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Abstract

Undisturbed branched-chain amino acids (BCAA) catabolism is necessary for normal heart function. The key enzyme in BCAA catabolism is a multienzyme branched-chain α-keto acid dehydro-genase complex (BCKDH). BCKDH activity is regulated mainly by reversible dephosphorylation (activa-tion)/phosphorylation (inactivation) cycle catalyzed by regulatory enzymes, a specific phosphatase (PPM1K) and kinase (BDK). 5-fluorouracil (5-FU) is widely used in the treatment of different types of cancer. 5-FU has the potential to cause a wide spectrum of cardiotoxicity, ranging from asymptomatic electrocardiographic changes to cardiomyopathy and subsequent cardiac failure. We hypothesize that 5-FU modifies BCKDH activity and affects cardiac muscle metabolism. The current study was aimed at the investigation of the in vivo effect of 5-FU on BCKDH activity and mRNA levels for E1, PPM1K and BDK. Wistar male rats were administered with 4 doses of 5-FU, 150 mg/kg b.wt. each (study group) or 0.3% methylcellulose (control group). BCKDH activity was assayed spectrophotometrically. The mRNA levels were quantified by real-time PCR. 5-FU treatment caused an increase in BCKDH activity that appears to result mainly from increased dephosphorylation of the complex and is associated with an increase of PPM1K mRNA level and reduction of BDK and E1 mRNA levels. It is conceivable that 5-FU stimulation of BCKDH is an adaptive reaction with the purpose of enhancing the BCAA catabolism and protecting from toxic effect caused by excessive accumulation of these amino acids in heart.
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Authors and Affiliations

Małgorzata Knapik-Czajka
1
Michał Jurczyk
2
Justyna Bieleń
1
Veronika Aleksandrovych
2
Anna Gawędzka
1
Paulina Stach
2
Jagoda Drąg
1
Krzysztof Gil
3

  1. Department of Biochemical Analytics, Jagiellonian University Medical College, Kraków, Poland
  2. Department of Pathophysiology, Jagiellonian University Medical College, Kraków, Poland
  3. 2Department of Pathophysiology, Jagiellonian University Medical College, Kraków, Poland
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Abstract

Background: Anorexia nervosa is a widely prevalent eating disorder that often leads to life-threatening complications. Since it mostly concerns females, many authors have focused on studying the reproductive system in anorexic women. Recently discovered telocytes may give a new insight into the pathophysiology of gynecological complications in these patients.

Material and Methods: We adopted an animal model of anorexia nervosa induced by voluntary physical activity. Sixteen female Wistar rats were divided into two groups: control and activity-based anorexia. When the weight loss of activity-based anorexia (ABA) rats reached 25% animals were euthanized. Size and weight measurements as well as histopathological analysis of the reproductive organs were performed. Additionally, we used immunohistochemical staining for detection of telocytes.

Results: Telocytes were identified in uteri of anorectic rats but no diff erences were observed when compared to the control group. Nevertheless, in the ABA group the weight of the uteri and the number of follicles in the ovaries decreased significantly.

Conclusions: Our rat model of anorexia nervosa mimics the effects of this eating disorder that occur in the female reproductive system since we reported ovarian dysfunction and uterine involution in the experimental animals. It supports its potential role in the further studies of anorexia pathophysiology and treatment possibilities.

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Authors and Affiliations

Kamil Skowron
Veronika Aleksandrovych
Magdalena Kurnik-Łucka
Paulina Stach
Agnieszka Baranowska
Beata Skowron
Krzysztof Gil
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Abstract

Anorexia nervosa (AN) is an eating disorder characterized by distinct etiopathogenetic concepts that are gradually being linked together to unravel the dominant pathophysiological pathways underlying the disease. Excessive food restrictions, often accompanied by over-exercise and undertaken to lose weight, lead to the development of numerous complications. The biological concept of neurohormonal dysfunc-tion in AN seems incomplete without demonstrating or excluding the role of the enteric nervous system (ENS). Using an animal model of activity-based anorexia (ABA), we conducted the preliminary assess-ment of the ENS structure. Here we show, in preparations stained by immunohistochemistry with anti- ChAT, anti-NOS, anti-PGP 9.5, anti-c-fos, and anti-TH antibodies, a lower density of cholinergic and nitrergic nerve fibers as well as reduced neuronal activity in myenteric plexus. Such structural and functional damage to the ENS may be responsible for a number of gastrointestinal symptoms that worsen the course of the disease. In addition, we expanded the study to address the unresolved issue of mechanical and thermal pain sensitivity in AN. The Von Frey and hot plate tests revealed, that in ABA animals, the pain threshold for mechanical stimulus decreases while for thermal increases. In this way, we have sig-nificantly supplemented the background of AN with potentially observable nervous system changes which may influence the evolution of the therapeutic approach in the future.
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Authors and Affiliations

Kamil Skowron
1
Paulina Stach
1
Magdalena Kurnik-Łucka
1
Katarzyna Chwaleba
1
Mateusz Giełczyński
1
Wiktoria Suchy
1
Veronika Aleksandrovych
1
Michał Jurczyk
1
Beata Kuśnierz-Cabala
2
Krzysztof Gil
1

  1. Department of Pathophysiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
  2. Chair of Clinical Biochemistry, Department of Diagnostics, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland

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