Publications by authors named "Justyna Hermanowicz"

20 Publications

  • Page 1 of 1

MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer.

Cancers (Basel) 2021 Jun 26;13(13). Epub 2021 Jun 26.

Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland.

Background And Aims: The purpose of the present study was to examine the pharmacodynamics features of MM-129 (1,2,4-triazine derivative) as a novel promising drug candidate against colon cancer.

Methods: MM-129 was assessed for antitumor activity through an in vivo study on Cby.Cg-Foxn1nu/cmdb mice. The mechanistic studies investigated cellular affinity of a new 1,2,4-triazine derivative by measuring levels of intracellular/extracellular signal molecules participating in tumorigenesis.

Results: The results revealed that MM-129 significantly reduced tumor growth in mice challenged with DLD-1 and HT-29 cells. It exerted the ability to inhibit intracellular molecules promoting tumorigenesis and inducing cell cycle arrest, like Akt, mTOR, and CDK2. Simultaneously, it was able to downregulate PD-L1 expression, which involves immunological self-tolerance. Combined administration of MM-129 and 5-fluorouracil (5-FU) additionally amplified these effects, which were manifest as an increase population of cells in the G0/G1 phase.

Conclusions: A novel 1,2,4-triazine derivative with a dual mechanism of antitumor activity-MM-129, may act as a chemosensitizer, overcoming chemoresistance against 5-FU, the first-line agent in the chemotherapy of colon cancer.
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http://dx.doi.org/10.3390/cancers13133203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268553PMC
June 2021

Not Only Immune Escape-The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis.

Cancers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland.

Background: The recently discovered phenomenon that cancer cells can avoid immune response has gained scientists' interest. One of the pathways involved in this process is tryptophan (TRP) metabolism through the kynurenine pathway (KP). Individual components involved in TRP conversion seem to contribute to cancerogenesis both through a direct impact on cancer cells and the modulation of immune cell functionality. Due to this fact, this pathway may serve as a target for immunotherapy and attempts are being made to create novel compounds effective in cancer treatment. However, the results obtained from clinical trials are not satisfactory, which raises questions about the exact role of KP elements in tumorigenesis. An increasing number of experiments reveal that TRP metabolites may either be tumor promoters and suppressors and this is why further research in this field is highly needed. The aim of this study is to present KP as a modulator of cancer development through multiple mechanisms and to point to its ambiguity, which may be a reason for failures in treatment based on the inhibition of tryptophan metabolism.
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http://dx.doi.org/10.3390/cancers13112667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198784PMC
May 2021

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer.

J Enzyme Inhib Med Chem 2021 Dec;36(1):535-548

Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and in women. The impact of the new pyrazolo[4,3-]tetrazolo[1,5-][1,2,4]triazine sulphonamide () was evaluated against human colon cancer and in zebrafish xenografts. Our results show that this new synthesised compound effectively inhibits cell survival in BTK-dependent mechanism. Its effectiveness is much higher at a relatively low concentration as compared with the standard chemotherapy used for CRC, i.e. 5-fluorouracil (5-FU). Flow cytometry analysis after annexin V-FITC and propidium iodide staining revealed that apoptosis was the main response of CRC cells to treatment. We also found that effectively inhibits tumour development in zebrafish embryo xenograft model, where it showed a markedly synergistic anticancer effect when used in combination with 5-FU. The above results suggest that this novel heterofused 1,2,4-triazine derivative may be a promising candidate for further evaluation as chemotherapeutic agent against CRC.
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http://dx.doi.org/10.1080/14756366.2021.1879803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850456PMC
December 2021

Response of Human Glioblastoma Cells to Vitamin B12 Deficiency: A Study Using the Non-Toxic Cobalamin Antagonist.

Biology (Basel) 2021 Jan 19;10(1). Epub 2021 Jan 19.

Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland.

