects of inhibitors of tubulin assembly on polymerization induced by discodermolide, epothilone B, and paclitaxel  

Microsoft Academic Search

Purpose To determine whether inhibitors of microtubule assembly inhibit polymerization induced by discodermolide and epothilone B, as well as paclitaxel, and to quantitatively measure such effects. Methods Inhibition was quantitated by measuring polymer formation either by turbidimetry or by centrifugation, and the amount of inhibitor required to inhibit 50% relative to an appropriate control reaction was determined. Results The inhibitory

Donnette A. Dabydeen; Gordon J. Florence; Ian Paterson; Ernest Hamel

2004-01-01

270

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

Microsoft Academic Search

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

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

2001-01-01

271

The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus (house musk shrew)  

Microsoft Academic Search

Considerable evidence implicates the endocannabinoid system as a neuromodulator of nausea and vomiting. The action of anandamide (AEA) can be prolonged by inhibiting its degradation, through the use of URB597 (URB), a Fatty Acid Amide Hydrolase (FAAH) enzyme inhibitor. Here we present evidence that the FAAH inhibitor, URB, interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus. In Experiment

L. A. Parker; C. L. Limebeer; E. M. Rock; D. L. Litt; M. Kwiatkowska; D. Piomelli

2009-01-01

272

Discovery of Indenopyrazoles as a New Class of Hypoxia Inducible Factor (HIF)-1 Inhibitors  

PubMed Central

The indenopyrazole framework was investigated as a new class of HIF-1? inhibitors. Indenopyrazole 2l was found to most strongly inhibit the hypoxia-induced HIF-1? transcriptional activity (IC50 = 0.014 ?M) among all of the known compounds having relatively simple structures, unlike manassantins. Indenopyrazole 2l suppressed HIF-1? transcriptional activity without affecting both HIF-1? protein accumulation and HIF-1?/HIF-1? heterodimerization in nuclei under the hypoxic conditions, suggesting that 2l probably affected the transcriptional pathway induced by the HIF-1?/HIF-1? heterodimer.

2013-01-01

273

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

NASA Astrophysics Data System (ADS)

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

Lee, Harold H.; Xu, Quanhan

1986-12-01

274

Orally available pyridinylpyrimidine derivatives as novel RANKL-induced osteoclastogenesis inhibitors.  

PubMed

An HTS campaign led to the identification of 4-pyrroldino-2-(pyridin-2-yl)pyrimidine compound 1 as an RANKL-induced osteoclastogenesis inhibitor. The compound 1 showed high clearance values in microsomes, however. Modification of the pyrrolidino group to a benzylamino group improved human microsomal stability with a slight loss of in vitro activity. Substitution at the ortho position of the benzyl group ameliorated in vitro activity, and further fluorination of the benzyl group improved microsomal stability in rodents. Representative members of this series, compounds 20 and 23, exhibited efficacy in RANKL-induced osteopenic mice when administered orally at 0.3 mg/kg. PMID:22853997

Miyata, Junji; Kasahara, Chiyoshi; Asano, Toru; Ito, Shinji; Seki, Norio; Kato, Yasuko; Morikawa, Noriyuki; Nozaki, Kazuyoshi; Nishimura, Kouji; Akamatsu, Hisashi; Taguchi, Yusuke; Yamaguchi, Tomonori; Abe, Yoshito; Ohkubo, Mitsuru; Watanabe, Toshihiro; Ohta, Mitsuaki; Takeuchi, Makoto

2012-09-01

275

Further studies of auxin and ACC induced feminization in the cucumber plant using ethylene inhibitors  

NASA Technical Reports Server (NTRS)

The present study was designed to establish the role of an essential hormone controlling sex expression in cucumber. A potent anti-ethylene agent, AgNO3, completely inhibited pistillate flower formation caused by IAA, ACC or ethephon. Inhibitors of ethylene biosynthesis, AVG and CoCl2 also suppressed feminization due to exogenous IAA or ACC. Though AVG also suppressed ethephon-induced feminization, this may be due to the second effect of AVG rather than the effect on ACC biosynthesis. These results confirm that ethylene is a major factor regulating feminization and that exogenous auxin induces pistillate flower formation through its stimulation of ethylene production, rather than ACC production.

Takahashi, H.; Jaffe, M. J.

1984-01-01

276

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.

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

2012-01-01

277

Peroxisome dynamics in cultured mammalian cells.  

PubMed

Despite the identification and characterization of various proteins that are essential for peroxisome biogenesis, the origin and the turnover of peroxisomes are still unresolved critical issues. In this study, we used the HaloTag technology as a new approach to examine peroxisome dynamics in cultured mammalian cells. This technology is based on the formation of a covalent bond between the HaloTag protein--a mutated bacterial dehalogenase which is fused to the protein of interest--and a synthetic haloalkane ligand that contains a fluorophore or affinity tag. By using cell-permeable ligands of distinct fluorescence, it is possible to image distinct pools of newly synthesized proteins, generated from a single genetic HaloTag-containing construct, at different wavelengths. Here, we show that peroxisomes display an age-related heterogeneity with respect to their capacity to incorporate newly synthesized proteins. We also demonstrate that these organelles do not exchange their protein content. In addition, we present evidence that the matrix protein content of pre-existing peroxisomes is not evenly distributed over new organelles. Finally, we show that peroxisomes in cultured mammalian cells, under basal growth conditions, have a half-life of approximately 2 days and are mainly degraded by an autophagy-related mechanism. The implications of these findings are discussed. PMID:19719477

Huybrechts, Sofie J; Van Veldhoven, Paul P; Brees, Chantal; Mannaerts, Guy P; Los, Georgyi V; Fransen, Marc

2009-11-01

278

Insulin sensitization with a peroxisome proliferator-activated receptor ? agonist prevents adrenocortical lipid infiltration and secretory changes induced by a high-sucrose diet.  

PubMed

It has been hypothesized that deviations in glucocorticoid secretion and/or action may contribute to somatic and biochemical changes observed in patients with and animal models of insulin resistance (IR). In this study, we analyzed changes in rat adrenocortical function and morphology associated with the development of IR, generated in male adult rats by the addition of 30% sucrose to the drinking water. Caloric intake, body and adipose tissue weights, and biochemical parameters associated with IR were determined. Expression levels of Star, Cyp11A1, Mc2r, Ppar? (Pparg), and Cd36 were evaluated by real-time PCR, histochemical analysis of the adrenal cortex was performed using Masson's trichrome and Sudan III staining, and corticosterone levels were measured by RIA. After 7 weeks of sucrose administration, higher serum glucose, insulin, and triglyceride levels and an altered glycemic response to an i.p. insulin test were detected. Adrenal glands showed a neutral lipid infiltration. An increase in Star, Cyp11A1, Mc2r, Pparg and Cd36 and a decrease in Mc2r levels were also found. Furthermore, sucrose-treated animals exhibited higher basal corticosterone levels and a blunted response to ACTH injection. Noteworthy, the adrenocortical (functional and histological) abnormalities were prevented in sucrose-treated rats by the simultaneous administration of an insulin-sensitizing PPAR? agonist. In conclusion, sucrose-induced IR affects adrenocortical morphology and function possibly via the generation of adipokines or lipid metabolites within the adrenal gland. These abnormalities are prevented by the administration of a PPAR? agonist by mechanisms involving both extra- and intra-adrenal effects. PMID:22700193

Martinez Calejman, Camila; Di Gruccio, Juan M; Mercau, María E; Repetto, Esteban M; Astort, Francisco; Sanchez, Rocío; Pandolfi, Matías; Berg, Gabriela; Schreier, Laura; Arias, Pablo; Cymeryng, Cora B

2012-09-01

279

Tumorigenicity of the hypolipidaemic peroxisome proliferator ethyl-alpha-p-chlorophenoxyisobutyrate (clofibrate) in rats.  

PubMed Central

Ethyl-alpha-p-chlorophenoxyisobutyrate), a hypolipidaemic drug which induces hepatomegaly and proliferation of peroxisomes in liver cells of rats and mice, was fed to 15 male F344 rats at a dietary concentration of 0.5% (v/w) for up to 28 months. Hepatocellular carcinomas developed in 10/11 (91%) rats killed between 24 and 28 months. Other tumours included carcinoma of the pancreas (2 rats), leiomyoma of the small intestine (1 rat) and a large dermatofibrosarcoma (1 rat). Clofibrate is the third hypolipidaemic peroxisome proliferator demonstrated to be hepatocarcinogenic in rats. These studies suggest that hypolipidaemic agents which are capable of producing a sustained hepatomegalic and peroxisome-proliferative effect also induce liver tumours. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6

Reddy, J. K.; Qureshi, S. A.

1979-01-01

280

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

281

cPLA2 is protective against COX inhibitor-induced intestinal damage.  

PubMed

Cytosolic phospholipase A(2) (cPLA(2)) is the rate-limiting enzyme responsible for the generation of prostaglandins (PGs), which are bioactive lipids that play critical roles in maintaining gastrointestinal (GI) homeostasis. There has been a long-standing association between administration of cyclooxygenase (COX) inhibitors and GI toxicity. GI injury is thought to be induced by suppressed production of GI-protective PGs as well as direct injury to enterocytes. The present study sought to determine how pan-suppression of PG production via a genetic deletion of cPLA(2) impacts the susceptibility to COX inhibitor-induced GI injury. A panel of COX inhibitors including celecoxib, rofecoxib, sulindac, and aspirin were administered via diet to cPLA(2)(-/-) and cPLA(2)(+/+) littermates. Administration of celecoxib, rofecoxib, and sulindac, but not aspirin, resulted in acute lethality (within 2 weeks) in cPLA(2)(-/-) mice, but not in wild-type littermates. Histomorphological analysis revealed severe GI damage following celecoxib exposure associated with acute bacteremia and sepsis. Intestinal PG levels were reduced equivalently in both genotypes following celecoxib exposure, indicating that PG production was not likely responsible for the differential sensitivity. Gene expression profiling in the small intestines of mice identified drug-related changes among a panel of genes including those involved in mitochondrial function in cPLA(2)(-/-) mice. Further analysis of enterocytic mitochondria showed abnormal morphology as well as impaired ATP production in the intestines from celecoxib-exposed cPLA(2)(-/-) mice. Our data demonstrate that cPLA(2) appears to be an important component in conferring protection against COX inhibitor-induced enteropathy, which may be mediated through affects on enterocytic mitochondria. PMID:20562220

Montrose, David C; Kadaveru, Krishna; Ilsley, Jillian N M; Root, Sierra H; Rajan, Thiruchanduri V; Ramesh, Manish; Nichols, Frank C; Liang, Bruce T; Sonin, Dmitry; Hand, Arthur R; Zarini, Simona; Murphy, Robert C; Belinsky, Glenn S; Nakanishi, Masako; Rosenberg, Daniel W

2010-09-01

282

cPLA2 Is Protective Against COX Inhibitor-Induced Intestinal Damage  

PubMed Central

Cytosolic phospholipase A2 (cPLA2) is the rate-limiting enzyme responsible for the generation of prostaglandins (PGs), which are bioactive lipids that play critical roles in maintaining gastrointestinal (GI) homeostasis. There has been a long-standing association between administration of cyclooxygenase (COX) inhibitors and GI toxicity. GI injury is thought to be induced by suppressed production of GI-protective PGs as well as direct injury to enterocytes. The present study sought to determine how pan-suppression of PG production via a genetic deletion of cPLA2 impacts the susceptibility to COX inhibitor–induced GI injury. A panel of COX inhibitors including celecoxib, rofecoxib, sulindac, and aspirin were administered via diet to cPLA2? / ? and cPLA2+ / + littermates. Administration of celecoxib, rofecoxib, and sulindac, but not aspirin, resulted in acute lethality (within 2 weeks) in cPLA2? / ? mice, but not in wild-type littermates. Histomorphological analysis revealed severe GI damage following celecoxib exposure associated with acute bacteremia and sepsis. Intestinal PG levels were reduced equivalently in both genotypes following celecoxib exposure, indicating that PG production was not likely responsible for the differential sensitivity. Gene expression profiling in the small intestines of mice identified drug-related changes among a panel of genes including those involved in mitochondrial function in cPLA2? / ? mice. Further analysis of enterocytic mitochondria showed abnormal morphology as well as impaired ATP production in the intestines from celecoxib-exposed cPLA2? / ? mice. Our data demonstrate that cPLA2 appears to be an important component in conferring protection against COX inhibitor–induced enteropathy, which may be mediated through affects on enterocytic mitochondria.

Montrose, David C.; Kadaveru, Krishna; Ilsley, Jillian N. M.; Root, Sierra H.; Rajan, Thiruchanduri V.; Ramesh, Manish; Nichols, Frank C.; Liang, Bruce T.; Sonin, Dmitry; Hand, Arthur R.; Zarini, Simona; Murphy, Robert C.; Belinsky, Glenn S.; Nakanishi, Masako; Rosenberg, Daniel W.

