| 1. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 2. |
- Pan, Lili, et al.
(författare)
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Expression of flTF and asTF splice variants in various cell strains and tissues
- 2019
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Ingår i: Molecular Medicine Reports. - : Spandidos Publications. - 1791-3004 .- 1791-2997. ; 19:3, s. 2077-2086
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Tidskriftsartikel (refereegranskat)abstract
- Tissue factor (TF) expressed at the protein level includes two isoforms: The membrane‑bound full‑length TF (flTF) and the soluble alternatively spliced TF (asTF). flTF is the major thrombogenic form of TF, whereas asTF is more closely associated with tumor growth, angiogenesis, metastasis and cell growth. In order to further investigate the different expression and functions of TF splice variants, the expression of these two splice variants were detected in numerous cell strains and tissues in the present study. Quantitative polymerase chain reaction was used to measure the transcript levels of the TF variants in 11 human cell lines, including cervical cancer, breast cancer, hepatoblastoma, colorectal cancer and umbilical vein cells, and five types of tissue specimen, including placenta, esophageal cancer, breast cancer, cervical cancer (alongside normal cervical tissues) and non‑small cell lung cancer (alongside adjacent and normal tissues). Furthermore, the effects of chenodeoxycholic acid (CDCA) and apolipoprotein M (apoM) on the two variants were investigated. The results demonstrated that flTF was the major form of TF, and the mRNA expression levels of flTF were higher than those of asTF in all specimens tested. CDCA significantly upregulated the mRNA expression levels of the two variants. Furthermore, overexpression of apoM promoted the expression levels of asTF in Caco‑2 cells. The mRNA expression levels of asTF in cervical cancer tissues were significantly higher than in the corresponding normal tissues. To the best of our knowledge, the present study is the first to compare the expression of flTF and asTF in various samples. The results demonstrated that CDCA and apoM may modulate TF isoforms in different cell lines, and suggested that asTF may serve a role in the pathophysiological mechanism underlying cervical cancer development. In conclusion, the TF isoforms serve important and distinct roles in pathophysiological processes.
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| 3. |
- Wang, Min, et al.
(författare)
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Apolipoprotein M induces inhibition of inflammatory responses via the S1PR1 and DHCR24 pathways
- 2019
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Ingår i: Molecular Medicine Reports. - 1791-2997. ; 19:2, s. 1272-1283
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Spandidos Publications. All rights reserved. Apolipoprotein M (ApoM) is a type of apolipoprotein. It is well known that high-density lipoprotein (HDL) decreases inflammatory responses via the apoM-sphingosine-1-phosphate (S1P) pathway. The present study further investigated the importance of ApoM in the inhibitory effects of HDL on inflammation. Mice with an apoM gene deficiency (apoM-/-) were employed to investigate the effects of ApoM on the expression of interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), S1P receptor-1 (S1PR1) and 3β-hydroxysterol Δ-24-reductase (DHCR24), as compared with in wild-type mice (apoM+/+). Furthermore, cell culture experiments were performed using a permanent human hybrid endothelial cell line (EA.hy926). Cells were cultured in the presence of recombinant human apoM (rec-apoM) or were induced to overexpress apoM (apoMTg); subsequently, cells were treated with tumor necrosis factor-α (TNF-α), in order to investigate the effects of ApoM on IL-1β and MCP-1. The results demonstrated that the mRNA expression levels of IL-1β and MCP-1 were significantly higher in the liver following administration of lipopolysaccharide in apoM-/- mice compared with in apoM+/+ mice. In cell culture experiments, when cells were pre-cultured with rec-apoM or were engineered to overexpress apoM (apoMTg), they exhibited decreased expression levels of IL-1β and MCP-1 following TNF-α treatment compared with in normal apoM-expressing cells (apoMTgN). Furthermore, the mRNA expression levels of IL-1β and MCP-1 were significantly elevated following addition of the S1PR1 inhibitor W146, but not by the scavenger receptor class B type I inhibitor, block lipid transport-1 (BLT-1), in apoMTg cells prior to TNF-α treatment. Conversely, there were no differences in these inflammatory biomarkers under the same conditions in apoMTgN cells. The mRNA expression levels of DHCR24 were significantly reduced by the addition of BLT-1 prior to TNF-α treatment in apoMTg cells; however, there was no difference in the expression of this inflammatory biomarker in apoMTgN cells. In conclusion, ApoM displayed inhibitory effects against the inflammatory response in vivo and in vitro; these effects may be induced via the S1PR1 and DHCR24 pathways.
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