China
Africa
Explore chapters and articles related to this topic
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.
TGF-β-induced CCR8 promoted macrophage transdifferentiation into myofibroblast-like cells
Published in Experimental Lung Research, 2022
Haijun Liu, Qingzhou Guan, Peng Zhao, Jiansheng Li
CCR8 was originally identified on monocytes.29 Impaired monocyte infiltration has been observed in a murine airway inflammation model in CCR8-KO mice. CCR8 is also expressed in macrophages in lung and liver tissue. Similarly, CCR8-KO mice displayed a significant reduction in macrophages in the lung after challenge by ovalbumin and reduced macrophage infiltration in CCl4-induced liver damage.14,30 Studies31 also found that CCR8 present in endothelial cells was a functional receptor of endotheliocytes and mediated the chemotaxis of endothelial cells in response to CCL1 and vCCL1. In our study, we found that CCR8 was significantly increased in macrophages exposed to TGF-β in a time- and dose-dependent manner. CCL1 has been shown to be the only high-affinity ligand for CCR8; it is involved in many physiological processes mediated by CCR8.32,33 However, the present results showed that the expression of CCL1 was decreased in a time- and a dose-dependent manner versus the increased expression of CCR8, which indicated that CCL1 did not participate in the CCR8 activities examined in this study. Further evidence34–36suggests that other chemokines, such as CCL16, CCL18, and MIP-1 (macrophage inflammatory protein-1), have been identified as other ligands for CCR8. However, whether any cytokines other than CCL1 participate in macrophage transdifferentiation requires further evaluation.
PTEN negatively regulates the expression of pro-inflammatory cytokines and chemokines of fibroblast-like synoviocytes in adjuvant-induced arthritis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Xiao-Feng Li, Xin Chen, Jing Bao, Le Xu, Lei Zhang, Cheng Huang, Xiao-Ming Meng, Jun Li
Along with FLSs activation and migration that is stimulated by several chemokines including CCL2 and CCL3 and these chemokines are abundantly expressed in the RA synovium, these chemokines may facilitate fibroblast recruitment to the synovium and subsequently induce activation of FLSs [32]. Interestingly, we also have measured inhibition of PTEN expression with bpv or PTEN-RNAi that could active the expression of CCL2 and CCL3 in AIA FLSs. Chemokines regulate chemotaxis in nearby responsive cells and are implicated in chronic inflammatory diseases, such as RA, atherosclerosis and adipose inflammation [33]. Furthermore, overexpression of PTEN with PTEN-GV141 could down-regulate expression of CCL2 and CCL3 mRNA in AIA FLSs. Rump et al. [34] proved the chemokines CCL7, CCL14, CCL16 and CCL22 occurred in RA synovial fluid and endothelial cells and have a highly significant correlation with the level of anti-CCP. In addition, with bpv or PTEN-RNAi of FLSs, the mRNA expression of VCAM-1 and VEGF-α were improved evidently. It has been proved that the serum VCAM-1 levels increased in RA, which could possibly be associated with the autoimmune and inflammatory reactions found in RA [35]. The VEGF-α is the most potent proangiogenic factor in RA angiogenesis and promotes the formation of invasive pannus, a thickened layer of synovial tissue that erodes cartilage and bone. More importantly, over-expression of PTEN with PTEN-GV141 reduced expression of VCAM-1 and VEGF-α mRNA. Consequently, PTEN also negatively regulates the expression of chemokines, VCAM-1 and VEGF-α of FLSs in AIA rats.
Targeted urine proteomics in lupus nephritis – a meta-analysis
Published in Expert Review of Proteomics, 2020
Ting Zhang, Valeria Duran, Kamala Vanarsa, Chandra Mohan
Other chemokines, including C-X-C motif chemokine 6 (CXCL6, or GCP-2), C-C motif chemokine 14 (CCL14 or HCC-1), C-C motif chemokine 16 (CCL16 or HCC-4), C-C motif chemokine 7 (CCL7 or MCP-3), C-C motif chemokine 13 (CCL13 or MCP-4), C-C motif chemokine 18 (CCL18 or PARC), and C-C motif chemokine 28 (CCL28), have not been well investigated or validated in LN. However, some of them have been implicated in other renal diseases. For instance, CXCL6 promotes renal interstitial fibrosis in diabetic nephropathy by activating JAK/STAT3 signaling [40]. Elevated urinary CCL14 predicts persistent acute kidney injury (AKI) in a large heterogeneous cohort of critically ill patients with severe AKI [41]. Indeed, it has been reported that a lupus relevant variant may lie within or in proximity of a haplotype encompassing the CCL14 gene [42]. CCL16 significantly enhances the effector and the antigen presenting function of macrophages and augments T cell lytic activity [43]. In addition, CCL16 also activates an angiogenic program in vascular endothelial cells [44]. B lymphocyte–derived CCL7 augments neutrophil and monocyte recruitment, exacerbating acute kidney injury [45]. CCL7 displays a dual role in the development of renal tubular interstitial fibrosis, deleterious in early stages but beneficial during later stages [46]. CCL13 has an important role in the recruitment and retention of monocytes/macrophages in renal inflammation [47]. CCL18 synergizes with high concentrations of glucose in stimulating fibronectin production in human renal tubuloepithelial cells [48]. CCL18 drives renal inflammation through CCR8-expressing cells and could serve as a biomarker for disease activity and renal relapse in ANCA-associated crescentic glomerulonephritis [49]. CCL28 displays strong homing capabilities for B and T cells at several mucosal and epithelial sites, and orchestrates the trafficking and functioning of lymphocytes [50]. Thus, the elevation of these chemokines in active LN may contribute to LN pathogenesis, but this needs to be formally tested.