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Abstract

Background: The histology of the lung includes a variety of cell types. Fibrosis is a universal process, occurring in the skin, intestine, heart, muscles, kidney, blood vessels, liver, and also the lungs. Telocytes are a type of cells with a wide range of properties, which were previously described in healthy and disease-affected organs of human and animal organisms.

Aim: This study aimed to identify telocytes in the lungs of rats and discuss their possible role in the development of pulmonary fibrosis.

Methods: Tissue samples were taken from a group of ten male Wistar rats. Further histological and immunohistochemical analysis was performed. Double immunolabeling for c-kit, vimentin, CD34, and PDGFRα has revealed telocytes in the lungs.

Results: In all tissue samples, telocytes have been identified (in the area of interalveolar septa, close to blood vessels, and between the airway epithelium).

Conclusion: Telocytes might be directly and indirectly (through contact with stem cells, secretomes, and reduction in number) involved in the development of pulmonary fibrosis. The heterogeneity of the telocyte population in different pathologies and their subtypes, as well as their tendency to be common stress their important role in pathological physiology.
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Bibliography

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11. Popescu L.M., Faussone-Pellegrini M.S.: TELOCYTES — a case of serendipity: the winding way from interstitial cells of Cajal (ICC), via interstitial Cajal-like cells (ICLC) to TELOCYTES. J Cell Mol Med. 2010; 14: 729–740.
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17. Wolnicki M., Aleksandrovych V., Gil A., Pasternak A., Gil K.: Relation between ureteral telocytes and the hydronephrosis development in children. Folia Med Cracov. 2019; 59 (3): 31–44.
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Authors and Affiliations

Anna Gil
1
Veronika Aleksandrovych
1

  1. Department of Pathophysiology, Jagiellonian University Medical College, Kraków, Poland
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Abstract

The interstitial cells known as telocytes have been described in various organs. Their role in the normal physiology and pathogenesis of numerous diseases is well known. They have been described in the context of various diseases (gallstone disease, endometriosis, uterine myoma, hydronephrosis, myocardial infraction, psoriasis, etc.), while their impact on inflammation, involvement in angiogenesis, and repair highlights their part in local homeostasis. What is known about their relationship with the immune system? Their secretomes, genome, immune profiles, contacts with surrounding cells, and specific loca-lization allow us to give a possible explanation for their involvement in pathological pathways. This review aims to present the roles and features of telocytes in the context of intestinal immunity (the largest in our body), in the spleen, their interactions with immunocytes, and their place in stem cell niches.
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Authors and Affiliations

Veronika Aleksandrovych
1
Anna Gil
2
Adrian Poniatowski
1 3

  1. Department of Pathophysiology, Jagiellonian University Medical College, ul. Czysta 18, 31-121 Kraków, Poland
  2. Department of Anatomy, Jagiellonian University Medical College, ul. Kopernika 12, 31-034 Kraków, Poland
  3. Vassar Brothers Medical Center, Department of Medicine, 45 Reade Place, Poughkeepsie, NY, USA
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Abstract

Background: Uterine leiomyoma is the most widespread benign tumor affecting women of childbearing age. There are still gaps in the understanding of its pathogenesis. Telocytes are unique cells found in more than 50 different locations inside the human body. The functional relationship between cells could clarify the pathogenesis of leiomyomata. Examination of membrane receptors on telocytes could explain their role in fibrosis, oxidative stress, and myometrial contractility.

Aim: This research was conducted to assess the density of telocytes in terms of their putative role in leiomyoma formation by focusing on their correlation with the expression of estrogen and progesterone receptors.

Methods: For gross evaluation of uterine tissue samples from leiomyoma, routine histology of adjacent and unaffected myometrium was performed. Immunohistochemical analysis of c-kit, tryptase, CD34, PDGFRα (telocyte-specific), and ER and PRs (estrogen and progesterone receptors) was performed to examine uterine telocytes and the expression of sex steroid receptors.

Results: The decline in telocyte density in leiomyoma foci was correlated with high progesterone expression and low estrogen receptor expression. The unchanged myometrium showed the opposite correlation and balance between both steroid hormone receptors. The difference in sex steroid receptor expression is correlated with the density of uterine telocytes, which emphasizes their conductor function.

Conclusions: A reduction in telocyte density and the changes in examined marker expression demon-strate the involvement of telocytes in local homeostasis. The expression of membrane receptors explicitly indicates their functional potential in the human myometrium, focusing attention on contractility and local homeostasis.