2010-01-01

283

Histone deacetylase inhibitors trichostatin A and suberoylanilide hydroxamic acid attenuate ventilator-induced lung injury.  

PubMed

The pathophysiology of ventilator-induced lung injury (VILI) involves multiple mechanisms including inflammation. Histone deacetylase inhibitors have been shown to exert anti-inflammation activity. The purpose of this study was to examine the protecting roles and mechanisms of the histone deacetylase inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) in ventilator-induced lung injury in normal rat lung. Male Sprague-Dawley rats were divided into four groups: lung-protective ventilation (LV), injurious ventilation (HV), HV+TSA and HV+ SAHA groups. Mechanical ventilation (MV) settings were 7 ml/kg VT and 3cm H2O positive end-expiratorypressure [PEEP], 40 breaths/min for LV group and 42 ml/kg VT, zero end-expiratoryvolume [ZEEP], 40 breaths/min for the HV, HV+TSA and HV+ SAHA groups. After 2 h of MV, acute lung injury (ALI) score, wet-to-dry (W/D) weight ratio and the activity of myeloperoxidase (MPO) were determined. The concentration of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-10 (IL-6) in the homogenized lung were measured by ELISA. The expression ICAM-1 was measured by both realtime PCR and Western blot assays. In addition, survival of each group was also assessed. Our results indicated that administration of TSA or SAHA alleviated ventilator-induced lung injury. This was accompanied by reduced neutrophil infiltration, reduced MPO activity, decreased intercellular adhesion molecule-1 (ICAM-1) expression in lung tissue, and lower TNF-alpha, IL-1beta and IL-6 levels. In addition, treatment with HDAC inhibitors significantly prolonged the survival time of ventilator-induced lung injury rats. Our data suggested that TSA and SAHA could significantly alleviate ventilator-induced rat lung injury and prolong the survival time of those rats by attenuate intrapulmonary inflammatory response. PMID:24601225

Chen, Hua-Yong; Li, Li; Fu, Zhi-Jian

2014-01-01

284

Protection from impulse noise-induced hearing loss with novel Src-protein tyrosine kinase inhibitors  

PubMed Central

Apoptosis is a significant mechanism of cochlear hair cell loss from noise. Molecules that inhibit apoptotic intracellular signaling reduce cochlear damage and hearing loss from noise. The current study is an extension of a previous study of the protective value of Src-protein tyrosine kinase inhibitors against noise (Harris et al., 2005). The current study tested three Src-inhibitors: the indole-based KX1-141, the biaryl-based KX2-329, and the ATP-competitive KX2-328. Each of the three drugs was delivered into the chinchillas’ cochleae by allowing the solutions to diffuse across the round window membrane thirty minutes prior to exposure to impulse noise. Hearing thresholds were measured using auditory evoked responses from electrodes in the inferior colliculi. Ears treated with KX2-329 showed significantly lower threshold shifts and outer hair cell losses than the control group. The cochleae treated with KX1-141 and KX2-328 did not show statistically significant protection from the impulse noise. The finding of protection with KX2-329 demonstrates that a biaryl-based Src inhibitor has protective capacity against noise-induced hearing loss that is as good as that demonstrated by KX1-004, a Src inhibitor drug that has been studied extensively as an otoprotectant against noise, and suggests that KX2-329 could be useful for protection against noise.

Bielefeld, Eric C.; Hangauer, David; Henderson, Donald

2011-01-01

285

Mitochondrial Complex I Inhibitors and Forced Oxidative Phosphorylation Synergize in Inducing Cancer Cell Death  

PubMed Central

Cancer cells generally rely mostly on glycolysis rather than oxidative phosphorylation (OXPHOS) for ATP production. In fact, they are particularly sensitive to glycolysis inhibition and glucose depletion. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Therefore, combined treatments targeting both glycolysis and mitochondria function, exploiting peculiar tumor features, might be lethal for cancer cells. In this study, we show that glucose deprivation and mitochondrial Complex I inhibitors synergize in inducing cancer cell death. In particular, our results reveal that low doses of Complex I inhibitors, ineffective on immortalized cells and in high glucose growth, become specifically cytotoxic on cancer cells deprived of glucose. Importantly, the cytotoxic effect of the inhibitors on cancer cells is strongly enhanced by forskolin, a PKA pathway activator, that we have previously shown to stimulate OXPHOS. Taken together, we demonstrate that induction in cancer cells of a switch from a glycolytic to a more respirative metabolism, obtained by glucose depletion or mitochondrial activity stimulation, strongly increases their sensitivity to low doses of mitochondrial Complex I inhibitors. Our findings might be a valuable approach to eradicate cancer cells.

Simonetto, Tiziana; Chiaradonna, Ferdinando

2013-01-01

286

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

PubMed Central

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

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

2013-01-01

287

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

PubMed

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

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

2013-10-15

288

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

PubMed Central

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

Reumann, Sigrun; Buchwald, Daniela; Lingner, Thomas

2012-01-01

289

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

290

Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction: A Review of Its Incidence, Pathophysiology, Clinical Relevance, and Treatment  

PubMed Central

Tyrosine kinase inhibitors (TKI) belong to a new class of molecular multitargeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. Since their introduction as adjunct treatment for renal cell carcinoma and gastrointestinal stromal tumors (GIST), a number of reports have demonstrated that TKI can induce thyroid dysfunction which was especially more common with sunitinib maleate. Many mechanisms with respect to this adverse effect of tyrosine kinase inhibitors have been proposed including their induction of thyroiditis, capillary regression in the thyroid gland, antithyroid peroxidase antibody production, and their ability to decrease iodine uptake by the thyroid gland. Of interest is the observation that TKI-induced thyroid dysfunction may actually be protective as it was shown to improve overall survival, and it was suggested that it may have a prognostic value. Followup on thyroid function tests while patients are maintained on tyrosine kinase inhibitor is strongly recommended. When thyroid dysfunction occurs, appropriate treatment should be individualized depending on patients symptoms and thyroid stimulating hormone level.

Salti, Ibrahim

2013-01-01

291

Effect of chitinase inhibitors on endotoxin-induced uveitis (EIU) in rabbits.  

PubMed

The acidic mammalian chitinase (AMCase) is significantly increased in tears of human allergic conjunctivitis. The aim of the study was to investigate the effects of chitinase inhibitors, allosamidin and caffeine versus dexamethasone, in rabbit endotoxin-induced uveitis (EIU). EIU was induced in rabbits by a single intravitreal injection of 100ng/10microl lipopolysaccharide (LPS). Drugs at four different concentrations (0.1, 0.01, 0.001 and 0.0001mM) were topically applied to the rabbit eye five times in 24h. Tears were collected at 0, 6 and 24h after LPS to measure the AMCase activity. The effect of treatment was also evaluated at the same time by slit lamp examination. Tear AMCase activity increased 6 and 24h after LPS injection. The AMCase activity was significantly inhibited in all treated groups with all doses of allosamidin and caffeine except with the lowest concentration. A higher AMCase inhibition at 24h was found with allosamidin and caffeine compared to dexamethasone. Moreover, topical administration of allosamidin, caffeine and dexamethasone produced a remarkable reduction of inflammatory signs, in the order: dexamethasone>caffeine>allosamidin. AMCase inhibitors showed in this rabbit model of uveitis a notable control of inflammatory response with a significant reduction of AMCase activity in tears with caffeine and allosamidin. These results support the key role of AMCase in the pathogenesis of human ocular inflammatory diseases and the therapeutic effect of AMCase inhibitors on experimental uveitis. PMID:18353673

Bucolo, Claudio; Musumeci, Maria; Maltese, Adriana; Drago, Filippo; Musumeci, Salvatore

2008-03-01

292

Rationalization of activity cliffs of a sulfonamide inhibitor of DNA methyltransferases with induced-fit docking.  

PubMed

Inhibitors of human DNA methyltransferases (DNMT) are of increasing interest to develop novel epi-drugs for the treatment of cancer and other diseases. As the number of compounds with reported DNMT inhibition is increasing, molecular docking is shedding light to elucidate their mechanism of action and further interpret structure-activity relationships. Herein, we present a structure-based rationalization of the activity of SW155246, a distinct sulfonamide compound recently reported as an inhibitor of human DNMT1 obtained from high-throughput screening. We used flexible and induce-fit docking to develop a binding model of SW155246 with a crystallographic structure of human DNMT1. Results were in excellent agreement with experimental information providing a three-dimensional structural interpretation of 'activity cliffs', e.g., analogues of SW155246 with a high structural similarity to the sulfonamide compound, but with no activity in the enzymatic assay. PMID:24566147

Medina-Franco, José L; Méndez-Lucio, Oscar; Yoo, Jakyung

2014-01-01

293

A protein synthesis inhibitor, cycloheximide does not alter cue-induced reinstatement of saccharin seeking.  

PubMed

A large body of evidence indicates that reactivation of aversive memories leads to protein synthesis-dependent memory reconsolidation which can be disrupted by cycloheximide and other protein synthesis inhibitors. The aim of the present study was to investigate whether cycloheximide would alter reconsolidation of the associations involving discrete cues paired with a sweet reward in an appetitive instrumental task. Rats trained to lever press for 0.1% saccharin were repeatedly tested for cue-induced reinstatement of non-reinforced responding for saccharin. CHX (3 mg/kg, s.c.) or its vehicle was injected immediately after each reinstatement session. The protein synthesis inhibitor did not alter the ability of the saccharin-paired cues to reinstate saccharin seeking. The present results suggest that passive re-exposure to saccharin-paired discrete cues in the reinstatement procedure does not lead to any cycloheximide-sensitive reconsolidation of the original associations. PMID:18590943

Mierzejewski, Pawel; Rogowski, Artur; Korkosz, Agnieszka; Bienkowski, Przemyslaw; Filip, Malgorzata; Samochowiec, Jerzy; Scinska, Anna

2008-08-01

294

The proteasome inhibitor MG132 reduces immobilization-induced skeletal muscle atrophy in mice  

PubMed Central

Background Skeletal muscle atrophy is a serious concern for the rehabilitation of patients afflicted by prolonged limb restriction. This debilitating condition is associated with a marked activation of NF?B activity. The ubiquitin-proteasome pathway degrades the NF?B inhibitor I?B?, enabling NF?B to translocate to the nucleus and bind to the target genes that promote muscle atrophy. Although several studies showed that proteasome inhibitors are efficient to reduce atrophy, no studies have demonstrated the ability of these inhibitors to preserve muscle function under catabolic condition. Methods We recently developed a new hindlimb immobilization procedure that induces significant skeletal muscle atrophy and used it to show that an inflammatory process characterized by the up-regulation of TNF?, a known activator of the canonical NF?B pathway, is associated with the atrophy. Here, we used this model to investigate the effect of in vivo proteasome inhibition on the muscle integrity by histological approach. TNF?, IL-1, IL-6, MuRF-1 and Atrogin/MAFbx mRNA level were determined by qPCR. Also, a functional measurement of locomotors activity was performed to determine if the treatment can shorten the rehabilitation period following immobilization. Results In the present study, we showed that the proteasome inhibitor MG132 significantly inhibited I?B? degradation thus preventing NF?B activation in vitro. MG132 preserved muscle and myofiber cross-sectional area by downregulating the muscle-specific ubiquitin ligases atrogin-1/MAFbx and MuRF-1 mRNA in vivo. This effect resulted in a diminished rehabilitation period. Conclusion These finding demonstrate that proteasome inhibitors show potential for the development of pharmacological therapies to prevent muscle atrophy and thus favor muscle rehabilitation.

2011-01-01

295

Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors  

PubMed Central

The in vivo effect of inhibitors of fatty acid amide hydrolase (FAAH) upon oedema volume and FAAH activity was evaluated in the carrageenan induced hind paw inflammation model in the mouse. Oedema was measured at two time points, 2 and 4?h, after intraplantar injection of carrageenan to anaesthetised mice. Intraperitoneal (i.p.) injections of the FAAH inhibitor URB597 (0.1, 0.3, 1 and 3?mg?kg?1) 30?min prior to carrageenan administration, dose-dependently reduced oedema formation. At the 4?h time point, the ED50 for URB597 was ?0.3?mg?kg?1. Indomethacin (5?mg?kg?1?i.p.) completely prevented the oedema response to carrageenan. The antioedema effects of indomethacin and URB597 were blocked by 3?mg?kg?1?i.p. of the CB2 receptor antagonist SR144528. The effect of URB597 was not affected by pretreatment with the peroxisome proliferator-activated receptor ? antagonist bisphenol A diglycidyl ether (30?mg?kg?1?i.p.) or the TRPV1 antagonist capsazepine (10?mg?kg?1?i.p.), when oedema was assessed 4?h after carrageenan administration. The CB1 receptor antagonists AM251 (3?mg?kg?1 i.p.) and rimonabant (0.5?mg?kg?1?i.p.) gave inconsistent effects upon the antioedema effect of URB597. FAAH measurements were conducted ex vivo in the paws, spinal cords and brains of the mice. The activities of FAAH in the paws and spinal cords of the inflamed vehicle-treated mice were significantly lower than the corresponding activities in the noninflamed mice. PMSF treatment almost completely inhibited the FAAH activity in all three tissues, as did the highest dose of URB597 (3?mg?kg?1) in spinal cord samples, whereas no obvious changes were seen ex vivo for the other treatments. In conclusion, the results show that in mice, treatment with indomethacin and URB597 produce SR144528-sensitive anti-inflammatory effects in the carrageenan model of acute inflammation.

