Review
Pharmacology & Pharmacy
Gennady G. Yegutkin
Summary: Extracellular purinergic signaling, led by ATP, ADP, and adenosine, play a crucial role in immunomodulatory, thromboregulatory, angiogenic, and vasoactive activities. Recent studies have highlighted the complexity of regulatory mechanisms and the importance of considering the entire purinome in biological effects. Key enzymes in the adenosine metabolic network, especially purine-converting ectoenzymes, are emerging as novel targets for cancer and vascular therapies.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Paulina Mierzejewska, Noemi Di Marzo, Magdalena A. Zabielska-Kaczorowska, Iga Walczak, Ewa M. Slominska, Marialuisa Lavitrano, Roberto Giovannoni, Barbara Kutryb-Zajac, Ryszard T. Smolenski
Summary: The vascular endothelium is a crucial target for immune and thrombotic responses in xenotransplantation. This study evaluated the effects of simultaneous expression of three human genes on mouse endothelial function. The results showed that the simultaneous expression of these genes had beneficial effects on the biochemical and functional aspects of the endothelium, reducing inflammatory responses and improving endothelial permeability.
Article
Gastroenterology & Hepatology
Karel P. Alcedo, Morgan A. Rouse, Gloria S. Jung, Dong Fu, Marquet Minor, Helen H. Willcockson, Kevin G. Greene, Natasha T. Snider
Summary: The study demonstrates that hepatocyte CD73 supports long-term metabolic liver homeostasis through regulating the AMPK signaling pathway in a sex-dependent manner. CD73-LKO mice develop liver disease after 21 weeks, with more severe symptoms observed in male mice. These findings have implications for human liver diseases marked by CD73 dysregulation.
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2021)
Article
Neurosciences
Francisco Q. Goncalves, Filipe C. Matheus, Henrique B. Silva, Joana I. Real, Daniel Rial, Ricardo J. Rodrigues, Jean-Pierre Oses, Antonio C. Silva, Nelio Goncalves, Rui D. Prediger, Angelo R. Tome, Rodrigo A. Cunha
Summary: The increased release of ATP and the subsequent formation of extracellular adenosine, which activates A(2A)R, play a key role in the abnormal synaptic plasticity associated with the onset of motor symptoms in Parkinson's disease.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Karolina Losenkova, Akira Takeda, Symantas Ragauskas, Marc Cerrada-Gimenez, Maria Vahatupa, Simon Kaja, Marius L. Paul, Constanze C. Schmies, Georg Rolshoven, Christa E. Mueller, Jouko Sandholm, Sirpa Jalkanen, Giedrius Kalesnykas, Gennady G. Yegutkin
Summary: ATP and adenosine play important roles as signaling molecules in vascular remodeling, retinal functioning, and neurovascular coupling in the eye. This study characterized the whole pattern of purine metabolism in mouse and human eyes using various techniques, and identified major ocular ecto-nucleotidases involved in purinergic signaling. The study also highlighted the critical role of CD73 in maintaining the functional activity of retinal cells.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Review
Oncology
Pengcheng Sun, Xiao Zheng, Xiaodong Li
Summary: CD73 is a promising immunotherapy target in GI cancer, and combining it with other therapies can improve prognosis and survival rate.
JOURNAL OF ONCOLOGY
(2022)
Review
Oncology
Maria Saigi, Oscar Mesia-Carbonell, David A. Barbie, Raquel Guillamat-Prats
Summary: CD73 and adenosine are playing important roles in lung cancer research. CD73 is an enzyme that is crucial for the production of adenosine and is found in various cells in the lungs, including immune cells. The expression of CD73 is increased in lung tumor cells, especially in non-small cell lung cancer. Researchers propose targeting CD73 and adenosine to enhance the effectiveness of immune checkpoint inhibitors. CD73 acts as a stop signal for immune cells fighting cancer, and blocking CD73 may amplify treatment effectiveness.
