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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.
Environmental chemicals and adverse pregnancy outcomes: Placenta as a target and possible driver of pre- and postnatal effects
Published in Critical Reviews in Environmental Science and Technology, 2023
Jing Li, Adrian Covaci, Da Chen
Fetal growth has been reported to be associated with aberrant methylation of LINE1, IGF2, NR3C1, 11β-HSD2, DIO3, as well as several others. DNA methylation within LINE1 repetitive elements, which represent about 20% of the overall genome, has been frequently used as surrogate markers for global methylation (Zhao et al., 2016). NR3C1, the glucocorticoid receptor gene, is a known mediator of glucocorticoid signaling (Zhao et al., 2016). IGF2 is a crucial modulator of the fetus growth and development (Zhao et al., 2016). Both placental 11β-HSD2 and IGF2 methylation were related to exposure to PBDEs (Zhao et al., 2019). Importantly, IGF2 methylation mediated about 38.5% of the effects of the sum of PBDEs (from BDE-17 to BDE-190) in umbilical cord blood on IUGR (Zhao et al., 2019). PBDE (e.g., BDE-66, −153, and −209) exposure was significantly associated with decreased DNA methylation of LINE1, NR3C1 and IGF2 (Zhao et al., 2016). Also, maternal exposure to BDE-47 is associated with DNA methylation of DIO3 in the placenta of female infants (Kim et al., 2019). Moreover, seven CpG sites mediated the association between BDE-47 and neonatal anthropometry measures, and genes annotating the top differentially methylated CpG sites were enriched in pathways related to differentiation of embryonic cells (Ouidir et al., 2020). Changes in placental DNA methylation might be part of the underlying biological pathway between in utero PBDE exposure and adverse fetal growth.
Transgenerational male reproductive effect of prenatal arsenic exposure: abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse
Published in International Journal of Environmental Health Research, 2022
Guoying Yin, Liting Xia, Yaxing Hou, Yaoyan Li, Deqing Cao, Yanan Liu, Jingshan Chen, Juan Liu, Liwen Zhang, Qiaoyun Yang, Qiang Zhang, Naijun Tang
H19 and Igf2 are expressed in a monoallelic fashion from the maternal and paternal chromosomes, respectively. Methylation of H19 DMR and Igf2 DMR2 plays a critical role in Igf2 and H19 allelic transcription. On the maternal allele, CTCF insulator binds to the unmethylated H19 DMR and blocks the access of enhancer to the Igf2 promoter, resulting in H19 expression and Igf2 repression. On the paternal allele, H19 DMR is methylated and binding of CTCF is blocked, thus inactivating H19 and promoting Igf2 expression (Doshi et al. 2013). DMR2 is an Igf2 enhancer located in the sixth exon and a deletion of DMR2 could reduce Igf2 mRNA expression level (Murrell et al. 2001). In our study, hypomethylation of H19 DMR in testis occurs among arsenic-treated lineage mice, thus resulting in H19 overexpression. Although both H19 DMR and Igf2 DMR2 are hypomethylated, the mRNA expression levels of Igf2 in the testis are increased in arsenic-treated lineage. In addition to H19 DMR and Igf2 DMR2, Igf2 DMR0 and Igf2 DMR1 are also involved in the regulation of Igf2 expression. Constância et al. (2000) reported that deletion of DMR1 results in biallelic expression of Igf2. A recent study indicates that DMR0 is methylated on the active paternal allele in all tissues and may function similarly to mouse DMR1 (Murrell et al. 2008). It has been reported that exposure of mouse preimplantation embryos to 2,3,7,8-tetrachlorodibenzo-pdioxin, or TCDD, increased the methylation of Igf2/H19 imprint control region and decreased the mRNA expression of imprinted genes Igf2 and H19 (Wu et al. 2004). The heterogeneity of Igf2 expression may be caused by different environmental exposures and further studies are needed to clarify the interaction between methylation/expression defects of H19 and Igf2 of prenatal arsenic exposure.