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Organic Nanocarriers for Brain Drug Delivery
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Marlene Lúcio, Carla M. Lopes, Eduarda Fernandes, Hugo Gonẹalves, Maria Elisabete C. D. Real Oliveira
In the physiological activities of the BBB as a transport barrier, the RMT route is used for transport of macromolecules which are necessary for brain function, such as (i) transferrin (Tf), (ii) lactoferrin (Lf), (iii) insulin (Ins), (iv) low-density lipoproteins (LDLs) and (v) leptin (Lep). The transport of these molecules is possible because of the expression of several specific receptors on the luminal side of the BBB: (i) Tf receptors (TfRs), (ii) Lf receptors (LfRs), (iii) Ins receptors (InsRs) and Ins-like growth factor receptors (IGF1R and IGF2R), (iv) LDL receptors (LDLRs), acetylated LDLR (AceLDLR), LDLR-related protein (LRP) and scavenger receptors class B type which are also receptors for LDL (SR-B) and (v) Lep receptors (LepRs) [2, 7, 9]. By conjugating the surface of the NCs with ligands which specifically bind to these receptors, it is possible to achieve an active targeting strategy which helps NCs to transpose the BBB and enter the brain [2, 7, 9].
Epigenetic and Assisted Reproduction Experimental Studies
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Serafín Pérez-Cerezales, Noelia Fonseca Balvís, Benjamín Planells, Isabel Gómez-Redondo, Eric Marqués-García, Ricardo Laguna-Barraza, Eva Pericuesta, Raul Fernández-González, Alfonso Gutiérrez-Adán
Taking this into consideration, some studies have shown the effects of ART in humans. ART-conceived children have a higher risk of birth defects, increased rate of low birthweight, prematurity, and perinatal morbi-mortality than children conceived naturally (48,49). Ceelen et al. (2008) reported that ART children had higher systolic and diastolic blood pressure compared to children conceived naturally (50). Recently, it has been reported that DNA methylation differences observed between ART and in vivo conceptions are associated with some aspect of ART protocols and not simply by the underlying infertility (51). In the near future, it will be important to define if ART children present these effects in adulthood (47). Other studies have suggested an increase in the incidence of some imprinting disorders in ART children, that may cause Beckwith-Wiedemann, Angelman, and Silver-Russell syndromes (52) (Figure 11.1), but the absolute risk of conceiving a child with imprinting disorder after ART is still very low (53,54). Furthermore, it has also been shown alterations in DNA methylation and in the transcriptional level of a number of genes, such as those controlling growth (insulin-like growth factor [IGF]2/H19 and its receptor, IGF2R), in cord blood and placentae (55).
Genetics of gastric cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
MSI predisposes the genome to the mutational inactivation of tumor suppressor genes that have microsatellite repeats in their exons, such as transforming growth factor β receptor type II (TGFBR2), BAX, insulin-like growth factor II receptor (IGF2R), and E2F4. Duval et al. studied a series of 22 gastric cancers and found the following results: TCF4 mutations 9% (2/22), TGFBR2 mutations 86% (n = 19/22), BAX mutations 14% (n = 3/22), IGFR2 mutations 32% (n = 7/22), MSH3 mutations 9% (n = 2/21), and MSH6 mutations 54% (n = 5/23) (Duval et al., 1999). The inactivation of these genes appears to be part of a unique pathway of gastric carcinogenesis that can be distinguished from tumors that display chromosomal instability (CIN). For example, TP53 mutations occur uncommonly in MSI gastric cancers but are observed in the majority of microsatellite stable (MSS) cancers consistent with there being two distinct pathways that lead to gastric cancer formation (Luinetti et al., 1998; Renault et al., 1996; Strickler et al., 1994; Yamamoto et al., 1999). In addition, low level MSI (1 microsatellite locus shifted) has been detected in a subset of pre-neoplastic lesions in the stomach or in adenomas (Leung et al., 2000; Ottini et al., 1997; Semba et al., 1996; Tamura et al., 1995). The significance of this finding remains to be demonstrated but it suggests that at least some of these lesions are truly pre-malignant and that they have acquired pre-cancerous genetic alterations. Also of interest, MSI gastric cancers display intratumoral histologic and genetic heterogeneity consistent with a state of increased genomic instability (Chong et al., 1994; Chung et al., 1997, 1999; Ohue et al., 1996). TGFBR2 and BAX mutations occur most frequently throughout these genetically heterogeneous tumors, suggesting they occur early in the development of gastric adenocarcinomas and are important in the acquisition of the malignant phenotype (Chung et al., 1997; Ohue et al., 1996).