Article
Chemistry, Medicinal
Mirko Scortichini, Riham Mohammed Idris, Susanne Moschuetz, Antje Keim, Veronica Salmaso, Clemens Dobelmann, Paola Oliva, Karolina Losenkova, Heikki Irjala, Samuli Vaittinen, Jouko Sandholm, Gennady G. Yegutkin, Norbert Straeter, Anna Junker, Christa E. Mueller, Kenneth A. Jacobson
Summary: This study expands the structure-activity relationship of pyrimidine nucleotides as human CD73 inhibitors. By N-4-benzyloxy substitution, the inhibitory potency is greatly enhanced and functionality is added, making them potential anticancer drugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Bruna C. Galgaro, Liziane R. Beckenkamp, Martha van den M. Nunnenkamp, Vitoria G. Korb, Liliana I. S. Naasani, Katarzyna Roszek, Marcia R. Wink
Summary: Mesenchymal stem cells (MSCs) have various important functions in tissue homeostasis, damage repair, and immune modulation, and their therapeutic potential is closely related to the CD73/adenosine-mediated signaling pathway. Further research is needed to fully understand the role of CD73 and adenosine in the therapeutic functions of MSCs.
MEDICINAL RESEARCH REVIEWS
(2021)
Review
Biochemistry & Molecular Biology
Herbert Zimmermann
Summary: Geoffrey Burnstock is recognized for establishing a new field of intercellular communication through nucleotide signaling. Purinergic signaling involves intracellular storage, release, extracellular hydrolysis of nucleotides, and their effects on target tissues. Ectonucleotidases play key roles in inactivating nucleotides, generating active hydrolysis products, and facilitating nucleoside recycling.
PURINERGIC SIGNALLING
(2021)
Review
Immunology
Enio Setsuo Arakaki Pacini, Naiara Ayako Satori, Edwin Kerry Jackson, Rosely Oliveira Godinho
Summary: Adenosine modulates inflammation and immune responses via activation of G protein-coupled receptors. In addition to extracellular adenosine generated from the metabolism of extracellular ATP released from damaged cells, there is evidence for the existence of the cAMP-adenosine pathway. The cAMP-adenosine pathway plays a significant role in the efficacy of beta(2)-adrenoceptor agonists in the airways and has potential implications in chronic respiratory inflammatory disorders.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Elisabetta Caiazzo, Ida Cerqua, Roberta Turiello, Maria Antonietta Riemma, Giacomo De Palma, Armando Ialenti, Fiorentina Roviezzo, Silvana Morello, Carla Cicala
Summary: The study demonstrates the important role of CD73 in allergic asthma, with mice lacking CD73 showing different responses to allergens compared to wild type mice, suggesting CD73 as a potential therapeutic target for allergic asthma.
Article
Multidisciplinary Sciences
Daniella A. Lefteri, Steven R. Bryden, Marieke Pingen, Sandra Terry, Emily F. Beswick, Georgi Georgiev, Marleen Van der Laan, Valeria Mastrullo, Paola Campagnolo, Robert Waterhouse, Margus Varjak, Andres Merits, Rennos Fragkoudis, Stephen Griffin, Kave Shams, Emilie Pondeville, Clive S. McKimmie
Summary: Viruses transmitted by Aedes mosquitoes are a significant global cause of disease. The enhancement of virus infection by mosquito saliva is mediated by a gene product called sialokinin, which rapidly reduces endothelial barrier integrity. This mechanism is absent in Anopheles mosquitoes, explaining their incompetence in transmitting arthropod-borne viruses. Therapeutic strategies targeting sialokinin have potential in reducing disease severity following infection with Aedes-mosquito-borne viruses.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Chemistry, Medicinal
Gustavo Machado das Neves, Luciano Porto Kagami, Ana Maria Oliveira Battastini, Fabricio Figueiro, Vera Lucia Eifler-Lima
Summary: Purinergic signaling is being explored as a potential therapeutic approach for cancer treatment. ATP acts as a chemotactic agent and has in vitro antineoplastic activity, while adenosine functions as an immunosuppressor and is associated with neoangiogenesis, vasculogenesis, and evasion from the immune system. Inhibitors of ecto-5'-NT can prevent tumor progression, lower adenosine concentrations, and impede cancer growth by preventing immune system evasion.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Neurosciences
Marija Adzic Bukvic, Danijela Laketa, Milorad Dragic, Irena Lavrnja, Nadezda Nedeljkovic
Summary: In neuroinflammatory states, functionally distinct eN/CD73 glycovariants appear, which may play a role in the development of the reactive astrocyte phenotype.
