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Chalcone (1,3-Diphenyl-2-Propene-1-One) Scaffold Bearing Natural Compounds as Nitric Oxide Inhibitors: Promising Antiedema Agents
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Vivek Asati
It has recently observed that overexpression of this component leads to precipitation of both acute inflammation and chronic inflammation in tissues.11 For the treatment of such conditions, few natural and synthetic inhibitors have been identified so far which acts as a potent NO production inhibitor by directly modulating the three isoforms.12 The mediators of the immune system, the macrophages play a critical role in the defense system against various foreign agents and results in the production of NO.13 The loss of macrophage activity is found to be associated with cellular activation after treating with endotoxins.14 The major component of bacterial (gram-negative bacteria) cell walls, lipopolysaccharide (LPS) aggravates the proinflammatory cytokine production by swiftly activating the macrophages.15 LPS-stimulated NO synthesis has been perceived to enhance the apoptotic process.16 Glycine propionyl-L-carnitine, a well known dietary supplement has been recently observed clinically in amplifying the levels of NO.17 NO enhances the Ca2+ channel currents by stimulating the guanylate cyclase component present in photoreceptor rod cells.18 Inhibition of NO in LPS-stimulated cells is considered to be an attractive target in the management of chronic inflammation, platelet count, and thrombosis.19
The Role of Nitric Oxide Signaling in the Pathogenesis of Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Anatoly Grishin, Patrick T. Delaplain, Jin Wang, Michael Mallicote, Michelle Nguyen, Michael Philippe-Auguste, Christopher P. Gayer, Henri R. Ford
NO-cGMP-PKG cascade: In a variety of cell types, soluble NO-dependent guanylate cyclase (NO-GC) serves as a specific high-affinity NO receptor. Guanylate cyclase activity converts GTP into cGMP, an intracellular second messenger. NO-GC is a heme-containing heterodimer consisting of α- and β-subunits. Binding of NO to the heme prosthetic group increases guanylate cyclase activity of NO-GC two orders of magnitude (27). NO-GC was found in all tissues tested (28), particularly in the intestine (29), where it is histochemically prominent in fibroblast-like cells, neurons, interstitial cells of Cajal, and smooth muscle cells (30) and functionally expressed in the epithelium (31–33). NO-GC–derived cGMP activates the isoforms of cGMP-dependent protein kinase (PKG) (34), which in turn phosphorylates multiple substrates whose repertory in various cell types determines the physiological outcomes of NO-cGMP-PKG signaling (34). Although low (nanomolar) concentrations of eNOS- or nNOS-derived NO are typically sufficient for activation of the NO-cGMP-PKG cascade, this cascade cannot be insulated from high concentrations of iNOS-derived NO (35). Accordingly, sustained activation of NO-cGMP-PKG signaling should be considered to occur under inflammatory conditions. An important consequence of such sustained activation is the loss of homeostatic effects of NO, which require a delicate balance with other stimuli.
Critical care, neurology and analgesia
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Mechanisms leading to severe PPHN are poorly understood, but they include altered pulmonary vascular reactivity and structural remodeling. A PPHN animal model has been developed in fetal lambs by ductal constriction or ligation a few days before delivery. In this model, eNOS mRNA protein and its activity have been found to be significantly decreased [16,17], suggesting a rationale for inhaled NO replacement therapy. However, several other critical steps of the NO downsignaling pathway may be altered in PPHN, including reduced soluble guanylate cyclase activity and high type-5 phosphodiesterase activity, which suggest the potential for using specific inhibitors, such as sildenafil [18]. Impaired prostacyclin (PgI2), or conversely increased thromboxane A2 release, elevated endothelin-1 (ET-1) levels and/or modified ET-1 receptor subtypes, may also play a significant role in PPHN. From a clinical perspective, failure of inhaled NO therapy may occur when the lung is not adequately inflated, thereby explaining the synergistic effects of inhaled NO with exogenous surfactant therapy and high-frequency oscillatory ventilation (HFOV). It is often associated with either pulmonary hypoplasia, such as in congenital diaphragmatic hernia [19], or misalignment of the pulmonary vessels, such as in alveolar capillary dysplasia [20].
Zinc improves sexual and erectile function in HAART-treated rats via the upregulation of erectogenic enzymes and maintenance of redox balance
Published in The Aging Male, 2023
R. E. Akhigbe, M. A. Hamed, A. F. Odetayo, T. M. Akhigbe, P. A. Oyedokun
Erectile function is maintained by NO/cGMP signaling [41,42]. On sexual stimulation, NO is released from the parasympathetic nerves into the smooth muscle cells of the arteries of the corporal cavernosum to activate soluble guanylate cyclase (sGC), which converts guanosine triphosphate to cGMP that in turn causes the smooth muscle relaxation and increased blood flow to the penis via protein kinase G [41,42]. The expression and activity of cGMP are inhibited by PGE-5, an enzyme that degrades cGMP to inactive GMP [43]. The observed decline in cGMP levels in HAART-treated rats may be due to HAART-driven rise in PDE-5, which may cause rapid hydrolysis of cGMP. This may explain the noted impaired penile erection seen in HAART-treated rats as cGMP is essential for the relaxation of the trabecular smooth muscle, increased penile blood flow, and erection.
Novel therapeutic approaches in the management of chronic kidney disease: a narrative review
Published in Postgraduate Medicine, 2023
Panagiotis Theofilis, Aikaterini Vordoni, Rigas G. Kalaitzidis
The administration of guanylate cyclase (GC) activators could also be efficacious in improving the treatment targets in diabetic CKD. In humans, soluble guanylate cyclase is a receptor for nitric oxide (NO). It is an important and established target in improving cardiovascular and renal diseases. It is expressed in the arterial system of the kidneys and neuroendocrine cells, contributing to the regulation of renal perfusion and renin excretion [56]. GC is activated by NO and induces the production of cyclic guanin monophosphate (cGMP) from guanosine triphosphate [57]. The complex NO/cGMP has an important effect on renal blood flow, along with anti-inflammatory, anti-fibrotic, and anti-proliferative actions in vascularized and non-vascularized regions of the renal cortex [58]. The dysregulation of NO-GC-cGMP is associated with an increased risk of CKD. It is believed that targeting the NO-sGC-cGMP axis is a potential therapeutic target, which may confer renal protection in experimental models. sGC can also be activated pharmacologically through specialized stimulators and activators, such as BI 685,509. Several trials are underway (NCT04750577, NCT04736628), and the role of this drug class in renal protection is still to be determined.
A review on pharmacological options for the treatment of erectile dysfunction: state of the art and new strategies
Published in Expert Opinion on Pharmacotherapy, 2023
Mattia Longoni, Alessandro Bertini, Nicolò Schifano, Emanuele Zaffuto, Paolo Maggio, Rossi Piercarlo, Sara Baldini, Giulio Carcano, Gabriele Antonini, Andrea Salonia, Francesco Montorsi, Federico Dehò, Paolo Capogrosso
The nitric oxide (NO) pathway has emerged as a fundamental and essential element of penile vasodilation; upon sexual stimulation, the cavernous nerves release NO and acetylcholine directly, generating a more sustained release of NO [10]. NO activates soluble guanylate cyclase, an enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). The increased levels of cGMP play a critical role in the activation of protein kinase G (PKG) [7], thus leading to cytosolic free calcium depletion. As a consequence of free cytosolic calcium drop in smooth muscle cells of penile arteries and corporal erectile tissue, the actin–myosin cross-bridge formation occurs, leading to muscular relaxation and subsequent vasodilation. With vasodilation, penile blood flow increases, and the corporal bodies become engorged with blood [7].