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The Journal of Experimental Medicine May 2018Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this... (Review)
Review
Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this detection mechanism also poses a challenge to the host as to how to distinguish foreign DNA from abundant self-DNA. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP), which binds and activates the adaptor protein STING. However, cGAS can be activated by double-stranded DNA irrespective of the sequence, including self-DNA. Although how cGAS is normally kept inactive in cells is still not well understood, recent research has provided strong evidence that genomic DNA damage leads to cGAS activation to stimulate inflammatory responses. This review summarizes recent findings on how genomic instability and DNA damage trigger cGAS activation and how cGAS serves as a link from DNA damage to inflammation, cellular senescence, and cancer.
Topics: Animals; Cellular Senescence; DNA Damage; Humans; Inflammation; Neoplasms; Nucleotides, Cyclic; Nucleotidyltransferases
PubMed: 29622565
DOI: 10.1084/jem.20180139 -
Critical Reviews in Biochemistry and... Feb 2021The focus of this review is the human de novo purine biosynthetic pathway. The pathway enzymes are enumerated, as well as the reactions they catalyze and their physical... (Review)
Review
The focus of this review is the human de novo purine biosynthetic pathway. The pathway enzymes are enumerated, as well as the reactions they catalyze and their physical properties. Early literature evidence suggested that they might assemble into a multi-enzyme complex called a metabolon. The finding that fluorescently-tagged chimeras of the pathway enzymes form discrete puncta, now called purinosomes, is further elaborated in this review to include: a discussion of their assembly; the role of ancillary proteins; their locus at the microtubule/mitochondria interface; the elucidation that at endogenous levels, purinosomes function to channel intermediates from phosphoribosyl pyrophosphate to AMP and GMP; and the evidence for the purinosomes to exist as a protein condensate. The review concludes with a consideration of probable signaling pathways that might promote the assembly and disassembly of the purinosome, in particular the identification of candidate kinases given the extensive phosphorylation of the enzymes. These collective findings substantiate our current view of the de novo purine biosynthetic metabolon whose properties will be representative of how other metabolic pathways might be organized for their function.
Topics: Adenosine Monophosphate; Biosynthetic Pathways; Cyclic AMP; Cyclic GMP; Guanosine Monophosphate; Humans; Microtubules; Mitochondria; Multienzyme Complexes; Phosphoribosyl Pyrophosphate; Phosphorylation; Proteins; Purines; Signal Transduction
PubMed: 33179964
DOI: 10.1080/10409238.2020.1832438 -
Journal of the American College of... Oct 2022Doses of sacubitril/valsartan (Sac/Val) achieved in clinical trials of heart failure with reduced ejection fraction (HFrEF) are often not reached in clinical practice.
BACKGROUND
Doses of sacubitril/valsartan (Sac/Val) achieved in clinical trials of heart failure with reduced ejection fraction (HFrEF) are often not reached in clinical practice.
OBJECTIVES
The purpose of this study was to investigate associations among Sac/Val doses and changes in prognostic biomarkers, health status, and cardiac remodeling among individuals with HFrEF through 12 months of treatment with Sac/Val administered per usual care.
METHODS
A total of 794 persons with HFrEF (ejection fraction [EF] ≤40%) were categorized according to average daily doses of Sac/Val divided into tertiles. Change from baseline to 12 months in biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, soluble ST2, atrial natriuretic peptide, urinary cyclic guanosine monophosphate), Kansas City Cardiomyopathy Questionnaire-23 scores, and parameters of cardiac reverse remodeling (left ventricular EF, indexed left atrial and ventricular volumes, and E/e') were assessed.
RESULTS
The average daily dose was 112 mg in Tertile 1 (low dose), 342 mg in Tertile 2 (moderate dose), and 379 mg in Tertile 3 (high dose). Similar changes in prognostic biomarkers were observed in all dose tertiles. Gains in Kansas City Cardiomyopathy Questionnaire-23 scores were comparable regardless of dose category. Consistent reverse cardiac remodeling in all dose categories occurred; the median absolute left ventricular EF improvement across HF dose groups was 9.3%, 8.7%, and 10.2%, for low, moderate, and high doses, respectively; similar improvements in left atrial and ventricular volumes and E/e' were also observed across dose categories.
