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Prof. Dariusz Pawlak
1. Department of Pharmacodynamics, Medical University, Białystok, Poland

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Research Keywords & Expertise

0 Chronic Kidney Disease
0 renal osteodystrophy
0 Kynurenine pathway
0 Osteoblastogenesis
0 Uraemic Toxins

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Kynurenine pathway
Chronic Kidney Disease
renal osteodystrophy
Osteoblastogenesis

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Journal article
Published: 07 August 2021 in Pharmaceutics
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MM-129 is a novel inhibitor targeting BTK/PI3K/AKT/mTOR and PD-L1, as it possesses antitumor activity against colon cancer. To evaluate the safety profile of MM-129, we conducted a toxicity study using the zebrafish and rodent model. MM-129 was also assessed for pharmacokinetics features through an in vivo study on Wistar rats. The results revealed that MM-129 exhibited favorable pharmacokinetics with quick absorption and 68.6% of bioavailability after intraperitoneal administration. No serious adverse events were reported for the use of MM-129, confirming a favorable safety profile for this compound. It was not fatal and toxic to mice at an anticancer effective dose of 10 μmol/kg. At the end of 14 days of administering hematological and biochemical parameters, liver and renal functions were all at normal levels. No sublethal effects were either detected in zebrafish embryos treated with a concentration of 10 μM. MM-129 has the potential as a safe and well-tolerated anticancer formulation for future treatment of patients with colon cancer.

ACS Style

Justyna Magdalena Hermanowicz; Bartlomiej Kalaska; Krystyna Pawlak; Beata Sieklucka; Joanna Miklosz; Mariusz Mojzych; Dariusz Pawlak. Preclinical Toxicity and Safety of MM-129—First-in-Class BTK/PD-L1 Inhibitor as a Potential Candidate against Colon Cancer. Pharmaceutics 2021, 13, 1222 .

AMA Style

Justyna Magdalena Hermanowicz, Bartlomiej Kalaska, Krystyna Pawlak, Beata Sieklucka, Joanna Miklosz, Mariusz Mojzych, Dariusz Pawlak. Preclinical Toxicity and Safety of MM-129—First-in-Class BTK/PD-L1 Inhibitor as a Potential Candidate against Colon Cancer. Pharmaceutics. 2021; 13 (8):1222.

Chicago/Turabian Style

Justyna Magdalena Hermanowicz; Bartlomiej Kalaska; Krystyna Pawlak; Beata Sieklucka; Joanna Miklosz; Mariusz Mojzych; Dariusz Pawlak. 2021. "Preclinical Toxicity and Safety of MM-129—First-in-Class BTK/PD-L1 Inhibitor as a Potential Candidate against Colon Cancer." Pharmaceutics 13, no. 8: 1222.

Journal article
Published: 26 June 2021 in Cancers
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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.

ACS Style

Justyna Hermanowicz; Krystyna Pawlak; Beata Sieklucka; Robert Czarnomysy; Iwona Kwiatkowska; Adam Kazberuk; Arkadiusz Surazynski; Mariusz Mojzych; Dariusz Pawlak. MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer. Cancers 2021, 13, 3203 .

AMA Style

Justyna Hermanowicz, Krystyna Pawlak, Beata Sieklucka, Robert Czarnomysy, Iwona Kwiatkowska, Adam Kazberuk, Arkadiusz Surazynski, Mariusz Mojzych, Dariusz Pawlak. MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer. Cancers. 2021; 13 (13):3203.

Chicago/Turabian Style

Justyna Hermanowicz; Krystyna Pawlak; Beata Sieklucka; Robert Czarnomysy; Iwona Kwiatkowska; Adam Kazberuk; Arkadiusz Surazynski; Mariusz Mojzych; Dariusz Pawlak. 2021. "MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer." Cancers 13, no. 13: 3203.

Review
Published: 26 June 2021 in Cells
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Neurodegenerative disorders are chronic and life-threatening conditions negatively affecting the quality of patients’ lives. They often have a genetic background, but oxidative stress and mitochondrial damage seem to be at least partly responsible for their development. Recent reports indicate that the activation of the kynurenine pathway (KP), caused by an activation of proinflammatory factors accompanying neurodegenerative processes, leads to the accumulation of its neuroactive and pro-oxidative metabolites. This leads to an increase in the oxidative stress level, which increases mitochondrial damage, and disrupts the cellular energy metabolism. This significantly reduces viability and impairs the proper functioning of central nervous system cells and may aggravate symptoms of many psychiatric and neurodegenerative disorders. This suggests that the modulation of KP activity could be effective in alleviating these symptoms. Numerous reports indicate that tryptophan supplementation, inhibition of KP enzymes, and administration or analogs of KP metabolites show promising results in the management of neurodegenerative disorders in animal models. This review gathers and systematizes the knowledge concerning the role of metabolites and enzymes of the KP in the development of oxidative damage within brain cells during neurodegenerative disorders and potential strategies that could reduce the severity of this process.

ACS Style

Adrian Mor; Anna Tankiewicz-Kwedlo; Anna Krupa; Dariusz Pawlak. Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders. Cells 2021, 10, 1603 .

AMA Style

Adrian Mor, Anna Tankiewicz-Kwedlo, Anna Krupa, Dariusz Pawlak. Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders. Cells. 2021; 10 (7):1603.

Chicago/Turabian Style

Adrian Mor; Anna Tankiewicz-Kwedlo; Anna Krupa; Dariusz Pawlak. 2021. "Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders." Cells 10, no. 7: 1603.