The most important biological function of vitamin B12 is to accomplish DNA synthesis, which is necessary for cell division. Cobalamin deficiency may be especially acute for rapidly dividing cells, such as glioblastoma cells. Therefore, cobalamin antagonists offer a medicinal potential for developing anti-glioma agents. In the present study, we developed an in vitro model of cobalamin deficiency in glioblastoma cells. Long-term treatment of cells with the cobalamin analogue, hydroxycobalamin [-lactam] (HCCL) was applied to induce an increase of hypocobalaminemia biomarker. Cytometric assays demonstrated that vitamin B12 promoted glioblastoma cells proliferation, whereas the treatment of cells with HCCL caused a dramatic inhibition of cell proliferation and an induction of cell cycle arrest at the G2/M phase. Vitamin B12 counteracted all the observed effects of HCCL. In the in silico study, we characterized the molecular interactions between HCCL and transcobalamin II (TCII). We have demonstrated that HCCL shares similar interactions with TCII as naturally occurring cobalamins and therefore may act as a competitive inhibitor of this key transporter protein. We assessed the impact of HCCL on the mortality or developmental malformations of zebrafish embryos. Collectively, our findings suggest that the use of cobalamin transport antagonists as potential anti-glioma agents would be worth exploring further.
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http://dx.doi.org/10.3390/biology10010069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835758PMC
January 2021

Oxidative Storm Induced by Tryptophan Metabolites: Missing Link between Atherosclerosis and Chronic Kidney Disease.

Oxid Med Cell Longev 2020 29;2020:6656033. Epub 2020 Dec 29.

Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2c, 15-222 Bialystok, Poland.

Chronic kidney disease (CKD) occurrence is rising all over the world. Its presence is associated with an increased risk of premature death from cardiovascular disease (CVD). Several explanations of this link have been put forward. It is known that in renal failure, an array of metabolites cannot be excreted, and they accumulate in the organism. Among them, some are metabolites of tryptophan (TRP), such as indoxyl sulfate and kynurenine. Scientists have become interested in them in the context of inducing vascular damage in the course of chronic kidney impairment. Experimental evidence suggests the involvement of TRP metabolites in the progression of chronic kidney disease and atherosclerosis separately and point to oxidative stress generation as one of the main mechanisms that is responsible for worsening those states. Since it is known that blood levels of those metabolites increase significantly in renal failure and that they generate reactive oxygen species (ROS), which lead to endothelial injury, it is reasonable to suspect that products of TRP metabolism are the missing link in frequently occurring atherosclerosis in CKD patients. This review focuses on reports that shed a light on TRP metabolites as contributing factors to vascular damage in the progression of impaired kidney function.
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http://dx.doi.org/10.1155/2020/6656033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787774PMC
December 2020

Astrogliosis in an Experimental Model of Hypovitaminosis B12: A Cellular Basis of Neurological Disorders due to Cobalamin Deficiency.

Cells 2020 10 9;9(10). Epub 2020 Oct 9.

Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland.

Cobalamin deficiency affects human physiology with sequelae ranging from mild fatigue to severe neuropsychiatric abnormalities. The cellular and molecular aspects of the nervous system disorders associated with hypovitaminosis B12 remain largely unknown. Growing evidence indicates that astrogliosis is an underlying component of a wide range of neuropathologies. Previously, we developed an in vitro model of cobalamin deficiency in normal human astrocytes (NHA) by culturing the cells with -lactam of hydroxycobalamin (-lactam OH-Cbl). We revealed a non-apoptotic activation of caspases (3/7, 8, 9) in cobalamin-deficient NHA, which may suggest astrogliosis. The aim of the current study was to experimentally verify this hypothesis. We indicated an increase in the cellular expression of two astrogliosis markers: glial fibrillary acidic protein and vimentin in cobalamin-deficient NHA using Western blot analysis and immunocytochemistry with confocal laser scanning microscopy. In the next step of the study, we revealed -lactam OH-Cbl as a potential non-toxic vitamin B12 antagonist in an in vivo model using zebrafish embryos. We believe that the presented results will contribute to a better understanding of the cellular mechanism underlying neurologic pathology due to cobalamin deficiency and will serve as a foundation for further studies.
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http://dx.doi.org/10.3390/cells9102261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600008PMC
October 2020

The intensification of anticancer activity of LFM-A13 by erythropoietin as a possible option for inhibition of breast cancer.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1697-1711

Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.

