Dietary Deficiency of Calcium and/or Iron, an Age-Related Risk Factor for Renal Accumulation of Cadmium in Mice.

The major route of cadmium (Cd) intake by non-smokers is through food ingestion. Cd is a non-essential metal absorbed through one or more transporters of essential metal ions. Expression of these transporters is affected by nutritional status. To investigate the risk factors for Cd toxicity, the effects of deficiency of essential metals on hepatic and renal accumulation of Cd were studied in mice of different ages. Mice were administered a control diet or one of the essential metal-deficient diets, administered Cd by gavage for 6 weeks, and killed; then, Cd accumulation was evaluated. Iron deficiency (FeDF) or calcium deficiency (CaDF) resulted in remarkable increases in hepatic and renal Cd accumulation compared with control-diet mice and other essential metal-deficient mice. Cd accumulation in hepatic and renal tissue was increased significantly at all ages tested in FeDF and CaDF mice. Renal Cd concentrations were higher in 4-week-old mice than in 8- and 25-week-old mice. Increase in intestinal mRNA expression of calcium transporter (CaT)1, divalent metal ion transporter-1, and metallothionein (MT)1 was also higher in 4-week-old mice than in other mice. Renal accumulation of Cd showed strong correlation with intestinal mRNA expression of CaT1 and MT1. These data suggest that CaDF and FeDF at younger ages can be a risk factor for Cd toxicity.

Effects of zinc deficiency and supplementation on leptin and leptin receptor expression in pregnant mice.

Leptin is an adipose-derived hormone that primarily regulates energy balance in response to nutrition. Human placental cells produce leptin, whereas murine placental cells produce soluble leptin receptors (Ob-R). However, the roles of these proteins during pregnancy have not been elucidated completely. As an essential metal, zinc (Zn) is central to insulin biosynthesis and energy metabolism. In the present study, the effects of Zn deficiency and supplementation on maternal plasma leptin and soluble Ob-R regulation in pregnant mice placentas were examined using enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, and Western blotting. Nutritional Zn deficiency significantly reduced plasma insulin concentrations and fetal and placental weights in pregnant mice. Plasma leptin concentrations in pregnant mice also increased 20- to 40-fold compared with those in non-pregnant mice. Although dietary Zn deficiency and supplementation did not affect plasma leptin concentrations in non-pregnant mice, Zn-deficient pregnant mice had significantly reduced plasma leptin concentrations and adipose leptin mRNA expression. In contrast, Zn-supplemented pregnant mice had increased plasma leptin concentrations without increased adipose leptin mRNA expression. Placental soluble Ob-R mRNA expression also decreased in Zn-deficient mice and tended to increase in Zn-supplemented mice. These results indicate that Zn influences plasma leptin concentrations by modulating mRNA expression of soluble Ob-R in the placenta, and leptin in visceral fat during pregnancy. These data suggest that both adipose and placenta-derived leptin system are involved in the regulation of energy metabolism during fetal growth.

Involvement of the essential metal transporter Zip14 in hepatic Cd accumulation during inflammation.

Upregulation of Zip14 contributes to hepatic zinc (Zn) and non-transferrin-bound iron (Fe) uptake during infection and inflammation. We investigated whether this essential metal transporter is also involved in hepatic cadmium (Cd) uptake under these conditions. An injection of lipopolysaccharide (LPS), turpentine oil (Tur) and n-hexane (Hex) resulted in an decrease in plasma Zn and Fe concentrations to 25-50% and an increase in hepatic concentrations of both metals to 150-200% of control mice. LPS significantly increased plasma interleukin (IL)-6 levels more rapidly than Tur or Hex. Tur or Hex significantly increased hepatic Zip14 mRNA expression and decreased ferroportin 1 mRNA expression following continuous increase of IL-6 level. Hepatic Cd and Zn concentrations increased significantly after repeated injections of Cd in Tur- or Hex-treated mice fed a control diet. Treatment with Tur or Hex additionally increased hepatic Cd accumulation in Zn-deficient mice, unlike in Fe-deficient mice. These results suggest that Zn transporters, such as Zip14, may be involved in hepatic Cd uptake during inflammation.

Increased hepatic accumulation of ingested Cd is associated with upregulation of several intestinal transporters in mice fed diets deficient in essential metals.

Essential metals (EMs) can affect the metabolism of nonessential metals. It has been suggested that Fe deficiency increases intestinal absorption of Cd via divalent metal transporter 1 (DMT1). To investigate whether EM nutritional status is a host risk factor for Cd accumulation, we studied the effect of nutritional status of Ca, Cu, Mg, Zn, and Fe that most often ingested by humans at levels below recommended dietary allowances on tissue accumulation of orally administered Cd. Mice were divided into groups and given different EM-deficient (EMDF) diets (CaDF, CuDF, MgDF, ZnDF, or FeDF) for 4 weeks. EMDF mice had significantly (p < 0.05) lower plasma or hepatic concentrations of the deficient EM than did mice receiving control diets. Hepatic Cd accumulation was significantly (p < 0.05) increased after oral Cd administration in all EMDF mice, but not in any EM-supplemented mice. Intestinal expression of mRNAs for the Fe-transporters DMT1 and ferroportin was increased in FeDF mice, but not in other EMDF mice, causing an increase in hepatic Fe concentration. Similarly, intestinal expression of mRNA for calcium transporter 1 was significantly increased in CaDF mice, but not in other EMDF mice. These results suggest that DMT1 is not the sole transporter of Cd, and that Cd is absorbed and accumulated through multiple pathways that maintain EM homeostasis in EMDF condition. Therefore, EM nutritional status is a risk factor for increasing hepatic accumulation of ingested Cd.