Holt, Sandra; Comelli, Francesca; Costa, Barbara; Fowler, Christopher J

2005-01-01

296

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.

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

297

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

298

Nonhypoxic regulation and role of hypoxia-inducible factor 1 in aromatase inhibitor resistant breast cancer  

PubMed Central

Introduction Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2. Methods In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ER?, HER2, and HIF-1? (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ER? to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1? to determine its importance. Results Basal HIF-1? protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF-1? expression in AI-resistant cells is likely regulated by HER2 activated-phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1? affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP. Conclusions One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target.

2014-01-01

299

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

PubMed Central

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

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

2008-01-01

300

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

EPA Science Inventory

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

301

Recombinant alpha 1-proteinase inhibitor blocks antigen- and mediator-induced airway responses in sheep.  

PubMed

Alpha(1)-proteinase inhibitor (alpha(1)-PI) is a natural serine protease inhibitor. Although mainly thought to protect the airways from neutrophil elastase, alpha(1)-PI may also regulate the development of airway hyperresponsiveness (AHR), as indicated by our previous findings of an inverse relationship between lung alpha(1)-PI activity and the severity of antigen-induced AHR. Because allergic stimulation of the airways causes release of elastase, tissue kallikrein, and reactive oxygen species (ROS), all of which can reduce alpha(1)-PI activity and contribute to AHR, we hypothesized that administration of exogenous alpha(1)-PI should protect against pathophysiological airway responses caused by these agents. In untreated allergic sheep, airway challenge with elastase, xanthine/xanthine oxidase (which generates ROS), high-molecular-weight kininogen, the substrate for tissue kallikrein, and antigen resulted in bronchoconstriction. ROS and antigen also induced AHR to inhaled carbachol. Treatment with 10 mg of recombinant alpha(1)-PI (ralpha(1)-PI) blocked the bronchoconstriction caused by elastase, high-molecular-weight kininogen, and ROS, and the AHR induced by ROS and antigen. One milligram of ralpha(1)-PI was ineffective. These are the first in vivo data demonstrating the effects of ralpha(1)-PI. Our results are consistent with and extend findings obtained with human plasma-derived alpha(1)-PI and suggest that alpha(1)-PI may be important in the regulation of airway responsiveness. PMID:12433933

Scuri, Mario; Botvinnikova, Yelena; Lauredo, Isabel T; Abraham, William M

2002-12-01

302

Inhibition of Glucose-Induced Release of Insulin by Aldose Reductase Inhibitors  

PubMed Central

Aldose reductase (alditol: NADP oxidoreductase, EC 1.1.1.21) is the enzyme responsible for the conversion of glucose to its sugar alcohol, sorbitol. In this study, aldose reductase and a closely related enzyme, L-hexonate dehydrogenase (L-gulonate: NADP oxidoreductase, EC 1.1.1.19), were purified from rat pancreas. Glutaric acid, 2,4-dimethyl glutaric acid, 3,3-tetramethylene glutaric acid, and colchicine inhibited both enzymes, albeit with different potencies. These compounds also inhibited both phases of glucose-induced release of insulin by the perfused rat pancreas. The potencies of these inhibitors in depressing the release of insulin correlated with their effectiveness in inhibiting aldose reductase. At higher concentrations of inhibitors, tolbutamide-induced release of insulin was also depressed. The addition of exogenous sorbitol to pancreases treated with glutaric acid restored their ability to respond to glucose and tolbutamide. These findings suggest that the conversion of free intracellular glucose to sorbitol in the beta cell is an essential step in the glucose-induced release mechanism.

Gabbay, Kenneth H.; Tze, Wah Jun

1972-01-01

303

EGFR inhibitors sensitize non-small cell lung cancer cells to TRAIL-induced apoptosis  

PubMed Central

Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be regulated by the epidermal growth factor (EGF) signaling pathway. In this study, recombinant adenoviral vectors that encode TRAIL gene from the hTERT/RGD promoter (AdTRAIL) was combined with drugs including gefitinib, elotinib, and cetuximab that inhibit EGFR and the EGF signaling pathway in non–small cell lung cancer (NSCLC) cell lines to investigate their antitumor activity. In vitro, compared to single reagent, AdTRAIL combined with EGFR inhibitors reduced proliferation and enhanced apoptosis in H460, A549, and SW1573 cell lines. Western blot results suggested that these effects were relative to upregulation of pro-apoptosis protein BAX and down-regulation of p-AKT. In vivo, AdTRAIL combined with cetuximab resulted in a significant growth reduction in H460 xenografts without damage to the main organs of nude mice. Histological examination and TUNEL analyses of xenografts showed that cetuximab enhanced cell apoptosis induced by AdTRAIL. These results indicate that EGFR inhibitors enhanced AdTRAIL anti-tumor activity in NSCLC cell lines and that inhibiting the AKT pathway played an important role in this enhancement.

Xu, Fei; Tian, Ying; Huang, Yan; Zhang, Ling-Ling; Guo, Zheng-Zheng; Huang, Jia-Jia; Lin, Tong-Yu

2011-01-01

304

EGFR inhibitors sensitize non-small cell lung cancer cells to TRAIL-induced apoptosis.  

PubMed

Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be regulated by the epidermal growth factor (EGF) signaling pathway. In this study, recombinant adenoviral vectors that encode TRAIL gene from the hTERT/RGD promoter (AdTRAIL) was combined with drugs including gefitinib, elotinib, and cetuximab that inhibit EGFR and the EGF signaling pathway in non-small cell lung cancer (NSCLC) cell lines to investigate their antitumor activity. In vitro, compared to single reagent, AdTRAIL combined with EGFR inhibitors reduced proliferation and enhanced apoptosis in H460, A549, and SW1573 cell lines. Western blot results suggested that these effects were relative to up-regulation of pro-apoptosis protein BAX and down-regulation of p-AKT. In vivo, AdTRAIL combined with cetuximab resulted in a significant growth reduction in H460 xenografts without damage to the main organs of nude mice. Histological examination and TUNEL analyses of xenografts showed that cetuximab enhanced cell apoptosis induced by AdTRAIL. These results indicate that EGFR inhibitors enhanced AdTRAIL anti-tumor activity in NSCLC cell lines and that inhibiting the AKT pathway played an important role in this enhancement. PMID:21959047

Xu, Fei; Tian, Ying; Huang, Yan; Zhang, Ling-Ling; Guo, Zheng-Zheng; Huang, Jia-Jia; Lin, Tong-Yu

2011-10-01

305

Genetics Home Reference: Peroxisomal acyl-CoA oxidase deficiency  

MedlinePLUS

... a process called the peroxisomal fatty acid beta-oxidation pathway. This process shortens the VLCFA molecules by ... leukodystrophy ; molecule ; muscle tone ; nervous system ; neurological ; oxidase ; oxidation ; peroxisomes ; polydactyly ; prevalence ; recessive ; regression ; tissue ; white matter ...

306

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

307

Peroxisome ca(2+) homeostasis in animal and plant cells.  

PubMed

Ca(2+) homeostasis in peroxisomes has been an unsolved problem for many years. Recently novel probes to monitor Ca(2+) levels in the lumen of peroxisomes in living cells of both animal and plant cells have been developed. Here we discuss the contrasting results obtained in mammalian cells with chemiluminecsent (aequorin) and fluorescent (cameleon) probes targeted to peroxisomes. We briefly discuss the different characteristics of these probes and the possible pitfalls of the two approaches. We conclude that the contrasting results obtained with the two probes may reflect a heterogeneity among peroxisomes in mammalian cells. We also discuss the results obtained in plant peroxisomes. In particular we demonstrate that Ca(2+) increases in the cytoplasm are mirrored by similar rises of Ca(2+) concentration the lumen of peroxisomes. The increases in peroxisome Ca(2+) level results in the activation of a catalase isoform, CAT3. Other functional roles of peroxisomal Ca(2+) changes in plant physiology are briefly discussed. PMID:23821146

Costa, Alex; Drago, Ilaria; Zottini, Michela; Pizzo, Paola; Pozzan, Tullio

2013-01-01

308

Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis  

PubMed Central

Background and aim Mucosal healing in inflammatory bowel disease (IBD) can be achieved by improvement of intestinal barrier protection. Activation of hypoxia-inducible factor (HIF) has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis. Methods The efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn’s disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis. Results TRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome. Conclusion Our findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor ameliorates IBD in disease models. These findings highlight the potential of TRC160334 for its clinical application in the treatment of IBD.

Gupta, Ram; Chaudhary, Anita R; Shah, Binita N; Jadhav, Avinash V; Zambad, Shitalkumar P; Gupta, Ramesh Chandra; Deshpande, Shailesh; Chauthaiwale, Vijay; Dutt, Chaitanya

2014-01-01

309

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

310

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.

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

2005-01-01

311

Anmindenols A and B, Inducible Nitric Oxide Synthase Inhibitors from a Marine-Derived Streptomyces sp.  

PubMed

Anmindenols A (1) and B (2), inhibitors of inducible nitric oxide synthase (iNOS), were isolated from a marine-derived bacterium Streptomyces sp. Their chemical structures were elucidated by interpreting various spectroscopic data, including IR, MS, and NMR. Anmindenols A and B are sesquiterpenoids possessing an indene moiety with five- and six-membered rings derived from isoprenyl units. The absolute configuration of C-4 in anmindenol B was determined by electronic circular dichroism (ECD) of a dimolybdenum complex. Anmindenols A (1) and B (2) inhibited nitric oxide production in stimulated RAW 264.7 macrophage cells with IC50 values of 23 and 19 ?M, respectively. PMID:24878306

Lee, Jihye; Kim, Hiyoung; Lee, Tae Gu; Yang, Inho; Won, Dong Hwan; Choi, Hyukjae; Nam, Sang-Jip; Kang, Heonjoong

2014-06-27

312

Olprinone, a phosphodiesterase III inhibitor, does not affect hypoxia-induced pial arteriolar dilatation in rabbits  

Microsoft Academic Search

Purpose  Olprinone, a phosphodiesterase III inhibitor, is used for the treatment of heart failure or asthma. Such patients may suffer\\u000a from hypoxia. However, the effect of olprinone on the cerebrai vasodilator response to hypoxia remains unclear.\\u000a \\u000a \\u000a \\u000a Methods  Rabbits were anesthetized and ventilated mechanically. The pial arteriolar diameter was determined using a cranial window\\u000a and intravital microscopy. Hypoxia was induced twice in the

Masayuki Miyabe; Keiichi Tajima; Hiroshi Takahashi; Hidenori Toyooka

2003-01-01

313

Expression of the Salmonella Spp. Virulence Factor SifA in Yeast Alters Rho1 Activity on Peroxisomes  

PubMed Central

The Salmonella typhimurium effector protein SifA regulates the assembly and tubulation of the Salmonella phagosome. SifA localizes to the phagosome and interacts with the membrane via its prenylated tail. SifA is a structural homologue of another bacterial effector that acts as a GTP-exchange factor for Rho family GTPases and can bind GDP-RhoA. When coexpressed with a bacterial lipase that is activated by RhoA, SifA can induce tubulation of mammalian endosomes. In an effort to develop a genetic system to study SifA function, we expressed SifA and characterized its activity in yeast. GFP-SifA predominantly localized to yeast peroxisomal membranes. Under peroxisome-inducing conditions, GFP-SifA reduced the number of free peroxisomes and promoted the formation of large peroxisomes with membrane invaginations. GFP-SifA activity depended on the recruitment to peroxisomes of wild-type Rho1p and Pex25p, a receptor for Rho1p. GFP-SifA could also rescue the actin organization defects in pex25? and rho1 mutants, suggesting that SifA may recruit and potentiate Rho1p activity. We reexamined the distribution of GFP-SifA in mammalian cells and found the majority colocalizing with LAMP1-positive compartment and not with the peroxisomal marker PMP70. Together, these data suggest that SifA may use a similar mode of action via Rho proteins to alter yeast peroxisomal and mammalian endosomal membranes. Further definition of SifA activity on yeast peroxisomes could provide more insight into its role in regulating host membrane dynamics and small GTPases.

Vinh, Dani B. N.; Ko, Dennis C.; Rachubinski, Richard A.; Aitchison, John D.

