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2. Proteoglycans: Systems-Level Insight into Their Expression in Healthy and Diseased Placentas

Author

Oravecz, O, Balogh, A, Romero, R, Xu, Y, Juhasz, K, Gelencser, Z, Xu, Z, Bhatti, G, Pique-Regi, R, Peterfia, B, Hupuczi, P, Kovalszky, I, Murthi, P, Tarca, AL, Papp, Z, Matko, J, Than, NG, Oravecz, O, Balogh, A, Romero, R, Xu, Y, Juhasz, K, Gelencser, Z, Xu, Z, Bhatti, G, Pique-Regi, R, Peterfia, B, Hupuczi, P, Kovalszky, I, Murthi, P, Tarca, AL, Papp, Z, Matko, J, and Than, NG

Abstract

Proteoglycan macromolecules play key roles in several physiological processes (e.g., adhesion, proliferation, migration, invasion, angiogenesis, and apoptosis), all of which are important for placentation and healthy pregnancy. However, their precise roles in human reproduction have not been clarified. To fill this gap, herein, we provide an overview of the proteoglycans' expression and role in the placenta, in trophoblast development, and in pregnancy complications (pre-eclampsia, fetal growth restriction), highlighting one of the most important members of this family, syndecan-1 (SDC1). Microarray data analysis showed that of 34 placentally expressed proteoglycans, SDC1 production is markedly the highest in the placenta and that SDC1 is the most upregulated gene during trophoblast differentiation into the syncytiotrophoblast. Furthermore, placental transcriptomic data identified dysregulated proteoglycan genes in pre-eclampsia and in fetal growth restriction, including SDC1, which is supported by the lower concentration of syndecan-1 in maternal blood in these syndromes. Overall, our clinical and in vitro studies, data analyses, and literature search pointed out that proteoglycans, as important components of the placenta, may regulate various stages of placental development and participate in the maintenance of a healthy pregnancy. Moreover, syndecan-1 may serve as a useful marker of syncytialization and a prognostic marker of adverse pregnancy outcomes. Further studies are warranted to explore the role of proteoglycans in healthy and complicated pregnancies, which may help in diagnostic or therapeutic developments.

Published
2022

8. Syndecan-1 in Liver Diseases

Author

Regős E, Karászi K, Reszegi A, Kiss A, Schaff Zs, Baghy K, and Kovalszky I

Subjects
carbohydrates (lipids), animal structures, Liver, Cirrhosis, Hepatocellular carcinoma, embryonic structures, Syndecan-1, Metastasis
Abstract

Liver diseases such as liver cirrhosis, primary and metastatic liver cancers are still a major medical challenge. Syndecan-1 is one of the most important proteoglycans in the liver. Syndecan-1 is normally expressed on the surfaces of hepatocytes and cholangiocytes. Due to liver diseases the amount of syndecan-1 increases in the liver. Despite the emerging data of the biological function of syndecan-1, the clinical usefulness of this proteoglycan is still unknown. In our study we correlated syndecan-1 expression to clinico-pathological data. We found that syndecan-1 proved to be a good marker for hepatitis C virus based hepatocellular carcinoma and increased with liver dysfunction.

Published
2019

14. Molecular and therapeutic aspects of advanced urachal cancer

Author

Modos, O., primary, Keresztes, D., additional, Nyirády, P., additional, Szendröi, A., additional, Tímár, J., additional, Szász, A.M., additional, Reis, H., additional, Niedworok, C., additional, Hadaschik, B., additional, Hollósi, P., additional, Baghy, K., additional, Kovalszky, I., additional, Okon, K., additional, Golabek, T., additional, Chlosta, P., additional, Shariat, S.F., additional, Peyronnet, B., additional, Mathieu, R., additional, Ablat, J., additional, Black, P., additional, and Szarvas, T., additional

Published
2017
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17. Mutation analysis of EGFR signal transduction pathway in urachal carcinoma

Author

Modos, O., primary, Szarvas, T., additional, Reis, H., additional, Niedworok, C., additional, Rübben, H., additional, Szendröi, A., additional, Szasz, AM., additional, Hollosi, P., additional, Baghy, K., additional, Kovalszky, I., additional, Okon, K., additional, Golabek, T., additional, Chlosta, P., additional, Shariat, SF., additional, Peyronnet, B., additional, Mathieu, R., additional, and Nyirády, P., additional

Published
2015
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20. Development of second generation peptides modulating cellular adiponectin receptor responses

Author

Otvos, L, Knappe, D, Hoffmann, R, Kovalszky, I, Olah, J, Hewitson, TD, Stawikowska, R, Stawikowski, M, Cudic, P, Lin, F, Wade, JD, Surmacz, E, Lovas, S, Otvos, L, Knappe, D, Hoffmann, R, Kovalszky, I, Olah, J, Hewitson, TD, Stawikowska, R, Stawikowski, M, Cudic, P, Lin, F, Wade, JD, Surmacz, E, and Lovas, S

