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Article ; Online: GPR39: An orphan receptor begging for ligands.

Doboszewska, Urszula / Maret, Wolfgang / Wlaź, Piotr

2023 Volume 29, Issue 2, Page(s) 103861

Abstract: Progress in the understanding of the receptor GPR39 is held up by inconsistent pharmacological data. First, the endogenous ligand(s) remain(s) contentious. Data pointing to zinc ions ( ... ...

Abstract	Progress in the understanding of the receptor GPR39 is held up by inconsistent pharmacological data. First, the endogenous ligand(s) remain(s) contentious. Data pointing to zinc ions (Zn
MeSH term(s)	Ligands ; Drug Inverse Agonism ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Carrier Proteins
Chemical Substances	Ligands ; Receptors, G-Protein-Coupled ; Carrier Proteins
Language	English
Publishing date	2023-12-19
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1324988-5
ISSN	1878-5832 ; 1359-6446
ISSN (online)	1878-5832
ISSN	1359-6446
DOI	10.1016/j.drudis.2023.103861
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Zs.A 4725: Show issues

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Article ; Online: GPR39 deorphanization: The long and winding road to eicosanoids and a crosstalk between GPR39 and hedgehog signaling in angiogenesis.

Doboszewska, Urszula / Maret, Wolfgang / Wlaź, Piotr

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 28, Page(s) e2308227120

MeSH term(s)	Hedgehog Proteins ; Signal Transduction ; Receptors, G-Protein-Coupled/genetics ; Eicosanoids
Chemical Substances	Hedgehog Proteins ; Receptors, G-Protein-Coupled ; Eicosanoids
Language	English
Publishing date	2023-07-03
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2308227120
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Zs.A 1148: Show issues

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Article ; Online: Role of Adipose Tissue Hormones in Pathogenesis of Cryptoglandular Anal Fistula.

Włodarczyk, Marcin / Włodarczyk, Jakub / Maryńczak, Kasper / Waśniewska-Włodarczyk, Anna / Doboszewska, Urszula / Wlaź, Piotr / Dziki, Łukasz / Fichna, Jakub

International journal of molecular sciences

2024 Volume 25, Issue 3

Abstract: The cryptoglandular perianal fistula is a common benign anorectal disorder that is managed mainly with surgery and in some cases may be an extremely challenging condition. Perianal fistulas are often characterized by significantly decreased patient ... ...

Abstract	The cryptoglandular perianal fistula is a common benign anorectal disorder that is managed mainly with surgery and in some cases may be an extremely challenging condition. Perianal fistulas are often characterized by significantly decreased patient quality of life. Lack of fully recognized pathogenesis of this disease makes it difficult to treat it properly. Recently, adipose tissue hormones have been proposed to play a role in the genesis of cryptoglandular anal fistulas. The expression of adipose tissue hormones and epithelial-to-mesenchymal transition (EMT) factors were characterized based on 30 samples from simple fistulas and 30 samples from complex cryptoglandular perianal fistulas harvested during surgery. Tissue levels of leptin, resistin, MMP2, and MMP9 were significantly elevated in patients who underwent operations due to complex cryptoglandular perianal fistulas compared to patients with simple fistulas. Adiponectin and E-cadherin were significantly lowered in samples from complex perianal fistulas in comparison to simple fistulas. A negative correlation between leptin and E-cadherin levels was observed. Resistin and MMP2 levels, as well as adiponectin and E-cadherin levels, were positively correlated. Complex perianal cryptoglandular fistulas have a reduced level of the anti-inflammatory adipokine adiponectin and have an increase in the levels of proinflammatory resistin and leptin. Abnormal secretion of these adipokines may affect the integrity of the EMT in the fistula tract. E-cadherin, MMP2, and MMP9 expression levels were shifted in patients with more advanced and complex perianal fistulas. Our results supporting the idea of using mesenchymal stem cells in the treatment of cryptoglandular perianal fistulas seem reasonable, but further studies are warranted.
MeSH term(s)	Humans ; Leptin ; Resistin ; Matrix Metalloproteinase 2 ; Matrix Metalloproteinase 9 ; Treatment Outcome ; Quality of Life ; Adiponectin ; Rectal Fistula/etiology ; Adipose Tissue/metabolism ; Cadherins
Chemical Substances	Leptin ; Resistin ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Adiponectin ; Cadherins
Language	English
Publishing date	2024-01-25
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/ijms25031501
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Article ; Online: GPCR oligomerization as a target for antidepressants: Focus on GPR39.

Mlyniec, Katarzyna / Siodłak, Dominika / Doboszewska, Urszula / Nowak, Gabriel

Pharmacology & therapeutics

2021 Volume 225, Page(s) 107842

Abstract: At present most of the evidence for the relevance of oligomerization for the pharmacology of depression comes from in vitro studies which identified oligomers, and from neuropsychopharmacological studies of receptors which participate in oligomerization. ...