2010-01-01

314

Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis  

PubMed Central

Background Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with pathological processes, in particular tumour development, and is a target for the development of new therapies. We have investigated the anti-angiogenic potential of two naturally occurring stilbene glycosides (compounds 1 and 2) isolated from the medicinal plant Boswellia papyriferai using large and smallvessel-derived endothelial cells. Compound 1 (trans-4',5'-dihydroxy-3-methoxystilbene-5-O-{?-L-rhamnopyranosyl-(1?2)-[?-L-rhamnopyranosyl-(1?6)}-?-D-glucopyranoside was the more hydrophilic and inhibited FGF-2-induced proliferation, wound healing, invasion in Matrigel, tube formation and angiogenesis in large and small vessel-derived endothelial cells and also in the chick chorioallantoic membrane assay. Using a binding assay we were able to show compound 1 reduced binding of FGF-2 to fibroblast growth factor receptors-1 and -2. In all cases the concentration of compound 1 which caused 50% inhibition (IC50) was determined. The effect of compound 1 on EGF and VEGF-induced proliferation was also investigated. Results Compound 1 inhibited all stages of FGF-2 induced angiogenesis with IC50 values in the range 5.8 ± 0.18 – 48.90 ± 0.40 ?M but did not inhibit EGF or VEGF-induced angiogenesis. It also inhibited FGF-2 binding to FGF receptor-1 and -2 with IC50 values of 5.37 ± 1.04 and 9.32 ± 0.082 ?M respectively and with concommotant down-regulation of phosphorylated-ERK-1/-2 expression. Compound 2 was an ineffective inhibitor of angiogenesis despite its structural homology to compound 1. Conclusion Compound 1 inhibited FGF-2 induced angiogenesis by binding to its cognate receptors and is an addition to the small number of natural product inhibitors of angiogenesis

Hussain, Sajjad; Slevin, Mark; Ahmed, Nessar; West, David; Choudhary, Muhammad Iqbal; Naz, Humera; Gaffney, John

2009-01-01

315

Salutary effect of NF?B inhibitor and folacin in hyperhomocysteinemia-hyperlipidemia induced vascular dementia.  

PubMed

Dementia of vascular origin or vascular dementia (VaD) is considered as the second commonest form of dementia after Alzheimer's disease (AD). In the last ten years various researchers have reported a strong association of hyperhomocysteinemia (HHcy), hyperlipidemia (HL) and dementia. This study investigates the salutary effect of natrium diethyl dithio carbamate trihydrate (NDDCT), a nuclear factor-kappaB (NF-?B) inhibitor as well as folacin (Vitamin-B(9)) in HHcy-HL induced VaD. l-methionone was used to induce HHcy-HL and associated VaD. Morris water-maze (MWM) was used for testing learning and memory. Vascular system assessment was done by testing endothelial function. Biochemical estimations were performed to assess HHcy (serum homocysteine), HL (serum cholesterol), oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species and brain glutathione), nitric oxide levels (serum nitrite/nitrate) and cholinergic activity (brain acetyl cholinesterase activity). L-methionine treated animals have shown HHcy-HL, endothelial dysfunction, impairment of learning, memory, reduction in serum nitrite/nitrate levels and brain glutathione (GSH) along with increase in serum and brain thiobarbituric acid reactive species (TBARS), and brain acetylcholinesterase activity. NDDCT, folacin and donepezil (positive control) significantly improved HHcy-HL induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. l-methionine induced HHcy-HL has caused VaD development in rats. NF?-B inhibitors and folacin may be considered as potential agents for the management of HHcy-HL induced VaD. PMID:22510463

Sharma, Bhupesh; Singh, Nirmal

2012-08-01

316

Use of a soluble epoxide hydrolase inhibitor in smoke-induced chronic obstructive pulmonary disease.  

PubMed

Tobacco smoke-induced chronic obstructive pulmonary disease (COPD) is a prolonged inflammatory condition of the lungs characterized by progressive and largely irreversible airflow limitation attributable to a number of pathologic mechanisms, including bronchitis, bronchiolitis, emphysema, mucus plugging, pulmonary hypertension, and small-airway obstruction. Soluble epoxide hydrolase inhibitors (sEHIs) demonstrated anti-inflammatory properties in a rat model after acute exposure to tobacco smoke. We compared the efficacy of sEHI t-TUCB (trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid) and the phosphodiesterase-4 (PDE4) inhibitor Rolipram (Biomol International, Enzo Life Sciences, Farmingdale, NY) to reduce lung injury and inflammation after subacute exposure to tobacco smoke over a period of 4 weeks. Pulmonary physiology, bronchoalveolar lavage, cytokine production, and histopathology were analyzed to determine the efficacy of sEHI and Rolipram to ameliorate tobacco smoke-induced inflammation and injury in the spontaneously hypertensive rat. Both t-TUCB and Rolipram inhibited neutrophil elevation in bronchoalveolar lavage. sEHI t-TUCB suppressed IFN-?, while improving lung function by reducing tobacco smoke-induced total respiratory resistance and tissue damping (small-airway and peripheral tissue resistance). Increases in tobacco smoke-induced alveolar airspace size were attenuated by t-TUCB. Rolipram inhibited the production of airway mucus. Both t-TUCB and Rolipram inhibited vascular remodeling-related growth factor. These findings suggest that sEHI t-TUCB has therapeutic potential for treating COPD by improving lung function and attenuating the lung inflammation and emphysematous changes caused by tobacco smoke. To the best of our knowledge, this is the first report to demonstrate that sEHI exerts significant protective effects after repeated, subacute tobacco smoke-induced lung injury in a rat model of COPD. PMID:22180869

Wang, Lei; Yang, Jun; Guo, Lei; Uyeminami, Dale; Dong, Hua; Hammock, Bruce D; Pinkerton, Kent E

2012-05-01

317

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.

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

2014-01-01

318

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.

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

319

Saxagliptin: a dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer's disease.  

PubMed

Type 2 diabetes (T2D) is one of the major risk factors associated with Alzheimer's disease (AD). Recent studies have found similarities in molecular mechanisms that underlie the respective degenerative developments in the two diseases. Pharmacological agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, which increase the level of glucagon-like peptide-1 (GLP-1) and ameliorate T2D, have become valuable candidates as disease modifying agents in the treatment of AD. In addition, endogenous GLP-1 levels decrease amyloid beta (A?) peptide and tau phosphorylation in AD. The present study examines the efficacy of Saxagliptin, a DPP-4 inhibitor in a streptozotocin (STZ) induced rat model of AD. Three months following induction of AD by intracerebral administration of streptozotocin, animals were orally administered Saxagliptin (0.25, 0.5 and 1 mg/kg) for 60 days. The effect of the DPP-4 inhibitor on hippocampal GLP-1 levels, A? burden, tau phosphorylation, inflammatory markers and memory retention were evaluated. The results reveal an attenuation of A?, tau phosphorylation and inflammatory markers and an improvement in hippocampal GLP-1 and memory retention following treatment. This remarkable therapeutic effect of Saxagliptin mediated through DPP-4 inhibition demonstrates a unique mechanism for A? and tau clearance by increasing GLP-1 levels and reverses the behavioural deficits and pathology observed in AD. PMID:23603201

Kosaraju, Jayasankar; Gali, Chaitanya Chakravarthi; Khatwal, Rizwan Basha; Dubala, Anil; Chinni, Santhivardhan; Holsinger, R M Damian; Madhunapantula, V Subba Rao; Muthureddy Nataraj, Satish Kumar; Basavan, Duraiswamy

2013-09-01

320

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

321

Pex11p?-mediated maturation of peroxisomes.  

PubMed

Peroxisomes are highly dynamic, multifunctional organelles that display remarkable changes in morphology, number and enzyme content. Peroxisomes multiply by growth and division of pre-existing organelles, but they can also form de novo from the ER. Growth and division of peroxisomes in mammalian cells involves elongation, membrane constriction and final fission and requires the peroxisome biogenesis Pex11 proteins as well as the recruitment of Dynamin-like protein DLP1/Drp1. We recently exploited the division-inhibiting properties of a unique Pex11p?-YFP fusion protein to further dissect the process of peroxisomal growth and division. By applying life cell imaging and the HaloTag technology, our study revealed that Pex11p?-mediated growth (elongation) and division of peroxisomes follows a multistep maturation pathway, which is initiated by the formation of an early peroxisomal membrane compartment from a pre-existing peroxisome and its stepwise conversion into a mature, metabolically active peroxisome compartment. Our observations support the view that peroxisomes formed by growth and division of pre-existing ones contain new membrane and matrix components. Peroxisome division is an asymmetric process, which is more complex than simple (symmetric) division of a preexisting organelle and equal distribution of the protein content. Our findings are in favor of Pex11p? acting as a peroxisomal membrane shaping protein. PMID:21509178

Delille, Hannah K; Dodt, Gabriele; Schrader, Michael

2011-01-01

322

Heat-shock protein 70 antisense oligomers enhance proteasome inhibitor-induced apoptosis.  

PubMed Central

Recent evidence supports a role for heat-shock protein 70 (hsp70) and the 26 S proteasome in regulating apoptosis, although the precise nature of their involvement is not known. In the present study, control and Bcl-x(L)-overexpressing, interleukin-3-dependent FL5.12 cell lines were treated with the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132). Basal proteasome activity appeared to be approximately 30% lower in bcl-x(L) cells compared with control cells using a substrate for the chymotrypsin-like activity. However, no difference in proteasome activity was detected using substrates for the trypsin-like or peptidylglutamyl peptide-hydrolysing activities. In addition, protein levels of the 20 S proteasome beta-subunit, as determined by Western blot analyses, were similar in control and bcl-x(L) cells, leading to the conclusion that proteasome activities were the same in these two cell lines. At 24 h after treatment with 500 nM MG132, apoptosis in bcl-x(L) cells (22%) was less than that observed in control cells (34%). Concomitantly, caspase activity in control cells, as assessed by N-acetyl-l-aspartyl-l-glutamyl-l-valyl-l-aspartyl-7-amino-4-methylcou marin (Ac-DEVD-AMC), was twice that observed in bcl-x(L) cells. By 48 h after MG132 treatment, apoptosis and caspase activity in bcl-x(L) cells were similar to those observed in control cells at 24 h. Proteasome inhibition stimulated increases in hsp70 protein levels in control and bcl-x(L) cells by 12 h, although the maximal increases found in bcl-x(L) cells were less. Blocking this induction with hsp70 antisense oligonucleotides potentiated apoptosis after treatment with MG132. Inhibiting caspase activity with a broad-spectrum caspase inhibitor, t-butoxycarbonyl-Asp(OMe)-fluoromethyl ketone, prevented MG132-induced apoptosis. The more specific caspase-3 inhibitor, Ac-DEVD-aldehyde, afforded less protection, although both inhibitors completely inhibited Ac-DEVD-AMC cleavage. These data indicate that both hsp70 and Bcl-x(L) provide some protection against proteasome inhibitor-induced apoptosis.

Robertson, J D; Datta, K; Biswal, S S; Kehrer, J P

1999-01-01

323

Pharmacologic profiling of phosphoinositide 3-kinase inhibitors as mitigators of ionizing radiation-induced cell death.  

PubMed

Ionizing radiation (IR) induces genotoxic stress that triggers adaptive cellular responses, such as activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling cascade. Pluripotent cells are the most important population affected by IR because they are required for cellular replenishment. Despite the clear danger to large population centers, we still lack safe and effective therapies to abrogate the life-threatening effects of any accidental or intentional IR exposure. Therefore, we computationally analyzed the chemical structural similarity of previously published small molecules that, when given after IR, mitigate cell death and found a chemical cluster that was populated with PI3K inhibitors. Subsequently, we evaluated structurally diverse PI3K inhibitors. It is remarkable that 9 of 14 PI3K inhibitors mitigated ?IR-induced death in pluripotent NCCIT cells as measured by caspase 3/7 activation. A single intraperitoneal dose of LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], administered to mice at 4 or 24 hours, or PX-867 [(4S,4aR,5R,6aS,9aR,Z)-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,7,10-trioxo-1-(pyrrolidin-1-ylmethylene)-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-H]isochromen-5-yl acetate (CID24798773)], administered 4 hours after a lethal dose of ?IR, statistically significantly (P < 0.02) enhanced in vivo survival. Because cell cycle checkpoints are important regulators of cell survival after IR, we examined cell cycle distribution in NCCIT cells after ?IR and PI3K inhibitor treatment. LY294002 and PX-867 treatment of nonirradiated cells produced a marked decrease in S phase cells with a concomitant increase in the G1 population. In irradiated cells, LY294002 and PX-867 treatment also decreased S phase and increased the G1 and G2 populations. Treatment with LY294002 or PX-867 decreased ?IR-induced DNA damage as measured by ?H2AX, suggesting reduced DNA damage. These results indicate pharmacologic inhibition of PI3K after IR abrogated cell death. PMID:24068833

Lazo, John S; Sharlow, Elizabeth R; Epperly, Michael W; Lira, Ana; Leimgruber, Stephanie; Skoda, Erin M; Wipf, Peter; Greenberger, Joel S

2013-12-01

324

Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo  

PubMed Central

Human interferon-inducible protein 10 (IP-10), a member of the alpha chemokine family, inhibits bone marrow colony formation, has antitumor activity in vivo, is chemoattractant for human monocytes and T cells, and promotes T cell adhesion to endothelial cells. Here we report that IP-10 is a potent inhibitor of angiogenesis in vivo. IP-10 profoundly inhibited basic fibroblast growth factor-induced neovascularization of Matrigel (prepared by H. K. Kleinman) injected subcutaneously into athymic mice. In addition, IP-10, in a dose-dependent fashion, suppressed endothelial cell differentiation into tubular capillary structures in vitro. IP-10 had no effect on endothelial cell growth, attachment, and migration as assayed in vitro. These results document an important biological property of IP-10 and raise the possibility that IP-10 may participate in the regulation of angiogenesis during inflammation and tumorigenesis.

