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Article: Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy.

Ciwun, Marianna / Tankiewicz-Kwedlo, Anna / Pawlak, Dariusz

2024 Volume 16, Issue 6

Abstract: Naltrexone (NTX) is a non-selective antagonist of opioid receptors, primarily used in the therapy of opioid and alcohol dependence. Low-dose naltrexone (LDN) exhibits antagonistic action against the opioid growth factor receptor (OGFr), whose signaling ... ...

Abstract	Naltrexone (NTX) is a non-selective antagonist of opioid receptors, primarily used in the therapy of opioid and alcohol dependence. Low-dose naltrexone (LDN) exhibits antagonistic action against the opioid growth factor receptor (OGFr), whose signaling is associated with the survival, proliferation, and invasion of cancer cells. The mechanism of action of LDN depends on the dose and duration of the OGFr blockade, leading to a compensatory increase in the synthesis of the opioid growth factor (OGF), which has an inhibitory effect on carcinogenesis. Numerous studies on in vitro and in vivo models provide evidence of LDN's positive impact on inhibiting the OGF-OGFr axis in cancers. LDN's unique mechanism of action on cancer cells, lack of direct cytotoxic effect, and immunomodulating action form the basis for its use as an adjuvant in chemotherapy and immunotherapy of cancerous lesions.
Language	English
Publishing date	2024-03-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16061240
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Dose-dependent exposure to indoxyl sulfate alters AHR signaling, sirtuins gene expression, oxidative DNA damage, and bone mineral status in rats.

Karbowska, Malgorzata / Pawlak, Krystyna / Sieklucka, Beata / Domaniewski, Tomasz / Lebkowska, Urszula / Zawadzki, Radoslaw / Pawlak, Dariusz

Scientific reports

2024 Volume 14, Issue 1, Page(s) 2583

Abstract: Indoxyl sulfate (IS), an agonist of aryl hydrocarbon receptors (AhR), can accumulate in patients with chronic kidney disease, but its direct effect on bone is not clear. The present study investigated the effect of chronic exposure to low (100 mg/kg b.w.; ...

Abstract	Indoxyl sulfate (IS), an agonist of aryl hydrocarbon receptors (AhR), can accumulate in patients with chronic kidney disease, but its direct effect on bone is not clear. The present study investigated the effect of chronic exposure to low (100 mg/kg b.w.; 100 IS) and high (200 mg/kg b.w.; 200 IS) dose of IS on bone AhR pathway, sirtuins (SIRTs) expression, oxidative DNA damage and bone mineral status in Wistar rats. The accumulation of IS was observed only in trabecular bone tissue in both doses. The differences were observed in the bone parameters, depending on the applied IS dose. The exposure to 100 IS increased AhR repressor (AhRR)-CYP1A2 gene expression, which was associated with SIRT-1, SIRT-3 and SIRT-7 expression. At the low dose group, the oxidative DNA damage marker was unchanged in the bone samples, and it was inversely related to the abovementioned SIRTs expression. In contrast, the exposure to 200 IS reduced the expression of AhRR, CYP1A, SIRT-3 and SIRT-7 genes compared to 100 IS. The level of oxidative DNA damage was higher in trabecular bone in 200 IS group. Femoral bone mineral density was decreased, and inverse relations were noticed between the level of trabecular oxidative DNA damage and parameters of bone mineral status. In conclusion, IS modulates AhR-depending signaling affecting SIRTs expression, oxidative DNA damage and bone mineral status in a dose dependent manner.
MeSH term(s)	Humans ; Rats ; Animals ; Indican ; Rats, Wistar ; Receptors, Aryl Hydrocarbon/metabolism ; Oxidative Stress ; Gene Expression ; Sirtuins/genetics ; Sirtuins/metabolism
Chemical Substances	Indican (N187WK1Y1J) ; Receptors, Aryl Hydrocarbon ; Sirtuins (EC 3.5.1.-)
Language	English
Publishing date	2024-01-31
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-53164-3
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Article: Modern Immunotherapy in the Treatment of Triple-Negative Breast Cancer.