CONCLUSIONS
Among patients with HFrEF, similar improvement in prognostic biomarkers, health status, and cardiac remodeling were observed across various Sac/Val doses. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183.
Topics: Aminobutyrates; Atrial Natriuretic Factor; Biomarkers; Biphenyl Compounds; Dose-Response Relationship, Drug; Guanosine Monophosphate; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Natriuretic Peptide, Brain; Stroke Volume; Troponin T; Valsartan; Ventricular Dysfunction, Left; Ventricular Remodeling
PubMed: 36229089
DOI: 10.1016/j.jacc.2022.08.737 -
Cardiovascular Therapeutics 2022Heart failure with reduced ejection fraction (HFrEF) is the inability of the heart to adequately contract or eject blood. This heart is unable to produce adequate... (Review)
Review
Heart failure with reduced ejection fraction (HFrEF) is the inability of the heart to adequately contract or eject blood. This heart is unable to produce adequate cardiac output to perfuse vital tissues. At a fundamental level, it is known that the cardioprotective pathway of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate is impaired in heart failure patients. Vericiguat is a novel, orally used, small molecule, and direct stimulator of the soluble guanylate cyclase, and thus, it enhances the production of cyclic guanosine monophosphate. Vericiguat was approved by the FDA in January of 2021 to reduce the risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic heart failure and ejection fraction less than 45%. In this review, we describe the chemical and mechanistic aspects, pharmacokinetics, adverse effects, and contraindications of vericiguat so as to facilitate its optimal therapeutic use.
Topics: Humans; Heart Failure; Soluble Guanylyl Cyclase; Guanosine Monophosphate; Stroke Volume
PubMed: 36618548
DOI: 10.1155/2022/1554875 -
Journal of Innate Immunity 2019Cyclic dimeric guanosine monophosphate (c-di-GMP) is a universally conserved second messenger that contributes to the pathogenicity of numerous bacterial species. In... (Review)
Review
Cyclic dimeric guanosine monophosphate (c-di-GMP) is a universally conserved second messenger that contributes to the pathogenicity of numerous bacterial species. In recent years, growing evidence has shown that bacterial extracellular c-di-GMP can interact with the innate immune system and regulate host immune responses. This review summarizes our current understanding on the dual roles of bacterial c-di-GMP in pathogen-host interaction: activation of the antibacterial innate immune response through the cytosolic surveillance pathway and inhibition of innate immune defense for iron restriction.
Topics: Cyclic GMP; DEAD-box RNA Helicases; Host-Pathogen Interactions; Humans; Immunity, Innate; Lipocalin-2; Membrane Proteins
PubMed: 30253386
DOI: 10.1159/000492679 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Oct 2021Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a... (Review)
Review
Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.
Topics: Animals; Colitis; Inflammatory Bowel Diseases; Phosphodiesterase 4 Inhibitors
PubMed: 34986542
DOI: 10.3724/zdxbyxb-2021-0170 -
Frontiers in Immunology 2023Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self-DNA in the cytoplasm.... (Review)
Review
Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self-DNA in the cytoplasm. Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein stimulator of interferon genes (STING), which then activates the kinases IKK and TBK1 to induce the secretion of interferons and other cytokines. Recently, a series of studies demonstrated that the cGAS-STING pathway, a vital component of host innate immunity, might play an important role in anticancer immunity, though its mechanism remains to be elucidated. In this review, we highlight the latest understanding of the cGAS-STING pathway in tumor development and the advances in combination therapy of STING agonists and immunotherapy.
