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Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica.

Geiser J, De Lisle RC, Finkelstein D, Adlard PA, Bush AI, Andrews GK - PLoS ONE (2013)

Bottom Line: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed.In contrast, dietary CQ in conjunction with zinc supplementation was highly effective.These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.

ABSTRACT

Background: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed.

Methods/principal findings: Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4 (intest KO) phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver.

Conclusions: These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

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Dietary CQ with excess zinc in the drinking water (CQ/Zn) can rescue Zip4intest KO mice from the lethal effects of extreme zinc deficiency.Mice homozygous for the floxed Zip4 gene and positive for the vil-CreERT2 gene (Zip4 intest KO) and littermates homozygous for the floxed Zip4 gene but negative for the vil-CreERT2 gene (control) were injected for 3 consecutive days with tamoxifen beginning 2 to 3 weeks after weaning and their body weights were monitored thereafter. These mice were fed normal chow and provided access to deionized water after weaning and then fed chow containing CQ and/or provided water containing excess zinc beginning on the indicated days. (A) Mice were fed chow containing CQ (CQ) or CQ chow plus water containing excess zinc (CQ/Zn) beginning 3 days after initiation of the intestine knockout. Only representative mice are shown for the sake of clarity in the figure. (B) On d8 after initiation of the intestine knockout mice were provided with water containing excess zinc. (C) On d8 after initiation of the intestine knockout these mice were fed chow containing CQ and provided access to drinking water containing excess zinc. Among these mice 6/8 thrived while (D) 2 did not thrive and one appeared to be blind in one eye.
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pone-0072543-g002: Dietary CQ with excess zinc in the drinking water (CQ/Zn) can rescue Zip4intest KO mice from the lethal effects of extreme zinc deficiency.Mice homozygous for the floxed Zip4 gene and positive for the vil-CreERT2 gene (Zip4 intest KO) and littermates homozygous for the floxed Zip4 gene but negative for the vil-CreERT2 gene (control) were injected for 3 consecutive days with tamoxifen beginning 2 to 3 weeks after weaning and their body weights were monitored thereafter. These mice were fed normal chow and provided access to deionized water after weaning and then fed chow containing CQ and/or provided water containing excess zinc beginning on the indicated days. (A) Mice were fed chow containing CQ (CQ) or CQ chow plus water containing excess zinc (CQ/Zn) beginning 3 days after initiation of the intestine knockout. Only representative mice are shown for the sake of clarity in the figure. (B) On d8 after initiation of the intestine knockout mice were provided with water containing excess zinc. (C) On d8 after initiation of the intestine knockout these mice were fed chow containing CQ and provided access to drinking water containing excess zinc. Among these mice 6/8 thrived while (D) 2 did not thrive and one appeared to be blind in one eye.

Mentions: We previously reported that Zip4intest KO mice could be rescued from precipitous weight loss and death by giving them access to zinc in the drinking water (250 ppm ZnS04) beginning on the day the knockout was initiated [26]. However, the efficacy of zinc supplementation, under these experimental conditions, rapidly diminishes if administration is delayed. For example, within 2 days after initiation of the knockout providing zinc supplementation does not reliably stimulate growth or significantly extend longevity in these mice (n = 9; data not shown). This observation prompted us to examine whether the zinc ionophore CQ (Fig. 1) could increase the efficacy of zinc supplementation to reverse the catabolic state in these mice and support long term survival and growth. Mouse chow containing CQ (250 ppm) in the presence or absence of zinc supplementation in drinking water was provided to Zip4intestKO mice starting on d3 after initiation of the knockout (Fig. 2A). Dietary CQ alone failed to rescue these mice and they were euthanized within 9 to 14 days after initiation of the knockout (n = 5). In sharp contrast, dietary CQ along with zinc supplementation in the drinking water (CQ/Zn) was highly effective (n = 5). Many of the Zip4intest KO mice treated in this manner thrived (3 out of 5 mice). They grew similarly to their control littermates and appeared healthy for the duration of this experiment (32 days). Two of these mice failed to gained weight but lived for the duration of this experiment before being euthanized (data not shown).


Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica.

