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The Beneficial Effect of Omega-3 PUFA and L-Arginine on Endothelial Nitric Oxide (NO) Bioavailability
Published in Robert Fried, Richard M. Carlton, Flaxseed, 2023
Robert Fried, Richard M. Carlton
NO diffuses across the muscle cell membrane and binds to guanylyl cyclase. Guanylyl cyclase in turn catalyzes the synthesis of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). cGMP then activates a cGMP-dependent protein kinase, which stimulates the uptake of calcium by the endoplasmic reticulum of the smooth muscle cell. The reduced levels of cytoplasmic calcium cause the muscle cell to relax.
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.
Nontoxic RsDPLA As a Potent Antagonist of Toxic Lipopolysaccharide
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Nilofer Qureshi, Bruce W. Jarvis, Kuni Takayama
The formation of cGMP from GTP is catalyzed by an enzyme called guanylate cyclase. The cellular effects of cGMP appear to be mediated by several types of cGMP receptor proteins. The best characterized are the cGMP-dependent protein kinases, which are a class of closely related enzymes. Cyclic GMP-dependent protein kinases are serine/threonine protein kinases that belong to the very large protein kinase family. There are two catalytic site inhibitors of the cGMP-dependent protein kinase: the isoquinoline H-8 and KT5823 (68). These inhibitors selectively inhibit purified cGMP-dependent protein kinase with a Ki of 0.48 μM and 0.234 μM, respectively. These compounds also inhibit cAMP-dependent protein kinase but with much higher Ki of 1.2 μM and >10 μjlM, respectively. Cyclic GMP plays a major role in pathological situations, which range from endotoxic shock to various types of cardiovascular disorders, hypertension, and atherosclerosis (69).
Spirulina extract improves age-induced vascular dysfunction
Published in Pharmaceutical Biology, 2022
Michal Majewski, Mercedes Klett-Mingo, Carlos M. Verdasco-Martín, Cristina Otero, Mercedes Ferrer
Ageing is a physiological process associated with vascular dysfunction that includes altered release and function of endothelial factors and vascular remodelling (Brandes et al. 2005; Thijssen et al. 2016; Ungvari et al. 2018). The crucial role of endothelial nitric oxide (NO) in vasomotor tone regulation is widely recognised. One of the major downstream events after NO release is an increase in cyclic guanosine monophosphate (cGMP) formation through soluble guanylate cyclase (sGC) stimulation, and the subsequent activation of cGMP-dependent protein kinase (cGK; Lincoln et al. 2001). On the other hand, NO bioavailability is determined by the rate of NO production and by its scavenging by superoxide anion, and several studies have shown increased vascular formation of superoxide anion with ageing (Wu et al. 2014; Daiber et al. 2017).
Signaling mechanisms of the platelet glycoprotein Ib-IX complex
Published in Platelets, 2022
Yaping Zhang, Samuel M Ehrlich, Cheng Zhu, Xiaoping Du
Both VWF and low-dose thrombin induce elevation of intracellular cGMP (cyclic guanosine monophosphate), which activates the cGMP-dependent protein kinase (PKG) [88]. cGMP plays biphasic role in platelet activation: low concentrations of cGMP generated in the early phase of platelet activation, via PKG, promote integrin activation and granule secretion mediated by GPIb-IX and other receptors [88,90]. High concentrations of cGMP and cGMP generated at later phases of thrombus formation inhibit platelet activation and limit the growth of platelet thrombi [88,91] via PKG and PKA-dependent signaling pathways [12]. The biphasic role of cGMP provides a potential explanation as to why GPIb-IX-mediated platelet activation is often seen as “measured” or “weak” and platelets adherent on the surface of a thrombus exposed to high shear appear less activated despite clear evidence of integrin activation.
PDE1 inhibitors: a review of the recent patent literature (2008-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Mei-Ling Le, Mei-Yan Jiang, Chuan Han, Yi-Yi Yang, Yinuo Wu
Like other PDE subfamilies, PDE1 consists of a variable amino terminal domain, a conserved catalytic domain, and a variable carboxyl terminal domain [25] (Figure 1). The amino-terminal domain contains some protein sites in charge of enzymatic activities as well as the phosphorylation of cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) [26]. The catalytic domain has a substrate binding pocket for cAMP and cGMP, the residues of which are highly conserved among PDEs. It has been demonstrated that Gln421 and Phe424 are two conserved residues in the binding pocket, the interaction of which is important for the high affinity [27]. In addition, a hydrophobic pocket, a metal binding site, and a core pocket were also observed in the binding pocket. The difference of PDE1 from other PDEs is that it has two Ca2+/calmodulin (CaM) binding sites [28]. This is why the catalytic ability of PDE1 is regulated by the concentration of Ca2+/CaM.