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Motilin and Gastric Inhibitory Polypeptide (GIP)
Published in Craig A. Johnston, Charles D. Barnes, Brain-Gut Peptides and Reproductive Function, 2020
Insulin is found both in the pancreas and the brain (Havrankova et al., 1978; Bernstein et al., 1984), but the major reproductive hormone-related actions of insulin are probably exerted peripherally. Both insulin and insulin-like growth factors are thought to play a role in the regulation of ovarian function. Receptors for both peptides have been found in ovarian tissues of animals and man, and these are present in stromal and follicular tissue and isolated granulosa cells (Adashi et al., 1985; Poretsky and Kalin, 1987). There have been numerous studies demonstrating an effect of insulin on steroidogenesis, and secretion of progesterone, estrogen, androstenedione, and testosterone have all been reported to be increased (Poretsky and Kalin, 1987). There appear to be a number of pathways which are influenced by insulin. These include effects on uptake and metabolism of lipoproteins (Veldhuis et al., 1986) and on levels of cytochrome P450 side-chain cleavage enzyme (Veldhuis et al., 1983), 3β-hydroxysteroid dehydrogenase (Blanco et al., 1981) and aromatase (Garzo and Dorrington, 1984). Other actions include modulation of LH and FSH receptor number, synergistic activity with FSH and/or LH, and enhancement of cell viability (Poretsky and Kalin, 1987). It is not clear whether insulin's action on ovarian tissue is mediated via interaction with insulin or insulin-like growth factor receptors, or both (Adashi et al., 1985).
Effects of Drugs
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
The effects of insulin and insulin-like growth factors on the replication of PC12 cells were investigated by Dahmer and Perlman (1988a). Addition of insulin to cells in a low serum medium increased the incorporation of tritiated thymidine into the cells, increased the number of cells in the cultures, and decreased the percentage of cells in the G0/G1 phase of the cell cycle. Insulin-like growth factors also increased thymidine incorporation. These data suggest that insulin and insulin-like growth factors are growth factors for PC12 cells and that the growth-promoting effects of these agents may be mediated by a type I insulin-like growth factor receptor on these cells.
General Biology of Cancer and Metastasis
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Included among these genes are genes that control glucose uptake and metabolism [such as the Glut1 (glucose transporter protein) and various glycolytic enzymes], extracellular pH (such as carbonic anhydrase IX), angiogenesis (such as VEGF), erythropoiesis (such as erythropoietin), and mitogenesis [such as transforming growth factor-a (TGF-α) and platelet-derived growth factor-β (PDGF-β)]. Signaling occurs through various cell surface receptors, including EGFR, HER2, VEGFR, and type I insulin-like growth factor receptor. These considerations explain the frequent overproduction of HIF, as well as its downstream targets, in RCC. pVHL binds to other cellular proteins, some of which may also be polyubiquitinated or in some other way modulated by pVHL. These proteins include the atypical protein kinase C family members, Sp1, heteronuclear ribonucleoprotein hnRNP A2, specific RNA Pol II subunits (Rpb1 and hsRBP7), Jade-1, Vdu1/2, fibronectin, proteins associated with microtubules, nuclear factor kappa B, and metalloproteinases (MMPs).
Targets for MAbs: innovative approaches for their discovery & validation, LabEx MAbImprove 6th antibody industrial symposium, June 25-26, 2018, Montpellier, France
Published in mAbs, 2019
Pierre Martineau, Hervé Watier, Andre Pèlegrin, Andrei Turtoi
IGF-1R. Insulin-like growth factor receptor (IGF-1R) has been recognized for decades for its role in tumorigenesis and growth. In addition, overexpression of IGF-1R has been largely documented in numerous tumor tissues such as squamous NSCLC, squamous head and neck cancer, ER+ breast cancer, prostate cancer and some types of sarcomas. However, so far, therapeutic approaches based on naked mAbs and tyrosine kinase inhibitors failed to show clinical benefit in patients. W0101 is an ADC consisting in a hzIgG1 antibody specific for IGF-1R conjugated to a microtubule-targeting agent F554443 (DAR4). Pre-clinical pharmacology data suggest that the mAb component of W0101 effectively delivers the cytotoxic drug to tumor cells and that the sensitivity correlates with dose and expression level. A companion diagnostic test was developed, and a first-in-human trial of W0101 was initiated to address clinical safety and to find the MTD (NCT03316638).13
Blood-brain barrier receptors and transporters: an insight on their function and how to exploit them through nanotechnology
Published in Expert Opinion on Drug Delivery, 2019
Rui Pedro Moura, Cláudia Martins, Soraia Pinto, Flávia Sousa, Bruno Sarmento
The insulin receptor (InsR) is a tetrameric glycoprotein, composed of two α- and β- subunits, cross-linked by sulfide bonds. It has an approximate molecular weight of around 350–400 kDa at the BBB. Regarding the peripheral tissues, InsR seems to have a higher molecular weight, of about 420 kDa [53,54]. It is a tyrosine-kinase type receptor, and its main ligands are insulin and insulin-like growth factors. Nonetheless, there is also the insulin-like growth factor receptor [IGF-R], which is structurally similar to InsR that has a higher affinity for insulin-like growth factors [55]. InsR is produced as a single chain pre-receptor, coupled with a signal peptide, that is cleaved after synthesis. Then, the receptor undergoes post-translational modifications, including folding, dimerization, and glycosylation, essential for its activity and ligand-binding affinity [56]. Insulin, is synthesized by beta cells of the pancreas as the precursor preproinsulin. Afterward, preproinsulin is cleaved of its signal peptide, releasing proinsulin. Lastly, the exposure of proinsulin to proteases promotes the cleavage of the middle linking peptide, the C peptide to form mature insulin [57].
Nanocarriers for brain specific delivery of anti-retro viral drugs: challenges and achievements
Published in Journal of Drug Targeting, 2018
Nila Mary Varghese, Venkatachalam Senthil, Shailendra K. Saxena
INSR is a heterotetramer, with a molecular weight of 300 kDa and two extracellular alpha and transmembrane beta subunits, that transports insulin from blood to brain [43]. Insulin or an anti- insulin receptor monoclonal antibody (29B4) was attached to HSA nanoparticle loaded with loperamide and the results showed these nanocarriers crossed the BBB, compared to the normal drug which was unable to cross [44]. Dieu et al. [45] formulated and studied the binding, cellular uptake and intracellular trafficking of amphiphilic diblock copolymer poly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline), poly(dimethylsiloxane)-block-poly (2-methyl-2-oxazoline) polymersomes conjugated to the anti-human insulin receptor antibody, 83–14 monoclonal antibody (mAb), in brain endothelial cells. In another study, Shilo et al. [46] formulated insulin targeted gold nanoparticles and did a quantitative investigation to find out the amount of the conjugated nanocarrier that crosses BBB and suggested that targeting insulin receptors could be an effective way for the transcytosis of drugs to reach brain. Monoclonal antibodies Mab83–7 and Mab83–14 actively bound to the insulin receptor on BBB and demonstrated fast transcytosis in rhesus monkeys in vivo [47]. In another study, increased brain uptake of the drug delivery system conjugated with the monoclonal antibody, 83–14-SA, within 3 h was observed when compared with non-conjugated ones in rhesus monkey [48]. The potential of human chimeric form of human insulin receptor monoclonal antibody to deliver genes and drugs across the BBB has been studied and was found to have a rapid transportation to all parts of the brain [49]. The insulin-like growth factor receptor (IGFR) also mediates the transcytosis of molecules through the same mechanism as that of insulin receptor and is composed of IGFR1 and IGFR2 [50].