cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2019, Volume and Issue: 393(2), P. 287 - 302

Published: Dec. 18, 2019

Abstract Cyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets variety of downstream effector molecules and, thus, elicits very broad cellular effects. Its production triggered by stimulation either soluble guanylyl cyclase (sGC) or particulate (pGC); both enzymes exist isoforms. cGMP-induced effects are regulated endogenous receptor ligands such as nitric oxide (NO) natriuretic peptides (NPs). Depending on the distribution sGC pGC formation ligands, this pathway regulates not only cardiovascular system but also kidney, lung, liver, brain function; addition, involved pathogenesis fibrosis, inflammation, neurodegeneration may play role infectious diseases malaria. Moreover, new pharmacological approaches being developed which target sGC- pGC-dependent pathways for treatment various diseases. Therefore, it key interest to understand from scratch, beginning with molecular basis generation, structure function cyclases targets; research efforts focus subsequent signaling cascades, their potential crosstalk, translational ultimately, clinical implications modulation. This review tries summarize contributions “9th International Conference Generators, Effectors Therapeutic Implications” held Mainz 2019. Presented data will be discussed extended light recent landmark findings ongoing activities field preclinical research.

Language: Английский

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Nitric oxide signalling in the brain and its control of bodily functions

British Journal of Pharmacology, Journal Year: 2019, Volume and Issue: 177(24), P. 5437 - 5458

Published: July 26, 2019

Nitric oxide (NO) is a versatile molecule that plays key roles in the development and survival of mammalian species by endowing brain neuronal networks with ability to make continual adjustments function response moment‐to‐moment changes physiological input. Here, we summarize progress field argue NO‐synthetizing neurons NO signalling provide core hub for integrating sensory‐ homeostatic‐related cues, control bodily functions, potential target new therapeutic opportunities against several neuroendocrine behavioural abnormalities.

Language: Английский

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Bridging free radical chemistry with drug discovery: A promising way for finding novel drugs efficiently

European Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 189, P. 112020 - 112020

Published: Dec. 30, 2019

Language: Английский

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The cGMP system: components and function

Biological Chemistry, Journal Year: 2019, Volume and Issue: 401(4), P. 447 - 469

Published: Nov. 19, 2019

Abstract The cyclic guanosine monophosphate (cGMP) signaling system is one of the most prominent regulators a variety physiological and pathophysiological processes in many mammalian non-mammalian tissues. Targeting this pathway by increasing cGMP levels has been very successful approach pharmacology as shown for nitrates, phosphodiesterase (PDE) inhibitors stimulators nitric oxide-guanylyl cyclase (NO-GC) particulate GC (pGC). This an introductory review to intended introduce those readers system, who do not work area. article does intend in-depth system. Signal transduction controlled generating enzymes GCs, degrading PDEs cGMP-regulated nucleotide-gated ion channels, cGMP-dependent protein kinases PDEs. Part A gives concise introduction components. B functions modulated cGMP. cites recent reviews want deeper insight.

Language: Английский

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Carbon Monoxide and Nitric Oxide as Examples of the Youngest Class of Transmitters

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(11), P. 6029 - 6029

Published: June 2, 2021

The year 2021 is the 100th anniversary of confirmation neurotransmission phenomenon by Otto Loewi. Over course hundred years, about 100 neurotransmitters belonging to many chemical groups have been discovered. In order celebrate neurotransmitters, we present an overview first two endogenous gaseous transmitters i.e., nitric oxide, and carbon monoxide, which are often termed as gasotransmitters.

Language: Английский

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The potential therapeutic effect of phosphodiesterase 5 inhibitors in the acute ischemic stroke (AIS)

Molecular and Cellular Biochemistry, Journal Year: 2023, Volume and Issue: 479(5), P. 1267 - 1278

Published: July 3, 2023

Acute ischemic stroke (AIS) is a focal neurological disorder that accounts for 85% of all types, due to occlusion cerebral arteries by thrombosis and emboli. AIS also developed hemodynamic abnormality. associated with the development neuroinflammation which increases severity AIS. Phosphodiesterase enzyme (PDEs) inhibitors have neuro-restorative neuroprotective effects against through modulation cyclic adenosine monophosphate (cAMP)/cyclic guanosine (cGMP)/nitric oxide (NO) pathway. PDE5 mitigation may decrease risk long-term AIS-induced complications. affect properties coagulation pathway are thrombotic complications in reduce activation pro-coagulant improve microcirculatory level patients disturbances mainly tadalafil sildenafil clinical outcomes regulation perfusion blood flow (CBF). reduced thrombomodulin, P-selectin, tissue plasminogen activator. Herein, In conclusion, potential roles management CBF, cAMP/cGMP/NO pathway, neuroinflammation, inflammatory signaling pathways. Preclinical studies recommended this regard.