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Authors and Affiliations

Veronika Aleksandrovych
Anna Gil
Anna Wrona
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Abstract

Knowledge of uterine fibroids has existed since the time of Hippocrates. However, there are still wide gaps in the understanding of its pathogenesis. No single theory explains the background of uterine fibroid pathology, which affects more than 50% of women worldwide. By contrast, a newly depicted cell type called telocytes was only recently identified in the past twenty years. Th ese cells have evoked ambivalent opinions in the scientific community. The unique features of telocytes coupled with experimental evidence by numerous researchers and our hypotheses and conceptions are discussed in this review. We emphasize the main telocyte interactions in the context of the uterine fibroid architecture. This review reveals the pivotal role of telocytes, describing their contacts with smooth muscle cells, fibroblasts, vessels and nerves, inflammatory cells and stem cells. Our data are based on the latest publications and our own results.

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Authors and Affiliations

Veronika Aleksandrovych
Artur Pasternak
Krzysztof Gil
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Abstract

I n t r o d u c t i o n: Hydronephrosis is an actual pediatric problem, affecting children in the anteand neonatal periods. Intrinsic stenosis is due to external obstruction and creates a pathophysiological basis of this urological pathology. Co-localization of ureter with a renal vasculature also could not be omitted from this point of view. Mesenchymal cells, partially telocytes, are important for local fibrosis development and hydronephrosis formation as well. In the current study, we focused on identification of telocytes in the human ureters to hypothesize their role in hydronephrosis pathophysiology.

M a t e r i a l a n d Me t h o d s: The samples were taken from 18 surgically treated patients with hydronephrosis (due to ureteral obstruction and crossing renal vessel). The control group consisted of 10 patients suffered from a non-obstructive disease of the urinary tract — predominantly renal tumors. Tissue samples from a ureter were stained for c-kit, tryptase, CD34 and PDGFRα to identify telocytes. Routine histology was performed to analyze tissue morphology, collagen deposits and mast cell’s profile.

R e s u l t s: Telocytes were detected in the ureteral wall. In patients with hydronephrosis we revealed decreasing density of telocytes, the prevalence of collagen, rise in mast cells amount and the ureteral wall thickening. In ureters with crossing renal vessels as a primary etiologic factor more telocytes have been observed in comparison with the obstructive hydronephrosis.

C o n c l u s i o n s: A declined density of telocytes accompanied hydronephrosis development. Increased number of mast cells in the ureteral wall reflects a local inflammation, while detailed observation of collagen/muscle deposits and density of telocytes reveal a difference depended on etiologic factor (obstruction or crossing vessel) in patients with hydronephrosis.

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Authors and Affiliations

Michał Wolnicki
Veronika Aleksandrovych
Anna Gil
Artur Pasternak
Krzysztof Gil
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Abstract

Up to 2% of pregnancies may be extrauterine. Despite reproductive problems, they might increase the risk of serious complications. We present a case report of a 31-year-old woman with two extrauterine pregnancies — tubal and ovarian, which occurred at the same side with little time difference. In addition, we aimed to examine possible reasons underlying this rare pathology. Thus, surgically removed tissue specimens were morphologically assessed and further compared with specimens from healthy control patients. Telocytes were analysed in detail due to their pivotal role in the female repro-ductive system. Our study had observational character and obvious limitations typical for a clinical case. Yet, such a clinical case of two ectopic pregnancies has not been previously reported in the literature.
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Authors and Affiliations

Anna Wrona
1
Veronika Aleksandrovych
2
Anna Gil
3
Magdalena Kurnik-Łucka
2
Jerzy A. Walocha
3
Krzysztof Gil
2

  1. Gynecology and Obstetrics Ward with Gynecologic Oncology Subdivision, J. Śniadecki’s Specialistic Hospital, Nowy Sącz, Poland
  2. Department of Pathophysiology, Jagiellonian University Medical College, Kraków, Poland
  3. Department of Anatomy, Jagiellonian University Medical College, Kraków, Poland
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Abstract

Introduction: Uterine leiomyoma is the most widespread benign tumor affecting women of childbearing age. There are still gaps in the understanding of its pathogenesiss. Telocytes are unique cells described in greater than 50 different locations inside the human body. The functional relationship of cells could clarify the pathogenesis of leiomyomata. In the current study, we focused on the identification of telocytes in all regions of the human uterus to explain their involvement in leiomyoma development.