Geiser J, De Lisle RC, Finkelstein D, Adlard PA, Bush AI, Andrews GK - PLoS ONE (2013)

Dietary CQ with excess zinc in the drinking water (CQ/Zn) can rescue Zip4intest KO mice from the lethal effects of extreme zinc deficiency.Mice homozygous for the floxed Zip4 gene and positive for the vil-CreERT2 gene (Zip4 intest KO) and littermates homozygous for the floxed Zip4 gene but negative for the vil-CreERT2 gene (control) were injected for 3 consecutive days with tamoxifen beginning 2 to 3 weeks after weaning and their body weights were monitored thereafter. These mice were fed normal chow and provided access to deionized water after weaning and then fed chow containing CQ and/or provided water containing excess zinc beginning on the indicated days. (A) Mice were fed chow containing CQ (CQ) or CQ chow plus water containing excess zinc (CQ/Zn) beginning 3 days after initiation of the intestine knockout. Only representative mice are shown for the sake of clarity in the figure. (B) On d8 after initiation of the intestine knockout mice were provided with water containing excess zinc. (C) On d8 after initiation of the intestine knockout these mice were fed chow containing CQ and provided access to drinking water containing excess zinc. Among these mice 6/8 thrived while (D) 2 did not thrive and one appeared to be blind in one eye.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3755987&req=5

pone-0072543-g002: Dietary CQ with excess zinc in the drinking water (CQ/Zn) can rescue Zip4intest KO mice from the lethal effects of extreme zinc deficiency.Mice homozygous for the floxed Zip4 gene and positive for the vil-CreERT2 gene (Zip4 intest KO) and littermates homozygous for the floxed Zip4 gene but negative for the vil-CreERT2 gene (control) were injected for 3 consecutive days with tamoxifen beginning 2 to 3 weeks after weaning and their body weights were monitored thereafter. These mice were fed normal chow and provided access to deionized water after weaning and then fed chow containing CQ and/or provided water containing excess zinc beginning on the indicated days. (A) Mice were fed chow containing CQ (CQ) or CQ chow plus water containing excess zinc (CQ/Zn) beginning 3 days after initiation of the intestine knockout. Only representative mice are shown for the sake of clarity in the figure. (B) On d8 after initiation of the intestine knockout mice were provided with water containing excess zinc. (C) On d8 after initiation of the intestine knockout these mice were fed chow containing CQ and provided access to drinking water containing excess zinc. Among these mice 6/8 thrived while (D) 2 did not thrive and one appeared to be blind in one eye.
Mentions: We previously reported that Zip4intest KO mice could be rescued from precipitous weight loss and death by giving them access to zinc in the drinking water (250 ppm ZnS04) beginning on the day the knockout was initiated [26]. However, the efficacy of zinc supplementation, under these experimental conditions, rapidly diminishes if administration is delayed. For example, within 2 days after initiation of the knockout providing zinc supplementation does not reliably stimulate growth or significantly extend longevity in these mice (n = 9; data not shown). This observation prompted us to examine whether the zinc ionophore CQ (Fig. 1) could increase the efficacy of zinc supplementation to reverse the catabolic state in these mice and support long term survival and growth. Mouse chow containing CQ (250 ppm) in the presence or absence of zinc supplementation in drinking water was provided to Zip4intestKO mice starting on d3 after initiation of the knockout (Fig. 2A). Dietary CQ alone failed to rescue these mice and they were euthanized within 9 to 14 days after initiation of the knockout (n = 5). In sharp contrast, dietary CQ along with zinc supplementation in the drinking water (CQ/Zn) was highly effective (n = 5). Many of the Zip4intest KO mice treated in this manner thrived (3 out of 5 mice). They grew similarly to their control littermates and appeared healthy for the duration of this experiment (32 days). Two of these mice failed to gained weight but lived for the duration of this experiment before being euthanized (data not shown).

Bottom Line: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed.In contrast, dietary CQ in conjunction with zinc supplementation was highly effective.These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.

ABSTRACT

Background: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed.

Methods/principal findings: Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4 (intest KO) phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver.

Conclusions: These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

Show MeSH
Related in: MedlinePlus