Review
Published: 23 June 2021 in Pharmaceuticals
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Malignancies are unquestionably a significant public health problem. Their effective treatment is still a big challenge for modern medicine. Tumors have developed a wide range of mechanisms to evade an immune and therapeutic response. As a result, there is an unmet clinical need for research on solutions aimed at overcoming this problem. An accumulation of tryptophan metabolites belonging to the kynurenine pathway can enhance neoplastic progression because it causes the suppression of immune system response against cancer cells. They are also involved in the development of the mechanisms responsible for the resistance to antitumor therapy. Kynurenine belongs to the most potent immunosuppressive metabolites of this pathway and has a significant impact on the development of malignancies. This fact prompted researchers to assess whether targeting the enzymes responsible for its synthesis could be an effective therapeutic strategy for various cancers. To date, numerous studies, both preclinical and clinical, have been conducted on this topic, especially regarding the inhibition of indoleamine 2,3-dioxygenase activity and their results can be considered noteworthy. This review gathers and systematizes the knowledge about the role of the kynurenine pathway in neoplastic progression and the findings regarding the usefulness of modulating its activity in anticancer therapy.

ACS Style

Adrian Mor; Anna Tankiewicz-Kwedlo; Dariusz Pawlak. Kynurenines as a Novel Target for the Treatment of Malignancies. Pharmaceuticals 2021, 14, 606 .

AMA Style

Adrian Mor, Anna Tankiewicz-Kwedlo, Dariusz Pawlak. Kynurenines as a Novel Target for the Treatment of Malignancies. Pharmaceuticals. 2021; 14 (7):606.

Chicago/Turabian Style

Adrian Mor; Anna Tankiewicz-Kwedlo; Dariusz Pawlak. 2021. "Kynurenines as a Novel Target for the Treatment of Malignancies." Pharmaceuticals 14, no. 7: 606.

Journal article
Published: 18 June 2021 in International Journal of Molecular Sciences
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Secondary hyperparathyroidism and abnormalities in tryptophan (TRP) metabolism are commonly observed in chronic kidney disease (CKD). The present study aimed to establish potential interactions between endogenous parathyroid hormone (PTH) and activation of the bone kynurenine (KYN) pathway in relation to bone turnover and strength in young rats after one month (CKD-1) and three months (CKD-3) of experimental CKD. TRP, KYN, KYN/TRP ratio and bone turnover markers (BTMs) were measured in trabecular and cortical bone tissue. Expression of aryl hydrocarbon receptor (AhR) and the genes involved in osteogenesis was determined in femoral bone. Biomechanical testing of femoral diaphysis and femoral neck was also performed. Activation of the KYN pathway in trabecular bone during CKD development intensified the expression of genes related to osteogenesis, which led to a decrease in cyclic adenosine monophosphate (cAMP) and BTMs levels, resulting in a stiffer and mechanically weaker femoral neck. In contrast, reduction of the KYN pathway in cortical bone allowed to unblock the PTH-dependent anabolic activating transcription factor 4/parathyroid hormone 1 receptor (PTH1R/ATF4) axis, led to cAMP accumulation, better bone turnover and strength in the course of CKD development. In summary, the paracrine KYN pathway in bone can interfere with the anabolic effects of PTH on bone through disrupting PTH-dependent molecular signaling.

ACS Style

Krystyna Pawlak; Beata Sieklucka; Dariusz Pawlak. Paracrine Kynurenic Pathway Activation in the Bone of Young Uremic Rats Can Antagonize Anabolic Effects of PTH on Bone Turnover and Strength through the Disruption of PTH-Dependent Molecular Signaling. International Journal of Molecular Sciences 2021, 22, 6563 .

AMA Style

Krystyna Pawlak, Beata Sieklucka, Dariusz Pawlak. Paracrine Kynurenic Pathway Activation in the Bone of Young Uremic Rats Can Antagonize Anabolic Effects of PTH on Bone Turnover and Strength through the Disruption of PTH-Dependent Molecular Signaling. International Journal of Molecular Sciences. 2021; 22 (12):6563.

Chicago/Turabian Style

Krystyna Pawlak; Beata Sieklucka; Dariusz Pawlak. 2021. "Paracrine Kynurenic Pathway Activation in the Bone of Young Uremic Rats Can Antagonize Anabolic Effects of PTH on Bone Turnover and Strength through the Disruption of PTH-Dependent Molecular Signaling." International Journal of Molecular Sciences 22, no. 12: 6563.

Review
Published: 04 June 2021 in Journal of Clinical Medicine
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Scientific interest in tryptophan metabolism via the kynurenine pathway (KP) has increased in the last decades. Describing its metabolites helped to increase their roles in many diseases and disturbances, many of a pro-inflammatory nature. It has become increasingly evident that KP can be considered an important part of emerging mediators of diabetes mellitus and metabolic syndrome (MS), mostly stemming from chronic systemic low-grade inflammation resulting in the aggravation of cardiovascular complications. An electronic literature search of PubMed and Embase up to March 2021 was performed for papers reporting the effects of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), xanthurenic acid (XA), anthranilic acid (AA), and quinolinic acid (QA), focusing on their roles in carbohydrate metabolism and the cardiovascular system. In this review, we discussed the progress in tryptophan metabolism via KP research, focusing particular attention on the roles in carbohydrate metabolism and its complications in the cardiovascular system. We examined the association between KP and diabetes mellitus type 2 (T2D), diabetes mellitus type 1 (T1D), and cardiovascular diseases (CVD). We concluded that tryptophan metabolism via KP serves as a potential diagnostic tool in assessing cardiometabolic risk for patients with T2D.