1995-01-01

325

Design and Synthesis of Novel Small-molecule Inhibitors of the Hypoxia Inducible Factor Pathway  

PubMed Central

Hypoxia, a reduction in partial oxygen pressure, is a salient property of solid tumors. Hypoxia drives malignant progression and metastasis in tumors and participates in tumor resistance to radio- and chemotherapies. Hypoxia activates the hypoxia-inducible factor (HIF) family of transcription factors, which induce target genes that regulate adaptive biological processes such as anaerobic metabolism, cell motility and angiogenesis. Clinical evidence has demonstrated that expression of HIF-1 is strongly associated with poor patient prognosis and activation of HIF-1 contributes to malignant behavior and therapeutic resistance. Consequently, HIF-1 has become an important therapeutic target for inhibition by small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 signaling pathway. Many of these compounds exhibit inhibitory activity in the nanomolar range. Separate mechanistic studies indicate that these inhibitors do not alter HIF-1 levels, but interfere with the HIF-1?/HIF-1?/p300/CBP complex formation by interacting with p300 and CBP.

Mooring, Suazette Reid; Jin, Hui; Devi, Narra S.; Jabbar, Adnan A.; Kaluz, Stefan; Liu, Yuan; Van Meir, Erwin G.; Wang, Binghe

2012-01-01

326

The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways.  

PubMed

Although calcineurin inhibitors (CNIs) are very useful in preventing allograft rejection, they can mediate a rapid progression of post-transplantation malignancies. The CNI cyclosporine A (CsA) can promote renal tumor growth through activation of the proto-oncogene ras and over-expression of the angiogenic cytokine VEGF; the ras activation also induces over-expression of the cytoprotective enzyme HO-1, which promotes survival of renal cancer cells. Here, we show that the natural product honokiol significantly inhibited CsA-induced and Ras-mediated survival of renal cancer cells through the down-regulations of VEGF and HO-1. Thus, honokiol treatment may help to prevent tumor-promoting effects of CsA in transplant patients. PMID:23752066

Banerjee, Pallavi; Basu, Aninda; Arbiser, Jack L; Pal, Soumitro

2013-09-28

327

Possible mechanisms underlying the vasodilatation induced by olprinone, a phosphodiesterase III inhibitor, in rabbit coronary artery  

PubMed Central

The possible mechanisms underlying the vasodilatation induced by olprinone, a phosphodiesterase type III inhibitor, were investigated in smooth muscle of the rabbit coronary artery. Isometric force and membrane potential were measured simultaneously using endothelium-denuded smooth muscle strips. Acetylcholine (ACh, 3??M) produced a contraction with a membrane depolarization (15.2±1.1?mV). In a solution containing 5.9?mM K+, olprinone (100??M) hyperpolarized the resting membrane and (i) caused the absolute membrane potential level reached with ACh to be more negative (but did not reduce the delta membrane potential seen with ACh, 15.2±1.8 mV) and (ii) attenuated the ACh-induced contraction. In a solution containing 30?mM K+, these effects were not seen with olprinone. Glibenclamide (10??M) blocked the olprinone-induced membrane hyperpolarization. 4-AP (0.1?mM) significantly attenuated the olprinone-induced resting membrane hyperpolarization but TEA (1?mM) had no such effect. Glibenclamide (10??M), TEA (1?mM) and 4-AP (0.1?mM), given separately, all failed to modify the inhibitory actions of olprinone on (i) the absolute membrane potential level seen with ACh and (ii) the ACh-induced contraction. It is suggested that olprinone inhibits the ACh-induced contraction through an effect on the absolute level of membrane potential achieved with ACh in smooth muscle of the rabbit coronary artery. It is also suggested that glibenclamide-sensitive, ATP-sensitive K+ channels do not play an important role in the olprinone-induced inhibition of the ACh-induced contraction.

Ohashi, Masuo; Dohi, Yasuaki; Itoh, Takeo

2000-01-01

328

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.

2014-01-01

329

A broad-spectrum caspase inhibitor blocks concanavalin A-induced hepatitis in mice.  

PubMed

Fulminant hepatic failure (FHF) is a clinical syndrome resulting from massive death of liver cells or sudden and severe impairment of liver function. The causes of FHF are diverse and the overall mortality is very high. Recently, it became clear that apoptosis of hepatocytes is the critical cause of acute hepatic failure in FHF. It is well known that a family of cysteine proteases called caspase is one of the key mediators of the apoptotic pathway. Thus, caspases are attractive potential targets for the treatment of disorders resulting from excessive apoptosis. In this report, we examined the activity of a new caspase inhibitor, Xyz 033 mp. This nonpeptide inhibitor showed broad-spectrum caspase-inhibiting activity and protected primary rat hepatocytes from apoptotic death. In a mouse model of FHF induced by concavalin A (Con A), Xyz 033 mp suppressed elevated AST and ALT and specifically reduced IL-1 beta concentration. Also, Xyz 033 mp rescued mice from lethal experimental hepatitis induced by Con A. In addition, histological examinations indicated that Xyz 033 mp protected hepatocytes from the fatal apoptogenic effect of Con A. These results suggest that Xyz 033 mp may be a candidate therapeutic agent for FHF caused by massive apoptotic death of hepatocytes. PMID:11112361

Kim, K M; Kim, Y M; Park, M; Park, K; Chang, H K; Park, T K; Chung, H H; Kang, C Y

2000-12-01

330

Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency.  

PubMed

Single-base lesions in DNA are repaired predominantly by base excision repair (BER). DNA polymerase beta (pol beta) is the polymerase of choice in the preferred single-nucleotide BER pathway. The characteristic phenotype of mouse fibroblasts with a deletion of the pol beta gene is moderate hypersensitivity to monofunctional alkylating agents, e.g., methyl methanesulfonate (MMS). Increased sensitivity to MMS is also seen in the absence of pol beta partner proteins XRCC1 and PARP-1, and under conditions where BER efficiency is reduced by synthetic inhibitors. PARP activity plays a major role in protection against MMS-induced cytotoxicity, and cells treated with a combination of non-toxic concentrations of MMS and a PARP inhibitor undergo cell cycle arrest and die by a Chk1-dependent apoptotic pathway. Since BER-deficient cells and tumors are similarly hypersensitive to the clinically used chemotherapeutic methylating agent temozolomide, modulation of DNA damage-induced cell signaling pathways, as well as BER, are attractive targets for potentiating chemotherapy. PMID:17113833

Horton, Julie K; Wilson, Samuel H

2007-04-01

331

The proteome of human liver peroxisomes: identification of five new peroxisomal constituents by a label-free quantitative proteomics survey.  

PubMed

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

Gronemeyer, Thomas; Wiese, Sebastian; 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

332

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.

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

333

The effects of 5HT uptake- and MAO-inhibitors on l-5HTP-induced excitation in rats  

Microsoft Academic Search

The behavioural syndrome caused by l-5-HTP in rats was used for the study of effects of selective 5-HT uptake inhibitors and inhibitors of MAO on central 5-HT receptors. A good correlation was found between the relative potencies of drugs in inhibiting the 5-HT uptake in the rat brain and in intensifying l-5-HTP-induced behavioural stimulation. The potentiation of the l-5-HTP syndrome

R. Ortmann; P. C. Waldmeier; E. Radeke; A. Felner; A. Delini-Stula

1980-01-01

334

Recovery of memory in chicks after disruption during learning: The reversibility of amnesia induced by protein synthesis inhibitors  

Microsoft Academic Search

Protein synthesis inhibitors given during learning are known to disrupt memory in various animal species in several models\\u000a of learning. However, there are suggestions that amnesia induced by protein synthesis inhibitors is not permanent-memory can\\u000a be recovered by a reminder procedure, i.e., by presenting the animal with one of the components of the external environment\\u000a which was part of the

K. A. Radyushkin; K. V. Anokhin

1999-01-01

335

Induced Resistance to Methionyl-tRNA Synthetase Inhibitors in Trypanosoma brucei Is Due to Overexpression of the Target  

PubMed Central

New classes of antiparasitic drugs active against Trypanosoma brucei are needed to combat human African trypanosomiasis. Inhibitors of methionyl-tRNA synthetase (MetRS) have excellent potential to be developed for this purpose (S. Shibata, J. R. Gillespie, A. M. Kelley, A. J. Napuli, Z. Zhang, K. V. Kovzun, R. M. Pefley, J. Lam, F. H. Zucker, W. C. Van Voorhis, E. A. Merritt, W. G. Hol, C. L. Verlinde, E. Fan, and F. S. Buckner, Antimicrob. Agents Chemother. 55:1982–1989, 2011). In order to assess the potential for resistance to develop against this new class of inhibitors, T. brucei cultures were grown in the presence of MetRS inhibitors or comparison drugs. Resistance up to ?50 times the baseline 50% inhibitory concentration (IC50) was induced against a MetRS inhibitor after ?120 days. A similar level of resistance to the clinical drug eflornithine was induced after ?50 days and for pentamidine after ?80 days. Thus, resistance was induced more slowly against MetRS inhibitors than against clinically used drugs. The parasites resistant to the MetRS inhibitor were shown to overexpress MetRS mRNA by a factor of 35 over the parental strain. Southern analysis indicated that the MetRS gene was amplified in the genome by nearly 8-fold. When injected into mice, the MetRS inhibitor-resistant parasites caused a reduced level of infection, indicating that the changes associated with resistance attenuated their virulence. This finding and the fact that resistance to MetRS inhibitors developed relatively slowly are encouraging for further development of this class of compounds. Published studies on other antitrypanosomal drugs have primarily shown that alterations in membrane transporters were the mechanisms responsible for resistance. This is the first published report of induced drug resistance in the African trypanosome due to overexpression of the target enzyme.

Ranade, Ranae M.; Gillespie, J. Robert; Shibata, Sayaka; Verlinde, Christophe L. M. J.; Fan, Erkang; Hol, Wim G. J.

2013-01-01

336

Induced resistance to methionyl-tRNA synthetase inhibitors in Trypanosoma brucei is due to overexpression of the target.  

PubMed

New classes of antiparasitic drugs active against Trypanosoma brucei are needed to combat human African trypanosomiasis. Inhibitors of methionyl-tRNA synthetase (MetRS) have excellent potential to be developed for this purpose (S. Shibata, J. R. Gillespie, A. M. Kelley, A. J. Napuli, Z. Zhang, K. V. Kovzun, R. M. Pefley, J. Lam, F. H. Zucker, W. C. Van Voorhis, E. A. Merritt, W. G. Hol, C. L. Verlinde, E. Fan, and F. S. Buckner, Antimicrob. Agents Chemother. 55:1982-1989, 2011). In order to assess the potential for resistance to develop against this new class of inhibitors, T. brucei cultures were grown in the presence of MetRS inhibitors or comparison drugs. Resistance up to ?50 times the baseline 50% inhibitory concentration (IC50) was induced against a MetRS inhibitor after ?120 days. A similar level of resistance to the clinical drug eflornithine was induced after ?50 days and for pentamidine after ?80 days. Thus, resistance was induced more slowly against MetRS inhibitors than against clinically used drugs. The parasites resistant to the MetRS inhibitor were shown to overexpress MetRS mRNA by a factor of 35 over the parental strain. Southern analysis indicated that the MetRS gene was amplified in the genome by nearly 8-fold. When injected into mice, the MetRS inhibitor-resistant parasites caused a reduced level of infection, indicating that the changes associated with resistance attenuated their virulence. This finding and the fact that resistance to MetRS inhibitors developed relatively slowly are encouraging for further development of this class of compounds. Published studies on other antitrypanosomal drugs have primarily shown that alterations in membrane transporters were the mechanisms responsible for resistance. This is the first published report of induced drug resistance in the African trypanosome due to overexpression of the target enzyme. PMID:23587950

Ranade, Ranae M; Gillespie, J Robert; Shibata, Sayaka; Verlinde, Christophe L M J; Fan, Erkang; Hol, Wim G J; Buckner, Frederick S

2013-07-01

337

Selective inhibitors for phosphodiesterase 3 and 4 in antigen-induced increase of cough reflex sensitivity in guinea pigs  

Microsoft Academic Search

Effects of the selective phosphodiesterase 3 (PDE3) inhibitor olprinone and the selective PDE4 inhibitor SB207499 were investigated on antigen-induced increase of cough reflex sensitivity and normal cough response to capsaicin in guinea pigs. Number of coughs elicited by inhalation of capsaicin (10?8, 10?6 and 10?4M) was counted 24h after an antigen challenge in actively sensitized guinea pigs, and then bronchoalveolar

Masaki Fujimura; Qi Liu

2007-01-01

338

The 5-lipoxygenase inhibitors ZD2138 and ZM230487 are potent and selective inhibitors of several antigen-induced guinea-pig pulmonary responses.  

