Article
Pharmacology & Pharmacy
Hasan Slika, Hadi Mansour, Suzanne A. Nasser, Abdullah Shaito, Firas Kobeissy, Alexander N. Orekhov, Gianfranco Pintus, Ali H. Eid
Summary: In 1957, cyclic adenosine monophosphate (cAMP) was identified as the first secondary messenger, and the cAMP-protein kinase A (PKA) pathway was discovered as the first signaling cascade. Recently, a new cAMP effector called exchange protein directly activated by cAMP (Epac) has emerged as a critical mediator of cAMP's actions, playing a role in various diseases and offering potential as a therapeutic target. This paper provides a comprehensive analysis of Epac's structure, distribution, compartmentalization, and signaling mechanisms, discussing the development of specific Epac modulators for future pharmacotherapeutics.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Rawan Altalhi, Nikoletta Pechlivani, Ramzi A. Ajjan
Summary: Hypofibrinolysis is a key abnormality in diabetes, with elevated levels of PAI-1 playing a significant role. Strategies to inhibit PAI-1 function may lead to new antithrombotic agents that reduce vascular complications in diabetes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Zhihui Fong, Caoimhin S. Griffin, Roddy J. Large, Mark A. Hollywood, Keith D. Thornbury, Gerard P. Sergeant
Summary: P2X1 receptors are inhibited by EPAC activators, while P2X2 current amplitudes are enhanced. PKA activators have no effect on P2X1 receptors but inhibit P2X2 receptors. The inhibitory effects of EPAC on P2X1 receptors can be prevented through mutations and an inhibitor of Rac1.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Alina Zorn, George Baillie
Summary: Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that hydrolyze cAMP and cGMP. This review focuses on human PDE7, which plays a role in T cell activation, inflammation, and physiological processes in the central nervous system. Increased expression of PDE7 has been detected in neurodegenerative diseases, auto-immune diseases, and cancer. Early studies suggest that PDE7 inhibitors may be a novel therapeutic strategy to target these diseases.
CELLULAR SIGNALLING
(2023)
Review
Pharmacology & Pharmacy
Shumin Ouyang, Qiyi Zhang, Linlin Lou, Kai Zhu, Zeyu Li, Peiqing Liu, Xiaolei Zhang
Summary: Reprogramming of cellular energy metabolism is an emerging feature of cancer, and SIRT3 plays a crucial role in regulating mitochondrial energy metabolism. The functions of SIRT3 vary in different types of cancer, showing specificity, and it plays a unique role by mediating interactions between mitochondria and intracellular signaling. The study of activators and inhibitors of SIRT3 contributes to a better understanding of its mechanisms and provides new strategies for cancer treatment.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Machteld Sillen, Paul J. Declerck
Summary: PAI-1 is the primary inhibitor of fibrinolysis, mainly through fast-acting inhibition of tPA and uPA, as well as interactions with biological ligands, affecting pericellular proteolysis and tissue remodeling.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Yeon-Jee Kahm, Rae-Kwon Kim
Summary: BIRC5, also known as survivin, is a protein that negatively regulates apoptosis by inhibiting caspase activation. Its overexpression enables cancer cells to survive and divide. BIRC5 is highly expressed in stem cells and may be involved in the regulation of cancer stem cells (CSCs). The study shows that BIRC5 is a key factor in CSCs and epithelial to mesenchymal transition (EMT) regulation, and it regulates the secretion of plasminogen activator inhibitor-1 (PAI-1), which is involved in signaling mechanisms regulating CSCs and EMT.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Immunology
Xinwei Cao, Yajun Li, Jianrong Shi, Huifang Tang
Summary: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosis disease caused by genetic susceptibility and other risk factors. EPAC, as a newly emerging cAMP downstream molecule, plays a vital role in inhibiting fibrosis and may be a novel target for drug development and treatment of IPF.