ACS Style

Małgorzata Kiluk; Janina Lewkowicz; Dariusz Pawlak; Anna Tankiewicz-Kwedlo. Crosstalk between Tryptophan Metabolism via Kynurenine Pathway and Carbohydrate Metabolism in the Context of Cardio-Metabolic Risk—Review. Journal of Clinical Medicine 2021, 10, 2484 .

AMA Style

Małgorzata Kiluk, Janina Lewkowicz, Dariusz Pawlak, Anna Tankiewicz-Kwedlo. Crosstalk between Tryptophan Metabolism via Kynurenine Pathway and Carbohydrate Metabolism in the Context of Cardio-Metabolic Risk—Review. Journal of Clinical Medicine. 2021; 10 (11):2484.

Chicago/Turabian Style

Małgorzata Kiluk; Janina Lewkowicz; Dariusz Pawlak; Anna Tankiewicz-Kwedlo. 2021. "Crosstalk between Tryptophan Metabolism via Kynurenine Pathway and Carbohydrate Metabolism in the Context of Cardio-Metabolic Risk—Review." Journal of Clinical Medicine 10, no. 11: 2484.

Review
Published: 28 May 2021 in Cancers
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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

ACS Style

Iwona Kwiatkowska; Justyna Hermanowicz; Alicja Przybyszewska-Podstawka; Dariusz Pawlak. Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis. Cancers 2021, 13, 2667 .

AMA Style

Iwona Kwiatkowska, Justyna Hermanowicz, Alicja Przybyszewska-Podstawka, Dariusz Pawlak. Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis. Cancers. 2021; 13 (11):2667.

Chicago/Turabian Style

Iwona Kwiatkowska; Justyna Hermanowicz; Alicja Przybyszewska-Podstawka; Dariusz Pawlak. 2021. "Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis." Cancers 13, no. 11: 2667.

Journal article
Published: 09 March 2021 in Pharmaceutics
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Protamine sulfate (PS) is the only available option to reverse the anticoagulant activity of unfractionated heparin (UFH), however it can cause cardiovascular and respiratory complications. We explored the toxicity of PS and its complexes with UFH in zebrafish, rats, and mice. The involvement of nitric oxide (NO) in the above effects was investigated. Concentration–dependent lethality, morphological defects, and decrease in heart rate (HR) were observed in zebrafish larvae. PS affected HR, blood pressure, respiratory rate, peak exhaled CO2, and blood oxygen saturation in rats. We observed hypotension, increase of HR, perfusion of paw vessels, and enhanced respiratory disturbances with increases doses of PS. We found no effects of PS on human hERG channels or signs of heart damage in mice. The hypotension in rats and bradycardia in zebrafish were partially attenuated by the inhibitor of endothelial NO synthase. The disturbances in cardiovascular and respiratory parameters were reduced or delayed when PS was administered together with UFH. The cardiorespiratory toxicity of PS seems to be charge–dependent and involves enhanced release of NO. PS administered at appropriate doses and ratios with UFH should not cause permanent damage of heart tissue, although careful monitoring of cardiorespiratory parameters is necessary.

ACS Style

Joanna Miklosz; Bartlomiej Kalaska; Piotr Podlasz; Małgorzata Chmielewska-Krzesińska; Miłosz Zajączkowski; Adam Kosiński; Dariusz Pawlak; Andrzej Mogielnicki. Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models. Pharmaceutics 2021, 13, 359 .

AMA Style

Joanna Miklosz, Bartlomiej Kalaska, Piotr Podlasz, Małgorzata Chmielewska-Krzesińska, Miłosz Zajączkowski, Adam Kosiński, Dariusz Pawlak, Andrzej Mogielnicki. Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models. Pharmaceutics. 2021; 13 (3):359.

Chicago/Turabian Style

Joanna Miklosz; Bartlomiej Kalaska; Piotr Podlasz; Małgorzata Chmielewska-Krzesińska; Miłosz Zajączkowski; Adam Kosiński; Dariusz Pawlak; Andrzej Mogielnicki. 2021. "Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models." Pharmaceutics 13, no. 3: 359.

Journal article
Published: 19 January 2021 in Biology
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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 [c-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.

ACS Style

Zuzanna Rzepka; Jakub Rok; Mateusz Maszczyk; Artur Beberok; Justyna Hermanowicz; Dariusz Pawlak; Dorota Gryko; Dorota Wrześniok. Response of Human Glioblastoma Cells to Vitamin B12 Deficiency: A Study Using the Non-Toxic Cobalamin Antagonist. Biology 2021, 10, 69 .

AMA Style

Zuzanna Rzepka, Jakub Rok, Mateusz Maszczyk, Artur Beberok, Justyna Hermanowicz, Dariusz Pawlak, Dorota Gryko, Dorota Wrześniok. Response of Human Glioblastoma Cells to Vitamin B12 Deficiency: A Study Using the Non-Toxic Cobalamin Antagonist. Biology. 2021; 10 (1):69.

Chicago/Turabian Style

Zuzanna Rzepka; Jakub Rok; Mateusz Maszczyk; Artur Beberok; Justyna Hermanowicz; Dariusz Pawlak; Dorota Gryko; Dorota Wrześniok. 2021. "Response of Human Glioblastoma Cells to Vitamin B12 Deficiency: A Study Using the Non-Toxic Cobalamin Antagonist." Biology 10, no. 1: 69.