Beneficial Effects of Plasma Rich in Growth Factors (PRGF) Versus Autologous Serum and Topical Insulin in Ocular Surface Cells
Published in Current Eye Research, 2023
Eduardo Anitua, María de la Fuente, Ronald M. Sánchez-Ávila, Borja de la Sen-Corcuera, Jesús Merayo-Lloves, Francisco Muruzábal
Although the mechanism by which insulin acts on ocular surface cells is not well known, it has been suggested that it acts through binding to IGF receptors.20 It has been suggested that corneal keratocytes differentiated from mesenchymal stem cells express the IGF-I receptor;22 however, the scarce studies published in the literature on IGF receptor expression by corneal keratocytes showed that this cell type express the IGF-2 receptor (IGF2R).31 IGF2R is a large transmembrane glycoprotein highly conserved in all vertebrates, and although its function is not well known, several studies suggest that it is a multifunctional receptor, but its main activity is to limit cell growth.32 This could explain why insulin-treated fibroblast cells grow similarly to non-stimulated cells and has no effect on myofibroblast cell reversion.
Vesiculin derived from IGF-II drives increased islet cell mass in a mouse model of pre-diabetes
Published in Islets, 2022
Kate L. Lee, Jacqueline F. Aitken, Xun Li, Kirsten Montgomery, Huai-L. Hsu, Geoffrey M. Williams, Margaret A. Brimble, Garth J.S. Cooper
Insulin-like growth factor II (IGF-II) has been shown to be produced and secreted by pancreatic islet β-cells. Often thought of as a neonatal growth factor, the role of IGF-II in adulthood is less well understood. Although adult humans have relatively large concentrations of circulating IGF-II, the vast majority is bound to binding proteins in complexes that suppress its bioactivity.1 There is no clear understanding of the role of circulating IGF-II in the healthy physiology of adults, although it is clear that dysregulation in IGF-II system, for example, through loss of imprinting if the IGF2 or the IGF2R locus, is related to inappropriate tissue growth.2 Tissue-specific expression of IGF-II in adulthood is likely to be a key factor in the regeneration of adult tissues through regulating adult stem cell differentiation.3–5
How successful has targeted RNA interference for hepatic fibrosis been?
Published in Expert Opinion on Biological Therapy, 2018
Mohube Betty Maepa, Abdullah Ely, Patrick Arbuthnot
The abundance of vitamin A receptors on HSC membranes has also been explored to enable HSC-targeted delivery. Encapsulation of siRNAs against collagen-specific chaperone molecule gene, gp46 [48], (the rat homolog of human HSP47) and matrix metalloproteinase-2 [12] in vitamin A-coupled lipoplexes resulted in preferential siRNA uptake by HSCs and resolution of hepatic fibrosis in rats (see above). Another recent study used lipid nanoparticles that contained vitamin A (ssPalmA) or vitamin E (ssPalmE) as scaffolds for HSC-specific delivery of siRNAs [65]. The ssPalmA showed the highest silencing efficiency and significantly inhibited collagen production. A candidate antifibrotic drug, ND-L02-s0201, which comprises a complex of vitamin A and HSP47-targeting siRNAs has shown impressive safety in early phases of clinical trial [50]. The drug is being developed in a partnership between Bristol-Myers Squibb and Nitto Denko. Recent studies have taken advantage of selective overexpression of insulin-like growth factor 2 receptor (IGF2R) in HSCs. An IGF2R-binding peptide [66] or aptamer [67] was used in formulations that delivered siRNAs targeting poly (rC) binding protein 2 gene (PCBP2) in HSCs. Both the peptide and the aptamer resulted in preferential uptake of the siRNA by the rat fibrotic liver to silence PCBP2, which is essential for type I collagen accumulation. The peptide resulted in improved targeting of HSCs when compared to vitamin A and cholesterol and better inhibition of migration of activated HSCs [66,67]. These studies demonstrate that significant strides are being made with advancing safe and efficient delivery of silencers that target fibrosis-inducing genes. Results augur well for the future of RNAi-based treatment of hepatic fibrosis.