Wesolowski, Jakub / Tankiewicz-Kwedlo, Anna / Pawlak, Dariusz

Cancers

2022 Volume 14, Issue 16

Abstract: Triple-Negative Breast Cancer is a subtype of breast cancer characterized by the lack of expression of estrogen receptors, progesterone receptors, as well as human epidermal growth factor receptor 2. This cancer accounts for 15-20% of all breast cancers ... ...

Abstract	Triple-Negative Breast Cancer is a subtype of breast cancer characterized by the lack of expression of estrogen receptors, progesterone receptors, as well as human epidermal growth factor receptor 2. This cancer accounts for 15-20% of all breast cancers and is especially common in patients under 40 years of age, as well as with the occurring BRCA1 mutation. Its poor prognosis is reflected in the statistical life expectancy of 8-15 months after diagnosis of metastatic TNBC. So far, the lack of targeted therapy has narrowed therapeutic possibilities to classic chemotherapy. The idea behind the use of humanized monoclonal antibodies, as inhibitors of immunosuppressive checkpoints used by the tumor to escape from immune system control, is to reduce immunotolerance and direct an intensified anti-tumor immune response. An abundance of recent studies has provided numerous pieces of evidence about the safety and clinical benefits of immunotherapy using humanized monoclonal antibodies in the fight against many types of cancer, including TNBC. In particular, phase three clinical trials, such as the IMpassion 130, the KEYNOTE-355 and the KEYNOTE-522 resulted in the approval of immunotherapeutic agents, such as atezolizumab and pembrolizumab by the US Food and Drug Administration in TNBC therapy. This review aims to present the huge potential of immunotherapy using monoclonal antibodies directed against immunosuppressive checkpoints-such as atezolizumab, avelumab, durvalumab, pembrolizumab, nivolumab, cemiplimab, tremelimumab, ipilimumab-in the fight against difficult to treat TNBCs as monotherapy as well as in more advanced combination strategies.
Language	English
Publishing date	2022-08-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14163860
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Article ; Online: Vitamin K-Dependent Carboxylation of Osteocalcin in Bone-Ally or Adversary of Bone Mineral Status in Rats with Experimental Chronic Kidney Disease?

Ziemińska, Marta / Pawlak, Dariusz / Sieklucka, Beata / Chilkiewicz, Katarzyna / Pawlak, Krystyna

Nutrients

2022 Volume 14, Issue 19

Abstract: Chronic kidney disease (CKD) commonly occurs with vitamin K (VK) deficiency and impaired bone mineralization. However, there are no data explaining the metabolism of endogenous VK and its role in bone mineralization in CKD. In this study, we measured ... ...

Abstract	Chronic kidney disease (CKD) commonly occurs with vitamin K (VK) deficiency and impaired bone mineralization. However, there are no data explaining the metabolism of endogenous VK and its role in bone mineralization in CKD. In this study, we measured serum levels of phylloquinone (VK1), menaquinone 4 and 7 (MK4, MK7), and VK-dependent proteins: osteocalcin, undercarboxylated osteocalcin (Glu-OC), and undercarboxylated matrix Gla protein (ucMGP). The carboxylated osteocalcin (Gla-OC), Glu-OC, and the expression of genes involved in VK cycle were determined in bone. The obtained results were juxtaposed with the bone mineral status of rats with CKD. The obtained results suggest that the reduced VK1 level observed in CKD rats may be caused by the accelerated conversion of VK1 to the form of menaquinones. The bone tissue possesses all enzymes, enabling the conversion of VK1 to menaquinones and VK recycling. However, in the course of CKD with hyperparathyroidism, the intensified osteoblastogenesis causes the generation of immature osteoblasts with impaired mineralization. The particular clinical significance seems to have a finding that serum osteocalcin and Glu-OC, commonly used biomarkers of VK deficiency, could be inappropriate in CKD conditions, whereas Gla-OC synthesized in bone appears to have an adverse impact on bone mineral status in this model.
MeSH term(s)	Animals ; Biomarkers ; Bone and Bones/metabolism ; Minerals/metabolism ; Osteocalcin ; Rats ; Renal Insufficiency, Chronic/complications ; Vitamin K ; Vitamin K 1 ; Vitamin K 2 ; Vitamin K Deficiency/etiology
Chemical Substances	Biomarkers ; Minerals ; Osteocalcin (104982-03-8) ; Vitamin K 2 (11032-49-8) ; Vitamin K (12001-79-5) ; Vitamin K 1 (84-80-0)
Language	English
Publishing date	2022-10-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14194082
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Article ; Online: Bruton's Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials.