Review article
Published: 29 December 2020 in Oxidative Medicine and Cellular Longevity
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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.

ACS Style

Iwona Kwiatkowska; Justyna M. Hermanowicz; Michal Mysliwiec; Dariusz Pawlak. Oxidative Storm Induced by Tryptophan Metabolites: Missing Link between Atherosclerosis and Chronic Kidney Disease. Oxidative Medicine and Cellular Longevity 2020, 2020, 1 -16.

AMA Style

Iwona Kwiatkowska, Justyna M. Hermanowicz, Michal Mysliwiec, Dariusz Pawlak. Oxidative Storm Induced by Tryptophan Metabolites: Missing Link between Atherosclerosis and Chronic Kidney Disease. Oxidative Medicine and Cellular Longevity. 2020; 2020 ():1-16.

Chicago/Turabian Style

Iwona Kwiatkowska; Justyna M. Hermanowicz; Michal Mysliwiec; Dariusz Pawlak. 2020. "Oxidative Storm Induced by Tryptophan Metabolites: Missing Link between Atherosclerosis and Chronic Kidney Disease." Oxidative Medicine and Cellular Longevity 2020, no. : 1-16.

Journal article
Published: 19 August 2020 in International Journal of Molecular Sciences
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An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy.

ACS Style

Adrian Mor; Krystyna Pawlak; Bartlomiej Kalaska; Tomasz Domaniewski; Beata Sieklucka; Marta Zieminska; Bogdan Cylwik; Dariusz Pawlak. Modulation of the Paracrine Kynurenic System in Bone as a New Regulator of Osteoblastogenesis and Bone Mineral Status in an Animal Model of Chronic Kidney Disease Treated with LP533401. International Journal of Molecular Sciences 2020, 21, 5979 .

AMA Style

Adrian Mor, Krystyna Pawlak, Bartlomiej Kalaska, Tomasz Domaniewski, Beata Sieklucka, Marta Zieminska, Bogdan Cylwik, Dariusz Pawlak. Modulation of the Paracrine Kynurenic System in Bone as a New Regulator of Osteoblastogenesis and Bone Mineral Status in an Animal Model of Chronic Kidney Disease Treated with LP533401. International Journal of Molecular Sciences. 2020; 21 (17):5979.

Chicago/Turabian Style

Adrian Mor; Krystyna Pawlak; Bartlomiej Kalaska; Tomasz Domaniewski; Beata Sieklucka; Marta Zieminska; Bogdan Cylwik; Dariusz Pawlak. 2020. "Modulation of the Paracrine Kynurenic System in Bone as a New Regulator of Osteoblastogenesis and Bone Mineral Status in an Animal Model of Chronic Kidney Disease Treated with LP533401." International Journal of Molecular Sciences 21, no. 17: 5979.

Journal article
Published: 22 April 2020 in Acta Biochimica Polonica
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One of the main mechanisms for avoiding immune response by cancer cells is by inducing an immunosuppressive environment in the tumor, following the activation of immune checkpoints i.e. PD-1 or CTLA-4 receptor inhibitors on T lymphocytes. Inhibiting the interaction between PD-1 or CTLA-4 and their ligands (PD-L1, CD80, and CD85) leads to unblocking T-lymphocyte function, and thus destroying cancer cells. Certain intracellular signaling pathways are also involved in the development of tumor cell immunoresistance. Blocking the activation of immunosuppressive pathways may increase immunological anti-tumor control

ACS Style

Justyna Hermanowicz; Beata Sieklucka; Krzysztof Nosek; Dariusz Pawlak. INTRACELLULAR MECHANISMS OF TUMOR CELL IMMUNORESISTANCE. Acta Biochimica Polonica 2020, 1 .

AMA Style

Justyna Hermanowicz, Beata Sieklucka, Krzysztof Nosek, Dariusz Pawlak. INTRACELLULAR MECHANISMS OF TUMOR CELL IMMUNORESISTANCE. Acta Biochimica Polonica. 2020; ():1.

Chicago/Turabian Style

Justyna Hermanowicz; Beata Sieklucka; Krzysztof Nosek; Dariusz Pawlak. 2020. "INTRACELLULAR MECHANISMS OF TUMOR CELL IMMUNORESISTANCE." Acta Biochimica Polonica , no. : 1.

Journal article
Published: 14 January 2020 in Journal of Pharmacology and Experimental Therapeutics
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Bleeding resulting from the application of low-molecular-weight heparins (LMWHs) may be treated with protamine sulfate but lacks efficiency; its action against anti-factor Xa activity is limited to ~60%. Moreover, protamine sulfate can cause life-threatening hypersensitivity reactions. We developed diblock heparin-binding copolymer (HBC) that can neutralize the anticoagulant activity of parenteral anticoagulants. In the present study, we explored the safety profile of HBC and its potential to reverse enoxaparin, nadroparin, dalteparin, and tinzaparin in human plasma and at in vivo conditions. HBC-LMWHs complexes were characterized using zeta potential, isothermal titration calorimetry, and dynamic light scattering. The rat cardiomyocytes and human endothelial cells were used for the assessment of in vitro toxicity. Male Wistar rats were observed for up to 4 days after HBC administration for clinical evaluation, gross necropsy, and biochemistry and histopathological analysis. Rats were treated with LMWHs alone or followed by short-time intravenous infusion of HBC, and bleeding time and anti-factor Xa activity were measured. HBC completely reversed anti-factor Xa activity prolonged in vitro by all LMWHs with an optimal weight ratio of 2.5:1. The complexes of HBC-LMWHs were below 5 µm. We observed no effects on the viability of cardiovascular cells treated with HBC at concentrations up to 0.05 mg/mL. Single doses up to 20 mg/kg of HBC were well-tolerated by rats. HBC completely reversed the effects of LMWHs on bleeding time and anti-factor Xa activity in vivo after 20 minutes, and retained ~80% and ~60% of reversal activity after 1 hour and 2 hours, respectively. Well-documented efficacy and safety of HBC both in vitro and in vivo make this polymer a promising candidate for LMWHs reversal. SIGNIFICANCE STATEMENT: Over the last decade, there has been significant progress in developing antidotes for the reversal of anticoagulants. Until now, there is no effective and safe treatment for patients with severe bleeding under low-molecular-weight heparin therapy. Based on our in vitro and in vivo studies, heparin-binding copolymer seems to be a promising candidate for neutralizing all clinically relevant low-molecular-weight heparins.