Abstract

The adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active adipokines, including adiponectin. Recently we developed and characterized a first-in-class peptide-based adiponectin receptor agonist by using in vitro and in vivo models of glioblastoma and breast cancer (BC). In the current study, we further explored the effects of peptide ADP355 in additional cellular models and found that ADP355 inhibited chronic myeloid leukemia (CML) cell proliferation and renal myofibroblast differentiation with mid-nanomolar IC50 values. According to molecular modeling calculations, ADP355 was remarkably flexible in the global minimum with a turn present in the middle of the peptide. Considering these structural features of ADP355 and the fact that adiponectin normally circulates as multimeric complexes, we developed and tested the activity of a linear branched dimer (ADP399). The dimer exhibited approximately 20-fold improved cellular activity inhibiting K562 CML and MCF-7 cell growth with high pM-low nM relative IC50 values. Biodistribution studies suggested superior tissue dissemination of both peptides after subcutaneous administration relative to intraperitoneal inoculation. After screening of a 397-member adiponectin active site library, a novel octapeptide (ADP400) was designed that counteracted 10-1000 nM ADP355- and ADP399-mediated effects on CML and BC cell growth at nanomolar concentrations. ADP400 induced mitogenic effects in MCF-7 BC cells perhaps due to antagonizing endogenous adiponectin actions or acting as an inverse agonist. While the linear dimer agonist ADP399 meets pharmacological criteria of a contemporary peptide drug lead, the peptide showing antagonist activity (ADP400) at similar concentrations will be an important target validation tool to study adiponectin functions.

Published
2014

25. Quantitative and qualitative alterations of heparan sulfate in fibrogenic liver diseases and hepatocellular cancer.

Author

Tatrai, P., Egedi, K., Somoracz, A., Kuppevelt, A.H.M.S.M. van, Dam, G.B. ten, Lyon, M., Deakin, J.A., Kiss, A., Schaff, Z., Kovalszky, I., Tatrai, P., Egedi, K., Somoracz, A., Kuppevelt, A.H.M.S.M. van, Dam, G.B. ten, Lyon, M., Deakin, J.A., Kiss, A., Schaff, Z., and Kovalszky, I.

Abstract

1 mei 2010, Contains fulltext : 89533.pdf (publisher's version ) (Closed access), Heparan sulfate (HS), due to its ability to interact with a multitude of HS-binding factors, is involved in a variety of physiological and pathological processes. Remarkably diverse fine structure of HS, shaped by non-exhaustive enzymatic modifications, influences the interaction of HS with its partners. Here we characterized the HS profile of normal human and rat liver, as well as alterations of HS related to liver fibrogenesis and carcinogenesis, by using sulfation-specific antibodies. The HS immunopattern was compared with the immunolocalization of selected HS proteoglycans. HS samples from normal liver and hepatocellular carcinoma (HCC) were subjected to disaccharide analysis. Expression changes of nine HS-modifying enzymes in human fibrogenic diseases and HCC were measured by quantitative RT-PCR. Increased abundance and altered immunolocalization of HS was paralleled by elevated mRNA levels of HS-modifying enzymes in the diseased liver. The strong immunoreactivity of the normal liver for 3-O-sulfated epitope further increased with disease, along with upregulation of 3-OST-1. Modest 6-O-undersulfation of HCC HS is probably explained by Sulf overexpression. Our results may prompt further investigation of the role of highly 3-O-sulfated and partially 6-O-desulfated HS in pathological processes such as hepatitis virus entry and aberrant growth factor signaling in fibrogenic liver diseases and HCC.

Published
2010

26. DNA methylation markers of left-sided colorectal cancer based on gene expression screening

Author

Péterfia, B, primary, Hollósi, P, additional, Kalmár, A, additional, Galamb, O, additional, Spisák, S, additional, Wichmann, B, additional, Tóth, K, additional, Leiszter, K, additional, Patai, VÁ, additional, Kubák, V, additional, Kiss, K, additional, Horváth, Z, additional, Tulassay, Z, additional, Kovalszky, I, additional, and Molnár, B, additional

Published
2013
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29. Increased CYP24A1 mRNA expression after 1,25-Dihydroxyvitamin D3 treatment of hepatocellular carcinoma cell lines in vitro and also in human liver cancer

Author

Horvath, E, primary, Lakatos, P, additional, Balla, B, additional, Kósa, PJ, additional, Kovalszky, I, additional, Pesti, V, additional, Németh, D, additional, Hasan, J, additional, Korompay, A, additional, Somorácz, Á, additional, Schaff, Z, additional, Kupcsulik, P, additional, and Szalay, F, additional

Published
2011
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47. Increased risk for cancer in multiple myeloma patients and their first-degree relatives.

Author

Varkonyi, J., Kovalszky, I., Nemeth, A., Demeter, J., and Raposa, T.