Rozkiewicz, Dariusz / Hermanowicz, Justyna Magdalena / Kwiatkowska, Iwona / Krupa, Anna / Pawlak, Dariusz

Molecules (Basel, Switzerland)

2023 Volume 28, Issue 5

Abstract: In the last few decades, there has been a growing interest in Bruton's tyrosine kinase (BTK) and the compounds that target it. BTK is a downstream mediator of the B-cell receptor (BCR) signaling pathway and affects B-cell proliferation and ... ...

Abstract	In the last few decades, there has been a growing interest in Bruton's tyrosine kinase (BTK) and the compounds that target it. BTK is a downstream mediator of the B-cell receptor (BCR) signaling pathway and affects B-cell proliferation and differentiation. Evidence demonstrating the expression of BTK on the majority of hematological cells has led to the hypothesis that BTK inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias and lymphomas. However, a growing body of experimental and clinical data has demonstrated the significance of BTK, not just in B-cell malignancies, but also in solid tumors, such as breast, ovarian, colorectal, and prostate cancers. In addition, enhanced BTK activity is correlated with autoimmune disease. This gave rise to the hypothesis that BTK inhibitors can be beneficial in the therapy of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren's syndrome (SS), allergies, and asthma. In this review article, we summarize the most recent findings regarding this kinase as well as the most advanced BTK inhibitors that have been developed to date and their clinical applications mainly in cancer and chronic inflammatory disease patients.
MeSH term(s)	Humans ; Agammaglobulinaemia Tyrosine Kinase/metabolism ; Autoimmune Diseases/drug therapy ; Signal Transduction ; Tyrosine Kinase Inhibitors/pharmacology ; Neoplasms/drug therapy
Chemical Substances	Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2) ; Tyrosine Kinase Inhibitors
Language	English
Publishing date	2023-03-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules28052400
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Article ; Online: 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.

Pawlak, Krystyna / Sieklucka, Beata / Pawlak, Dariusz

International journal of molecular sciences

2021 Volume 22, Issue 12

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Activating Transcription Factor 4/metabolism ; Animals ; Cancellous Bone/metabolism ; Cortical Bone/metabolism ; Cyclic AMP/metabolism ; Femur/metabolism ; Kynurenine/metabolism ; Male ; Paracrine Communication ; Parathyroid Hormone/metabolism ; Rats ; Rats, Wistar ; Receptor, Parathyroid Hormone, Type 1/metabolism ; Signal Transduction ; Uremia/metabolism
Chemical Substances	Atf4 protein, rat ; Parathyroid Hormone ; Pth1r protein, rat ; Receptor, Parathyroid Hormone, Type 1 ; Activating Transcription Factor 4 (145891-90-3) ; Kynurenine (343-65-7) ; Cyclic AMP (E0399OZS9N)
Language	English
Publishing date	2021-06-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22126563
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Article ; Online: Evaluation of Plasma Concentrations of Galectins-1, 2 and 12 in Psoriasis and Their Clinical Implications.