ACS Style

Bartlomiej Kalaska; Joanna Miklosz; Kamil Kamiński; Justyna Swieton; Aleksandra Jakimczuk; Shin-Ichi Yusa; Dariusz Pawlak; Maria Nowakowska; Krzysztof Szczubiałka; Andrzej Mogielnicki. Heparin-Binding Copolymer as a Complete Antidote for Low-Molecular-Weight Heparins in Rats. Journal of Pharmacology and Experimental Therapeutics 2020, 373, 51 -61.

AMA Style

Bartlomiej Kalaska, Joanna Miklosz, Kamil Kamiński, Justyna Swieton, Aleksandra Jakimczuk, Shin-Ichi Yusa, Dariusz Pawlak, Maria Nowakowska, Krzysztof Szczubiałka, Andrzej Mogielnicki. Heparin-Binding Copolymer as a Complete Antidote for Low-Molecular-Weight Heparins in Rats. Journal of Pharmacology and Experimental Therapeutics. 2020; 373 (1):51-61.

Chicago/Turabian Style

Bartlomiej Kalaska; Joanna Miklosz; Kamil Kamiński; Justyna Swieton; Aleksandra Jakimczuk; Shin-Ichi Yusa; Dariusz Pawlak; Maria Nowakowska; Krzysztof Szczubiałka; Andrzej Mogielnicki. 2020. "Heparin-Binding Copolymer as a Complete Antidote for Low-Molecular-Weight Heparins in Rats." Journal of Pharmacology and Experimental Therapeutics 373, no. 1: 51-61.

Review article
Published: 01 January 2020 in International Journal of Tryptophan Research
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Impaired kidney function and increased inflammatory process occurring in the course of Chronic Kidney Disease (CKD) contribute to the development of complex amino-acid alterations. The essential amino-acid tryptophan (TRP) undergoes extensive metabolism along several pathways, resulting in the production of many biologically active compounds. The results of many studies have shown that its metabolism via the kynurenine pathway is potently increased in the course of CKD. Metabolites of this pathway exhibit differential, sometimes opposite, roles in several biological processes. Their accumulation in the course of CKD may induce oxidative cell damage which stimulates inflammatory processes. They can also modulate the activity of numerous cellular signaling pathways through activation of the aryl hydrocarbon receptor, leading to the disruption of homeostasis of various organs. As a result, they can contribute to the development of the systemic disorders accompanying the course of chronic renal failure. This review gathers and systematizes reports concerning the knowledge connecting the kynurenine pathway metabolites to systemic disorders accompanying the development of CKD.

ACS Style

Adrian Mor; Bartlomiej Kalaska; Dariusz Pawlak. Kynurenine Pathway in Chronic Kidney Disease: What’s Old, What’s New, and What’s Next? International Journal of Tryptophan Research 2020, 13, 1 .

AMA Style

Adrian Mor, Bartlomiej Kalaska, Dariusz Pawlak. Kynurenine Pathway in Chronic Kidney Disease: What’s Old, What’s New, and What’s Next? International Journal of Tryptophan Research. 2020; 13 ():1.

Chicago/Turabian Style

Adrian Mor; Bartlomiej Kalaska; Dariusz Pawlak. 2020. "Kynurenine Pathway in Chronic Kidney Disease: What’s Old, What’s New, and What’s Next?" International Journal of Tryptophan Research 13, no. : 1.

Journal article
Published: 01 November 2019 in Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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Chronic kidney disease (CKD) is a pathological condition associated with renal osteodystrophy for which there are limited treatment options. Gut-derived serotonin (GDS) is one of the key signaling factors controlling the osteoblast proliferation. Previously, we shown that inhibition of GDS synthesis by LP533401 improved bone mineral status of rats with 5/6 nephrectomy-induced CKD model. Here, we investigated whether the use of LP533401 can modify GDS-dependent molecular pathway involved in osteoblast formation and bone mineralization in CKD rats. The 8-weeks of pharmacological manipulation after a complete CKD development reduced GDS and lead to the advantage of endogenous vitamin D [25(OH)D] over serotonin and parathyroid hormone (PTH) in rats treated with LP533401. The imbalance between GDS - 25(OH)D - PTH resulted in the intensified expression of cAMP- responsive element-binding protein (Creb), whereas the expression of myelocytomatosis oncogene (c-Myc) was simultaneously reduced. This lead to disruption of Foxo1- activating transcription factor 4 (Atf4) complex, and decrease in the expression of the major osteogenic markers. The weakening of excessive osteoblastogenesis was associated with better bone mineral status in all rats with CKD, and especially in LP533401-treated animals. In conclusion, the inhibition of GDS synthesis resulted in the mitigation of osteoblastogenesis observed in CKD, which translated into improvement of bone mineral status. This study provides key mechanistic insights into how modification of GDS-dependent molecular pathway affects bone mineral status in CKD and lays the groundwork for translating the role of functional serotonin signaling in the origin of impaired bone mineral status in patients with CKD.

