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Natriuretic Peptides and Cardiac Function
Published in Malcolm J. Lewis, Ajay M. Shah, Endothelial Modulation of Cardiac Function, 2020
Kazuhiro Yamamoto, Margaret M. Redfield, John C. Burnett
The mechanism for these actions on myocardial function is still controversial. Meulemans et al. demonstrated that effects of ANP on isolated mammalian papillary muscle were abolished by removing the endothelial surface and suggested that the effects might be mediated through receptors on the endothelium (Meulemans et al., 1988). However, direct actions of ANP on the myocyte have been demonstrated (Neyses and Vetter, 1989; Lin et al., 1995). A reduction in intracellular Ca2+ influx induced by increased intracellular cGMP has been demonstrated (Fischmeister and Hartzell, 1987; Wahler, Rusch and Sperelakis, 1989; Mery et al., 1991). The cGMP-induced attenuation of Ca2+ influx is attributed to a direct action of cGMP (Wahler, Rusch and Sperelakis, 1989; Mery et al., 1991) or to an indirect action of cGMP through an augmentation of cAMP hydrolysis via a cGMP-stimulated cyclic nucleotide phosphodiesterase (Hartzell and Fischmeister, 1986; Fischmeister and Hartzell, 1987). Several studies (Shah et al., 1994; Hajjar and Gwathmey, 1995) have attributed cGMP-induced changes in myocardial function to reduced myofilament response to Ca2+, not to changes in intracellular Ca2+ transient. Another possible mechanism of actions of ANP and/or BNP is phosphorylation of troponin I through cGMP-dependent protein kinase (Blumenthal, Stull and Gill, 1978; Lincoln and Corbin, 1978).
Hormones of the Moss Protonema
Published in R. N. Chopra, Satish C. Bhatla, Bryophyte Development: Physiology and Biochemistry, 2019
The enzyme which regulates the total amount of cAMP by degradation is cyclic nucleotide phosphodiesterase (PDE). It was first detected in Sphagnum among the mosses,117 and later it could be demonstrated in the suspension cultures of Funaria. The level depended on the cell density and, surprisingly, was highest at low cell densities, in contrast to auxin oxidase.24 However, this result fits well with the caulonema-chloronema distribution. High activities of PDE reduce the internal cAMP content and, therefore, favor the formation of caulonemata.
Overview of Mechanisms for Coupling of Receptor-Agonist Interactions With Physiological Effects
Published in John C. Matthews, Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
The activity of the adenylate cyclase enzyme is regulated by a receptor on the outside of the cell membrane through an intervening G protein. When the agonist binds to its receptor the stimulated receptor-agonist complex causes the G protein to exchange its bound GDP molecule for a molecule of GTP from inside the cell. The G protein-GTP complex, in turn, interacts with the adenylate cyclase to activate it. The G protein, which is a GTPase enzyme, then hydrolyzes the GTP to GDP. This terminates the ability of the G protein to activate adenylate cyclase. Meanwhile, cyclic nucleotide phosphodiesterase enzymes and protein phosphatase enzymes in the cell function to reverse the effects of the underlying receptor stimulation. They do so by converting cyclic AMP to AMP and by removing the phosphate groups from the phosphorylated proteins. As was true with the nicotinic acetyl choline receptor, the extracellular agonist will only be available to interact with its receptor for a short period of time. In addition to enzymatic degradation of the agonist, several cellular uptake processes are important for rapidly clearing receptor agonists from the extracellular space as a means of terminating receptor stimulation.
Anti-trypanosomatid structure-based drug design – lessons learned from targeting the folate pathway
Published in Expert Opinion on Drug Discovery, 2022
Joanna Panecka-Hofman, Ina Poehner, Rebecca C. Wade
Therefore, even in the best-controlled case of sleeping sickness, better treatments, that overcome resistance and have reduced side effects, are needed. Unfortunately, drug design efforts against trypanosomiases are not generally profitable for pharmaceutical companies, since these so-called ‘neglected diseases’ occur mostly in poor regions of the world [21]. However, in recent years, there have been several initiatives to advance drug design against neglected tropical diseases. These include (i) the Drugs for Neglected Diseases initiative (DNDi, https://dndi.org [22]), (ii) the Trypanogen and Trypanogen+ projects funded by AAS/Wellcome under the H3Africa initiative (http://trypanogen.net/ [23]), (iii) two EU-funded projects that focused on targeting specific biochemical pathways of parasites causing the diseases: New Medicines for Trypanosomatidic Infections (NMTrypI [24], https://fp7-nmtrypi.eu/ [25], https://cordis.europa.eu/project/id/603240 [26]) and Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases (PDE4NPD, https://cordis.europa.eu/project/id/602666 [27]). One of the focuses of the NMTrypI project, in which the authors of the present article participated, was targeting the parasite folate pathways. We here review recent efforts in anti-trypanosomatid structure-based drug design (SBDD) from this perspective.
The Wnt/β-catenin pathway in breast cancer therapy: a pre-clinical perspective of its targeting for clinical translation
Published in Expert Review of Anticancer Therapy, 2022
Dezaree Raut, Amisha Vora, Lokesh Kumar Bhatt
The non-canonical Wnt signaling pathway, also known as the β-catenin-independent pathway, is divided into the Wnt/Ca2+ pathway and planar cell polarity (PCP) pathway. In the Wnt/Ca2+ pathway, when Wnt binds to the frizzled (Fz) receptor, it causes intracellular binding of Dvl near the Fz receptor (FZD). In addition to Dvl, the Fz receptor also stimulated trimeric G-protein. Simultaneous stimulation of Dvl and D-protein can activate either Phospholipase (PLC) or Cyclic nucleotide phosphodiesterase (PDE). When PLC is activated, it causes activation of Inositol trisphosphate (IP3). IP3 causes an intracellular release of calcium which further causes calcineurin and CaMK11 activation. CaMK11 activates a nuclear factor of activated T-cells, responsible for cell adhesion, migrations, and tissue separation. On the other hand, calcineurin activates certain substances that interfere with the canonical Wnt signaling pathway to regulate dorsal axis formation negatively. If PDE gets activated, it causes inhibition of calcium release from ER. This pathway helps to regulate intracellular calcium levels by controlling the calcium release from the endoplasmic reticulum [16].
Asthma pharmacotherapy: an update on leukotriene treatments
Published in Expert Review of Respiratory Medicine, 2019
Hoang Kim Tu Trinh, So-Hee Lee, Thi Bich Tra Cao, Hae-Sim Park
Three LTRAs (montelukast, pranlukast and zafirlukast) are approved and listed in current treatment guidelines for asthma treatment. They are known to be potent, selective and competitive antagonists to CysLTR1, in which montelukast showed the highest binding affinity [12]. Recent studies demonstrated that these drugs can modulate diverse pathways aside from CysLTR1 antagonism, including cyclic nucleotide phosphodiesterase, 5-LO, nuclear factor kβ and microsomal prostaglandin (PG) E2 synthase-1 [12,13]. In addition, it is well tolerated in a broad-dose range and is administered in clinical trials for elderly asthmatics [14], patients with aspirin-exacerbated respiratory disease (AERD) [15] and smoker asthmatics [16]. Patients taking montelukast showed reduced risk of recurrent strokes (HR = 0.62, 95% CI, 0.38–0.99) and were associated with lower levels of biomarkers for cardiovascular disease [17,18], suggesting the potential effectiveness of montelukast in asthmatic patients with multimorbid conditions.