Language: Английский

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Green-Light-Triggered and Self-Calibrated Cascade Release of Nitric Oxide and Carbon Monoxide for Synergistic Glaucoma Therapy

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(44), P. 30361 - 30371

Published: Oct. 18, 2024

Glaucoma is an optic degenerative neuropathy that driven by a vicious cycle of oxidative stress and mechanical stress. Current clinical treatments aim exclusively at alleviating reducing the intraocular pressure (IOP). With unattended stress, recurrence deterioration are inevitable. Nitric oxide (NO) carbon monoxide (CO) endogenous gaseous signaling molecules for vasodilation anti-inflammation, respectively. Mounting evidence suggests intricate interplay between NO CO to mediate their biological roles, like how it takes two dance waltz. This leads concept "gas waltz therapy" glaucoma, in which released reduce IOP stoichiometric coreleased suppress

Language: Английский

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Modulation of Second Messenger Signaling in the Brain Through PDE4 and PDE5 Inhibition: Therapeutic Implications for Neurological Disorders

Cells, Journal Year: 2025, Volume and Issue: 14(2), P. 86 - 86

Published: Jan. 9, 2025

Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways crucial for brain development and the pathophysiology of neurological disorders. Among 11 PDE subtypes, PDE4 PDE5 are particularly significant due to their regulation cyclic adenosine monophosphate (cAMP) guanosine (cGMP) signaling, respectively, which vital learning, memory, neuroprotection. This review synthesizes current evidence on roles in health disease, focusing second messenger implications function. Elevated activity impairs synaptic plasticity by reducing cAMP levels protein kinase A (PKA) activity, contributing cognitive decline, acute injuries, neuropsychiatric conditions such as bipolar disorder schizophrenia. Similarly, dysregulation disrupts nitric oxide (NO) G (PKG) pathways, involved cerebrovascular homeostasis, recovery after ischemic events, neurodegenerative processes Alzheimer's, Parkinson's, Huntington's diseases. promising therapeutic targets Pharmacological modulation these offers potential enhance function mitigate pathological mechanisms underlying diseases, psychiatric Further research into will advance strategies conditions.

Language: Английский

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Therapeutic Potential of Phosphodiesterase Inhibitors against Neurodegeneration: The Perspective of the Medicinal Chemist

ACS Chemical Neuroscience, Journal Year: 2020, Volume and Issue: 11(12), P. 1726 - 1739

Published: May 13, 2020

Increasing human life expectancy prompts the development of novel remedies for cognitive decline: 44 million people worldwide are affected by dementia, and this number is predicted to triple 2050. Acetylcholinesterase N-methyl-d-aspartate receptors represent targets currently available drugs Alzheimer's disease, which characterized limited efficacy. Thus, search therapeutic agents with alternative or combined mechanisms action wide open. Since variations in 3′,5′-cyclic adenosine monophosphate, guanosine and/or nitric oxide levels interfere downstream pathways involved memory processes, evidence supporting potential phosphodiesterase (PDE) inhibitors contrasting neurodegeneration should be critically considered. For preparation Review, more than 140 scientific papers were retrieved searching PubMed Scopus databases. A systematic approach was adopted when overviewing different PDE isoforms, taking into account details on brain localization, molecular mechanisms, under study, according vitro vivo data. In context drug repurposing, a section focusing PDE5 introduced. Original computational studies performed rationalize emerging that suggests role as multi-target against neurodegeneration. Moreover, since such compounds must cross blood–brain barrier reach inhibitory concentrations central nervous system exert their activity, physicochemical parameters analyzed discussed. Taken together, literature data suggest some inhibitors, tadalafil, promising candidates.

Language: Английский

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IRAK3 modulates downstream innate immune signalling through its guanylate cyclase activity

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: Oct. 29, 2019

Abstract Interleukin-1 receptor associated kinase 3 (IRAK3) is a cytoplasmic homeostatic mediator of inflammatory responses and potentially useful as prognostic marker in inflammation. IRAK3 inhibits signalling cascades downstream myddosome complexes with toll like receptors. contains death domain that interacts other IRAK family members, pseudokinase C-terminus involved tumour necrosis factor 6 (TRAF6). Previous bioinformatic studies revealed contained guanylate cyclase centre its but role action unresolved. We demonstrate wildtype capable producing cGMP. Furthermore, we show specific point mutation the reduced cGMP production. Cells containing 4 nuclear kappa-light-chain-enhancer activated B cells (NFĸB) reporter system were transfected or mutant proteins. Cell-permeable treatment untransfected control suppresses through modulation NFĸB presence lipopolysaccharides. also suppress lipopolysaccharide induced activity absence exogenous Lipopolysaccharide was not suppressed cGMP-generating capacity. Whereas exogenously applied cell-permeable able to retain function by suppressing activity. increasing amount membrane permeable did affect IRAK3’s ability reduce These results suggest generated may be regulatory protein where selectively pathway(s) modulating binding and/or nearby proteins interact cascade.

Language: Английский

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