JOURNAL OF INFLAMMATION RESEARCH
(2021)
Article
Cell Biology
Ana Amaya-Garrido, Manon Brunet, Benedicte Buffin-Meyer, Alexis Piedrafita, Lucile Grzesiak, Ezechiel Agbegbo, Arnaud Del Bello, Ines Ferrandiz, Serban Ardeleanu, Marcelino Bermudez-Lopez, Camille Fedou, Mylene Camus, Odile Burlet-Schiltz, Jean Massines, Marie Buleon, Guylene Feuillet, Melinda Alves, Eric Neau, Audrey Casemayou, Benjamin Breuil, Jean-Sebastien Saulnier-Blache, Colette Denis, Jakob Voelkl, Griet Glorieux, Sam Hobson, Samsul Arefin, Awahan Rahman, Karolina Kublickiene, Peter Stenvinkel, Jean-Loup Bascands, Stanislas Faguer, Jose M. Valdivielso, Joost P. Schanstra, Julie Klein
Summary: Vascular calcification is a significant risk factor for cardiovascular mortality in patients with chronic kidney disease. A study found that circulating calprotectin is independently associated with calcification, cardiovascular outcomes, and mortality in CKD patients. Inhibition of calprotectin may be a promising strategy to prevent vascular calcification in these patients.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Review
Pharmacology & Pharmacy
Miriam Bettinetti-Luque, Laura Trujillo-Estrada, Eduardo Garcia-Fuentes, Juana Andreo-Lopez, Raquel Sanchez-Varo, Lourdes Garrido-Sanchez, Angela Gomez-Mediavilla, Manuela G. Lopez, Melissa Garcia-Caballero, Antonia Gutierrez, David Baglietto-Vargas
Summary: Adipose tissue is an important endocrine organ that plays a crucial role in energy metabolism and immune response. Recent studies have shown that the adipose tissue can affect brain function through adipokines, which may have implications for the development and treatment of Alzheimer's disease.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Cell Biology
Muhammad Bilal Ahmed, Abdullah A. A. Alghamdi, Salman Ul Islam, Joon-Seok Lee, Young-Sup Lee
Summary: Cancer, one of the leading causes of death globally, remains unclear in its fundamental principles. Understanding the key signaling mechanisms that cause cancer cell malignancy may help uncover new pharmaco-targets. Targeting cAMP and its effectors, crucial for tumor growth and development, may serve as a useful cancer treatment strategy.
Review
Biochemistry & Molecular Biology
Mariely A. Godoi, Angelo C. Camilli, Karen G. A. Gonzales, Vitoria B. Costa, Evangelos Papathanasiou, Fabio R. M. Leite, Morgana R. Guimaraes-Stabili
Summary: Several cytokines exert their functions in inflammatory diseases through the JAK/STAT signal transduction pathway. STATs translocate from the cytoplasm to the nucleus, binding to phosphorylated tyrosine residues and regulating the transcription of genes that control the inflammatory response. The persistent activation of JAK/STAT signaling pathway is associated with inflammatory bone diseases, and inhibitors of this pathway are being explored for their potential in preventing tissue destruction.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Yan-Yan Zhao, Li-Jun Zhang, Xiang-Yan Liang, Xiao-Chun Zhang, Jin-Rui Chang, Man Shi, Huan Liu, Ying Zhou, Zhuo Sun, Yu-Feng Zhao
Summary: Pyruvate activates PDEs to reduce cAMP levels and inhibits the cAMP-Epac-CREB signaling pathway, resulting in upregulation of FGF21 expression in hepatocytes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Alkebaier Aobulikasimu, Tao Liu, Jinying Piao, Shingo Sato, Hiroki Ochi, Atsushi Okawa, Kunikazu Tsuji, Yoshinori Asou
Summary: The role of SIRT6 in osteocytes was investigated in this study, using mice lacking Sirt6 and an osteocyte-like cell line. The results showed that Sirt6 deficiency led to increased expression of senescence-associated genes and decreased serum phosphate levels, resulting in low-turnover osteopenia. However, the effects were reversed in mice lacking PAI-1 gene. Further experiments revealed that senescence induction increased the expression of Fgf23 and Sost genes, and Sirt6 knockout and senescence induction enhanced the binding of HIF-1 alpha to Fgf23 enhancer sequence. These findings suggest that SIRT6 agonists or PAI-1 inhibitors may be potential therapeutic options for aging-related bone metabolism disruptions.
SCIENTIFIC REPORTS
(2023)
Article
Chemistry, Multidisciplinary
Wen-xia Yang, Yu Liu, Shu-min Zhang, Hua-fen Wang, Yi-fei Liu, Jia-lu Liu, Xiao-hui Li, Meng-ru Zeng, Yu-zhang Han, Fu-you Liu, Lin Sun, Li Xiao
Summary: Epac activation via 8-O-cAMP can ameliorate tubulointerstitial inflammation in DN through the C/EBP-beta/SOCS3/STAT3 pathway, reducing fibrosis in the kidney.
ACTA PHARMACOLOGICA SINICA
(2022)