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Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Jiang et al. (2013) have developed a novel mediation analysis approach to identify new expression quantitative trait loci (eQTLs) driving CYP2D6 activity by combining genotype, gene expression, and enzyme activity data. The authors have found 389,573 and 1,214,416 SNP–transcript–CYP2D6 activity trios that are strongly associated for two different genotype platforms, namely, Affymetrix and Illumina, respectively. In the Affymetrix data set, 295 SNPs correlate with at least 20 genes, which are used to check for overlapping with the results of mediation analysis. A total of 289 eQTL hotspots are found to correlate with 1542 gene expression profiles. The Illumina data set has found that 724 SNPs correlate with at least 20 genes, and 719 of the hotspots are significantly correlated with 2444 genes in mediation analysis. Nine hundred thirty-nine and 1420 genes are successfully mapped in the Ingenuity database for two platforms. The majority of eQTLs are trans-SNPs. Five (CCL16, CCL20, CMTM5, IL-6, and SPP1) and 7 (CCL16, CCL20, CKLF, CKLFSF5, EPO, FAM3C, and SPP1) cytokines, 5 (AR, NR1I2/PXR, NR1I3/CAR, NR2F6, and PPARα) and 7 (AR, ESR1, NR1I2/PXR, NR1I3/CAR, PPARα, RORα/NR1F1, and RORγ) nuclear receptors, and 80 and 113 transcription regulators are found to mediate the relationship between genetic variant and CYP2D6 activity for Affymetrix and Illumina data sets. Overlapped eQTL hotspots with the mediators lead to the identification of 64 transcription factors that can regulate CYP2D6 (Jiang et al. 2013). These transcription factors include AATF, ALYREF, ARHGAP35, ASB8, ATF4, CBX4, CEBPG, CSDA, DDIT3, E2F5, ETV7, FOXN3, FOXN3, FUBP1, GPS2, HDAC10, HMGN1, ID1, INVS, IRF9, KANK1, KAT2B, KHDRBS1, KLF12, MAF, MAML2, MEIS2, MLXIPL, MXD4, MYBBP1A, MYCL1, NCOA7, NCOR1, NFIA, NFKB2, NFYA, NOLC1, NPM1, PEX14, PYCARD, SAP18, SATB1, SIM2, SLC2A4RG, SMARCC1, SNAI3, SNW1, SOX5, TCERG1, TCF7L2, TEAD3, TEAD4, TFDP2, TFEB, TOB1, p53, YWHAB, YY1, ZGPAT, ZHX3, ZKSCAN1, ZNF132, ZNF256, and ZNF263 (Jiang et al. 2013). Among them, YY1 has been reported to putatively bind to human CYP2D6 or rat Cyp2d4 promoter and regulate the expression of CYP2D6 (Gong et al. 2013) and Cyp2d4 (Mizuno et al. 2003). This study has provided new insights into the complex regulatory network for hepatic CYP2D6. Addition of the p53 inhibitor cyclic PFT-α in HepG2 cells dose-dependently enhances CYP2D6 and 3A4 activity, whereas addition of the p53 activator NSC 66811 dose-dependently inhibits CYP2D6 and 3A4 activity (Xiao et al. 2015). Further functional and validation studies are certainly needed to verify the regulation of CYP2D6 by these genes.
Research Progress of circRNAs in Inflammatory Mechanisms of Diabetic Retinopathy: An Emerging Star with Potential Therapeutic Targets
Published in Current Eye Research, 2022
Shuai He, Chufeng Gu, Tong Su, Qinghua Qiu
CircEhmt1 was originally discovered to display a high level of upregulation in exosomes isolated from hypoxic-induced pericytes, serving as an important regulator in hypoxic-cultured pericytes.134 At the same time, the loss of pericytes was a main characteristic of DR135 and its abnormal interaction with endotheliocytes was verified to contribute to the retinal vascular leakage in the progression of DR.136 Through further research, the study discovered that increased exosomal circEhmt1 from hypoxia pericytes led to decreased apoptosis and increased angiogenesis in HG-cultured endotheliocytes by immunofluorescence staining and tube formation assays. What’s more, exosomal circEhmt1 released from hypoxia-pretreated pericytes downregulated the levels of NLRP3 and proinflammatory factors IL-1β and IL-18 expression in HG-induced endotheliocytes.134 All the above findings indicated that the increased exosomal circEhmt1 released from hypoxia pericytes protected endothelial cells induced by high glucose by inhibiting NLRP3 inflammasome and inflammatory cytokines production. Besides, the protective mechanism also lied in the upregulation of downstream NFIA (a transcription factor) expression, which was able to reverse the increased generation of IL-1β and IL-18 and modulated the inflammation response.134
A combined microRNA and proteome profiling to investigate the effect of ZnO nanoparticles on neuronal cells
Published in Nanotoxicology, 2020
Ankur Kumar Srivastava, Smriti Singh Yadav, Saumya Mishra, Sanjeev Kumar Yadav, Devendra Parmar, Sanjay Yadav
Expression of miR-141 (8.9-fold) and miR-153 (8.6-fold) have shown maximum upregulation in ZnO NPs exposed differentiated PC12 cells. The expression of both miRNAs has been reported to regulate neuronal differentiation. In our earlier studies using PC12 cells, we have shown that the miR-200 family directly regulates the differentiation of neurons, and miR-141 is one of the members of the miR-200 family (Pandey et al. 2015b). Similarly, studies of Tsai et al. (2014) have shown that over-expression of miR-153 prevents neuronal differentiation without altering neuroepithelial cell survival or proliferation. Our studies have identified nuclear receptors (SOX2, KLF4, NANOG, OCT4, and PAX6) as a target of miR-200 family members, and studies of Tsai et al. have identified Nfia (nuclear factor-1A) and its paralog, Nfib (nuclear factor-1b) as direct targets of miR-153.
Precise nanoinjection delivery of plasmid DNA into a single fibroblast for direct conversion of astrocyte
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Hang-Soo Park, Hyosung Kwon, Jewon Yu, Yeonju Bae, Jae-Yong Park, Kyung-Ah Choi, Yeonho Choi, Sunghoi Hong
In particular, we demonstrated a mechanism in which a single fibroblast is converted to an astrocyte; this was achieved by the activation of a Sox2-triggered GFAP regulator BMP2 but not of BMP4 or BMP6 and by the increase of an active CpG demethylase TET1 but not of TET2 and TET3. Since Yamanaka’s factors OSKM have been used to generate induced pluripotent stem cells as well as other types of tissue-specific cells [19,37], we also used OSKM to convert a fibroblast into an astrocyte although the transcription factors (NFIA, NFIB and SOX9) to define astroglial fate have been identified in a previous study [29], which suggests an alternative pathway for astroglial fate decision.