Abstract	At present most of the evidence for the relevance of oligomerization for the pharmacology of depression comes from in vitro studies which identified oligomers, and from neuropsychopharmacological studies of receptors which participate in oligomerization. For example, behavioural and biochemical studies in knockout animals suggest that GPR39 may mediate the antidepressant action of monoaminergic antidepressants. We have recently found long-lasting antidepressant-like effects of GPR39 agonist, thus suggesting GPR39 as a target for the development of novel antidepressant drugs. In vitro studies have shown that GPR39 oligomerizes with other GPCRs. Oligomerization of GPR39 should thus be considered in relation to the development of new antidepressants targeting this receptor as well as antidepressants targeting other receptors that may form complexes with GPR39. Here, we summarize recent data suggestive of the importance of oligomerization for the pharmacology of depression and discuss approaches for validation of this phenomenon.
MeSH term(s)	Animals ; Antidepressive Agents/pharmacology ; Receptors, G-Protein-Coupled
Chemical Substances	Antidepressive Agents ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2021-03-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2021.107842
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Zs.A 1183: Show issues

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Article ; Online: Salvinorin A Does Not Affect Seizure Threshold in Mice.

Socała, Katarzyna / Doboszewska, Urszula / Wlaź, Piotr

Molecules (Basel, Switzerland)

2020 Volume 25, Issue 5

Abstract: The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid ...

Abstract	The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1-10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.
MeSH term(s)	Animals ; Diterpenes, Clerodane/adverse effects ; Diterpenes, Clerodane/pharmacology ; Drug Evaluation, Preclinical ; Electroshock/adverse effects ; Injections, Intravenous ; Male ; Mice ; Muscle, Skeletal/drug effects ; Pentylenetetrazole/administration & dosage ; Pentylenetetrazole/toxicity ; Seizures/drug therapy ; Seizures/etiology
Chemical Substances	Diterpenes, Clerodane ; salvinorin A (T56W91NG6J) ; Pentylenetetrazole (WM5Z385K7T)
Language	English
Publishing date	2020-03-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules25051204
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Zs.MO 81: Show issues

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Article ; Online: Targeting zinc metalloenzymes in coronavirus disease 2019.

Doboszewska, Urszula / Wlaź, Piotr / Nowak, Gabriel / Młyniec, Katarzyna

British journal of pharmacology

2020 Volume 177, Issue 21, Page(s) 4887–4898

Abstract: Several lines of evidence support a link between the essential element zinc and the coronavirus disease 2019 (COVID-19). An important fact is that zinc is present in proteins of humans and of viruses. Some zinc sites in viral enzymes may serve as drug ... ...

Abstract	Several lines of evidence support a link between the essential element zinc and the coronavirus disease 2019 (COVID-19). An important fact is that zinc is present in proteins of humans and of viruses. Some zinc sites in viral enzymes may serve as drug targets and may liberate zinc ions, thus leading to changes in intracellular concentration of zinc ions, while increased intracellular zinc may induce biological effects in both the host and the virus. Drugs such as chloroquine may contribute to increased intracellular zinc. Moreover, clinical trials on the use of zinc alone or in addition to other drugs in the prophylaxis/treatment of COVID-19 are ongoing. Thereby, we aim to discuss the rationale for targeting zinc metalloenzymes as a new strategy for the treatment of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.
MeSH term(s)	Betacoronavirus/isolation & purification ; COVID-19 ; Chloroquine/pharmacology ; Coronavirus Infections/drug therapy ; Coronavirus Infections/enzymology ; Coronavirus Infections/virology ; Enzymes/metabolism ; Humans ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/enzymology ; Pneumonia, Viral/virology ; SARS-CoV-2 ; Zinc/metabolism ; COVID-19 Drug Treatment
Chemical Substances	Enzymes ; Chloroquine (886U3H6UFF) ; Zinc (J41CSQ7QDS)
Keywords	covid19
Language	English
Publishing date	2020-08-17
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.15199
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Article ; Online: Salvinorin A Does Not Affect Seizure Threshold in Mice

Katarzyna Socała / Urszula Doboszewska / Piotr Wlaź

Molecules, Vol 25, Iss 5, p

2020 Volume 1204

Abstract	The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1−10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.
Keywords	salvinorin a ; κ-opioid receptor ; seizure threshold ; anticonvulsant ; proconvulsant ; Organic chemistry ; QD241-441
Subject code	616
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Purinergic transmission in depressive disorders.

Szopa, Aleksandra / Socała, Katarzyna / Serefko, Anna / Doboszewska, Urszula / Wróbel, Andrzej / Poleszak, Ewa / Wlaź, Piotr

Pharmacology & therapeutics

2021 Volume 224, Page(s) 107821

Abstract: Purinergic signaling involves the actions of purine nucleotides and nucleosides (such as adenosine) at P1 (adenosine), P2X, and P2Y receptors. Here, we present recent data contributing to a comprehensive overview of the association between purinergic ... ...

