The cyclic AMP signaling pathway: Exploring targets for successful drug discovery (Review)

Yan, Kuo; Gao, Lina; Cui, Yuan‐Lu; Zhang, Yi; Zhou, Xin

doi:10.3892/mmr.2016.5005

Cited by 162 publications

(97 citation statements)

References 115 publications

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“…For vessels to contract or platelets to aggregate, intracellular calcium must be increased. Activation of PKA and/or engagement of EPAC in platelets or vascular smooth muscle cells results in immediate and profound reduction in levels of intracellular calcium through incompletely understood pathways (Yan et al, ).…”

Section: Role Of Cox‐2 In Cardiovascular Protection and The Cardiovasmentioning

confidence: 99%

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

Mitchell¹,

Kirkby²

2018

British J Pharmacology

178

123

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Eicosanoids represent a diverse family of lipid mediators with fundamental roles in physiology and disease. Within the eicosanoid superfamily are prostanoids, which are specifically derived from arachidonic acid by the enzyme cyclooxygenase (COX). COX has two isoforms; COX-1 and COX-2. COX-2 is the therapeutic target for the nonsteroidal anti-inflammatory drug (NSAID) class of pain medications. Of the prostanoids, prostacyclin, first discovered by Sir John Vane in 1976, remains amongst the best studied and retains an impressive pedigree as one of the fundamental cardiovascular protective pathways. Since this time, we have learnt much about how eicosanoids, COX enzymes and prostacyclin function in the cardiovascular system, knowledge that has allowed us, for example, to harness the power of prostacyclin as therapy to treat pulmonary arterial hypertension and peripheral vascular disease. However, there remain many unanswered questions in our basic understanding of the pathways, and how they can be used to improve human health. Perhaps, the most important and controversial outstanding question in the field remains; 'how do NSAIDs produce their much publicized cardiovascular side-effects?' This review summarizes the history, biology and cardiovascular function of key eicosanoids with particular focus on prostacyclin and other COX products and discusses how our knowledge of these pathways can applied in future drug discovery and be used to explain the cardiovascular side-effects of NSAIDs.

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Section: Role Of Cox‐2 In Cardiovascular Protection and The Cardiovasmentioning

confidence: 99%

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

Mitchell¹,

Kirkby²

2018

British J Pharmacology

178

123

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“…although a large number of signaling pathways underlying IPC have been identified in the past 30 years 8,9,11,12 .…”

mentioning

confidence: 99%

The role of ischemic preconditioning and pentoxifylline in intestinal ischemia/reperfusion injury of rats

Oliveira

F.²,

Simões

et al. 2017

Acta Cir. Bras.

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“…One of the novel observation of our study is the abundance of cAMP-mediated pathways within the RA-CCP POS B cell populations. cAMP is a vital secondary messenger that plays an essential role in cellular response to many hormones, GPCRs and growth factor receptors 72 . The intracellular concentrations of cAMP are determined by the activity of two opposing enzyme families, the adenylyl cyclases (AC) and cyclic nucleotide phosphodiesterases (PDEs).…”

Section: Discussionmentioning

confidence: 99%

Beyond autoantibodies: Biological roles of human autoreactive B cells in rheumatoid arthritis revealed by whole transcriptome profiling

Mahendra

Yang

Abnouf

et al. 2017

Preprint

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Although the contribution of B-cell derived autoreactive antibodies to rheumatoid arthritis (RA) has been studied extensively, the autoantibody-independent roles of B cells in the progression of the disease is not well-defined. Here we present the first comprehensive transcriptome profile of human autoreactive B cells in an autoimmune disease by performing RNA-sequencing of citrulline-specific B cells from RA patients. In order to facilitate a comprehensive understanding of the profile of these citrulline-specific (RA-CCPPOS) B cells, we performed comparative analyses to both citrulline-negative (RA-CCPNEG) B cells from the same donors, and identified 431 differentially expressed genes (DEGs); and hemagglutinin-specific (HA) B cells from healthy individuals and identified 1658 DEGs. Three-way comparisons of these B cell populations demonstrated that RA-CCPPOS B cells, in comparison to the RA-CCPNEG B cells, demonstrate a potential role in protein citrullination and inflammation; RA-CCPPOS B cells in comparison to HA-specific B cells demonstrate RA-specific signatures like the expression of pro-inflammatory cytokines, chemokines, costimulatory molecules and B-cell activation cascades; and all B cells from RA patients demonstrated a significant impact of the multitude of TNF signaling pathways. Furthermore, transcription factor profiling suggested that cyclic AMP (cAMP) related pathways and downstream signaling molecules are selectively enriched in RA-CCPPOS cells in comparison to the other two B cell subsets. We advanced the understanding of the citrulline reactive B cells in RA pathophysiology by documenting and validating two novel observations in independent cohorts of patients: (1) the expression of IL15Rα is restricted to citrulline-specific cells within RA patients and the concentration of soluble IL15Rα is elevated in the sera of RA patients, (2) B cells from RA patients are capable of producing epidermal growth factor ligand, amphiregulin (AREG) which in turn has a direct impact on the mechanistic effectors of RA, osteoclasts and fibroblastlike synoviocytes (FLS). Overall, our comprehensive dataset identifies several existing FDA-approved drugs that can potentially be repurposed for RA and can serve as a foundation for studying the multi-faceted roles of B cells in other autoimmune diseases.

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The cyclic AMP signaling pathway: Exploring targets for successful drug discovery (Review)

Cited by 162 publications

References 115 publications

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

The role of ischemic preconditioning and pentoxifylline in intestinal ischemia/reperfusion injury of rats

Beyond autoantibodies: Biological roles of human autoreactive B cells in rheumatoid arthritis revealed by whole transcriptome profiling

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