Recombinant human erythropoietin (Epo) is an effective and convenient treatment for cancer-related anaemia. In our study for the first time, we evaluated the effect of simultaneous use of Epo and Bruton's tyrosine kinase (BTK) inhibitor LFM-A13 on the viability and tumour development of breast cancer cells. The results demonstrated that Epo significantly intensifies the anticancer activity of LFM-A13 in MCF-7 and MDA-MB-231. The featured therapeutic scheme efficiently blocked the tumour development in zebrafish experimental cancer model. Epo and LFM-A13 administered together resulted in effective cell killing, accompanied by attenuation of the BTK signalling pathways, loss of mitochondrial membrane potential (MMP), accumulation of apoptotic breast cancer cells with externalised PS, a slight increase in phase G0/G1 and a reduction in cyclin D1 expression. Simultaneous use of Epo with LFM-A13 inhibited early stages of tumour progression. This therapeutic scheme may be rationale for further possible research.
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http://dx.doi.org/10.1080/14756366.2020.1818738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717683PMC
December 2020

Important players in carcinogenesis as potential targets in cancer therapy: an update.

Oncotarget 2020 Aug 11;11(32):3078-3101. Epub 2020 Aug 11.

Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza, Bialystok, Poland.

The development of cancer is a problem that has accompanied mankind for years. The growing number of cases, emerging drug resistance, and the need to reduce the serious side effects of pharmacotherapy are forcing scientists to better understand the complex mechanisms responsible for the initiation, promotion, and progression of the disease. This paper discusses the modulation of the particular stages of carcinogenesis by selected physiological factors, including: acetylcholine (ACh), peroxisome proliferator-activated receptors (PPAR), fatty acid-binding proteins (FABPs), Bruton's tyrosine kinase (Btk), aquaporins (AQPs), insulin-like growth factor-2 (IGF-2), and exosomes. Understanding their role may contribute to the development of more effective and safer therapies based on new binding sites.
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http://dx.doi.org/10.18632/oncotarget.27689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429179PMC
August 2020

Evaluation of the Anticancer Activities of Novel Transition Metal Complexes with Berenil and Nitroimidazole.

Molecules 2020 Jun 21;25(12). Epub 2020 Jun 21.

Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland.

Novel transition metal complexes (Au, Pd, Pt) with berenil and 2-(1-methyl-5-nitroimidazol-2-yl)ethanol were obtained through two-step synthesis. The cytotoxicity assay against MCF-7 and MDA-MB-231 breast cancer cells revealed that novel platinum and palladium complexes cause a reduction on the viability of MCF-7 and MDA-MB-231 breast cancer cells to a greater extent than cisplatin. The complexes showed lower cytotoxicity on normal MCF-10A human breast epithelial cells than on tumor cells. Furthermore, we observed that these complexes selectively concentrate in tumor cell mitochondria due to the characteristic for these cells increased membrane potential that may explain their increased proapoptotic activity. The activity of the synthesized compounds against topoisomerase type IIα and their increased impact on DNA defragmentation also were documented. The novel complexes also induced autophagosome changes and inhibited tumor growth in xenograft models (established using breast cancer cells).
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http://dx.doi.org/10.3390/molecules25122860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355748PMC
June 2020

Neurobehavioral effects of uremic toxin-indoxyl sulfate in the rat model.

Sci Rep 2020 06 11;10(1):9483. Epub 2020 Jun 11.

Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.