ACS Style

Dariusz Pawlak; Tomasz Domaniewski; Beata Sieklucka; Magdalena Jakuc; Krystyna Pawlak. Inhibition of peripheral serotonin synthesis by LP533401 and disturbances in calciotropic hormones attenuated excessive osteoblastogenesis with simultaneous improvement of bone mineral status in 5/6 nephrectomized rats. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2019, 1865, 165528 .

AMA Style

Dariusz Pawlak, Tomasz Domaniewski, Beata Sieklucka, Magdalena Jakuc, Krystyna Pawlak. Inhibition of peripheral serotonin synthesis by LP533401 and disturbances in calciotropic hormones attenuated excessive osteoblastogenesis with simultaneous improvement of bone mineral status in 5/6 nephrectomized rats. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2019; 1865 (11):165528.

Chicago/Turabian Style

Dariusz Pawlak; Tomasz Domaniewski; Beata Sieklucka; Magdalena Jakuc; Krystyna Pawlak. 2019. "Inhibition of peripheral serotonin synthesis by LP533401 and disturbances in calciotropic hormones attenuated excessive osteoblastogenesis with simultaneous improvement of bone mineral status in 5/6 nephrectomized rats." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1865, no. 11: 165528.

Journal article
Published: 17 September 2019 in Marine Drugs
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Protamine sulfate (PS) is a polycationic protein drug obtained from the sperm of fish, and is used to reverse the anticoagulant effect of unfractionated heparin (UFH). However, the interactions between PS, UFH, and platelets are still not clear. We measured the platelet numbers and collagen-induced aggregation, P-selectin, platelet factor 4, β-thromboglobulin, prostacyclin metabolite, D-dimers, activated partial thromboplastin time, prothrombin time, anti-factor Xa, fibrinogen, thrombus weight and megakaryocytopoiesis in blood collected from mice and rats in different time points.. All of the groups were treated intravenously with vehicle, UFH, PS, or UFH with PS. We found a short-term antiplatelet activity of PS in mice and rats, and long-term platelet-independent antithrombotic activity in rats with electrically-induced thrombosis. The antiplatelet and antithrombotic potential of PS may contribute to bleeding risk in PS-overdosed patients. The inhibitory effect of PS on the platelets was attenuated by UFH without inducing thrombocytopenia. Treatment with UFH and PS did not affect the formation, number, or activation of platelets, or the thrombosis development in rodents.

ACS Style

Joanna Miklosz; Bartlomiej Kalaska; Kamil Kaminski; Malgorzata Rusak; Krzysztof Szczubialka; Maria Nowakowska; Dariusz Pawlak; Andrzej Mogielnicki. The Inhibitory Effect of Protamine on Platelets is Attenuated by Heparin without Inducing Thrombocytopenia in Rodents. Marine Drugs 2019, 17, 539 .

AMA Style

Joanna Miklosz, Bartlomiej Kalaska, Kamil Kaminski, Malgorzata Rusak, Krzysztof Szczubialka, Maria Nowakowska, Dariusz Pawlak, Andrzej Mogielnicki. The Inhibitory Effect of Protamine on Platelets is Attenuated by Heparin without Inducing Thrombocytopenia in Rodents. Marine Drugs. 2019; 17 (9):539.

Chicago/Turabian Style

Joanna Miklosz; Bartlomiej Kalaska; Kamil Kaminski; Malgorzata Rusak; Krzysztof Szczubialka; Maria Nowakowska; Dariusz Pawlak; Andrzej Mogielnicki. 2019. "The Inhibitory Effect of Protamine on Platelets is Attenuated by Heparin without Inducing Thrombocytopenia in Rodents." Marine Drugs 17, no. 9: 539.

Journal article
Published: 01 September 2019 in Advances in Medical Sciences
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We aimed to determine the effect of quinolinic acid (QA) on hemostasis in rat and mouse models of thrombosis. Wistar rats (male, n = 72) received QA dissolved in drinking water in doses of 3, 10, 30 mg/kg or pure drinking water (vehicle control group -VEH) for 14 days. On the 14th day of the experiment the effect of QA on hemostasis was evaluated using electrically induced arterial thrombosis model. The following parameters were measured: thrombus weight, hematology, thromboelastometric (ROTEM) parameters, TXA2 and 6-keto-PGF1α concentration, coagulation and fibrinolytic markers activity and concentration. GFP mice (male, n = 30) were assigned to the group receiving QA (30 mg/kg) or VEH for 14 days and to the group receiving: single intravenous dose of QA (30 mg/kg) or VEH or the same dose of QA and anti-CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1) antibody conjugated with Alexa Fluor 647. The effect of QA on hemostasis was evaluated in the model of laser-induced injury of mesentery vein using intravital confocal microscopy. Administering QA for 14 days resulted in a divergent, depending on dose, increase in concentration of active form of tPA and PAI-1 and concentration of total PAI-1 and PAP complexes in rats' plasma. In turn, administering QA for 14 days in mice revealed its prothrombotic activity, while single-dose IV administration revealed its antithrombotic activity, through the up-regulation of PECAM-1 expression. We demonstrated the first evidence for the opposite biological effects of QA on hemostasis in rat and mouse thrombosis models.