PubMed

The non-redox 5-lipoxygenase inhibitor Zeneca ZD2138 (6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy- methyl]-1-methyl-2-quinolone) was evaluated for its ability to inhibit antigen-induced leukotriene release from guinea-pig lung in vitro and antigen-induced increases in pulmonary resistance in guinea pigs in vivo. ZD2138 inhibited antigen-induced release of leukotriene D4 and leukotriene B4 with IC50 values of 0.3 +/- 0.06 microM and 0.4 +/- 0.09 microM, respectively. At about ten times higher concentrations, ZD2138 had no effect on antigen-induced release of thromboxane B2, indicating selectivity for inhibition of 5-lipoxygenase vs. phospholipase A2, cyclooxygenase, or thromboxane synthetase. Similarly, ZD2138 did not inhibit histamine release, indicating that the compound did not have a generalized effect on the mediator release processes. Zeneca ZM230487-(6-[(3-fluoro-5-[4-methoxy- 3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1-ethyl-2-quinolone), the N-ethyl analog of ZD2138, was approximately equipotent toward inhibition of antigen-induced leukotriene D4 release, with an IC50 of 0.2 +/- 0.08 microM. The so-called 5-lipoxygenase activating protein (FLAP) inhibitor, MK-886 (3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2 ,2- dimethylpropanoic acid), and the iron ligand 5-lipoxygenase inhibitor zileuton (N-(1-benzo[b]thien-2-ylethyl)-N-hydroxy-urea) were also active, but less potent than ZD2138 with IC50 values for inhibition of antigen-induced leukotriene release in vitro of 9.3 +/- 3.2 microM and 14.8 +/- 1.8 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7522174

Kusner, E J; Buckner, C K; Dea, D M; DeHaas, C J; Marks, R L; Krell, R D

1994-05-23

339

Mutation of the Arabidopsis LON2 peroxisomal protease enhances pexophagy.  

PubMed

Peroxisomes are critical organelles housing various, often oxidative, reactions. Pexophagy, the process by which peroxisomes are selectively targeted for destruction via autophagy, is characterized in yeast and mammals but had not been reported in plants. In this article, we describe how the peroxisome-related aberrations of a mutant defective in the LON2 peroxisomal protease are suppressed when autophagy is prevented by mutating any of several key autophagy-related (ATG) genes. Our results reveal that plant peroxisomes can be degraded by selective autophagy and suggest that pexophagy is accelerated when the LON2 protease is disabled. PMID:24413187

Bartel, Bonnie; Farmer, Lisa M; Rinaldi, Mauro A; Young, Pierce G; Danan, Charles H; Burkhart, Sarah E

2014-03-01

340

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

341

Post-treatment of an NADPH oxidase inhibitor prevents seizure-induced neuronal death.  

PubMed

The present study sought to evaluate the neuroprotective effects of apocynin, an NADPH oxidase assembly inhibitor, on seizure-induced neuronal death. Apocynin, also known as acetovanillone, is a natural organic compound isolated from the root of Canadian hemp (Apocynum cannabium). It has been extensively studied to determine its disease-fighting capabilities and application in several brain insults, such as traumatic brain injury and stroke. Here we tested the hypothesis that post-treatment of apocynin may prevent seizure-induced neuronal death by suppression of NADPH oxidase-mediated superoxide production. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25mg/kg) in male rats. Apocynin (30mg/kg, i.p.) was injected into the intraperitoneal space two hours after seizure onset. A second injection was performed 24h after seizure. To test whether apocynin inhibits NADPH oxidase activation-induced reactive oxygen species (ROS) production, dihydroethidium (dHEt, 5mg/kg, i.p.) was injected before onset of seizure and ROS production was detected five hours after seizure onset. Neuronal oxidative injury (4HNE), neuronal death (Fluoro Jade-B), blood brain barrier (BBB) disruption (IgG leak), neurotrophil infiltration (MPO) and microglia activation (CD11b) in the hippocampus was evaluated at three days after status epilepticus (SE). Pilocarpine-induced seizure increased p47 immunofluorescence in the plasma membrane of hippocampal neurons at 12h post-insult and apocynin treatment prevented this increase. The present study found that apocynin post-treatment decreased ROS production and lipid peroxidation after seizure and decreased the number of degenerating hippocampal neurons. Apocynin also reduced seizure-induced BBB disruption, neurotrophil infiltration and microglial activation. Taken together, the present results suggest that inhibition of NADPH oxidase by apocynin may have a high therapeutic potential to reduce seizure-induced neuronal dysfunction. PMID:23313582

Kim, Jin Hee; Jang, Bong Geom; Choi, Bo Young; Kim, Hyeong Seop; Sohn, Min; Chung, Tae Nyoung; Choi, Hui Chul; Song, Hong Ki; Suh, Sang Won

2013-03-01

342

The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury.  

PubMed

Receptor-interacting protein (RIP)3 is a critical regulator of necroptosis and has been demonstrated to be associated with various diseases, suggesting that its inhibitors are promising in the clinic. However, there have been few RIP3 inhibitors reported as yet. B-Raf(V600E) inhibitors are an important anticancer drug class for metastatic melanoma therapy. In this study, we found that 6 B-Raf inhibitors could inhibit RIP3 enzymatic activity in vitro. Among them, dabrafenib showed the most potent inhibition on RIP3, which was achieved by its ATP-competitive binding to the enzyme. Dabrafenib displayed highly selective inhibition on RIP3 over RIP1, RIP2 and RIP5. Moreover, only dabrafenib rescued cells from RIP3-mediated necroptosis induced by the necroptosis-induced combinations, that is, tumor necrosis factor (TNF)?, TNF-related apoptosis-inducing ligand or Fas ligand plus Smac mimetic and the caspase inhibitor z-VAD. Dabrafenib decreased the RIP3-mediated Ser358 phosphorylation of mixed lineage kinase domain-like protein (MLKL) and disrupted the interaction between RIP3 and MLKL. Notably, RIP3 inhibition of dabrafenib appeared to be independent of its B-Raf inhibition. Dabrafenib was further revealed to prevent acetaminophen-induced necrosis in normal human hepatocytes, which is considered to be mediated by RIP3. In acetaminophen-overdosed mouse models, dabrafenib was found to apparently ease the acetaminophen-caused liver damage. The results indicate that the anticancer B-Raf(V600E) inhibitor dabrafenib is a RIP3 inhibitor, which could serve as a sharp tool for probing the RIP3 biology and as a potential preventive or therapeutic agent for RIP3-involved necroptosis-related diseases such as acetaminophen-induced liver damage. PMID:24901049

Li, J-X; Feng, J-M; Wang, Y; Li, X-H; Chen, X-X; Su, Y; Shen, Y-Y; Chen, Y; Xiong, B; Yang, C-H; Ding, J; Miao, Z-H

2014-01-01

343

Inhibition of polyamine oxidase prevented cyclin-dependent kinase inhibitor-induced apoptosis in HCT 116 colon carcinoma cells.  

PubMed

Roscovitine and purvalanol are novel cyclin-dependent kinase (CDK) inhibitors that prevent cell proliferation and induce apoptotic cell death in various cancer cell lines. Although a number of studies have demonstrated the potential apoptotic role of roscovitine, there is limited data about the therapeutic efficiency of purvalanol on cancer cells. The natural polyamines (PAs) putrescine, spermidine, and spermine have essential roles in the regulation of cell differentiation, growth, and proliferation, and increased levels of these compounds have been associated with cancer progression. Recently, depletion of intracellular PA levels because of modulation of PA catabolic enzymes was shown to be an indicator of the efficacy of chemotherapeutic agents. In this study, our aim was to investigate the potential role of PA catabolic enzymes in CDK inhibitor-induced apoptosis in HCT 116 colon carcinoma cells. Exposure of cells to roscovitine or purvalanol decreased cell viability in a dose- and time-dependent manner. The selected concentrations of roscovitine and purvalanol inhibited cell viability by 50 % compared with control cells and induced apoptosis by activating the mitochondria-mediated pathway in a caspase-dependent manner. However, the apoptotic effect of purvalanol was stronger than that of roscovitine in HCT 116 cells. In addition, we found that CDK inhibitors decreased PA levels and significantly upregulated expression of key PA catabolic enzymes such as polyamine oxidase (PAO) and spermine oxidase (SMO). MDL-72,527, a specific inhibitor of PAO and SMO, decreased apoptotic potential of CDK inhibitors on HCT 116 cells. Moreover, transient silencing of PAO was also reduced prevented CDK inhibitor-induced apoptosis in HCT 116 cells. We conclude that the PA catabolic pathway, especially PAO, is a critical target for understanding the molecular mechanism of CDK inhibitor-induced apoptosis. PMID:23892915

Gürkan, Ajda Coker; Arisan, Elif Damla; Obakan, Pinar; Palavan-Ünsal, Narçin

2013-12-01

344

Catalase degradation in sunflower cotyledons during peroxisome transition from glyoxysomal to leaf peroxisomal function. [Helianthus annuus  

SciTech Connect

First order rate constant for the degradation (degradation constants) of catalase in the cotyledons of sunflower (Helianthus annuus L.) were determined by measuring the loss of catalase containing /sup 14/C-labeled heme. During greening of the cotyledons, a period when peroxisomes change from glyoxysomal to leaf peroxisomal function, the degradation of glyoxysomal catalase is significantly slower than during all other stages of cotyledon development in light or darkness. The degradation constant during the transition stage of peroxisome function amounts to 0.205 day/sup -1/ in contrast to the constants ranging from 0.304 day/sup -1/ to 0.515 day/sup -1/ during the other developmental stages. Density labeling experiments comprising labeling of catalase with /sup 2/H/sub 2/O and its isopycnic centrifugation on CsCl gradients demonstrated that the determinations of the degradation constants were not substantially affected by reutilization of /sup 14/C-labeled compounds for catalase synthesis. The degradation constants for both glyoxysomal catalase and catalase synthesized during the transition of peroxisome function do not differ. This was shown by labeling the catalases with different isotopes and measuring the isotope ratio during the development of the cotyledons. The results are inconsistent with the concept that an accelerated and selective degradation of glyoxysomes underlies the change in peroxisome function. The data suggest that catalase degradation is at least partially due to an individual turnover of catalase and does not only result from a turnover of the whole peroxisomes.

Eising, R.; Gerhardt, B.

1987-06-01

345

PAS3, a Saccharomyces cerevisiae gene encoding a peroxisomal integral membrane protein essential for peroxisome biogenesis  

PubMed Central

Saccharomyces cerevisiae pas3-mutants are described which conform the pas-phenotype recently reported for the peroxisomal assembly mutants pas1-1 and pas2 (Erdmann, R., M. Veenhuis, D. Mertens, and W.-H Kunau, 1989, Proc. Natl. Acad. Sci. USA. 86:5419-5423). The isolation of pas3- mutants enabled us to clone the PAS3 gene by functional complementation. DNA sequence analysis revealed a 50.6-kD protein with at least one domain of sufficient length and hydrophobicity to span a lipid bilayer. To verify these predictions antibodies were raised against a truncated portion of the PAS3 coding region overexpressed in E. coli. Pas3p was identified as a 48 kD peroxisomal integral membrane protein. It is shown that a lack of this protein causes the peroxisome- deficient phenotype and the cytosolic mislocalization of peroxisomal matrix enzymes. Based on protease digestion experiments Pas3p is discussed to be anchored in the peroxisomal membrane by its amino- terminus while the bulk of the molecule is exposed to the cytosol. These findings are consistent with the possibility that Pas3p is one component of the peroxisomal import machinery.

1991-01-01

346

Metabolic functions of peroxisomes in health and disease.  