Nowowiejska, Julia / Baran, Anna / Hermanowicz, Justyna Magdalena / Sieklucka, Beata / Pawlak, Dariusz / Flisiak, Iwona

Biomolecules

2023 Volume 13, Issue 10

Abstract: Psoriasis is a complex disease that nowadays is considered not only a dermatosis but a kind of systemic disorder associated with many accompanying diseases. Metabolic complications leading to cardiovascular incidences are the cause of increased mortality ...

Abstract	Psoriasis is a complex disease that nowadays is considered not only a dermatosis but a kind of systemic disorder associated with many accompanying diseases. Metabolic complications leading to cardiovascular incidences are the cause of increased mortality in psoriatic patients. Galectins (gal) are beta-galactoside-binding lectins that exert different functions, including engagement in metabolic processes. Our aim was to assess the concentrations of gal-1, 2 and 12 in psoriatics, to establish their potential clinical implications, including in metabolic complications. Plasma galectins were assessed by ELISA in 60 psoriatic patients and 30 controls without dermatoses and a negative family history of psoriasis. Plasma concentrations of all galectins were significantly higher in patients than controls (gal-1 with
MeSH term(s)	Humans ; Galectin 3/metabolism ; Galectins/metabolism ; Galectin 2 ; Psoriasis ; Metabolic Diseases
Chemical Substances	1-nitrohydroxyphenyl-N-benzoylalanine (59921-69-6) ; Galectin 3 ; Galectins ; Galectin 2
Language	English
Publishing date	2023-09-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13101472
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Article: Kynurenines as a Novel Target for the Treatment of Malignancies.

Mor, Adrian / Tankiewicz-Kwedlo, Anna / Pawlak, Dariusz

Pharmaceuticals (Basel, Switzerland)

2021 Volume 14, Issue 7

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2021-06-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph14070606
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Article: The Possible Effect of β-Blocker Use on the Circulating MMP-2/TIMP-2 System in Patients with Chronic Kidney Disease on Conservative Treatment.

Kopańko, Magdalena / Zabłudowska, Magdalena / Pawlak, Dariusz / Sieklucka, Beata / Krupa, Anna / Sokołowska, Katarzyna / Ziemińska, Marta / Pawlak, Krystyna

Journal of clinical medicine

2024 Volume 13, Issue 7

Abstract: ... ...

Abstract	Background
Language	English
Publishing date	2024-03-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm13071847
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Article: Gasdermin B (GSDMB) in psoriatic patients-a preliminary comprehensive study on human serum, urine and skin.

Nowowiejska, Julia / Baran, Anna / Pryczynicz, Anna / Hermanowicz, Justyna Magdalena / Sieklucka, Beata / Pawlak, Dariusz / Flisiak, Iwona

Frontiers in molecular biosciences

2024 Volume 11, Page(s) 1382069

Abstract: Psoriasis is one of the most common skin diseases and a crucial issue to manage in contemporary dermatology. The search for the details of its pathogenesis, markers and treatment is continuously ongoing. Our aim was to investigate the role of gasdermin B ...

Abstract	Psoriasis is one of the most common skin diseases and a crucial issue to manage in contemporary dermatology. The search for the details of its pathogenesis, markers and treatment is continuously ongoing. Our aim was to investigate the role of gasdermin B (GSDMB) in psoriasis, the second protein from the gasdermin family, involved in cell death and proliferation. GSDMB serum and urinary concentrations have never been studied in psoriatics, neither tissue expression of GSDMB by immunohistochemistry. The study included 60 psoriatic patients and 30 volunteers without dermatoses as controls. The serum and urinary GSDMB were evaluated by ELISA. Tissue expression of GSDMB was analyzed by immunohistochemistry. The serum and absolute urine concentrations of GSDMB were significantly higher in psoriatic patients than controls without skin diseases (
Language	English
Publishing date	2024-04-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2024.1382069
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