| 2. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 6. |
- Lu, IT, et al.
(författare)
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(-)-Agelasidine A Induces Endoplasmic Reticulum Stress-Dependent Apoptosis in Human Hepatocellular Carcinoma
- 2022
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Ingår i: Marine drugs. - : MDPI AG. - 1660-3397. ; 20:2
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Tidskriftsartikel (refereegranskat)abstract
- Liver cancers, such as hepatocellular carcinoma (HCC), are a highly prevalent cause of cancer-related deaths. Current treatments to combat liver cancer are limited. (−)-Agelasidine A, a compound isolated from the methanol extract of Agelasnakamurai, a sesquiterpene guanidine derived from sea sponge, has antibacterial activity. We demonstrated its anticancer capabilities by researching the associated mechanism of (−)-agelasidine A in human liver cancer cells. We found that (−)-agelasidine A significantly reduced viability in Hep3B and HepG2 cells, and we determined that apoptosis was involved in the (−)-agelasidine A-induced Hep3B cell deaths. (−)-Agelasidine A activated caspases 9, 8, and 3, as well as PARP. This effect was reversed by caspase inhibitors, suggesting caspase-mediated apoptosis in the (−)-agelasidine A-treated Hep3B cells. Moreover, the reduced mitochondrial membrane potential (MMP) and the release of cytochrome c indicated that the (−)-agelasidine A-mediated mitochondrial apoptosis was mechanistic. (−)-Agelasidine A also increased apoptosis-associated proteins (DR4, DR5, FAS), which are related to extrinsic pathways. These events were accompanied by an increase in Bim and Bax, proteins that promote apoptosis, and a decrease in the antiapoptotic protein, Bcl-2. Furthermore, our results presented that (−)-agelasidine A treatment bridged the intrinsic and extrinsic apoptotic pathways. Western blot analysis of Hep3B cells treated with (−)-agelasidine A showed that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, truncated ATF6, and CHOP) were upregulated. Moreover, 4-PBA, an ER stress inhibitor, could also abrogate (−)-agelasidine A-induced cell viability reduction, annexin V+ apoptosis, death receptor (DR4, DR5, FAS) expression, mitochondrial dysfunction, and cytochrome c release. In conclusion, by activating ER stress, (−)-agelasidine A induced the extrinsic and intrinsic apoptotic pathways of human HCC.
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