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Precision medicine in osteoporosis and bone diseases
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Fatmanur Hacievliyagil Kazanci, Fatih Kazanci, M. Ramazan Yigitoglu, Mehmet Gunduz
The main purpose of pharmacological therapy in osteoporosis is to reduce the risk of fracture, not just increase BMD. Pharmacologic agents for the treatment of osteoporosis can be classified as either antiresorptive or anabolic. The antiresorptive agents are bisphosphonates, calcitonin, receptor activator of nuclear factor kappa-B ligand (RANKL) antibody, and selective estrogen receptor modulators (SERM). These agents suppress bone turnover by reducing bone resorption. Teriparatide is the only anabolic drug, which stimulates bone formation. Drugs and drug targets for osteoporosis are summarized in Table 13.1.
Regulation of Food Intake
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Surya Panicker Rajeev, Ian W. Seetho, John P.H. Wilding, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Amylin is co-secreted with insulin from the beta cells of the pancreas in response to food ingestion. In humans, amylin binds to AMY-receptor subtypes, which are calcitonin receptor complexes with receptor activity-modifying proteins [110]. In rats, amylin reduced the meal size and meal duration, thus demonstrating its anorectic effects [111]. Meal-induced amylin release activates area postrema neurons in the brain [112]. It enhances the anorectic effects of CCK, and this is likely to be via modulation in area postrema. Apart from reducing food intake, amylin delays gastric emptying, decreases gastric secretion, and reduces postprandial glucagon secretion. As such, pramlintide, a synthetic amylin analogue, is approved in the United States as an adjunct therapy in type 1 and type 2 diabetes [113,114].
Osteoimmunology in Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Lia Ginaldi, Daniela Di Silvestre, Maria Maddalena Sirufo, Massimo De Martinis
A complex receptor network mediates bone remodeling as well as the crosstalk between the bone and immune system. The main activation signal for bone resorption is the stimulation of the receptor RANK on osteoclasts and their precursors by its specific ligand RANKL expressed by osteoblasts and stromal cells. A central role in this system is also played by the ligand OPG, a decoy receptor of RANKL, which prevents bone resorption by acting as a competitive inhibitory receptor of RANKL [46]. The binding of RANKL to its receptor RANK on osteoclasts and their precursors is the main activation signal for bone resorption. The osteoblast-derived M-CSF links to its receptor c-fms on the surface of osteoclast cell precursors enabling the RANK/RANKL signal. Through the adapter protein tumor necrosis factor receptor-associated factor 6 (TRAF6), RANK receptor, expressed on osteoclast, activates NF-kB as well as other transcription factors, such as mitogen-activated protein kinases (MAPKs), c-fos, activator protein 1 (AP1), up to nuclear factor of activated T cells (NFATc1). Under the influence of the RANKL/RANK interaction, NFATc1 also induces the expression of DC-STAMP, which is crucial for the fusion of osteoclast precursors [47,48]. NFATc1 is the hub of various signaling pathways. Together with other transcription factors, it induces osteoclast differentiation and proliferation, leading to the activation of genes codifying for calcitonin receptor, cathepsin k, and TRAP [49,50]. Both integrins and CD44 facilitate the attachment of the osteoclast podosomes to the bone surface [51,52] and mediate the formation and maintenance of the ruffled border, which is essential for osteoclast activity, enabling the trafficking of lysosomal and endosomal components, such as TRAP, cathepsin K, and matrix metalloproteinase-9 (MMP-9). Cathepsin K expressed in osteoclasts is involved in bone matrix type I collagen degradation, in dendritic cell activation through the toll-like receptor (TLR) 9, and supports the secretion of interleukin (IL)-6 and IL-23 [53]. TRAP and MMP-9 play essential roles in bone matrix demineralization and degradation.
Atogepant: an emerging treatment for migraine
Published in Expert Opinion on Pharmacotherapy, 2022
Cecilia Rustichelli, Rossella Avallone, Anna Ferrari
The CGRP receptor complex involves three protein components: (i) the calcitonin receptor-like receptor (CLR), which consists of seven transmembrane domains coupled with G proteins; (ii) the receptor activity modifying protein-1 (RAMP1) of a single transmembrane protein; and (iii) the receptor component protein (RCP), which couples the receptor complex to the cellular-signaling pathway. Binding of CGRP to the CLR/RAMP1 receptor activates multiple-signaling pathways and the subsequent recruitment of many downstream effectors (Figure 1). An antagonist, such as atogepant, can compete with the initial binding of the C-terminal portion of CGRP to the receptor by blocking its activation or can potentially displace bound CGRP by effectively deactivating the receptor [32,33]. X-ray cocrystal and cryogenic electron microscopy studies showed that two parts of the molecular structure of telcagepant and olcegepant simulate the binding of the Phe-NH2 group of the C-terminus of CGRPα to Thr122 of CLR. The structural analogy of atogepant as compared with telcagepant and olcegepant, enables it to bind equally to the receptor [32].
Updated review on the link between cortical spreading depression and headache disorders
Published in Expert Review of Neurotherapeutics, 2021
Doga Vuralli, Hulya Karatas, Muge Yemisci, Hayrunnisa Bolay
The 37-amino acid potent vasodilator neuropeptide, CGRP, is expressed extensively in the trigeminal ganglia, trigeminal brainstem nucleus, cerebral cortex, limbic system and peripheral nervous system of mammals [113,114]. CGRP is known to act via multiple receptors [115–117]. In rodents and in postmortem human samples [115,116], there are two CGRP receptors determined to be responsive to CGRP and are called calcitonin receptor‐like receptor/receptor activity‐modifying protein 1 complex (CLR/RAMP1, simply CGRP receptor), and CGRP-responsive calcitonin receptor/RAMP1 complex (CTR/RAMP1, simply AMY1 receptor). CGRP causes vasodilation either via endothelium-independent manner by the activation of CGRP receptors on smooth muscle that directly relax vessels or via endothelium-dependent manner by activating receptors on endothelial cells and stimulating nitric oxide (NO) production leading to NO diffusion to nearby smooth muscle cells and hence relaxation [118].
CGRP inhibitors for migraine prophylaxis: a safety review
Published in Expert Opinion on Drug Safety, 2020
Eduardo Rivera-Mancilla, Carlos M. Villalón, Antoinette MaassenVanDenBrink
In addition to serotonin, histamine, and nitric oxide [28], CGRP plays an important role in the pathophysiology of migraine [4–7]. CGRP is a 37-amino acid neuropeptide localized in the peripheral and central sensory nervous system, acting as a potent vasodilator as well as a neurotransmitter [29,30]. CGRP mainly mediates its biological effects through its interactions with the CGRP receptor. This canonical receptor is a complex of two subunits, namely: (i) a G-coupled protein receptor called calcitonin receptor-like receptor (CLR); and (ii) a receptor activity-modifying protein 1 (RAMP1) [31] (see Figure 2). In humans, CGRP is present in two isoforms, α-CGRP and β-CGRP. Since α-CGRP is the principal isoform localized in the peripheral and central sensory nervous system [32], its biological activity seems more important in the pathophysiology of migraine. However, in terms of side effects, we cannot exclude the β-CGRP isoform (which plays a role in the enteric transmission) [33] since some CGRP-blocking drugs (i.e. monoclonal antibodies such as eptinezumab, fremanezumab, and galcanezumab) are not selective and can block both the α-CGRP and β-CGRP isoforms.