Subjects
*MULTIPLE myeloma, *MEDICAL genetics, *GENETIC disorders, *DISEASE risk factors
Abstract

Analyzing data of 125 multiple myeloma patients, the authors found a 40-fold increased tumor incidence among the patients and their first-degree relatives as compared to the average population. These tumors were the same as those usually found among Hungarians. There was no difference as to the patient's blood group antigens in the families of myeloma patients with or without other tumor. IgA-type disease was found to be relatively more frequent in the group of patients who had tumor besides myeloma. In a prospective study, authors could not find mutation of suppressor gene p53 in 14 patients and their 16 healthy first-degree relatives. This may indicate that there is no p53 suppressor gene alteration responsible for the high-risk condition for tumorgenesis in this population. [ABSTRACT FROM AUTHOR]

Published
2001
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48. Human and Experimental Hepatocarcinogenesis.

Author

Schaff, Z., Kovalszky, I., Nagy, P., Zalatnai, A., Jeney, A., and Lapis, K.

Subjects
*LIVER tumors, *ETIOLOGY of diseases, *ENZYMES, *CARCINOGENS, *TRANSFORMING growth factors
Abstract

Human liver cancer is increasing worldwide, including in Hungary. The detection of liver tumors in premalignant or early malignant states is essential for successful treatment. MC-29 virus-induced chicken hepatoma and rodent, fish and monkey models for chemical hepatocarcinogenesis were studied and compared to humans. Changes in phenotypic enzyme alterations and in the expression of certain oncogens and growth factors characterize the experimentally induced hepatomas, and might also be characteristic of human premalignant and malignant focal liver lesions. Fish hepatocarcinogenesis is useful for studying compounds in environmental pollution. Increased expression of transforming growth factor á can be observed both in experimental and human liver tumors. Increased tumor incidence was detected in transgene mice containing both transforming growth factor α and c-myc genes. Animal models of hepatocarcinogenesis help to understand the development of liver tumors. Methods applied in studies using those models are useful in the study of premalignant and malignant human liver lesions. [ABSTRACT FROM AUTHOR]

Published
1998
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49. Experimental and Human Liver Fibrogenesis.

Author

Kovalszky, I., Nagy, P., Szende, B., Lapis, K., Szalay, F., Jeney, A., and Schaff, Z.

Subjects
*TRANSFORMING growth factors-beta, *PROTEOGLYCANS, *LIVER
Abstract

In this work, we provide an overview of our results obtained by studying the role of transforming growth factor β1 and proteoglycans in liver fibrogenesis. It has been found that transforming growth factor β1 is one of the most important stimulators of extracellular matrix synthesis in the liver. In chronic liver injury, desmin-positive non-parenchymal liver cells expressed transforming growth factor β1. The extracellular localization of the growth factor correlated well with types I, III and IV procollagen-α, which were detected in the fibrous septa of chronically injured livers. A similar distribution pattern was observed in human specimens. To identify the role of transforming growth factor β1 in liver extracellular matrix protein synthesis, transforming growth factor β1-positive transgenic mice were generated. Animals expressing the growth factor in their liver showed spontaneous liver fibrosis. Proteoglycans also participate in fibrogenesis. The majority of liver-specific heparan sulfate proteoglycans, such as syndecan-1 and fibroglycan, are produced by hepatocytes. The extracellular matrix proteoglycans decorin and perlecan are synthesized by non-parenchymal liver cells. The amount of the latter is very low in normal liver, but increases dramatically in liver fibrosis. The effect of regulatory factors on liver proteoglycans seems to be cell type-specific. In contrast to previous observations, elevated amounts of decorin did not inhibit the action of transforming growth factor β1 in the liver. [ABSTRACT FROM AUTHOR]

Published
1998
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50. Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitis.

Author

Dudás, J, Kovalszky, I, Gallai, M, Nagy, J O, Schaff, Z, Knittel, T, Mehde, M, Neubauer, K, Szalay, F, and Ramadori, G

Abstract

Decorin is a small extracellular matrix proteoglycan. It binds and modulates transforming growth factor (TGF)-beta 1 action, the major stimulator of fibrogenesis. Its role in the pathogenesis of human liver cirrhosis is unknown. Therefore, we studied the relationship of the 2 proteins in normal human liver and in 43 chronic hepatitis and liver cirrhosis specimens. To understand the mechanism that maintains matrix deposition in stage IV hepatitis, we studied expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, as well as the activities of type IV collagenases. Gene expression was analyzed on messenger RNA and protein level by morphologic and biochemical approaches. Decorin proved to be an early marker of fibrogenesis, and its deposition increased parallel to that of TGF-beta 1 and to inflammatory activity. Liver fibrosis progressed despite high temporospatial expression of decorin with TGF-beta 1. Neither decorin nor TGF-beta 1 protein deposition increased further in cirrhosis with low inflammatory activity, suggesting that impaired extracellular matrix catabolism rather than active production plays a role in this stage. This possibility was supported by high message levels of metalloproteinase inhibitors, no 72-kd collagenase activities, and low 92-kd collagenase activities.

Published
2001
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