PubMed

Peroxisomes are subcellular organelles which are present in virtually every eukaryotic cell and catalyze a large number of metabolic functions. The importance of peroxisomes for humans is stressed by the existence of a large group of genetic diseases in which either the biogenesis of peroxisomes is impaired or one of its metabolic functions. Thanks to the work on Zellweger syndrome which is the prototype of the group of peroxisomal disorders, much has been learned about the metabolism and biogenesis of peroxisomes in humans. These metabolic functions include: (1.) fatty acid beta-oxidation; (2.) etherphospholipid biosynthesis; (3.) fatty acid alpha-oxidation, and (4.) glyoxylate detoxification. Since peroxisomes lack a citric acid cycle and a respiratory chain, peroxisomes are relatively helpless organelles which rely heavily on their cross-talk with other subcellular organelles in order to metabolize the end products of metabolism as generated in peroxisomes. The metabolic functions of peroxisomes in humans will be briefly described in this review with emphasis on the cross-talk with other subcellular organelles as well as the peroxisomal disorders in which one or more peroxisomal functions are impaired. PMID:24012550

Wanders, Ronald J A

2014-03-01

347

Defining the Plant Peroxisomal Proteome: From Arabidopsis to Rice  

PubMed Central

Peroxisomes are small subcellular organelles mediating a multitude of processes in plants. Proteomics studies over the last several years have yielded much needed information on the composition of plant peroxisomes. In this review, the status of peroxisome proteomics studies in Arabidopsis and other plant species and the cumulative advances made through these studies are summarized. A reference Arabidopsis peroxisome proteome is generated, and some unique aspects of Arabidopsis peroxisomes that were uncovered through proteomics studies and hint at unanticipated peroxisomal functions are also highlighted. Knowledge gained from Arabidopsis was utilized to compile a tentative list of peroxisome proteins for the model monocot plant, rice. Differences in the peroxisomal proteome between these two model plants were drawn, and novel facets in rice were expounded upon. Finally, we discuss about the current limitations of experimental proteomics in decoding the complete and dynamic makeup of peroxisomes, and complementary and integrated approaches that would be beneficial to defining the peroxisomal metabolic and regulatory roadmaps. The synteny of genomes in the grass family makes rice an ideal model to study peroxisomes in cereal crops, in which these organelles have received much less attention, with the ultimate goal to improve crop yield.

Kaur, Navneet; Hu, Jianping

2011-01-01

348

Aborted Autophagy and Nonapoptotic Death Induced by Farnesyl Transferase Inhibitor and LovastatinS?  

PubMed Central

Exposure of the human malignant peripheral nerve sheath tumor cell lines STS-26T, ST88-14, and NF90-8 to nanomolar concentrations of both lovastatin and farnesyl transferase inhibitor (FTI)-1 but not to either drug alone induced cell death. ST88-14 and NF90-8 cells underwent apoptosis, yet dying STS-26T cells did not. FTI-1 cotreatment induced a strong and sustained autophagic response as indicated by analyses of microtubule-associated protein-1 light chain 3 (LC3)-II accumulation in STS-26T cultures. Extensive colocalization of LC3-positive punctate spots was observed with both lysosome-associated membrane protein (LAMP)-1 and LAMP-2 (markers of late endosomes/lysosomes) in solvent or FTI-1 or lovastatin-treated STS-26T cultures but very little colocalization in lovastatin/FTI-1-cotreated cultures. The absence of colocalization in the cotreatment protocol correlated with loss of LAMP-2 expression. Autophagic flux studies indicated that lovastatin/FTI-1 cotreatment inhibited the completion of the autophagic program. In contrast, rapamycin induced an autophagic response that was associated with cytostasis but maintenance of viability. These studies indicate that cotreatment of STS-26T cells with lovastatin and FTI-1 induces an abortive autophagic program and nonapoptotic cell death.

Wojtkowiak, Jonathan W.; Sane, Komal M.; Kleinman, Miriam; Sloane, Bonnie F.; Reiners, John J.

2011-01-01

349

IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice.  

PubMed

IL-21 exerts pleiotrophic immunomodulatory activities on a variety of target cells including B cells that undergo class switch recombination (CSR) to IgE. In this study, we examined whether IgE-mediated systemic anaphylaxis was controlled by in vivo administration of IL-21 using the peanut allergy model in mice and investigated the molecular mechanisms underlying the IL-21-induced regulation of IgE. The anaphylactic reaction was completely abolished by the administration of recombinant mouse IL-21 or an IL-21 expression plasmid in terms of the change of body temperature and anaphylactic symptoms. The recombinant mouse IL-21 treatment remarkably suppressed IgE CSR in splenic B cells, resulting in significant decrease in serum concentrations of total as well as allergen-specific IgE. In the meanwhile, IL-21 provoked B cells in normal as well as allergic mice to express the inhibitor of differentiation 2 (Id2) gene that was shown to be crucially involved in the regulation of the activation-induced cytidine deaminase and IgE CSR. Moreover, mice genetically deficient for Id2 were completely unsusceptible to IL-21-induced prevention of IgE CSR and anaphylaxis. The present study strongly suggests that IL-21 is capable of regulating systemic allergic reactions by inducing the transcriptional regulator Id2, and the cytokine may be useful for clinical intervention for allergic diseases including anaphylaxis. PMID:18056403

Kishida, Tsunao; Hiromura, Yayoi; Shin-Ya, Masaharu; Asada, Hidetsugu; Kuriyama, Hiroko; Sugai, Manabu; Shimizu, Akira; Yokota, Yoshifumi; Hama, Takemitsu; Imanishi, Jiro; Hisa, Yasuo; Mazda, Osam

2007-12-15

350

Inhibition of cytokine-induced JAK-STAT signalling pathways by an endonuclease inhibitor aurintricarboxylic acid  

PubMed Central

Inducible nitric oxide (iNOS) is thought to involve in host defence and tissue damage in inflammatory loci. In previous study, we have found that the endonuclease inhibitor aurintricarboxylic acid (ATA) can protect macrophages from cell death induced by bacterial lipopolysaccharide. This action is through the interruption with signalling pathways for NF-?B and AP-1 activation, and thus iNOS expression. In this study we have addressed the effects of ATA on JAK-STAT signalling pathways. In murine RAW 264.7 macrophages, IFN-?-mediated NO production and iNOS expression were concentration-dependently reduced by the presence of 3–100 ?M ATA. IFN-?-induced STAT1 activation, as assessed from its tyrosine phosphorylation, nuclear translocation, binding to specific DNA response element and evoked IRF-1 reporter gene assay, were concomitantly inhibited by ATA. However, ATA did not alter IFN-? binding to RAW 264.7 cells. The activities of JAK1 and JAK2, the upstream kinases essential for STAT1 signalling in response to IFN-?, were also reduced by ATA. Moreover, IL-4, IL-10, GM-CSF and M-CSF elicited tyrosine phosphorylation of STAT3, STAT5 and/or STAT6 in macrophages were diminished by the presence of ATA. Taken together, we conclude that ATA can interfere JAK-STAT signalling pathways in response to cytokines. This action contributes to the inhibition of IFN-?-induced iNOS expression.

Chen, Ching-Wen; Chao, Yee; Chang, Ying-Hsin; Hsu, Ming-Jen; Lin, Wan-Wan

2002-01-01

351

Aldose reductase regulates hepatic peroxisome proliferator-activated receptor alpha phosphorylation and activity to impact lipid homeostasis.  

PubMed

Aldose reductase (AR) is implicated in the development of a number of diabetic complications, but the underlying mechanisms remain to be fully elucidated. We performed this study to determine whether and how AR might influence hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) activity and lipid metabolism. Our results in mouse hepatocyte AML12 cells show that AR overexpression caused strong suppression of PPARalpha/delta activity (74%, p < 0.001) together with significant down-regulation of mRNA expression for acetyl-CoA oxidase and carnitine palmitoyltransferase-1. These suppressive effects were attenuated by the selective AR inhibitor zopolrestat. Furthermore, AR overexpression greatly increased the levels of phosphorylated PPARalpha and ERK1/2. Moreover, AR-induced suppression of PPARalpha activity was attenuated by treatment with an inhibitor for ERK1/2 but not that for phosphoinositide 3-kinase, p38, or JNK. Importantly, similar effects were observed for cells exposed to 25 mm glucose. In streptozotocin-diabetic mice, AR inhibitor treatment or genetic deficiency of AR resulted in significant dephosphorylation of both PPARalpha and ERK1/2. With the dephosphorylation of PPARalpha, hepatic acetyl-CoA oxidase and apolipoprotein C-III mRNA expression was greatly affected and that was associated with substantial reductions in blood triglyceride and nonesterified fatty acid levels. These data indicate that AR plays an important role in the regulation of hepatic PPARalpha phosphorylation and activity and lipid homeostasis. A significant portion of the AR-induced modulation is achieved through ERK1/2 signaling. PMID:18445591

Qiu, Longxin; Wu, Xiaochun; Chau, Jenny F L; Szeto, Irene Y Y; Tam, Wing Yip; Guo, Zongsheng; Chung, Sookja K; Oates, Peter J; Chung, Stephen S M; Yang, James Y

2008-06-20

352

The human gene SLC25A17 encodes a peroxisomal transporter of coenzyme A, FAD and NAD+.  

PubMed

The essential cofactors CoA, FAD and NAD+ are synthesized outside the peroxisomes and therefore must be transported into the peroxisomal matrix where they are required for important processes. In the present study we have functionally identified and characterized SLC25A17 (solute carrier family 25 member 17), which is the only member of the mitochondrial carrier family that has previously been shown to be localized in the peroxisomal membrane. Recombinant and purified SLC25A17 was reconstituted into liposomes. Its transport properties and kinetic parameters demonstrate that SLC25A17 is a transporter of CoA, FAD, FMN and AMP, and to a lesser extent of NAD+, PAP (adenosine 3',5'-diphosphate) and ADP. SLC25A17 functioned almost exclusively by a counter-exchange mechanism, was saturable and was inhibited by pyridoxal 5'-phosphate and other mitochondrial carrier inhibitors. It was expressed to various degrees in all of the human tissues examined. Its main function is probably to transport free CoA, FAD and NAD+ into peroxisomes in exchange for intraperoxisomally generated PAP, FMN and AMP. The present paper is the first report describing the identification and characterization of a transporter for multiple free cofactors in peroxisomes. PMID:22185573

Agrimi, Gennaro; Russo, Annamaria; Scarcia, Pasquale; Palmieri, Ferdinando

2012-04-01

353

Subacute neurotoxicity induced in mice by potent organophosphorus neuropathy target esterase inhibitors.  

PubMed

The mouse is considered to be insensitive and the hen sensitive to clinical expression of organophosphorus-induced delayed neuropathy (OPIDN) which is associated with inhibition of neuropathy target esterase (NTE). This species difference is reevaluated with two optimized inhibitors of hen brain NTE by examining them for potential neurotoxic effects in mice. 2-Octyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (OBDPO) and ethyl octylphosphonofluoridate (EOPF) inhibit mouse brain NTE in vitro by 50% at 0.12 and 0.02 nM and induce neurotoxic signs in mice at 10 and 5 mg/kg, respectively. The action of these compounds in both l- and 6-month-old mice, sometimes after early transient cholinergic signs, involves ataxia, paralysis, and death in 1 to 3 days and is accordingly referred to as subacute neurotoxicity. The neurotoxic signs are associated with brain edema and severe vacuolation in the grey matter of the brain and spinal cord, particularly the neuropile. Subacute neurotoxic signs are always associated with at least 80% inhibition of brain NTE activity 16-24 hr after treatment. Acetylcholinesterase and butyrylcholinesterase are much less sensitive than NTE to inhibition by OBDPO and EOPF both in vitro and in vivo. Selected carbamates, thiocarbamates, phosphinates, and sulfanyl fluorides are prophylactic agents and dipentyl 2,2-dichlorovinyl phosphate is a promoter for OBDPO-induced subacute neurotoxicity. Although this type of neurotoxicity in mice is similar to OPIDN in the correlation with NTE inhibition and the prophylactic action of reversible NTE inhibitors, it differs from OPIDN in the delay time prior to onset, the sensitivity of both young and old animals, and the high incidence of fatality. A full neuropathological study is desirable to further characterize this subacute neurotoxicity. PMID:8685903

Wu, S Y; Casida, J E

1996-07-01

354

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

355

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

356

An Efficient Positive Selection Procedure for the Isolation of Peroxisomal Import and Peroxisome Assembly Mutants of Saccharomyces Cerevisiae  

PubMed Central

To study peroxisome biogenesis, we developed a procedure to select for Saccharomyces cerevisiae mutants defective in peroxisomal protein import or peroxisome assembly. For this purpose, a chimeric gene was constructed encoding the bleomycin resistance protein linked to the peroxisomal protein luciferase. In wild-type cells this chimeric protein is imported into the peroxisome, which prevents the neutralizing interaction of the chimeric protein with its toxic phleomycin ligand. Peroxisomal import and peroxisome assembly mutants are unable to import this chimeric protein into their peroxisomes. This enables the bleomycin moiety of the chimeric protein to bind phleomycin, thereby preventing its toxicity. The selection is very efficient: upon mutagenesis, 84 (10%) of 800 phleomycin resistant colonies tested were unable to grow on oleic acid. This rate could be increased to 25% using more stringent selection conditions. The selection procedure is very specific; all oleic acid non utilizing (onu) mutants tested were disturbed in peroxisomal import and/or peroxisome assembly. The pas (peroxisome assembly) mutants that have been used for complementation analysis represent 12 complementation groups including three novel ones, designated pas20, pas21 and pas22.

Elgersma, Y.; van-den-Berg, M.; Tabak, H. F.; Distel, B.