Materials and Methods: Tissue samples from a healthy and myomatous uterus were stained for c-kit, tryptase, CD34 and PDGFRα to identify telocytes. Routine histology was performed to analyze tissue morphology and collagen deposits.

Results: Telocytes were detected in the cervix, corpus of the uterus and leiomyoma. The density of telocytes in fibroid foci was reduced compared with normal myometrium.

Conclusions: Our results demonstrated the existence of telocytes in all parts of the human body affected and unaff ected by leiomyoma of the uterus. In addition, telocytes were also present in leiomyoma foci. Our results suggest that the reduced density of telocytes is important for the pathomechanisms of myometrial growth, demonstrating its value as a main component of the myomatous architecture.

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Authors and Affiliations

Veronika Aleksandrovych
Magdalena Białas
Artur Pasternak
Tomasz Bereza
Marek Sajewicz
Jerzy Walocha
Krzysztof Gil
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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

Telocyte (TC) is an interstitial cell type with a small cellular body and extremely long tentacle-like extensions. TCs were discovered a decade ago and have specific morphological characteristics, immunohistochemical and secretome profi les, electrophysiological properties, microRNA expression. Moreover, they are different in gene expression from other cells. TCs play an important role in plenty of processes. Apparently, they are involved in homeostasis, remodelling, regeneration, repair, embryogenesis, angiogenesis and even tumorigenesis. “Telocytes need the world”, was emphasized by Professor Popescu and it will be actual at any time. This review summarizes particular features of TCs in different organs and systems, emphasizing their involvement in physiological and pathophysiological processes.

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Authors and Affiliations

Veronika Aleksandrovych
Artur Pasternak
Paweł Basta
Marek Sajewicz
Jerzy A. Walocha
Krzysztof Gil
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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

5-fluorouracil (5-FU), which is a commonly used chemotherapy agent exerts undesired cardiac toxicity. Mitochondrial dysfunction is thought to be one of potentially important mechanisms of 5-FU- induced cardiotoxicity. α-ketoglutarate dehydrogenase (α-KGDHC) is the key regulatory enzyme of TCA cycle. The complex consists of multiple copies of three catalytic subunits: α-ketoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and dihydrolipoamide dehydrogenase (E3). α-KGDHC together with branched chain α-ketoacid dehydrogenase (BCKDHC) and pyruvate dehydrogenase (PDHC), are the members of 2-oxoacid dehydrogenases family that share some structural and functional similarities. Recently, it has been found that 5-FU stimulates BCKDHC in rat’s cardiac muscle. Therefore, we hypothesize that 5-FU modifies α-KGDHC activity and affects cardiac muscle metabolism. The aim of this study was to determine the effect of 5-FU on α-KGDHC activity and protein levels of E1 and E2 subunits of the complex in rat’s cardiac muscle. 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). α-KGDHC activity was assayed spectrophotometrically. The E1 and E2 proteins levels were quantified by Western blot. 5-FU administration resulted in stimulation of myocardial α-KGDHC activity in rats. In addition, E2 protein level increased in response to 5-FU treatment, while the E1 protein level remained unchanged. Up- regulation of α-KGDHC appears to result from change in E2 subunit protein level. However, the effect of 5-FU on factors modifying α-KGDHC activity at post-translational level cannot be excluded.
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Authors and Affiliations

Małgorzata Knapik-Czajka
1
Anna Gawędzka
1
Michał Jurczyk
2
Jagoda Drąg
1
Małgorzata Belczyk
1
Veronika Aleksandrovych
2
Anna Gil
3
Krzysztof Gil
1

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

Authors and Affiliations

Bernard Solewski
Tomasz Bereza
Veronika Aleksandrovych
Marek Sajewicz
Monika Konarska
Anna Natalia Wrona
Kinga Komnata
Aleksandra Maleszka
Paweł Depukat
Łukasz Warchoł

Authors and Affiliations

Maciej Lis
Bernard Solewski
Tomasz Bereza
Veronika Aleksandrovych
Marek Sajewicz
Monika Konarska
Anna Natalia Wrona
Barbara Gach-Kuniewicz
Kinga Komnata
Mateusz Paziewski
Aleksandra Maleszka
Paweł Depukat
Łukasz Warchoł

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