Article
Biochemistry & Molecular Biology
Marta Tomczyk, Talita Glaser, Henning Ulrich, Ewa M. Slominska, Ryszard T. Smolenski
Summary: This study aims to establish the role of huntingtin protein in cellular energy and nucleotide metabolism in cardiomyocytes. The results show that HTT null cardiomyocytes have decreased intracellular ATP and NAD(+) concentrations, as well as reduced total purines pool and IMP concentrations.
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS
(2022)
Article
Biochemistry & Molecular Biology
Agata Jedrzejewska, Barbara Kutryb-Zajac, Oliwia Krol, Gabriela Harasim, Marika Franczak, Patrycja Jablonska, Ewa Slominska, Ryszard Tomasz Smolenski
Summary: cN-IA activity is decreased in breast cancer patients, potentially due to the presence of specific autoantibodies, suggesting its potential as a biomarker for BC-associated polymyositis.
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS
(2022)
Article
Biochemistry & Molecular Biology
Patrycja Koszalka, Barbara Kutryb-Zajac, Paulina Mierzejewska, Marta Tomczyk, Joanna Wietrzyk, Pawel K. Serafin, Ryszard T. Smolenski, Ewa M. Slominska
Summary: This study found that the metabolic product 4PYR, which accumulates in the blood of cancer patients, promotes lung metastasis through multiple mechanisms. In vivo studies showed that 4PYR did not affect primary tumor growth but facilitated lung metastasis. In vitro studies demonstrated that 4PYR affected extracellular adenine nucleotide metabolism and intracellular energy status, leading to increased permeability of lung ECs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Elzbieta Sucajtys-Szulc, Alicja Debska-Slizien, Boleslaw Rutkowski, Ryszard Milczarek, Marek Szolkiewicz, Julian Swierczynski, Ryszard Tomasz Smolenski
Summary: Chronic kidney disease (CKD) is associated with elevated plasma fibrinogen concentration, with HNF1a gene upregulation leading to increased fibrinogen gene expression. The mRNA levels of liver fibrinogen and HNF1a are closely related to the progression of kidney disease. Decreasing HNF1a gene expression can reduce plasma fibrinogen concentration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Federica Borea, Marika A. Franczak, Maria Garcia, Matteo Perrino, Nadia Cordua, Ryszard T. Smolenski, Godefridus J. Peters, Rafal Dziadziuszko, Armando Santoro, Paolo A. Zucali, Elisa Giovannetti
Summary: Malignant Pleural Mesothelioma (MPM) is a rare neoplasm that is usually diagnosed at an advanced stage and requires systemic treatment due to its ineligibility for radical surgery. Chemotherapy has been the standard treatment for 20 years until immune checkpoint inhibitors were introduced. However, the prognosis remains poor, and targeted therapies for MPM have mostly failed in clinical trials. This review aims to explore the potential reasons for treatment failures and determine the need for further research in this area.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Marika A. Franczak, Oliwia Krol, Gabriela Harasim, Agata Jedrzejewska, Nadia Zaffaroni, Carlotta Granchi, Filippo Minutolo, Amir Avan, Elisa Giovannetti, Ryszard T. Smolenski, Godefridus J. Peters
Summary: Malignant mesothelioma (MM) is a highly aggressive and resistant tumor. In this study, the cytotoxicity of new inhibitors of glucose transporter type 1 (GLUT-1) and lactate dehydrogenase-A (LDH-A) in relation to ATP/NAD+ metabolism, glycolysis and mitochondrial respiration was investigated. The inhibitors showed cytotoxicity in MM cells, associated with a decrease in ATP and NAD+, and were most effective in cells with the highest metabolic modulation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Patrycja Maszka, Magdalena Kwasniak-Butowska, Dominik Cysewski, Jaroslaw Slawek, Ryszard T. Smolenski, Marta Tomczyk
Summary: The prevalence of neurodegenerative diseases (NDs) is increasing due to demographic changes. This review explores the alterations in brain metabolism in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Based on the findings, potential metabolic indicators or predictors of the diseases are proposed. Challenges and future directions of metabolomics studies in NDs are discussed. The integration of metabolomics with other omic techniques may be necessary to achieve clinically applicable results.
