REPRODUCTIVE TOXICOLOGY
·
2016
·
IF 2.85
Hua Wang,Ying Wang,Qing-Li Bo,Yan-Li Ji,Lu Liu,Yong-Fang Hu,Yuan-Hua Chen,Jun Zhang,Ling-Li Zhao,De-Xiang Xu
Cadmium (Cd) is linked with increased risk of fetal growth restriction (FGR). Nevertheless, the mechanism remains unknown. This study established a mouse model of Cd-induced FGR through two exposure methods. Pregnant mice were either administered with CdCl 2 (5, 50 and 250 ppm) throughout pregnancy through drinking water or intraperitoneally injected with CdCl 2 (4.5 mg/kg) on GD9. As expected, fetal weight and crown-rump length were reduced in a gender-independent manner. Interestingly, Mt1 and Mt2, two metallothionein genes, were up-regulated in maternal liver. Correspondingly, Cd accumulated mainly in maternal liver and kidney, and only trace amounts of Cd could pass from dam to placentas and fetuses. Further analysis showed that placental Zn concentration was elevated. Conversely, embryonic Zn concentration was reduced. Moreover, placental Znt1 and Znt2 , two zinc transporters, were down-regulated in Cd-exposed mice. These results suggest that maternal Cd exposure during pregnancy reduces placental Zn transport and induces fetal growth restriction.
研究领域:
毒理学
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生殖生物学
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营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EMBO REPORTS
·
2024
·
IF 6.5
LongYonghui,ZhuZhini,ZhouZixuan,YangChuanhui,ChaoYulin,WangYuwei,ZhouQingtong,WangMing-Wei,QuQianhui
Zinc transporter 1 (ZnT1), the principal carrier of cytosolic zinc to the extracellular milieu, is important for cellular zinc homeostasis and resistance to zinc toxicity. Despite recent advancements in the structural characterization of various zinc transporters, the mechanism by which ZnTs-mediated Zn2+ translocation is coupled with H+ or Ca2+ remains unclear. To visualize the transport dynamics, we determined the cryo-electron microscopy (cryo-EM) structures of human ZnT1 at different functional states. ZnT1 dimerizes via extensive interactions between the cytosolic (CTD), the transmembrane (TMD), and the unique cysteine-rich extracellular (ECD) domains. At pH 7.5, both protomers adopt an outward-facing (OF) conformation, with Zn2+ ions coordinated at the TMD binding site by distinct compositions. At pH 6.0, ZnT1 complexed with Zn2+ exhibits various conformations [OF/OF, OF/IF (inward-facing), and IF/IF]. These conformational snapshots, together with biochemical investigation and molecular dynamic simulations, shed light on the mechanism underlying the proton-dependence of ZnT1 transport.
研究领域:
分子生物学
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结构生物学
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细胞生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2015
·Vol. 56
·期 13
·8166-8178
·
IF 3.404
Guoxu Xu,Daohuan Kang,Chaoyang Zhang,Hui Lou,Chen Sun,Qian Yang,Lixia Lu,Guo-Tong Xu,Jingfa Zhang,Fang Wang
Purpose:Zinc transporter 8 (ZnT8) was downregulated in hypoxic retina, which could be rescued by hypoxia-inducible factor-1α (HIF-1α) inhibition. Erythropoietin (EPO) protects retinal cells in diabetic rats through inhibiting HIF-1α as one of its mechanisms. We hence tried to explore the effect of EPO in regulating ZnT8 and protecting retinal cells in diabetic rats and possible mechanisms.Methods:Diabetes was induced in Sprague-Dawley rats. Intravitreal injection of EPO was performed 1 month after diabetes onset. The CoCl2-treated rat Müller cell line (rMC-1) was cotreated with EPO, soluble EPO receptor (sEPOR), digoxin, or U0126. Cell viability, cell death, and intracellular zinc level were examined. The expression of ZnT8, HIF-1α, AKT, and ERK was studied.Results:In diabetic rat retinas, EPO significantly decreased HIF-1α expression and increased ZnT8 expression. In CoCl2-treated rMC-1 cells, EPO increased cell viability and decreased intracellular zinc. Erythropoietin or digoxin could activate ERK pathway, downregulate HIF-1α, and upregulate ZnT8. The effect of EPO was abolished by sEPOR and U0126. Transient knockdown of ZnT8 increased intracellular zinc level, but not to a degree that would decrease cell viability or cause cell death.Conclusions:In diabetic retinas, EPO maintains zinc homeostasis through activating the ERK pathway and downregulating HIF-1α, and thus upregulating ZnT8 expression. This work proposed a possible new protective mechanism for EPO in, and indicated a potential target for, the treatment of diabetic retinopathy.
研究领域:
眼科学
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内分泌学
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细胞生物学
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分子生物学
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糖尿病研究
✓ 已验证
DOI
PubMed
高影响因子
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