ACS Style

Agnieszka Leszczyńska; Tomasz Misztal; Natalia Marcińczyk; Tomasz Kamiński; Karol Kramkowski; Ewa Chabielska; Dariusz Pawlak. Effect of quinolinic acid – A uremic toxin from tryptophan metabolism – On hemostatic profile in rat and mouse thrombosis models. Advances in Medical Sciences 2019, 64, 370 -380.

AMA Style

Agnieszka Leszczyńska, Tomasz Misztal, Natalia Marcińczyk, Tomasz Kamiński, Karol Kramkowski, Ewa Chabielska, Dariusz Pawlak. Effect of quinolinic acid – A uremic toxin from tryptophan metabolism – On hemostatic profile in rat and mouse thrombosis models. Advances in Medical Sciences. 2019; 64 (2):370-380.

Chicago/Turabian Style

Agnieszka Leszczyńska; Tomasz Misztal; Natalia Marcińczyk; Tomasz Kamiński; Karol Kramkowski; Ewa Chabielska; Dariusz Pawlak. 2019. "Effect of quinolinic acid – A uremic toxin from tryptophan metabolism – On hemostatic profile in rat and mouse thrombosis models." Advances in Medical Sciences 64, no. 2: 370-380.

Original research
Published: 12 March 2019 in Expert Opinion on Therapeutic Targets
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Background: Klotho is a key regulator of phosphate and Ca2+- transport in the kidney. Recently, we showed that treatment with LP533401 improved bone health in rats with chronic kidney disease (CKD) via the normalization of serum phosphate resulting from the reduced renal expression of phosphate co-transporters, including Klotho. Methods: We evaluated the effect of LP533401 therapy on Klotho-expression dependent Ca2+- transporters, renal calcium handling and the potential consequences for the bone of uremic rats. Results: Treatment with LP533401 and its vehicle, resulted in the inhibition of transient receptor potential vanilloid receptor subtypes 5 and 6 (TRPV5, TRPV6) and calbidin (CaBP-28k, CaBP-9k) expression. The compensatory acceleration in renal expression of Na+/Ca2+-exchanger (NCX1), 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1), the intensification of vitamin D metabolism and disruption of sophisticated balance between 1,25-dihydroxyvitamin D – serotonin was observed, especially in rats treated with LP533401. The imbalance between 1,25-dihydroxyvitamin D – serotonin levels led to intensified bone remodeling and improvement in bone geometry, mineral status and strength in animals treated with LP533401. Conclusion: The modulation of circulating serotonin and its relation to other regulators of calcium handling can play an important role in calcium homeostasis and bone integrity in CKD rats treated with LP533401.

ACS Style

Dariusz Pawlak; Tomasz Domaniewski; Beata Znorko; Krystyna Pawlak. The use of LP533401 as a therapeutic option for renal osteodystrophy affects, renal calcium handling, vitamin D metabolism, and bone health in uremic rats. Expert Opinion on Therapeutic Targets 2019, 23, 353 -364.

AMA Style

Dariusz Pawlak, Tomasz Domaniewski, Beata Znorko, Krystyna Pawlak. The use of LP533401 as a therapeutic option for renal osteodystrophy affects, renal calcium handling, vitamin D metabolism, and bone health in uremic rats. Expert Opinion on Therapeutic Targets. 2019; 23 (4):353-364.

Chicago/Turabian Style

Dariusz Pawlak; Tomasz Domaniewski; Beata Znorko; Krystyna Pawlak. 2019. "The use of LP533401 as a therapeutic option for renal osteodystrophy affects, renal calcium handling, vitamin D metabolism, and bone health in uremic rats." Expert Opinion on Therapeutic Targets 23, no. 4: 353-364.

Journal article
Published: 04 February 2019 in Immunopharmacology and Immunotoxicology
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Objective: Rheumatoid arthritis (RA) is characterized by expansion of fibroblast-like synoviocytes (FLS) in inflamed joints and activation of lymphocytes. Tryptophan (trp) is an essential amino acid indispensable for the biosynthesis of proteins and critical for survival of lymphocytes. Indoleamine 2,3-dioxygenase (IDO) that initiates the degradation of trp and tryptophanyl-tRNA synthetase (TTS) essential for tryptophan synthesis, regulate trp bioavailability. Here, we tested the hypothesis that triggered by cytokines, enhanced IDO activity modulate regulatory function of otherwise non-tolerogenic FLS isolated from RA patients. Materials and methods: IDO and TTS mRNA expression were evaluated by RT-PCR. IDO enzymatic activity was confirmed using HPLC. Resting or PHA-activated PBMC from healthy volunteers and RA patients were co-cultured with IDO expressing untreated (FLSC) or IFNγ-treated (FLSIFNγ) RA FLS. Lymphocyte survival and proliferation were evaluated by flow cytometry analysis and tritiated thymidine incorporation, respectively. Results: RA FLSIFNγ produce functionally active IDO and constitutively express TTS. RA FLSC and FLSIFNγ increased survival of resting lymphocytes in both studied groups, and decreased proliferation of healthy, but not RA, PBMC. Only FLSIFNγ diminished survival of activated CD3+CD4-, but not CD3+CD4+, healthy T cells and similar tendency was observed in rheumatoid cells. Importantly, IDO inhibitor, 1-methyl-DL-tryptophan (1-MT), failed to reverse this effect. PBMC, irrespective of their state (resting versus activated) or origin (healthy or RA), expressed high level of TTS mRNA. Conclusions: We suggest that RA FLS express functionally active IDO but control survival and expansion of healthy cells in IDO-independent mechanism and exert weaker, if any, suppressive effect on rheumatoid cells.

