Dataset Information

Site-specific intestinal DMT1 silencing to mitigate iron absorption using pH-sensitive multi-compartmental nanoparticulate oral delivery system.

ABSTRACT: Iron is a nutrient metal, but excess iron promotes tissue damage. Since iron chelation therapies exhibit multiple off-target toxicities, there is a substantial demand for more specific approaches to decrease iron burden in iron overload. While the divalent metal transporter 1 (DMT1) plays a well-established role in the absorption of dietary iron, up-regulation of intestinal DMT1 is associated with iron overload in both humans and rodents. Hence, we developed a novel pH-sensitive multi-compartmental particulate (MCP) oral delivery system that encapsulates DMT1 siRNA and validated its efficacy in mice. Using the gelatin NPs coated with Eudragit® L100-55, we demonstrated that DMT1 siRNA-loaded MCPs down-regulated DMT1 mRNA levels in the duodenum, which was consistent with decreased intestinal absorption of orally-administered 59Fe. Together, the Eudragit® L100-55-based oral siRNA delivery system could provide an effective strategy to specifically down-regulate duodenal DMT1 and mitigate iron absorption.

SUBMITTER: Fan Y

PROVIDER: S-EPMC6904526 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Site-specific intestinal DMT1 silencing to mitigate iron absorption using pH-sensitive multi-compartmental nanoparticulate oral delivery system.

Fan Yingfang Y Dhaliwal Harkiranpreet Kaur HK Menon Archita Venugopal AV Chang JuOae J Choi Jee Eun JE Amiji Mansoor M MM Kim Jonghan J

Nanomedicine : nanotechnology, biology, and medicine 20191015

Iron is a nutrient metal, but excess iron promotes tissue damage. Since iron chelation therapies exhibit multiple off-target toxicities, there is a substantial demand for more specific approaches to decrease iron burden in iron overload. While the divalent metal transporter 1 (DMT1) plays a well-established role in the absorption of dietary iron, up-regulation of intestinal DMT1 is associated with iron overload in both humans and rodents. Hence, we developed a novel pH-sensitive multi-compartmen ...[more]

PMID: 31626992

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Project description:Lymphatic filariasis and onchocerciasis are neglected parasitic diseases which pose a threat to public health in tropical and sub-tropical regions. Strategies for control and elimination of these diseases by mass drug administration (MDA) campaigns are designed to reduce symptoms of onchocerciasis and transmission of both parasites to eventually eliminate the burden on public health. Drugs used for MDA are predominantly microfilaricidal, and prolonged rounds of treatment are required for eradication. Understanding parasite biology is crucial to unravelling the complex processes involved in host-parasite interactions, disease transmission, parasite immune evasion, and the emergence of drug resistance. In nematode biology, large gaps still exist in our understanding of iron metabolism, iron-dependent processes and their regulation. The acquisition of iron from the host is a crucial determinant of the success of a parasitic infection. Here we identify a filarial ortholog of Divalent Metal Transporter 1 (DMT1), a member of a highly conserved family of NRAMP proteins that play an essential role in the transport of ferrous iron in many species. We cloned and expressed the B. malayi NRAMP ortholog in the iron-deficient fet3fet4 strain of Saccharomyces cerevisiae, performed qPCR to estimate stage-specific expression, and localized expression of this gene by immunohistochemistry. Results from functional iron uptake assays showed that expression of this gene in the iron transport-deficient yeast strain significantly rescued growth in low-iron medium. DMT1 was highly expressed in adult female and male B. malayi and Onchocerca volvulus. Immunolocalization revealed that DMT1 is expressed in the intestinal brush border, lateral chords, and reproductive tissues of males and females, areas also inhabited by Wolbachia. We hypothesize based on our results that DMT1 in B. malayi functions as an iron transporter. The presence of this transporter in the intestine supports the hypothesis that iron acquisition by adult females requires oral ingestion and suggests that the intestine plays a functional role in at least some aspects of nutrient uptake.

Project description:Iron is a trace metal, key for the development of living organisms. Its absorption process is complex and highly regulated at the transcriptional, translational and systemic levels. Recently, the internalization of the DMT1 transporter has been proposed as an additional regulatory mechanism at the intestinal level, associated to the mucosal block phenomenon. The short-term effect of iron exposure in apical uptake and initial absorption rates was studied in Caco-2 cells at different apical iron concentrations, using both an experimental approach and a mathematical modeling framework. This is the first report of short-term studies for this system. A non-linear behavior in the apical uptake dynamics was observed, which does not follow the classic saturation dynamics of traditional biochemical models. We propose a method for developing mathematical models for complex systems, based on a genetic programming algorithm. The algorithm is aimed at obtaining models with a high predictive capacity, and considers an additional parameter fitting stage and an additional Jackknife stage for estimating the generalization error. We developed a model for the iron uptake system with a higher predictive capacity than classic biochemical models. This was observed both with the apical uptake dataset used for generating the model and with an independent initial rates dataset used to test the predictive capacity of the model. The model obtained is a function of time and the initial apical iron concentration, with a linear component that captures the global tendency of the system, and a non-linear component that can be associated to the movement of DMT1 transporters. The model presented in this paper allows the detailed analysis, interpretation of experimental data, and identification of key relevant components for this complex biological process. This general method holds great potential for application to the elucidation of biological mechanisms and their key components in other complex systems.

Dataset Information

Site-specific intestinal DMT1 silencing to mitigate iron absorption using pH-sensitive multi-compartmental nanoparticulate oral delivery system.

Publications

Site-specific intestinal DMT1 silencing to mitigate iron absorption using pH-sensitive multi-compartmental nanoparticulate oral delivery system.

Similar Datasets

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