Iron (Fe) plays essential roles in biological processes, whereas cadmium (Cd) is a toxic and non-essential metal. Two metal transporters, divalent metal transporter 1 (DMT1) and metal transporter protein 1 (MTP1), are responsible for Fe transport in mammals. Here, we studied the effect of dietary Fe on the expression of these metal transporters in peripheral tissues, and the uptake by these tissues of Cd. Mice were fed an Fe-sufficient (FeS: 120 mg Fe/kg) or Fe-deficient (FeD: 2-6 mg Fe/kg) diet for 4 weeks. The total Fe levels in the body were evaluated by measuring tissue Fe concentrations. Tissue Cd concentrations were determined 24 h after the mice received a single oral dose of Cd. Animals fed a FeD diet showed depletion of body Fe levels and accumulated 2.8-fold higher levels of Cd than the FeS group. Quantitative real time RT-PCR revealed that whereas DMT1 and MTP1 were both ubiquitously expressed in all FeS peripheral tissues studied, DMT1 was highly expressed in brain, kidney, and testis, whereas MTP1 was highly expressed in liver and spleen. Depletion of the body Fe stores dramatically upregulated DMT1 and MTP1 mRNA expression in the duodenum as well as moderately upregulating their expression in several other peripheral tissues. The iron response element positive isoform of DMT1 was the most prominently upregulated isoform in the duodenum. Thus, DMT1 and MTP1 may play an important role in not only maintaining Fe levels but also facilitating the accumulation of Cd in the body of mammals.
Many
neurodegenerative disorders (NDDs) are characterized by aggregation
of aberrant proteins and extensive oxidative stress in brain cells.
As a treatment option for NDDs, RNA interference (RNAi) is a promising
approach to suppress the activation of abnormal genes and negative
regulators of antioxidant genes. Efficient neuro-targeted siRNA delivery
requires a delicate optimization of nucleic acid carriers, quite distinct
from putative pDNA carriers in regard to stable condensation and serum
protection of siRNA, blood–brain barrier (BBB) bypass, effective
siRNA delivery to brain cells, and functional release of bioactive
siRNA at therapeutic levels. Here, we propose that a myristic acid
conjugated, cell-penetrating peptide (transportan; TP), equipped with
a transferrin receptor-targeting peptide (myr-TP-Tf), will lead to
stable encapsulation of siRNA and targeted delivery of siRNA to brain
cells overcoming the BBB. Myr-TP-Tf was successfully prepared by solid-phase
peptide synthesis with high purity. Myr-TP-Tf–siRNA complexes
formulated at a 20:1 (peptide–siRNA) molar ratio provided prolonged
siRNA stability against serum and ribonuclease treatment. Fluorescence
images clearly indicated that siRNA uptake was successfully achieved
by myr-TP-Tf complexes in both a murine brain endothelioma and a human
glioma cell line. The luciferase assay and the human placental alkaline
phosphatase (hPAP) reporter assay results demonstrated the functional
gene silencing effect of myr-TP-Tf–siRNA complexes in a human
glioma cell line as well as in primary murine neurons/astrocytes,
supportive of successful release of bioactive siRNA into the cytosol.
Finally, the transcytosis assay revealed that favorable siRNA transport
via receptor-mediated transcytosis was mediated by myr-TP-Tf complexes.
In summary, these data suggest that myr-TP-Tf peptides possess promising
properties as a vehicle for neuro-targeted siRNA delivery. We will
further study this peptide in vitro and in
vivo for transport mechanism kinetics and to validate its
capability to deliver siRNA to the brain, respectively.
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