China
Africa
Explore chapters and articles related to this topic
Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Further microarray studies in CYP2D6-humanized transgenic mice have shown that seven transcription factors, namely, activating transcription factor 5 (ATF5), early growth response 1 (EGR1), forkhead box protein A3 (FOXA3), JUNB, KLF9, KLF10, and REV-ERBα, are upregulated in mouse liver during pregnancy (Koh et al. 2014b). KLF9 itself is a weak transactivator of CYP2D6 promoter but significantly enhances CYP2D6 promoter transactivation by HNF-4α, a known transcriptional activator of CYP2D6 expression. The results from deletion and mutation analysis of CYP2D6 promoter activity have identified a KLF9 putative binding motif at the –22/-14 region to be critical in the potentiation of HNF-4α–induced transactivation of CYP2D6 (Koh et al. 2014b). KLF9, a member of the KLF transcription factor family of zinc finger DNA-binding proteins, can either activate or repress target gene expression in a promoter-specific context. KLF9 is involved in cell differentiation of B cells, keratinocytes, and neurons. Biologic actions of KLF9 are mediated either by its direct binding to the promoters of its target genes such as CYPIAI or by coactivation of other transcription factors (Kaczynski et al. 2002; Shields and Yang 1998; Zhang et al. 1998). KLF9 is also a key transcriptional regulator for uterine endometrial cell proliferation, adhesion, and differentiation, all factors that are essential during the process of pregnancy and are switched off during tumorigenesis (Pabona et al. 2012; Shimizu et al. 2010; Simmen et al. 2008, 2015). In endometrial cells, KLF9 binds to progesterone receptors and enhances transcriptional activation of the target genes (Zhang et al. 2003).
Emerging ergogenic aids for strength/power development
Published in Jay R Hoffman, Dietary Supplementation in Sport and Exercise, 2019
Betaine has been shown to produce some other responses that potentially could contribute to body composition and performance improvements. Betaine has been suggested to increase lipolysis, inhibit lipogenesis, increase insulin-like growth factor 1(IGF-1) and modulate IGF-1 receptor signalling (2). Two weeks of betaine supplementation (2.5 g per day) was shown to augment the growth hormone (GH) and IGF-1 responses to an acute bout of exercise while reducing the cortisol response (2). Resting skeletal muscle total Akt, maintenance of p70S6k phosphorylation and decreased inhibition from AMPK phosphorylation were also seen, indicating potential to augment anabolic signalling (2). Because betaine functions as a methyl donor, DNA methylation affects myogenesis, or the process of skeletal muscle fibre generation. In C2C12 skeletal muscle myoblasts only high doses (10 mM) of betaine were shown to increase IGF-1 signalling and subsequent myoblast differentiation and myotube size (52). Similarly, betaine (up to 15 mM in a dose-dependent manner) was shown to decrease myoblast proliferation (via reduced mRNA expression of JAK1, Sirt2 and Runx1, and increased expression of KLF10, SRF and myostatin), increase myoblast differentiation (via up-regulation of MyoG, MRF4, troponin and MYH6 mRNA), increase myotube formation, fusion, length and area, and induce fibre-type transitions towards oxidative slow-twitch fibres (19). In bone, betaine has been shown to increase osteoblast differentiation via increasing osteogenic gene expression of transcription factors such as RUNX2 and OSX and the bone marker proteins osteopontin (OPN) and bone sialoprotein (BSP) (60). Betaine also increased calcium influx, ERK signalling and IGF-1 mRNA in human osteoblasts (60).
