Dynamin 2 Regulates Riboflavin Endocytosis in Human Placental Trophoblasts

Foraker, Amy B.; Ray, Abhijit; Silva, Tatiana Claro da; Bareford, Lisa M.; Hillgren, Kathleen M.; Schmittgen, Thomas D.; Swaan, Peter W.

doi:10.1124/mol.107.037101

Cited by 17 publications

(16 citation statements)

References 40 publications

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“…Vitamin E (and specifically α‐tocopherol) bound to high‐density lipoproteins was recovered mostly in the caveolae fraction after exposure to endothelial cells, and caveolae were implicated in α‐tocopherol transcytosis mediated by scavenger receptor BI and LDL receptors [136]. Riboflavin (vitamin B 2 ) is also at least partially internalized through caveolae [137]. Tocotrienol (another member of the vitamin E family) increased association of Cav‐1 with p38 MAPK and Src kinase in the heart which prevented ischemia‐induced apoptosis [138].…”

Section: Nutrition and Caveolae Function: Implication In Inflammatorymentioning

confidence: 99%

The role of caveolae in endothelial cell dysfunction with a focus on nutrition and environmental toxicants

Majkova

Toborek

Hennig

2010

J Cellular Molecular Medi

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Complications of vascular diseases, including atherosclerosis, are the number one cause of death in Western societies. Dysfunction of endothelial cells is a critical underlying cause of the pathology of atherosclerosis. Lipid rafts, and especially caveolae, are enriched in endothelial cells, and down-regulation of the caveolin-1 gene may provide protection against the development of atherosclerosis. There is substantial evidence that exposure to environmental pollution is linked to cardiovascular mortality, and that persistent organic pollutants can markedly contribute to endothelial cell dysfunction and an increase in vascular inflammation. Nutrition can modulate the toxicity of environmental pollutants, and evidence suggests that these affect health and disease outcome associated with chemical insults. Because caveolae can provide a regulatory platform for pro-inflammatory signalling associated with vascular diseases such as atherosclerosis, we suggest a link between atherogenic risk and functional changes of caveolae by environmental factors such as dietary lipids and organic pollutants. For example, we have evidence that endothelial caveolae play a role in uptake of persistent organic pollutants, an event associated with subsequent production of inflammatory mediators. Functional properties of caveolae can be modulated by nutrition, such as dietary lipids (e.g. fatty acids) and plant-derived polyphenols (e.g. flavonoids), which change activation of caveolae-associated signalling proteins. The following review will focus on caveolae providing a platform for pro-inflammatory signalling, and the role of caveolae in endothelial cell functional changes associated with environmental mediators such as nutrients and toxicants, which are known to modulate the pathology of vascular diseases.

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Section: Nutrition and Caveolae Function: Implication In Inflammatorymentioning

confidence: 99%

The role of caveolae in endothelial cell dysfunction with a focus on nutrition and environmental toxicants

Majkova

Toborek

Hennig

2010

J Cellular Molecular Medi

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“…Studies investigating the uptake mechanism of riboflavin have provided contradicting results. While some studies suggest riboflavin uptake to be dynamin-dependent and therefore driven via receptor-mediated endocytosis (Huang et al, 2003; Foraker et al, 2007; Bareford et al, 2008), other studies indicate a non-endocytic uptake route via carrier-mediated transport (Patel et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics

et al. 2019

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The retention and cellular internalization of drug delivery systems and theranostics for cancer therapy can be improved by targeting molecules. Since an increased uptake of riboflavin was reported for various cancers, riboflavin and its derivatives may be promising binding moieties to trigger internalization via the riboflavin transporters (RFVT) 1, 2, and 3. Riboflavin is a vitamin with pivotal role in energy metabolism and indispensable for cellular growth. In previous preclinical studies on mice, we showed the target-specific accumulation of riboflavin-functionalized nanocarriers in cancer cells. Although the uptake mechanism of riboflavin has been studied for over a decade, little is known about the riboflavin transporters and their expression on cancer cells, tumor stroma, and healthy tissues. Furthermore, evidence is lacking concerning the representativeness of the preclinical findings to the situation in humans. In this study, we investigated the expression pattern of riboflavin transporters in human squamous cell carcinoma (SCC), melanoma and luminal A breast cancer samples, as well as in healthy skin, breast, aorta, and kidney tissues. Low constitutive expression levels of RFVT1–3 were found on all healthy tissues, while RFVT2 and 3 were significantly overexpressed in melanoma, RFVT1 and 3 in luminal A breast cancer and RFVT1–3 in SCC. Correspondingly, the SCC cell line A431 was highly positive for all RFVTs, thus qualifying as suitable in vitro model. In contrast, activated endothelial cells (HUVEC) only presented with a strong expression of RFVT2, and HK2 kidney cells only with a low constitutive expression of RFVT1–3. Functional in vitro studies on A431 and HK2 cells using confocal microscopy showed that riboflavin uptake is mostly ATP dependent and primarily driven by endocytosis. Furthermore, riboflavin is partially trafficked to the mitochondria. Riboflavin uptake and trafficking was significantly higher in A431 than in healthy kidney cells. Thus, this manuscript supports the hypothesis that addressing the riboflavin internalization pathway may be highly valuable for tumor targeted drug delivery.

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“… 46 − 48 Similarly, riboflavin-functionalized rhodamine is shown to enter into cells via both caveolae- and clathrin-mediated endocytosis. 49 We have recently shown that the zwitterionic–lipophilic surface chemistry and <10 multivalency of nanoprobes can minimize clathrin-mediated endocytosis and induce predominate caveolae- or lipid-raft endocytosis. 44 , 50 In the present case, predominate lipid-raft endocytosis can be explained because of the zwitterionic surface chemistry and 3/4 multivalency of folate-/riboflavin-functionalized QDs that are prepared via the host–guest interaction.…”

Section: Resultsmentioning

confidence: 99%

Supramolecular Host–Guest Chemistry-Based Folate/Riboflavin Functionalization and Cancer Cell Labeling of Nanoparticles

2017

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Nanoparticle-based cellular probes are commonly designed via covalent conjugation with affinity biomolecules. Those nanobioconjugates selectively interact with cell surface receptors and induce endocytosis followed by intracellular trafficking. However, this approach requires functional modification of biomolecules that may alter their biochemical activity. Here, we show that supramolecular host–guest chemistry can be utilized as an alternative approach in nanoparticle functionalization and selective cell labeling. We have used cyclodextrin-conjugated quantum dots (QDs) for supramolecular host–guest interaction-based functionalization with folate (QD-folate) and riboflavin (QD-riboflavin), where cyclodextrin acts as a host for the folate/riboflavin guest. We demonstrate that QD-folate and QD-riboflavin selectively label cells that have over-expressed folate/riboflavin receptors and induce the endocytosis pathway similar to covalently conjugated folate-/riboflavin-based nanoprobes. However, labeling is highly sensitive to the molar ratio of folate/riboflavin to cyclodextrin and incubation time. The presented functionalization/labeling approach is unique as it does not require covalent conjugation and may be extended for in vivo targeting application via simultaneous delivery of host and guest molecules.

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Dynamin 2 Regulates Riboflavin Endocytosis in Human Placental Trophoblasts

Cited by 17 publications

References 40 publications

The role of caveolae in endothelial cell dysfunction with a focus on nutrition and environmental toxicants

The role of caveolae in endothelial cell dysfunction with a focus on nutrition and environmental toxicants

Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics

Supramolecular Host–Guest Chemistry-Based Folate/Riboflavin Functionalization and Cancer Cell Labeling of Nanoparticles

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