Chronic kidney disease (CKD) is deemed to be a worldwide health concern connected with neurological manifestations. The etiology of central nervous system (CNS) disorders in CKD is still not fully understood, however particular attention is currently being paid to the impact of accumulated toxins. Indoxyl sulfate (IS) is one of the most potent uremic toxins. The purpose of the present study was to assess IS concentrations in the cerebellum, brainstem, cortex, hypothalamus, and striatum with hippocampus of rats chronically exposed to IS. To evaluate IS impact on neurochemical and behavioral alterations, we examined its influence on brain levels of norepinephrine, epinephrine, dopamine, serotonin and their metabolites, as well as changes in behavioral tests (open field test, elevated plus maze test, chimney test, T maze test, and splash test). Our results show the highest IS accumulation in the brainstem. IS leads to behavioral alterations involving apathetic behavior, increased stress sensitivity, and reduced locomotor and exploratory activity. Besides, IS contributes to the impairment of spatial memory and motor coordination. Furthermore, we observed reduced levels of norepinephrine, dopamine or serotonin, mainly in the brainstem. Our findings indicate that IS can be one of the crucial uremic factors responsible for altered mental status in CKD.
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http://dx.doi.org/10.1038/s41598-020-66421-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289875PMC
June 2020

Intracellular mechanisms of tumor cells' immunoresistance.

Acta Biochim Pol 2020 Apr;67(2):143-148

Department of Pharmacodynamics, Medical University of Bialystok, Białystok, Poland.

One of the main mechanisms for avoiding immune response by cancer cells is mediated by inducing an immunosuppressive environment in the tumor following activation of immune checkpoints, i.e. PD-1 or CTLA-4 receptor inhibitors on T lymphocytes. Interaction inhibition between PD-1 or CTLA-4 and their ligands (PD-L1, CD80, and CD85) leads to unblocking of the T-lymphocyte function, and thus destroys cancer cells. Certain intracellular signaling pathways are also involved in the development of tumor cell immunoresistance. Immunosuppressive pathways' activation blocking may increase the immunological anti-tumor control.
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http://dx.doi.org/10.18388/abp.2020_2878DOI Listing
April 2020

Synthesis and cellular effects of novel 1,3,5-triazine derivatives in DLD and Ht-29 human colon cancer cell lines.

Invest New Drugs 2020 08 13;38(4):990-1002. Epub 2019 Sep 13.

Department of Organic Chemistry, Medical University of Bialystok, Białystok, Poland.

This study provides new information on the cellular effects of 1,3,5-triazine nitrogen mustards with different peptide groups in DLD and Ht-29 human colon cancer cell lines. A novel series of 2,4,6-trisubstituted 1,3,5-triazine derivatives bearing 2-chloroethyl and oligopeptide moieties was designed and synthesized. The most cytotoxic derivative was triazine with an Ala-Ala-OMe substituent on the ring (compound 7b). This compound induced time- and dose-dependent cytotoxicity in the DLD-1 and HT-29 colon cancer cell lines. The triazine derivative furthermore induced apoptosis through intracellular signaling pathway attenuation. Compound 7b may be a candidate for further evaluation as a chemotherapeutic agent against colorectal cancer.
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http://dx.doi.org/10.1007/s10637-019-00838-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340680PMC
August 2020

Erythropoietin Intensifies the Proapoptotic Activity of LFM-A13 in Cells and in a Mouse Model of Colorectal Cancer.

Int J Mol Sci 2018 Apr 23;19(4). Epub 2018 Apr 23.

Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland.

The Bruton’s tyrosine kinase (BTK) inhibitor LFM-A13 has been widely employed as an antileukemic agent, but applications in solid cancer have been found recently. The compound promotes apoptosis, has an antiproliferative effect, and increases cancer cell sensitivity to chemotherapy drugs. We decided to assess the impact of the simultaneous use of erythropoietin (Epo) and LFM-A13 on signal transduction in colon DLD-1 and HT-29 cells, as well as in tumor xenografts. The induction of apoptosis by Epo and LFM-A-13 in the cells was confirmed by phosphatidylserine externalization, loss of mitochondrial membrane potential, and modulation of the expression of apoptotic protein BAX and antiapoptotic protein BCL-2 in colon adenocarcinoma cells. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM-A13 in order to evaluate the degree of tumor regression. The simultaneous use of Epo and LFM-A13 severely inhibited cell growth, activated apoptosis, and also inhibited tumor growth in xenografts. The addition of Epo to LFM-A13 intensified the antiproliferative effect of LFM-A13, confirmed by the loss of mitochondrial membrane potential and the accumulation of apoptotic colon cancer cells with externalized phosphatidylserine (PS). These preclinical results suggest that the combination of Epo and LFM-A13 has a high proapoptotic activity and should be tested in the clinic for the treatment of solid tumors such as colon cancer.
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http://dx.doi.org/10.3390/ijms19041262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979332PMC
April 2018

Simultaneous use of erythropoietin and LFM-A13 as a new therapeutic approach for colorectal cancer.