Involvement of intestinal calcium transporter 1 and metallothionein in cadmium accumulation in the liver and kidney of mice fed a low-calcium diet.

Essential metals can affect the metabolism of nonessential metals. Calcium (Ca) is an essential mineral that is commonly lacking in the diet. When we fed 5-week-old male mice for 4 weeks on a purified diet containing 0.005% Ca (CaDF mice), the Ca concentration in the plasma, liver and kidneys did not decreased. Cd accumulation increased in the liver and kidneys of CaDF mice given 1mg/kg Cd orally each day for 5 days, but not in those given intraperitoneal injections of Cd or Cd-metallothionein (Cd-MT). The zinc (Zn) concentration increased significantly in the intestinal cytosol and plasma during the time the mice were fed the low-Ca diet, and expression of both MT-1 and ZnT-1 sharply increased with a similar time course. Intestinal mRNA expression of CaT1, a Ca transporter, was more than 10 times higher in CaDF mice than in controls, although expression of other transporters, including DMT1, decreased in CaDF mice. These results suggest that CaT1 may stimulate the intestinal absorption of Cd and Zn, and some Cd may be distributed to the kidneys along with MT induced by Zn.

Upregulation of sodium-dependent vitamin C transporter 2 expression in adrenals increases norepinephrine production and aggravates hyperlipidemia in mice with streptozotocin-induced diabetes.

The hyperglycemia and hyperoxidation that characterize diabetes lead to reduced vitamin C (L-ascorbic acid, AA) levels in diabetic humans and animals. We examined the possibility that diabetes-induced low plasma AA levels impair AA distribution to various tissues and that these changes are closely related to the development of diabetic complications. AA levels were markedly decreased in the plasma and increased in the adrenals of mice with streptozotocin (STZ)-induced diabetes. Consistently with these results, in [1-(14)C]AA accumulation assays, the efficiency of [1-(14)C]AA accumulation was significantly higher in the adrenals (which had the greatest ability to accumulate [1-(14)C]AA) of diabetic mice than in those of controls. Expression of sodium-dependent vitamin C transporter (SVCT)-2, a transporter of AA, was upregulated in diabetic adrenals. Furthermore, increased AA incorporation into the diabetic adrenals by SVCT-2 led to increased plasma norepinephrine, triglyceride and free fatty acid levels in mice with STZ-induced diabetes. Therefore, oversupplementation with AA could be deleterious in diabetic patients, because overexpression of adrenal SVCT-2 in diabetes could lead to excessive AA uptake, thus enhancing norepinephrine production and exacerbating some diabetic complications. Interestingly, however, treatment with AA dose-dependently abolished the increased expression of adrenal SVCT-2 and normalized the abovementioned plasma parameters in diabetic mice. These results suggest SVCT-2-mediated increases in AA uptake by the adrenals followed by excessive production of plasma norepinephrine may play a pivotal role in the development of diabetic complications.

Effects of ellagic acid and 2-(2,3,6-trihydroxy-4-carboxyphenyl)ellagic acid on sorbitol accumulation in vitro and in vivo.

Caesalpinia ferrea MART. (Leguminosae) called as Juca is one of the medicinal plants in Brazil used for diabetes. From the fruits of this plant, ellagic acid (EA) and 2-(2,3,6-trihydroxy-4-carboxyphenyl)ellagic acid (TEA) have been recently isolated as aldose reductase (AR) inhibitors. In this study, we examined to prove the inhibitory activity against AR of EA and TEA in vitro, and EA in vivo by measurement of the accumulation of sorbitol, which is the product of glucose reduction catalyzed by AR. TEA was not examined in vivo because of its shortage of yield from the fruits. EA and TEA significantly and dose-dependently inhibited sorbitol accumulation in erythrocytes, lens and sciatic nerve under incubating with glucose in vitro. EA at a dose of 75 mg/kg/d showed the most potent inhibition of sorbitol accumulation in erythrocytes, lens and sciatic nerve at 50, 75 and 100 mg/kg/d in vivo. These results suggest that the inhibitory activity of EA against AR causes to inhibit sorbitol accumulation by in vitro and in vivo experiments. EA is distributed in fruits and vegetables, so that taking them might be able to relieve diabetic complications.

A new isoflavone glycoside from Ceiba pentandra (L.) Gaertner.

From the 80% EtOH extract of the bark of Ceiba pentandra (L.) Gaertner, a new isoflavone glycoside was isolated along with known isoflavones, vavain and vavain glucoside. The structure was elucidated by spectroscopic analysis as 5-hydroxy-7,4',5'-trimethoxyisoflavone 3'-O-alpha-L-arabinofuranosyl(1-->6)-beta-D-glucopyranoside.