Jette E Svendsen

Publications (3)7.43 Total impact

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  Available from: ku.dk

  Article: PPARα and PPARγ are co‐expressed, functional and show positive interactions in the rat urinary bladder urothelium

  Frederikke Lihme Egerod, Nils Brünner, Jette E. Svendsen, Martin B. Oleksiewicz
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  ABSTRACT: Some dual-acting PPARα + γ agonists cause cancer in the rat urinary bladder, in some cases overrepresented in males, by a mechanism suggested to involve chronic stimulation of PPARα and PPARγ, i.e. exaggerated pharmacology. By western blotting, we found that the rat urinary bladder urothelium expressed PPARα at higher levels than the liver and heart, and comparable to kidney. Urothelial expression of PPARγ was above that of fat, heart, skeletal muscle and kidney. Male rats exhibited a higher PPARα/PPARγ expression balance in the bladder urothelium than did female rats. Rats were treated by gastric gavage with rosiglitazone (PPARγ agonist), fenofibrate (PPARα agonist) or a combination of rosiglitazone and fenofibrate for 7 days. In the urothelium, the transcription factor Egr-1 was induced to significantly higher levels in rats co-administered rosiglitazone and fenofibrate than in rats administered either rosiglitazone or fenofibrate alone. Egr-1 was also induced in the heart and liver of rats treated with fenofibrate, but a positive interaction between rosiglitazone and fenofibrate with regards to Egr-1 induction was only seen in the urothelium. Thus, in the rat urinary bladder urothelium, PPARα and PPARγ were expressed at high levels, were functional and exhibited positive interactions. Interestingly, fenofibrate induced the peroxisome membrane protein PMP70 not only in liver, but also in the bladder urothelium, opening the possibility that oxidative stress may contribute to rat urothelial carcinogenesis by dual-acting PPARα + γ agonists. Copyright © 2009 John Wiley & Sons, Ltd.
  Journal of Applied Toxicology 09/2009; 30(2):151 - 162. · 2.48 Impact Factor
• Article: PPARalpha and PPARgamma are co-expressed, functional and show positive interactions in the rat urinary bladder urothelium.

  Frederikke Lihme Egerod, Nils Brünner, Jette E Svendsen, Martin B Oleksiewicz
  [show abstract] [hide abstract]
  ABSTRACT: Some dual-acting PPARalpha + gamma agonists cause cancer in the rat urinary bladder, in some cases overrepresented in males, by a mechanism suggested to involve chronic stimulation of PPARalpha and PPARgamma, i.e. exaggerated pharmacology. By western blotting, we found that the rat urinary bladder urothelium expressed PPARalpha at higher levels than the liver and heart, and comparable to kidney. Urothelial expression of PPARgamma was above that of fat, heart, skeletal muscle and kidney. Male rats exhibited a higher PPARalpha/PPARgamma expression balance in the bladder urothelium than did female rats. Rats were treated by gastric gavage with rosiglitazone (PPARgamma agonist), fenofibrate (PPARalpha agonist) or a combination of rosiglitazone and fenofibrate for 7 days. In the urothelium, the transcription factor Egr-1 was induced to significantly higher levels in rats co-administered rosiglitazone and fenofibrate than in rats administered either rosiglitazone or fenofibrate alone. Egr-1 was also induced in the heart and liver of rats treated with fenofibrate, but a positive interaction between rosiglitazone and fenofibrate with regards to Egr-1 induction was only seen in the urothelium. Thus, in the rat urinary bladder urothelium, PPARalpha and PPARgamma were expressed at high levels, were functional and exhibited positive interactions. Interestingly, fenofibrate induced the peroxisome membrane protein PMP70 not only in liver, but also in the bladder urothelium, opening the possibility that oxidative stress may contribute to rat urothelial carcinogenesis by dual-acting PPARalpha + gamma agonists.
  Journal of Applied Toxicology 09/2009; 30(2):151-62. · 2.48 Impact Factor
• Article: MCF-7 human mammary adenocarcinoma cells exhibit augmented responses to human insulin on a collagen IV surface.

  Nicolai Listov-Saabye, Marianne Blirup Jensen, Benedicte Kiehr, Erik W Hansen, Jette E Svendsen, Anders Lundby, Gitte-Mai Nelander Holm, Martin B Oleksiewicz
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  ABSTRACT: Human mammary cell lines are extensively used for preclinical safety assessment of insulin analogs. However, it is essentially unknown how mitogenic responses can be optimized in mammary cell-based systems. We developed an insulin mitogenicity assay in MCF-7 human mammary adenocarcinoma cells, under low serum (0.1% FCS) and phenol red-free conditions, with 3H thymidine incorporation as endpoint. Based on EC50 values determined from 10-fold dilution series, beta-estradiol was the most potent mitogen, followed by human IGF-1, human AspB10 insulin and native human insulin. AspB10 insulin was significantly more mitogenic than native insulin, validating the ability of the assay to identify hypermitogenic human insulin analogs. With MCF-7 cells on a collagen IV surface, the ranking of mitogens was maintained, but fold mitogenic responses and dynamic range and steepness of dose-response curves were increased. Also, PI3K pathway activation by insulin was enhanced on a collagen IV surface. This study provided the first determination and ranking of the mitogenic potencies of standard reference compounds in an optimized MCF-7 assay. The optimized MCF-7 assay described here is of relevance for in vitro toxicological testing and carcinogenicity safety assessment of new insulin compounds.
  Journal of Applied Toxicology 03/2009; 29(6):470-7. · 2.48 Impact Factor