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Drug Targeting: Principles and Applications
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Drug Delivery Approaches and Nanosystems, 2017
Ruslan G. Tuguntaev, Ahmed Shaker Eltahan, Satyajeet S. Salvi, Xing-Jie Liang
Cancer-associated fibroblasts (CAFs) are heterogeneous subpopulation of fibroblasts, which derived from various cells, such as normal fibroblasts, bone marrow-derived stromal cells, endothelial cells, and malignant or normal epithelial cells either via endothelial-mesenchymal transition (EndMT) or epithelial-mesenchymal transition (EMT) (Allen et al., 2011; Marsh et al., 2013; Quante et al., 2011; Räsänen et al., 2010). CAFs are one of the most abundant cell types in tumor microenvironment and play a key role in tumor progression. There is abundant evidence, that CAFs can support tumor growth, by secreting multiple factors. Among them are classical growth factors, such as epidermal growth factor (EGF), hepatocyte growth factor (HGF), and transforming growth factor beta (TGF-β) (Kalluri et al., 2006). Moreover, cancer-associated fibroblasts produce a number of additional factors, which can improve proliferative, metastatic and invasive properties of cancer cells. Among these factors are chemokines and cell surface molecules like integrin α11 or syndecan-1; proteases, like matrix metalloproteinase-2 (MMP2); mitogenic factors, such as secreted frizzled-related protein 1 (SFRP1); insulin-like growth factor 1 (IGF1) and insulin-like growth factor 2 (IGF2) (Östman et al., 2009). In order to facilitate angiogenesis, CAFs release proangiogenic factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), and platelet-derived growth factor (PDGF). In addition, CAFs can recruit bone marrow-derived cells or immune cells into the tumor progression (Cirri et al., 2012). Thus, it can be concluded, that the role of CAFs in tumor progression is significant and hence, targeting to various CAFs factors is a promising strategy in cancer therapy.
Applications of Pluripotent Stem Cells in the Therapy and Modeling of Diabetes and Metabolic Diseases
Published in Deepak A. Lamba, Patient-Specific Stem Cells, 2017
Suranjit Mukherjee, Shuibing Chen
Thus, the fact that iPSCs are derived from patients with T2DM or forms of lipodystrophy holds enormous potential to reveal mechanisms and phenotypes that result in human adipocyte dysfunction via disease modeling. Currently, only a limited number of protocols to differentiate human PSCs to human adipocytes have been reported. Early studies for hES cell-derived adipocytes exhibited limited analysis on expression of maturity markers such as CEBPα as well as minimal characterization of functional properties, such as adiponectin and leptin secretion and glucose uptake in the presence of insulin (34,35). More recently, published studies have emerged demonstrating robust generation of white and brown adipocytes from hESCs using both lentiviral and growth factor cocktail-based differentiation strategies (36,37). The differentiation of white adipocytes from hESCs and iPSCs was achieved using lentiviral-based expression of PPARγ. At the end of the differentiation period, lipid-filled white adipocytes emerged, expressing maturity markers such as CEBPα, fatty acid binding protein 4, hormone-sensitive lipase, and lipoprotein lipase. The white adipocytes also demonstrated functional activities, including glycerol release, glucose uptake in the presence of insulin, and leptin and adiponectin secretion. Using the same lentiviral-based approach, brown adipocytes were derived from hESCs and iPSCs via overexpression of PPARγ, CEBPβ, and/or PRDM16. The derived brown adipocytes express maturity markers, such as uncoupling protein 1 (UCP1), PGC1α, and cytochrome c1 (CYC1), as well as functional properties, such as elevated oxygen consumption. The drawback of this lentiviral-based differentiation protocol is that it cannot be used to study the defects related to genes upstream of the PPARγ signaling pathway. The second reported protocol for brown adipocyte differentiation used embryoid bodies in a hemopoietin growth factor cocktail containing KIT ligand, FLT3 ligand, interleukin-6, vascular endothelial growth factor, insulin-like growth factor-2, and BMP4 and BMP7 in two different phases. The reported brown adipocytes expressed maturity markers such as UCP1, PGC1α, CIDEA, CYC1, ELOVL3, and proliferator-activated receptor-α. The transplantation of these brown adipocytes into mice demonstrated improved fasting blood glucose and triglyceride levels when compared to vehicle control.
Epigenotoxicity: a danger to the future life
Published in Journal of Environmental Science and Health, Part A, 2023
Farzaneh Kefayati, Atoosa Karimi Babaahmadi, Taraneh Mousavi, Mahshid Hodjat, Mohammad Abdollahi
Paternal obesity causes hypomethylation of the IGF2 gene. It can influence insulin-like growth factor 2 protein production, which has a key role in prenatal growth and development. The exciting result of this epidemiological study was the occurrence of psychiatric disorders in the under-observed group.[239] It has been also demonstrated that dysregulation of neuregulin 3, which has a key role in the inhibition of the amygdala, caused by miR-190b overexpression, correlates with mental disorders such as ADHD.[27]