Article
Chemistry, Medicinal
Magdalena A. Zabielska-Kaczorowska, Alicja Braczko, Iwona Pelikant-Malecka, Ewa M. Slominska, Ryszard T. Smolenski
Summary: Myocardial ischemia leads to a decrease in adenosine production, which affects its protective functions. This study tested the relationship between cardiac adenine nucleotide pool (TAN) and adenosine production. Results showed that after 1 min ischemia at 85 min, adenosine production decreased to less than 15% of that at 40 min, accompanied by a decrease in ATP and TAN. However, when adenosine was infused after 10 min ischemia, adenosine production was partially restored. These findings suggest that only a fraction of the cardiac adenine nucleotide pool is available for adenosine production.
Article
Cell Biology
Ewelina Czuba-Pakula, Iwona Pelikant-Malecka, Grazyna Lietzau, Slawomir Wojcik, Ryszard T. Smolenski, Przemyslaw Kowianski
Summary: Hypercholesterolemia affects the glycolytic efficiency and energy metabolism of cerebral blood vessel endothelial cells by modulating the activity of nucleotide metabolism-regulating enzymes. This may contribute to the development of neurodegenerative processes.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Agata Jedrzejewska, Ada Kawecka, Alicja Braczko, Marzena Romanowska-Kocejko, Klaudia Stawarska, Milena Deptula, Malgorzata Zawrzykraj, Marika Franczak, Oliwia Krol, Gabriela Harasim, Iga Walczak, Michal Pikula, Marcin Hellmann, Barbara Kutryb-Zajac
Summary: This study investigated the activities of circulating ADA isoenzymes in patients 8 weeks after mild COVID-19 and related them to inflammation and microvascular/endothelial function parameters. The study found that post-COVID patients had microvascular dysfunction associated with changes in endothelial dysfunction and inflammatory activation parameters. Additionally, the circulating activities of ADA1 and ADA2 were diminished in post-COVID patients, and this study suggests a possible role of ADA isoenzymes in cardiovascular complications after mild COVID-19.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Paulina Mierzejewska, Noemi Di Marzo, Magdalena A. Zabielska-Kaczorowska, Iga Walczak, Ewa M. Slominska, Marialuisa Lavitrano, Roberto Giovannoni, Barbara Kutryb-Zajac, Ryszard T. Smolenski
Summary: The vascular endothelium is a crucial target for immune and thrombotic responses in xenotransplantation. This study evaluated the effects of simultaneous expression of three human genes on mouse endothelial function. The results showed that the simultaneous expression of these genes had beneficial effects on the biochemical and functional aspects of the endothelium, reducing inflammatory responses and improving endothelial permeability.
Article
Biochemistry & Molecular Biology
Magdalena A. Zabielska-Kaczorowska, Barbara Wierzbicka, Andreas Kalmes, Ewa M. Slominska, Magdi H. Yacoub, Ryszard T. Smolenski
Summary: RNS60 has been shown to provide cardioprotection during myocardial hypoxia and cardioplegic arrest, potentially through improved cardiac energetics.
CURRENT ISSUES IN MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
M. A. Zabielska-Kaczorowska, A. E. Bogucka, K. Macur, P. Czaplewska, S. A. Watson, F. Perbellini, C. M. Terracciano, R. T. Smolenski
Summary: In this study, a special in vitro model using ultrathin cardiac slices was used to investigate the proteomic changes in response to electromechanical stimulation. The findings revealed significant alterations related to mitochondrial respiration, energy metabolism, and muscle contraction in stretched slices and fresh myocardial slices cultured without electromechanical stimulation.
SCIENTIFIC REPORTS
(2022)