ACS Style

Magdalena Massalska; Ewa Kuca-Warnawin; Iwona Janicka; Magdalena Plebanczyk; Dariusz Pawlak; Tomas Dallos; Anna Olwert; Anna Radzikowska; Pawel Maldyk; Ewa Kontny; Włodzimierz Maśliński. Survival of lymphocytes is not restricted by IDO-expressing fibroblast from rheumatoid arthritis patients. Immunopharmacology and Immunotoxicology 2019, 41, 214 -223.

AMA Style

Magdalena Massalska, Ewa Kuca-Warnawin, Iwona Janicka, Magdalena Plebanczyk, Dariusz Pawlak, Tomas Dallos, Anna Olwert, Anna Radzikowska, Pawel Maldyk, Ewa Kontny, Włodzimierz Maśliński. Survival of lymphocytes is not restricted by IDO-expressing fibroblast from rheumatoid arthritis patients. Immunopharmacology and Immunotoxicology. 2019; 41 (2):214-223.

Chicago/Turabian Style

Magdalena Massalska; Ewa Kuca-Warnawin; Iwona Janicka; Magdalena Plebanczyk; Dariusz Pawlak; Tomas Dallos; Anna Olwert; Anna Radzikowska; Pawel Maldyk; Ewa Kontny; Włodzimierz Maśliński. 2019. "Survival of lymphocytes is not restricted by IDO-expressing fibroblast from rheumatoid arthritis patients." Immunopharmacology and Immunotoxicology 41, no. 2: 214-223.

Nephrology original paper
Published: 07 January 2019 in International Urology and Nephrology
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Indoxyl sulfate (IS) is one of the most potent uremic toxins involved in chronic kidney disease (CKD) progression, induction of inflammation, oxidative stress, and cardiovascular diseases occurrence. It is proved that hypertension is a common CVD complication and a major death risk factor as well as contributes for decline in a renal function. The aim of our study was to investigate how implementing of antihypertensive therapy impact IS concentrations and the associations between IS and markers of renal function, inflammation and oxidative stress. Study was conducted on 50 patients diagnosed with CKD and hypertension, divided into three groups: without hypotensive therapy (CKD-NONE), hypotensive monotherapy (CKD-MONO), and hypotensive polypharmacotherapy (CKD-POLI), and 18 healthy volunteers. The markers of inflammation [interleukin-6, tumor necrosis factor-alpha (TNF-α), high-sensitive C-reactive protein (hs-CRP), neopterin, ferritin], oxidative status [superoxide dismutase (Cu/Zn-SOD), antibodies against oxidized low-density lipoprotein (oxLDL-abs)], and selectins were determinate using immunoenzymatic methods. IS levels were assayed using high-performance liquid chromatography and other parameters were analysed using routine laboratory techniques. Then cross-sectional analysis was performed. Elevated levels of IS, indicators of kidney function, markers of inflammation and blood pressure values were observed in each CKD subgroups. There was no effect of antihypertensive therapy on IS levels between studied groups, as well as there was no clear relationship between IS and blood pressure values in each studied group. The positive associations between IS and Cu/Zn SOD, neopterin, hs-CRP, creatinine and neutrophils/lymphocytes ratio were observed in CKD-NONE and CKD-POLI subgroups. Additionally, in CKD-POLI group IS positively correlated with TNF-α, ferritin and neutrophils. In CKD-MONO group, IS was positively related to oxLDL-abs, neopterin, E-selectin and creatinine, whereas it was inversely associated with hs-CRP. Our study showed for the first time that the antihypertensive therapy has no impact on IS levels in CKD patients with hypertension. However, the introduction of the antihypertensive therapy modified the dependencies between IS and the studied markers of kidney function, inflammation, oxidative stress and hematological parameters that are crucial for mortality and morbidity amongst the CKD patients with hypertension.

ACS Style

Tomasz W. Kaminski; Krystyna Pawlak; Malgorzata Karbowska; Beata Znorko; Adrian L. Mor; Michal Mysliwiec; Dariusz Pawlak. The impact of antihypertensive pharmacotherapy on interplay between protein-bound uremic toxin (indoxyl sulfate) and markers of inflammation in patients with chronic kidney disease. International Urology and Nephrology 2019, 51, 491 -502.

AMA Style

Tomasz W. Kaminski, Krystyna Pawlak, Malgorzata Karbowska, Beata Znorko, Adrian L. Mor, Michal Mysliwiec, Dariusz Pawlak. The impact of antihypertensive pharmacotherapy on interplay between protein-bound uremic toxin (indoxyl sulfate) and markers of inflammation in patients with chronic kidney disease. International Urology and Nephrology. 2019; 51 (3):491-502.

Chicago/Turabian Style

Tomasz W. Kaminski; Krystyna Pawlak; Malgorzata Karbowska; Beata Znorko; Adrian L. Mor; Michal Mysliwiec; Dariusz Pawlak. 2019. "The impact of antihypertensive pharmacotherapy on interplay between protein-bound uremic toxin (indoxyl sulfate) and markers of inflammation in patients with chronic kidney disease." International Urology and Nephrology 51, no. 3: 491-502.