Dataset Information

Oral Gavage of Ginger Nanoparticle-Derived Lipid Vectors Carrying Dmt1 siRNA Blunts Iron Loading in Murine Hereditary Hemochromatosis.

ABSTRACT: Nanoparticles (NPs) have been utilized to deliver drugs to the intestinal epithelium in vivo. Moreover, NPs derived from edible plants are less toxic than synthetic NPs. Here, we utilized ginger NP-derived lipid vectors (GDLVs) in a proof-of-concept investigation to test the hypothesis that inhibiting expression of divalent metal-ion transporter 1 (Dmt1) would attenuate iron loading in a mouse model of hereditary hemochromatosis (HH). Initial experiments using duodenal epithelial organ cultures from intestine-specific Dmt1 knockout (KO) (Dmt1int/int) mice in the Ussing chamber established that Dmt1 is the only active iron importer during iron-deficiency anemia. Further, when Dmt1int/int mice were crossed with mice lacking the iron-regulatory hormone, hepcidin (Hepc-/-), iron loading was abolished. Hence, intestinal Dmt1 is required for the excessive iron absorption that typifies HH. Additional experiments established a protocol to produce GDLVs carrying functional Dmt1 small interfering RNAs (siRNAs) and to target these gene delivery vehicles to the duodenal epithelium in vivo (by incorporating folic acid [FA]). When FA-GDLVs carrying Dmt1 siRNA were administered to weanling Hepc-/- mice for 16 days, intestinal Dmt1 mRNA expression was attenuated and tissue iron accumulation was blunted. Oral delivery of functional siRNAs by FA-GDLVs is a suitable therapeutic approach to mitigate iron loading in murine HH.

SUBMITTER: Wang X

PROVIDER: S-EPMC6401192 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Oral Gavage of Ginger Nanoparticle-Derived Lipid Vectors Carrying Dmt1 siRNA Blunts Iron Loading in Murine Hereditary Hemochromatosis.

Wang Xiaoyu X Zhang Mingzhen M Flores Shireen R L SRL Woloshun Regina R RR Yang Chunhua C Yin Liangjie L Xiang Ping P Xu Xiaodong X Garrick Michael D MD Vidyasagar Sadasivan S Merlin Didier D Collins James F JF

Molecular therapy : the journal of the American Society of Gene Therapy 20190112 3

Nanoparticles (NPs) have been utilized to deliver drugs to the intestinal epithelium in vivo. Moreover, NPs derived from edible plants are less toxic than synthetic NPs. Here, we utilized ginger NP-derived lipid vectors (GDLVs) in a proof-of-concept investigation to test the hypothesis that inhibiting expression of divalent metal-ion transporter 1 (Dmt1) would attenuate iron loading in a mouse model of hereditary hemochromatosis (HH). Initial experiments using duodenal epithelial organ cultures ...[more]

PMID: 30713087

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Project description:IntroductionHigh salt intake is a widespread cardiovascular risk factor with systemic effects. These effects include an expansion of plasma volume, which may interfere with postexercise hypotension (PEH). However, the effects of high salt intake on central and peripheral indices of PEH remain unknown. We tested the hypothesis that high salt intake would attenuate central and peripheral PEH.MethodsNineteen healthy adults (7 female/12 male; age, 25 ± 4 yr; body mass index, 23.3 ± 2.2 kg·m; V[Combining Dot Above]O2peak, 41.6 ± 8.7 mL·min·kg; systolic blood pressure (BP), 112 ± 9 mm Hg; diastolic BP, 65 ± 9 mm Hg) participated in this double-blind, randomized, placebo-controlled crossover study. Participants were asked to maintain a 2300 mg·d sodium diet for 10 d on two occasions separated by ≥2 wk. Total salt intake was manipulated via ingestion of capsules containing either table salt (3900 mg·d) or placebo (dextrose) during each diet. On the 10th day, participants completed 50 min of cycling at 60% V[Combining Dot Above]O2peak. A subset of participants (n = 8) completed 60 min of seated rest (sham trial). Beat-to-beat BP was measured in-laboratory for 60 min after exercise via finger photoplethysmography. Brachial and central BPs were measured for 24 h after exercise via ambulatory BP monitor.ResultsTen days of high salt intake increased urinary sodium excretion (134 ± 70 (dextrose) vs 284 ± 74 mmol per 24 h (salt), P < 0.001), expanded plasma volume (7.2% ± 10.8%), and abolished PEH during in-laboratory BP monitoring (main effect of diet, P < 0.001). Ambulatory systolic BPs were higher for 12 h after exercise during the salt and sham trials compared with the dextrose trial (average change, 3.6 ± 2.1 mm Hg (dextrose), 9.9 ± 1.4 mm Hg (salt), 9.8 ± 2.5 mm Hg (sham); P = 0.01). Ambulatory central systolic BP was also higher during the salt trial compared with dextrose trial.ConclusionHigh salt intake attenuates peripheral and central PEH, potentially reducing the beneficial cardiovascular effects of acute aerobic exercise.

Dataset Information

Oral Gavage of Ginger Nanoparticle-Derived Lipid Vectors Carrying Dmt1 siRNA Blunts Iron Loading in Murine Hereditary Hemochromatosis.

Publications

Oral Gavage of Ginger Nanoparticle-Derived Lipid Vectors Carrying Dmt1 siRNA Blunts Iron Loading in Murine Hereditary Hemochromatosis.

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