Br J Pharmacol 2018 03 25;175(5):743-762. Epub 2018 Jan 25.

Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.

Background And Purpose: Bruton's tyrosine kinase (Btk) is a non-receptor tyrosine kinase involved in the activation of signalling pathways responsible for cell maturation and viability. Btk has previously been reported to be overexpressed in colon cancers. This kind of cancer is often accompanied by anaemia, which is treated with an erythropoietin supplement. The goal of the present study was to assess the effects of combination therapy with erythropoietin β (Epo) and LFM-A13 (Btk inhibitor) on colon cancer in in vitro and in vivo models.

Experimental Approach: DLD-1 and HT-29 human colon adenocarcinoma cells were cultured with Epo and LFM-A13. Cell number and viability, and mRNA and protein levels of Epo receptors, Btk and Akt were assessed. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM-A13.

Key Results: The combination of Epo and LFM-A13 mostly exerted a synergistic inhibitory effect on colon cancer cell growth. The therapeutic scheme used effectively killed the cancer cells and attenuated the Btk signalling pathways. Epo + LFM-A13 also prevented the normal process of microtubule assembly during mitosis by down-regulating the expression of Polo-like kinase 1. The combination of Epo and LFM-A13 significantly reduced the growth rate of tumour cells, while it showed high safety profile, inducing no nephrotoxicity, hepatotoxicity or changes in the haematological parameters.

Conclusion And Implications: Epo significantly enhances the antitumour activity of LFM-A13, indicating that a combination of Epo and LFM-A13 has potential as an effective therapeutic approach for patients with colorectal cancer.
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http://dx.doi.org/10.1111/bph.14099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811618PMC
March 2018

Erythropoietin Enhances the Cytotoxic Effect of Hydrogen Peroxide on Colon Cancer Cells.

Curr Pharm Biotechnol 2017 ;18(2):127-137

Department of Monitored Pharmacotherapy Medical University of Bialystok, Mickiewicza 2C, 15-222 Białystok, Poland.

Background: Cancer patients treated with alkylating agents and radiotherapy are exposed to high level of reactive oxygen species (ROS) in tissues. ROS can involve superoxide free radicals, peroxynitrite, singlet oxygen, nitric oxide and hydrogen peroxide. It is well documented that increased exposure to oxygen through a high metabolic rate could lead to a shortened life span. Ionizing radiation, use of drugs and the development of cancer can lead to cancer-induced anemia. Recombinant human erythropoietin (Epo) supplementation is one of the methods for treating anemia. Erythropoietin through an increase in the number of erythrocytes, improves oxygenation tissue. The aim of this work was to study the effect of Epo on colon adenocarcinoma cells (DLD-1) given alone or in combination with hydrogen peroxide (H2O2). Cell proliferation and number were measured.

Methods: Expression of EpoR, Bcl-2 and Akt1 protein was assessed by RT-PCR, Western blot, and confocal microscopy.

Results: The results show that the coadministration of Epo and H2O2 indicates antitumor action, which occurs via a dose-dependent inhibition of DLD-1 cell growth and proliferation. Moreover, the coadministration of Epo and H2O2 resulted in a decrease of cell numbers, as well as Bcl-2 expression. The incubation of DLD-1 cells with those agents led to a decrease in EpoR and phosphorylated EpoR expression and an increase in Akt1 and phosphorylated Akt expression. The addition of Epo to H2O2 intensified the cytotoxic effect of the latter.

