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Pathogenesis: Molecular mechanisms of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Anastasia E. Markatseli, Theodora E. Markatseli, Alexandros A. Drosos
Active vitamin D acts in the following three ways: (a) it increases calcium absorption in the small intestine from 10%–15% to 30%–40%, and, in parallel, it augments phosphorus absorption from 60% to 80% (74–76). Calcium absorption is accomplished through the interaction of vitamin D with the vitamin D receptor-retinoic acid x-receptor complex (VDR-RXR), which in turn enhances the expression of the epithelial calcium channel TRPV6 and the calcium-binding protein calbindin 9K (82). (b) It increases the expression of RANKL in osteoblasts, and consequently, it induces the maturation of osteoclast precursors to osteoclasts. This process of osteoclastogenesis mobilizes calcium stores from the skeleton to maintain calcium homeostasis. (c) It decreases the synthesis and secretion of PTH from the parathyroid glands (82).
Nonclassical Ion Channels and Ischemia
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
TRP channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its expression is dramatically increased in numerous types of cancer [43]. In ischemia, myelin is damaged in Ca2+ involved pathway which is devoted to glutamate release activating NMDA receptors. The H+-gated [Ca2+]i elevation is mediated by channels with characteristics of TRPA1, which could be inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout, suggesting that TRPA1-containing ion channels performs a potential value in white matter ischemia [44]. In edema, ischemic stroke can be prevented by TRPV4, because TRPV4 is activated by body temperature and is enhanced by heating through glutamate receptors [45]. TRPV4 is a calcium-permeable cation channel that is also sensitive to cell swelling, modulating the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathways that regulate cell apoptosis when activated [46]. Up-regulation of TRPV4 is mediated through NR2B-NMDAR down-regulating the Akt signaling pathway for neurotoxicity [47]. In the penumbra, peri-infarct depolarizations (PIDs) are accompanied by strong intracellular calcium elevations in astrocytes and neurons, thereby negatively affecting infarct size and clinical outcome. TRPV4 channels contribute to calcium influx into astrocytes and neurons and subsequent extracellular glutamate accumulation ameliorate the PID-induced calcium overload during acute stroke [48]. TRPM2 has a high sensitivity to oxidative damage, so the oxidative stress and the release of extracellular Ca2+, hydrogen peroxide, adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate can change the activity of TRPM2 in the central nervous system and the immune system [49]. As a result, N-acetyl-l-cysteine (NAC) treatment can provide neuroprotection via regulation of TRPM2 [50]. Besides, the suppression of TRPM7 channels reduce delayed neuronal cell death and preserved neuronal functions in global cerebral ischemia [13]. And the TRPA1 is expressed by primary afferent nerve fibers, which is also a ‘receptor-operated’ channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch. It functions as a low-threshold sensor for structurally diverse electrophilic irritants, which may act as an attractive target for novel analgesic therapies [51]. Zn2+ is transferred from endolysosomal vesicles to the cytosol through the TRPML1 channel, and its sensitivity of Ca2+ play critical roles in neuronal function [52]. The TRPC5 ion channel is involved in ischemia which is related to endothelial cell sprouting and angiogenesis. Riluzole, the TRPC5 activator, are tested on ischemic injury regulating nuclear factor of activated T cell isoform c3 and angiopoietin-1 which could provide the mechanism for the angiogenic function of TRPC5 [53].
Advances in venom peptide drug discovery: where are we at and where are we heading?
Published in Expert Opinion on Drug Discovery, 2021
Taylor B. Smallwood, Richard J. Clark
The soricidin peptide is a 54-amino acid paralytic toxin isolated from the submaxillary saliva glands of the northern short tailed shew (Blarina brevicauda). The peptide is reported to inhibit calcium uptake via the transient receptor potential of vanilloid type 6 (TRPV6) [61]. Based off the C terminal region of soricidin, two smaller peptides, SOR-C13 and SOR-C27 were developed. Both are found to bind to the TRPV6 channel with high affinity and selectivity [62]. TRPV6 is highly selective to calcium and contributes significantly to calcium homeostasis in the body. The channel is widely distributed in tissues found in the intestine, pancreas and placenta [63]. TRPV6 is found to play a central role in tumor development and progression, with enhanced expression found in many cancer cells including breast, colon, prostate, and thyroid [64]. SOR-C13 is highly selective for TRPV6 and once bound, disrupts the function of the channel by inhibiting calcium influx [65]. The peptide has undergone Phase I clinical trials for a dose escalation safety study in adults with advanced solid tumors of epithelial origin (NCT01578564). The study found that SOR-C13 was well tolerated in patients and provided preliminary indications of anticancer activity – with two out of four patients with advanced ovarian cancer showed stable disease after two cycles of treatments [66]. A second study is currently recruiting to identify side effects and the best dose of SOR-C13 in treating patients with solid tumors that have metastasized and do not respond to conventional treatment (NCT03784677).
Approaching Target Selectivity by De Novo Drug Design
Published in Expert Opinion on Drug Discovery, 2019
Thomas Fischer, Silvia Gazzola, Rainer Riedl
The selective calcium channel of transient receptor potential vanilloid 6 (TRPV6) is overexpressed in advanced prostate cancer and various other carcinomas. It is suggested that inhibition of calcium transport through this channel might control cancer cell proliferation. Because crystallographic data of the target was absent, a ligand-based approach was followed, starting from the known weak TRPV6 inhibitor 23 (Figure 3) with an IC50 of 90 μM as a seed molecule [97]. Two successive rounds of ligand-based virtual screening, where 3D fingerprints were compared, yielded 24 (Figure 3) with an IC50 of 0.32 μM [97,98]. As the method perceives shape and pharmacophores of the initial molecule without considering connectivity patterns, a significantly diverse scaffold is obtained. Inhibitor 24 displayed high selectivity against other calcium channels and related TRP targets.
The use of LP533401 as a therapeutic option for renal osteodystrophy affects, renal calcium handling, vitamin D metabolism, and bone health in uremic rats
Published in Expert Opinion on Therapeutic Targets, 2019
Dariusz Pawlak, Tomasz Domaniewski, Beata Znorko, Krystyna Pawlak
Our previous study showed that VEH and LP533401 treatment can inhibit renal VDR/FGF1R/Klotho/type II sodium-dependent phosphate cotransporters axis [16]. Since VDR, PTHR, and particularly Klotho gene expression are important regulators for Ca transporting proteins in kidney [9–12,18,19], the effect of 8-week administration of VEH and LP533401 on renal TRPV5, TRPV6, CaBP-28k, CaBP-9k, PMCA1b, NCX1, and PTHR mRNA expression was measured (Figure 1). The significantly declined mRNA levels of TRPV5 (A), CaBP-28k (B), CaBP-9k (C), and PTHR (G) were observed in rats treated with VEH and LP in comparison to animals with CKD and controls. TRPV6 gene expression was increased in CKD compared to CON; the administration of VEH and LP led to normalization of TRPV6 expression (Figure 1(d)). Similarly, PMCA1b gene expression in CKD animals was higher than in controls; both VEH administration and LP treatment decreased this gene expression in the dose-dependent manner (Figure 1(e)). In contrast, the significantly increased mRNA levels of NCX1 were observed in rats treated with VEH, and particularly with LP in comparison to animals with CKD and controls (Figure 1(f)).