Abstract	Purinergic signaling involves the actions of purine nucleotides and nucleosides (such as adenosine) at P1 (adenosine), P2X, and P2Y receptors. Here, we present recent data contributing to a comprehensive overview of the association between purinergic signaling and depression. We start with background information on adenosine production and metabolism, followed by a detailed characterization of P1 and P2 receptors, with an emphasis on their expression and function in the brain as well as on their ligands. We provide data suggestive of altered metabolism of adenosine in depressed patients, which might be regarded as a disease biomarker. We then turn to considerable amount of preclinical/behavioral data obtained with the aid of the forced swim test, tail suspension test, learned helplessness model, or unpredictable chronic mild stress model and genetic activation/inactivation of P1 or P2 receptors as well as nonselective or selective ligands of P1 or P2 receptors. We also aimed to discuss the reason underlying discrepancies observed in such studies.
MeSH term(s)	Depressive Disorder/metabolism ; Humans ; Receptors, Purinergic/metabolism ; Signal Transduction
Chemical Substances	Receptors, Purinergic
Language	English
Publishing date	2021-02-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2021.107821
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Zs.A 1183: Show issues

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Article: Targeting zinc metalloenzymes in coronavirus disease 2019

Doboszewska, Urszula / Wlaz, Piotr / Nowak, Gabriel / Mlyniec, Katarzyna

Br. j. pharmacol

Abstract	Several lines of evidence support a link between the essential element zinc and the coronavirus disease 2019 (COVID-19). An important fact is that zinc is present in proteins of humans and of viruses. Some zinc sites in viral enzymes may serve as drug targets and may liberate zinc ions, thus leading to changes in intracellular concentration of zinc ions, while increased intracellular zinc may induce biological effects in both the host and the virus. Drugs such as chloroquine may contribute to increased intracellular zinc. Moreover, clinical trials on the use of zinc alone or in addition to other drugs in the prophylaxis/treatment of COVID-19 are ongoing. Thereby, we aim to discuss the rationale for targeting zinc metalloenzymes as a new strategy for the treatment of COVID-19.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #646312
Database	COVID19

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Article ; Online: Dietary Zinc Differentially Regulates the Effects of the GPR39 Receptor Agonist, TC-G 1008, in the Maximal Electroshock Seizure Test and Pentylenetetrazole-Kindling Model of Epilepsy.

Doboszewska, Urszula / Socała, Katarzyna / Pieróg, Mateusz / Nieoczym, Dorota / Sawicki, Jan / Sajnóg, Adam / Szewczyk, Bernadeta / Mlyniec, Katarzyna / Sowa, Ireneusz / Barałkiewicz, Danuta / Wlaź, Piotr

Cells

2023 Volume 12, Issue 2

Abstract: The G-protein coupled receptor 39 (GPR39) is gaining increasing attention as a target for future drugs, yet there are gaps in the understanding of its pharmacology. Zinc is an endogenous agonist or an allosteric modulator, while TC-G 1008 is a synthetic, ...

Abstract	The G-protein coupled receptor 39 (GPR39) is gaining increasing attention as a target for future drugs, yet there are gaps in the understanding of its pharmacology. Zinc is an endogenous agonist or an allosteric modulator, while TC-G 1008 is a synthetic, small molecule agonist. Zinc is also a positive allosteric modulator for the activity of TC-G 1008 at GPR39. Activation of GPR39 by TC-G 1008 facilitated the development of epileptogenesis in the pentylenetetrazole (PTZ)-induced kindling model of epilepsy. Congruently, TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure threshold (MEST) test. Here, we investigated the effects of TC-G 1008 under the condition of zinc deficiency. Mice were fed a zinc-adequate diet (ZnA, 50 mg Zn/kg) or a zinc-deficient diet (ZnD, 3 mg Zn/kg) for 4 weeks. Following 4 weeks of dietary zinc restriction, TC-G 1008 was administered as a single dose and the MEST test was performed. Additional groups of mice began the PTZ-kindling model during which TC-G 1008 was administered repeatedly and the diet was continued. TC-G 1008 administered acutely decreased the seizure threshold in the MEST test in mice fed the ZnD diet but not in mice fed the ZnA diet. TC-G 1008 administered chronically increased the maximal seizure severity and the percentage of fully kindled mice in those fed the ZnA diet, but not in mice fed the ZnD diet. Our data showed that the amount of zinc in a diet is a factor contributing to the effects of TC-G 1008 in vivo.
MeSH term(s)	Mice ; Animals ; Pentylenetetrazole ; Electroshock/adverse effects ; Epilepsy/drug therapy ; Seizures/drug therapy ; Receptors, G-Protein-Coupled/agonists ; Zinc
Chemical Substances	Pentylenetetrazole (WM5Z385K7T) ; GPR39-C3 ; Receptors, G-Protein-Coupled ; Zinc (J41CSQ7QDS) ; GPR39 protein, mouse
Language	English
Publishing date	2023-01-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12020264
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