Conclusion: These preclinical results suggest that Epo during chemotherapy or radiotherapy may possess potential benefits in colon cancer patients.
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http://dx.doi.org/10.2174/1389201018666161116092907DOI Listing
December 2017

Are anti-Müllerian hormone and its receptor polymorphism associated with the hormonal condition of undescended testes?

Adv Med Sci 2016 Sep 26;61(2):288-292. Epub 2016 Mar 26.

Department of Pediatric Surgery, Medical University of Bialystok, Bialystok, Poland. Electronic address:

Purpose: Numerous genetic and endocrine factors are involved in the process of testicular descent, but only a few genetic causes have been reported in human. The aim of this study was to investigate the density and distribution of single nucleotide polymorphisms (SNPs) anti-Müllerian hormone (AMH) and AMHRII receptors in cryptorchid patients and determine potential hormone imbalance connected with undescended testes by assessing the levels of AMH, Insulin-like factor 3 (INSL3) and inhibin B.

Materials And Methods: The serum hormone levels (AMH, INSL3 and inhibin B) were compared in the two groups - cryptorchidism (n=105) and control group (n=58). The frequency of AMHRII -482 A>G, AMHRII IVS 10+77 A>G, AMHRII IVS 5-6 C>T, and AMH Ile49Ser polymorphisms among cryptorchid boys were compared with the control group.

Results: None of the hormones levels were different between the cryptorchid and the control groups. All cases of IVS 5-6 C>T homozygote and heterozygote mutation were accompanied by an IVS 10+77 A>G and 482 A>G homozygote and heterozygote mutation. Interestingly, in most cases of all four polymorphisms, homozygote recessive genotype was associated with cases of cryptorchidism. However, the groups of patients were too small to draw definite conclusions.

Conclusion: The AMHRII -482 A>G, AMHRII IVS 10+77 A>G, AMHRII IVS 5-6 C>T and AMH Ile49Ser genotypes should be determined in a much larger group of boys with cryptorchidism.
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http://dx.doi.org/10.1016/j.advms.2016.03.004DOI Listing
September 2016

Impact of aliskiren on some hemostatic parameters in experimental arterial thrombosis in rats.

Pharmacol Rep 2015 Apr 6;67(2):173-8. Epub 2014 Sep 6.

Higher State Vocational School, Institute of Health Care, Suwałki, Poland.

Background: Aliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. A number of studies show a link between aliskiren and intravascular thrombosis.

Materials And Methods: The goal of the present study was to investigate the impact of aliskiren on arterial thrombosis in normotensive and renovascular hypertensive rats. The contribution of each coagulation and fibrinolytic parameters in the mode of aliskiren action was determined. Six weeks after clipping of the left renal artery rats developed hypertension which was confirmed by the "tail cuff" method. Animals were treated with aliskiren (10, 30 and 100mg/kg/day) per os for 10 days. Arterial thrombosis was induced by electrical stimulation of the common carotid artery.

Results: It was found that aliskiren in a dose-dependent manner decreased weight of the arterial thrombus in normotensive and hypertensive rats. It has been shown that this result was not associated with the effects on blood pressure, TF, PT, APTT, fibrinogen and hematological parameters. It was found that aliskiren caused increase of t-PA activity and decrease of its inhibitor activity.

Conclusions: The presented results indicate that aliskiren inhibits hemostasis in the arterial thrombosis in rats. The antithrombotic effect is related with improvement of the fibrinolytic balance, and also depends on antiplatelet action.
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http://dx.doi.org/10.1016/j.pharep.2014.08.021DOI Listing
April 2015

Aliskiren inhibits experimental venous thrombosis in two-kidney one- clip hypertensive rats.

Thromb Res 2013 Jan 20;131(1):e39-44. Epub 2012 Nov 20.

Department of Pharmacodynamics, Medical University of Bialystok, Poland.