Analysis of single-cell sequencing results of an elderly patient with myeloid leukemia reveals high expression of multiple oncogenes in monocytes and hematopoietic stem cells
Published in Hematology, 2023
Xiaoli Xu, Minjian Xiong, Haiyan Ye, Yonglei Qi, Ying Zhao
Since the patient was AML-M5, we primarily analyzed the DEGs of monocytes in peripheral blood and bone marrow. A total of 7990 DEGs were identified. Figure 2(A) shows the heatmap of the top 40 DEGs in monocytes compared to peripheral blood with bone marrow. There were 20 DEGs that presented significantly higher/lower expression in peripheral blood than in bone marrow. Among these 40 DEGs, there were 14 genes that significantly correlated with the occurrence and development of tumors or malignant tumors such as MYB Proto-Oncogene (MYB), Regulator Of Cell Cycle (RGCC), and JunB Proto-Oncogene (JUNB) (Figure 3). Genes associated with hematological malignancies included Complement C5a Receptor 1 (C5AR1) and Kruppel Like Factor 10 (KLF10) in addition to MYB and JUNB. In addition, several genes are closely linked to each other, such as Elastase (ELANE) is an important paralog of Proteinase 3 (PRTN3), Cathepsin G (CTSG) is an important paralog of Azurocidin 1 (AZU1), and ZFP36 Ring Finger Protein Like 1 (ZFP36L1) and ZFP36 Ring Finger Protein (ZFP36) belong to the same family of RNA-binding proteins involved in messenger RNA (mRNA) metabolism pathways.
Strategies to improve pharmacogenomic-guided treatment options for patients with β-hemoglobinopathies
Published in Expert Review of Hematology, 2021
George P. Patrinos, David H. K Chui, Ross C. Hardison, Martin H. Steinberg
There are few studies focused on PGx of HbF response to HU in SCD and even fewer in β-thalassemia [4,5]. Genome-wide association studies (GWAS) have revealed strong associations between the quantitative trait loci (QTL) Xmnl-HBG2 within the human β-globin gene cluster and the HBS1L-MYB and BCL11A loci and HbF levels [4]. In a candidate gene-based association study, where the increment in HbF at 2 years after institution of HU in SCD was the outcome measure, Ma and coworkers [6] showed significant association of variants in the linkage peaks of 6q22.3–23.2 representing the HBS1L-MYB QTL and 8q11-q12, which had previous been associated with HbF levels. Genomic variants in the MAP3K5, TOX, NOS1, NOS2, ARG2, and FLT genes were also associated with HbF response. An association between SAR1 gene promoter variants and response to HU was also demonstrated [7]. In 2012, Borg and coworkers [8] showed, using whole-transcriptome analysis, that genomic variants in the KLF10 gene also modulated HbF levels in response to HU treatment, a finding that has been confirmed in two subsequent retrospective studies [9,10]. The latter study also showed that genomic variants within the MAP3K5, NOS2A, ARG2 genes could be also correlated with HU treatment response, confirming previous findings by Ma and coworkers.
Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma
Published in Journal of Extracellular Vesicles, 2018
Tatyana Vagner, Cristiana Spinelli, Valentina R. Minciacchi, Leonora Balaj, Mandana Zandian, Andrew Conley, Andries Zijlstra, Michael R. Freeman, Francesca Demichelis, Subhajyoti De, Edwin M. Posadas, Hisashi Tanaka, Dolores Di Vizio
L-EVs and S-EVs were isolated from the plasma of these mice, and L-EV DNA tested by dPCR for the specific SCNV that had been found in both PC3 cells and derived L-EVs: MYC, AKT1, PTEN, PTK2 and KLF10. MYC, AKT1, PTK2 and KLF10 were amplified, as expected (Figure 4(f)); however, their CN in vivo appeared to be generally lower compared to their respective CN in vitro (Figure 3(d)). Surprisingly, we could not detect PTEN deletion in plasma-derived L-EVs. This might be due to non-specific binding of the human-specific dPCR probes to mouse sequences, which would “dilute” the tumour signal for the amplified genes (MYC, AKT1, PTK2 and KLF10) and generate a “false-positive” signal for the deletion (PTEN). These results, collectively, suggest that gene amplifications of the tumour cells are reported in L-EVs in vivo even if the signal is diluted. Furthermore, circulating L-EVs might report tumour-specific SCNV in patients with mCRPC.