The prevalence of iron overload in Tibetans in Tibet is higher than that in Han. DNA methylation (DNAm) is closely related to iron metabolism and iron level. Nevertheless, the epigenetic status of Tibetans with iron overload is unknown, and we therefore aimed to explore whether the phenomenon observed in the Tibetan population is regulated by epigenetics. The results showed that 2.26% of cytosine was methylated in the whole genome, and that the rate of CG cytosine methylation was higher in individuals in the iron overload (TH) group than in those in the iron normal (TL) group. We analyzed differentially methylated genes (DMGs) in whole-genome bisulfite sequencing data from the TH and TL groups of high-altitude Tibetans. Protein-protein interaction and pathway analyses of candidate DMGs related to iron uptake and transport showed that epigenetic changes in 10 candidate genes (ACO1, CYBRD1, FLVCR1, HFE, HMOX2, IREB2, NEDD8, SLC11A2, SLC40A1 and TFRC) are likely to relate to iron overload. This work reveals, for the first time, changes of DNAm in Tibetan people with iron overload, which suggest that DNAm is a mechanism underlying differences in iron content between individuals in the high-altitude Tibetan population. Our findings should contribute to the study of iron metabolism and the overall health status of Tibetans.
So far, relatively few small molecules
have been reported to promote
tubulin degradation. Our previous studies have found that compound 2, a noncovalent colchicine-site ligand, was capable of promoting
αβ-tubulin degradation. To further improve its antiproliferative
activity, 66 derivatives or analogues of 2 were designed
and synthesized based on 2-tubulin cocrystal structure.
Among them, 12b displayed nanomolar potency against a
variety of tumor cells, including paclitaxel- and adriamycin-resistant
cell lines. 12b binds to the colchicine site and promotes
αβ-tubulin degradation in a concentration-dependent manner
via the ubiquitin–proteasome pathway. The X-ray crystal structure
revealed that 12b binds in a similar manner as 2, but there is a slight conformation change of the B ring,
which resulted in better interaction of 12b with surrounding
residues. 12b effectively suppressed tumor growth at
an i.v. dose of 40 mg/kg (3 times a week) on both A2780S (paclitaxel-sensitive)
and A2780T (paclitaxel-resistant) ovarian xenograft models, with respective
TGIs of 92.42 and 79.75% without obvious side effects, supporting
its potential utility as a tumor-therapeutic compound.
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