A substantial amount of evidence links the renin-angiotensin system with thrombosis. For example, ACE inhibitors and angiotensin receptor blockers possess independent of the hemodynamic changes, antithrombotic activity. Aliskiren direct renin inhibitor belongs to a new very promising antihypertensive drug that effectively inhibits the renin-angiotensin system. The aim of study was to determine the influence of aliskiren on stasis-induced venous thrombosis in renovascular hypertensive and normotensive rats. The involvement of nitric oxide and prostacyclin in the potential antithrombotic action was also elucidated. Six weeks after clipping of the left renal artery rats developed hypertension which was confirmed by the "tail cuff" method. Hypertensive and normotensive rats were treated with aliskiren (10, 30 and 100mg/kg/day) per os for 10days. Venous thrombosis was induced by stasis of vena cava inferior. Aliskiren at the highest dose induced a significant decrease in systolic blood pressure in hypertensive, but did not change this parameter in normotensive rats. Oral administration of aliskiren resulted in dose-dependent decrease of venous thrombus weight in hypertensive and normotensive rats. The antithrombotic activity of aliskiren was abolished both by NO synthase inhibitor and prostacyclin synthesis inhibitor. Aliskiren decreased collagen-induced platelet aggregation, increased plasma level of tissue plasminogen activator activity whereas no changes in plasminogen activator inhibitor activity and coagulation parameters were found. We showed that aliskiren prevents the development of venous thrombosis by enhanced fibrinolysis and the blood platelet inhibition via nitric oxide and/or prostacyclin-dependent mechanism.
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http://dx.doi.org/10.1016/j.thromres.2012.11.001DOI Listing
January 2013

N-methylnicotinamide failed to induce endothelial prostacyclin release in perfused rat hindquarters.

Pharmacol Rep 2008 Nov-Dec;60(6):1025-9

Department of Pharmacodynamics, Medical University of Białystok, Mickiewicza 2C, PL 15-089 Białystok, Poland.

N-methylnicotinamide, a nicotinamide derivative, possesses anti-thrombotic activity, although the mechanism of its action is unclear. Using a rat model of isolated perfused hindlimb, we tested whether this metabolite of nicotinamide is able to inhibit the vasoconstrictive effects of epinephrine, norepinephrine, and angiotensin II, thereby releasing prostacyclin from the endothelium. We found that N-methylnicotinamide administration by infusion or bolus injection did not change the course of perfusion pressure and did not inhibit the vasoconstrictive action of epinephrine, norepinephrine, or angiotensin II. In contrast, prazosin was able to completely abolish the constriction induced by epinephrine. Moreover, we did not find any changes in the level of a stable prostacyclin analog measured in the collected perfusate samples. Thus, we did not observe any endothelial prostacyclin-releasing properties of N-methylnicotinamide in the perfused rat hindquarters model.
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April 2009

Pharmacokinetics and pharmacodynamics of aliskiren, an oral direct renin inhibitor.

Pharmacol Rep 2008 Sep-Oct;60(5):623-31

Department of Pharmacodynamics, Medical University of Białystok, Mickiewicza 2C, PL 15-089 Białystok, Poland.

Intensive efforts have been spent to discover therapeutic, non-peptide and orally effective hypertensive drugs. One drug that emerged from this effort is aliskiren, a direct human renin inhibitor that blocks the conversion of angiotensinogen to angiotensin I (Ang I). In contrast to other antihypertensive agents, aliskiren decreases plasma renin activity (PRA). In healthy human subjects, doses of between 40 and 640 mg of aliskiren exert a dose-dependent reduction in PRA and Ang I and Ang II levels. The bioavailability of aliskiren is low (2%), peak plasma concentrations are reached within one to three hours and the binding with plasma proteins achieves approximately 47-51%. Aliskiren is slightly metabolized (20%) by CYP3A4. The most common adverse events include diarrhea, headache, back pain and gastrointestinal disorders. Aliskiren is well tolerated, and may be used alone or in combination with other antihypertensive agents. Aliskiren belongs to a new class of agents that effectively and specifically inhibit the RAS. This drug functions through a novel mechanism of action and has the potential to become a true alternative to angiotensin converting enzyme inhibitors and angiotensin receptor blockers in the therapy of hypertension and other cardiovascular and renal disorders.
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February 2009
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