1993-01-01

357

IKK? inhibitor in combination with bortezomib induces cytotoxicity in breast cancer cells  

PubMed Central

Bortezomib is a proteasome inhibitor with remarkable clinical antitumor activity in multiple myeloma (MM) and is under evaluation in clinical trials in various types of cancer including breast cancer. Although the initial rationale for its use in cancer treatment was the inhibition of NF-?B activity by blocking proteasomal degradation of I?B?, direct evidence indicating inhibition of constitutive NF-?B activity by bortezomib in tumor cells in patients has not yet been reported. Moreover, recent studies have shown that bortezomib activates constitutive NF-?B activity via stimulating the canonical pathway in MM cells. In this study, we first examined protein expression of I?B? after bortezomib treatment. We observed that bortezomib upregulated the phosphorylation and downregulated I?B? protein expression in a dose- and time-dependent manner in MCF7 and T47D cells, associated with phosphorylation of IKK?. Since I?B? is an inhibitor of nuclear translocation of NF-?B, we further examined alteration of NF-?B activity by bortezomib. Importantly, bortezomib significantly upregulates NF-?B activity in both MCF7 and T47D in a dose-dependent fashion, demonstrated by electrophoretic mobility shift analysis (EMSA). Furthermore, immunocytochemical analysis confirmed enhanced nuclear translocation of p65 NF-?B (RelA) by bortezomib treatment. Supershift assay showed supershifted bands by anti-p65 and -p50 antibodies. Taken together, these results indicate that bortezomib activates the canonical NF-?B pathway in both cell lines. Finally, we demonstrated that IKK? inhibitor enhanced cytotoxicity, associated with inhibition of NF-?B activity induced by bortezomib in MCF7 and T47D breast cancer cells.

HIDESHIMA, HIROMASA; YOSHIDA, YASUHIRO; IKEDA, HIROSHI; HIDE, MAYA; IWASAKI, AKINORI; ANDERSON, KENNETH C.; HIDESHIMA, TERU

2014-01-01

358

Matrix metalloproteinase inhibitors attenuate endotoxemia induced cardiac dysfunction: a potential role for MMP-9.  

PubMed

Enhanced cardiac generation of peroxynitrite contributes to septic cardiomyopathy. Since matrix metalloproteinases (MMPs) are activated in vitro by peroxynitrite, we hypothezised that MMPs may contribute to cardiac mechanical dysfunction in sepsis. Rats were injected (i.p.) with either lipopolysaccharide (LPS, 4 mg/kg) or vehicle. MMP inhibitors, either Ro 31-9790 (20 mg/kg), doxycycline (4 mg/kg), or vehicle were administered i.p. 30 min after LPS. At 6 h, when the symptoms of endotoxemia peak, hearts were excised and perfused as working hearts with Krebs-Henseleit buffer at 37 degrees C. Cardiac work (cardiac output x peak systolic pressure product) was measured. Perfusate and ventricle samples were analyzed by gelatin zymography to quantify MMP activity. Cardiac function was significantly depressed in LPS-treated rats compared to control rats (control: 55 +/- 4, LPS: 26 +/- 6 mmHg*mL*min(-1)). LPS also caused a loss of 72 kDa MMP-2 activity in the ventricles and the perfusate. Although MMP-9 activity was not detected in the ventricles, LPS resulted in an increase in perfusate 92 kDa MMP-9 activity. The MMP inhibitors significantly improved cardiac function of LPS-treated rats (Ro 31-9790: 38 +/- 3, doxycycline: 51 +/- 3 mmHg*mL*min(-1)), had no effect on the loss of MMP-2 activity, and significantly reduced the MMP-9 activity in the perfusate. These results demonstrate, for the first time, that LPS induced cardiac dysfunction is associated with a loss in ventricular MMP-2 activity and the release of MMP-9 from the heart. MMP inhibitors can significantly preserve cardiac mechanical function during septic shock. PMID:14575305

Lalu, Manoj M; Gao, Cindy Q; Schulz, Richard

2003-09-01

359

Natural Product-Based Inhibitors of Hypoxia-Inducible Factor-1 (HIF-1)  

PubMed Central

The transcription factor hypoxia-inducible factor-1 (HIF-1) regulates the expression of more than 70 genes involved in cellular adaptation and survival under hypoxic stress. Activation of HIF-1 is associated with numerous physiological and pathological processes that include tumorigenesis, vascular remodeling, inflammation, and hypoxia/ischemia-related tissue damage. Clinical studies suggested that HIF-1 activation correlates directly with advanced disease stages and treatment resistance among cancer patients. Preclinical studies support the inhibition of HIF-1 as a major molecular target for antitumor drug discovery. Considerable effort is underway, in government laboratories, industry and academia, to identify therapeutically useful small molecule HIF-1 inhibitors. Natural products (low molecular weight organic compounds produced by plants, microbes, and animals) continue to play a major role in modern antitumor drug discovery. Most of the compounds discovered to inhibit HIF-1 are natural products or synthetic compounds with structures that are based on natural product leads. Natural products have also served a vital role as molecular probes to elucidate the pathways that regulate HIF-1 activity. Natural products and natural product-derived compounds that inhibit HIF-1 are summarized in light of their biological source, chemical class, ancd effect on HIF-1 and HIF-mediated gene regulation. When known, the mechanism(s) of action of HIF-1 inhibitors are described. Many of the substances found to inhibit HIF-1 are non-druggable compounds that are too cytotoxic to serve as drug leads. The application of high-throughput screening methods, complementary molecular-targeted assays, and structurally diverse chemical libraries hold promise for the discovery of therapeutically useful HIF-1 inhibitors.

Nagle, Dale G.; Zhou, Yu-Dong

2010-01-01

360

Induction by perfluorinated fatty acids with different carbon chain length of peroxisomal ?-oxidation in the liver of rats  

Microsoft Academic Search

The potency of the induction of peroxisomal ?-oxidation was compared between perfluorinated fatty acids (PFCAs) with different carbon chain lengths in the liver of male and female rats. In male rats, perfluoroheptanoic acid (PFHA) has little effect, although perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) potentially induced the activity. By contrast, PFHA and PFOA did not induce

Naomi Kudo; Naoki Bandai; Erika Suzuki; Masanori Katakura; Yoichi Kawashima

2000-01-01

361

PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis.  

PubMed

Peroxisomes are components of virtually all eukaryotic cells. While much is known about peroxisomal matrix protein import, our understanding of how peroxisomal membrane proteins (PMPs) are targeted and inserted into the peroxisome membrane is extremely limited. Here, we show that PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes. Furthermore, mislocalization of PEX19 to the nucleus leads to nuclear accumulation of newly synthesized PMPs. At steady state, PEX19 is bimodally distributed between the cytoplasm and peroxisome, with most of the protein in the cytoplasm. We propose that PEX19 may bind newly synthesized PMPs and facilitate their insertion into the peroxisome membrane. This hypothesis is supported by the observation that the loss of PEX19 results in degradation of PMPs and/or mislocalization of PMPs to the mitochondrion. PMID:10704444

Sacksteder, K A; Jones, J M; South, S T; Li, X; Liu, Y; Gould, S J

2000-03-01

362

Pex19 Binds Multiple Peroxisomal Membrane Proteins, Is Predominantly Cytoplasmic, and Is Required for Peroxisome Membrane Synthesis  

PubMed Central

Peroxisomes are components of virtually all eukaryotic cells. While much is known about peroxisomal matrix protein import, our understanding of how peroxisomal membrane proteins (PMPs) are targeted and inserted into the peroxisome membrane is extremely limited. Here, we show that PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes. Furthermore, mislocalization of PEX19 to the nucleus leads to nuclear accumulation of newly synthesized PMPs. At steady state, PEX19 is bimodally distributed between the cytoplasm and peroxisome, with most of the protein in the cytoplasm. We propose that PEX19 may bind newly synthesized PMPs and facilitate their insertion into the peroxisome membrane. This hypothesis is supported by the observation that the loss of PEX19 results in degradation of PMPs and/or mislocalization of PMPs to the mitochondrion.

Sacksteder, Katherine A.; Jones, Jacob M.; South, Sarah T.; Li, Xiaoling; Liu, Yifei; Gould, Stephen J.

2000-01-01

363

Apoptotic death in adenocarcinoma cell lines induced by butyrate and other histone deacetylase inhibitors.  

PubMed

n-Butyrate inhibits the growth of colon cancer cell lines. In the HCT 116 cell line, butyrate-induced growth inhibition is almost fully reversible, whereas in the VACO 5 cell line, a subpopulation undergoes apoptosis within 30 hr of treatment with butyrate. Concurrent treatment of VACO 5 cells with butyrate and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) accelerates and increases the incidence of cell death to nearly 100% of the population, whereas HCT 116 cells largely remain alive during treatment with this combination. The action of butyrate as an inhibitor of histone deacetylase was assessed in these cell lines by examining extracted core histones for their electrophoretic mobility in Triton/acid/urea gels. The concentrations of butyrate that were effective for inducing apoptosis were similar to the concentrations that caused hyperacetylation of core histones in the VACO 5 cell line. Furthermore, an examination of other carboxylic acids for induction of apoptosis revealed a rank order that corresponded to the order of potency in causing hyperacetylation of core histones. Specifically, the active acids were 3-5 carbons in length and lacked substitution at the 2-position. Isovaleric and propionic acids, in particular, proved to be effective inducers of both hyperacetylation and apoptosis at 5 mM concentrations, a finding of potential relevance to the unusual pancytopenia occurring after acidotic episodes in isovaleric and propionic acidemias. The duration of butyrate treatment required for chromatin fragmentation (10-20 hr) corresponded to the time required for histone H4 to become predominantly tetraacetylated. Furthermore, trichostatin A, a structurally dissimilar inhibitor of histone deacetylase, mimicked butyrate-induced apoptosis of VACO 5 cells and growth inhibition of HCT 116 cells. The dramatic enhancement of VACO 5 cell death by TPA, and the high level resistance of HCT 116 cells to butyrate were not evident from histone acetylation determinations. Thus, applications of butyrate for cytoreduction therapy will benefit from pharmacodynamic assessment of histone acetylation, but will require additional work to predict susceptibility to butyrate-induced death. PMID:9214697

McBain, J A; Eastman, A; Nobel, C S; Mueller, G C

1997-05-01

364

Selectively targeting an inactive conformation of interleukin-2-inducible T-cell kinase by allosteric inhibitors.  

PubMed

ITK (interleukin-2-inducible T-cell kinase) is a critical component of signal transduction in T-cells and has a well-validated role in their proliferation, cytokine release and chemotaxis. ITK is an attractive target for the treatment of T-cell-mediated inflammatory diseases. In the present study we describe the discovery of kinase inhibitors that preferentially bind to an allosteric pocket of ITK. The novel ITK allosteric site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology and X-ray crystallography. Initial screening hits bound to both the allosteric pocket and the ATP site. Successful lead optimization was achieved by improving the contribution of the allosteric component to the overall inhibition. NMR competition experiments demonstrated that the dual-site binders showed higher affinity for the allosteric site compared with the ATP site. Moreover, an optimized inhibitor displayed non-competitive inhibition with respect to ATP as shown by steady-state enzyme kinetics. The activity of the isolated kinase domain and auto-activation of the full-length enzyme were inhibited with similar potency. However, inhibition of the activated full-length enzyme was weaker, presumably because the allosteric site is altered when ITK becomes activated. An optimized lead showed exquisite kinome selectivity and is efficacious in human whole blood and proximal cell-based assays. PMID:24593284

Han, Seungil; Czerwinski, Robert M; Caspers, Nicole L; Limburg, David C; Ding, WeiDong; Wang, Hong; Ohren, Jeffrey F; Rajamohan, Francis; McLellan, Thomas J; Unwalla, Ray; Choi, Chulho; Parikh, Mihir D; Seth, Nilufer; Edmonds, Jason; Phillips, Chris; Shakya, Subarna; Li, Xin; Spaulding, Vikki; Hughes, Samantha; Cook, Andrew; Robinson, Colin; Mathias, John P; Navratilova, Iva; Medley, Quintus G; Anderson, David R; Kurumbail, Ravi G; Aulabaugh, Ann

2014-06-01

365

Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes.  

PubMed

Our previous work showed that the nuclear scaffold (NS) protease is required for apoptosis of both thymocytes and chronic lymphocytic leukemic (CLL) lymphocytes. Because partial sequencing of one of the subunits of the NS protease revealed homology to the proteasome, we tested the effects of classical proteasome inhibitors on apoptosis in CLL cells. Here we report that proteasome inhibition caused high levels of DNA fragmentation in all patients analyzed, including those resistant to glucocorticoids or nucleoside analogs, in vitro. Proteasome inhibitor-induced DNA fragmentation was associated with activation of caspase/ICE family cysteine protease(s) and was blocked by the caspase antagonist, zVADfmk. Analysis of the biochemical mechanisms involved showed that proteasome inhibition resulted in mitochondrial dysregulation leading to the release of cytochrome c and a drop in mitochondrial transmembrane potential (triangle upPsi). These changes were associated with inhibition of NFkappaB, a proteasome-regulated transcription factor that has been implicated in the suppression of apoptosis in other systems. Together, our results suggest that drugs that target the proteasome might be capable of bypassing resistance to conventional chemotherapy in CLL. PMID:9834227

Chandra, J;