Topics: Humans; Guanosine Monophosphate; Membrane Proteins; Nucleotidyltransferases; Cyclic GMP; Neoplasms; DNA; Interferons; Immunotherapy
PubMed: 37153627
DOI: 10.3389/fimmu.2023.1121603 -
Journal of the American College of... May 2012Cyclic guanosine monophosphate (cGMP) is an important intracellular second messenger that mediates multiple tissue and cellular responses. The cGMP pathway is a key... (Review)
Review
Cyclic guanosine monophosphate (cGMP) is an important intracellular second messenger that mediates multiple tissue and cellular responses. The cGMP pathway is a key element in the pathophysiology of the heart and its modulation by drugs such as phosphodiesterase (PDE)-5 inhibitors and guanylate cyclase activators may represent a promising therapeutic approach for acute myocardial infarction, cardiac hypertrophy, heart failure, and doxorubicin cardiotoxicity in patients. In addition, PDE-5 inhibitors may prove to be innovative therapeutic agents for enhancing the chemosensitivity of doxorubicin while providing concurrent cardiac benefit.
Topics: Animals; Guanosine Monophosphate; Heart Diseases; Humans; Myocytes, Cardiac; Phosphodiesterase 5 Inhibitors; Signal Transduction
PubMed: 22624832
DOI: 10.1016/j.jacc.2011.09.086 -
Nature Communications Nov 2023Previous studies have demonstrated that bis-(3',5')-cyclic diguanosine monophosphate (bis-3',5'-c-di-GMP) is a ubiquitous second messenger employed by bacteria. Here, we...
Previous studies have demonstrated that bis-(3',5')-cyclic diguanosine monophosphate (bis-3',5'-c-di-GMP) is a ubiquitous second messenger employed by bacteria. Here, we report that 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) controls the important biological functions, quorum sensing (QS) signaling systems and virulence in Ralstonia solanacearum through the transcriptional regulator RSp0980. This signal specifically binds to RSp0980 with high affinity and thus abolishes the interaction between RSp0980 and the promoters of target genes. In-frame deletion of RSp0334, which contains an evolved GGDEF domain with a LLARLGGDQF motif required to catalyze 2',3'-cGMP to (2',5')(3',5')-cyclic diguanosine monophosphate (2',3'-c-di-GMP), altered the abovementioned important phenotypes through increasing the intracellular 2',3'-cGMP levels. Furthermore, we found that 2',3'-cGMP, its receptor and the evolved GGDEF domain with a LLARLGGDEF motif also exist in the human pathogen Salmonella typhimurium. Together, our work provides insights into the unusual function of the GGDEF domain of RSp0334 and the special regulatory mechanism of 2',3'-cGMP signal in bacteria.
Topics: Humans; Virulence; Guanosine Monophosphate; Ralstonia solanacearum; Bacterial Proteins; Cyclic GMP; Second Messenger Systems; Gene Expression Regulation, Bacterial; Biofilms
PubMed: 37996405
DOI: 10.1038/s41467-023-43461-2 -
Postepy Higieny I Medycyny... Dec 2016Intracellular concentration of cGMP depends on the activity of guanylate cyclase, responsible for its synthesis, on the activity of cyclic nucleotide degrading enzymes -... (Review)
Review
Intracellular concentration of cGMP depends on the activity of guanylate cyclase, responsible for its synthesis, on the activity of cyclic nucleotide degrading enzymes - phosphodiesterases (PDEs). There are two forms of guanylate cyclase: the membrane-bound cyclase and the soluble form. The physiological activators of the membrane guanylate cyclase are natriuretic peptides (NPs), and of the cytosolic guanylate cyclase - nitric oxide (NO) and carbon monoxide (CO). Intracellular cGMP signaling pathways arise from its direct effect on the activity of G protein kinases, phosphodiesterases and cyclic nucleotide dependent cation channels. It has been shown in recent years that cGMP can also affect other signal pathways in cell signaling activity involving Wnt proteins and sex hormones. The increased interest in the research on the role of cGMP, resulted also in the discovery of its role in the regulation of phototransduction in the eye, neurotransmission, calcium homeostasis, platelet aggregation, heartbeat, bone remodeling, lipid metabolism and the activity of the cation channels. Better understanding of the mechanisms of action of cGMP in the regulation of cell function can create new opportunities for the cGMP affecting drugs use in the pharmacotherapy.
Topics: Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Guanosine Monophosphate; Guanylate Cyclase; Humans; Nitric Oxide; Receptors, Cytoplasmic and Nuclear; Signal Transduction
PubMed: 28026830
DOI: No ID Found