MicroRNAs Are Absorbed in Biologically Meaningful Amounts from Nutritionally Relevant Doses of Cow Milk and Affect Gene Expression in Peripheral Blood Mononuclear Cells, HEK-293 Kidney Cell Cultures, and Mouse Livers

Baier, Scott R.; Nguyen, Christopher; Xie, Fang; Wood, Jennifer R.; Zempleni, Janos

doi:10.3945/jn.114.196436

Cited by 386 publications

(550 citation statements)

References 41 publications

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“…Human-milk-derived mEVs have been shown to modulate the functionality of immune cells [12,31]. Similar to human mEVs, bovine mEVs may have a biological function, as described previously [16]. It is possible that mEVs from bovine milk can be used as an immunomodulatory agent.…”

Section: Discussionmentioning

confidence: 96%

“…In the previous report, mEVs were internalized into human macrophage cells [15]. Another report demonstrated that mEVs from bovine milk deliver biologically functional miRNA into human cells and affect gene expression of recipient cells [16]. From these results, mEVs are useful DDS for the delivery of nucleic acid medicine, such as miRNA and siRNA.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Biocompatibility of highly purified bovine milk‐derived extracellular vesicles

Somiya

Yoshioka²,

Ochiya³

2018

J of Extracellular Vesicle

206

168

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Extracellular vesicles (EVs) deliver biologically active cargos from donor cells to recipient cells for intercellular communication. Since the existence of RNA cargo was discovered, EVs have been considered to be useful drug-delivery systems. Specifically, EVs from bovine milk (mEV) are one of the most promising platforms, since bovine milk is a scalable source of EVs for mass production. However, it is still difficult to isolate pure EVs from bovine milk owing to the complexity of raw materials. Furthermore, the biocompatibility and immunotoxicity of mEVs are still unclear. In this study, we developed a new method for isolating bovine milk-derived EVs by employing acid treatment and ultracentrifugation. Isolated mEVs are spherical in shape, measure 120 nm in diameter and contain typical EV marker proteins, such as tetraspanins. Compared with the previously reported method, our method can isolate purer mEVs. When mEVs are contacted with the mouse macrophage cell line Raw264.7, mEVs are readily taken up by the cells without a cytotoxic effect, suggesting that mEVs can deliver the cargo molecules into cells. While systemic administration of mEVs into mice resulted in the absence of systemic toxicity, certain types of cytokines were slightly induced. No anaphylaxis effect was observed after serial administration of mEVs in mice. Thus, mEVs isolated using our method are well tolerated in vivo and may be useful for the drug-delivery application.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

Biocompatibility of highly purified bovine milk‐derived extracellular vesicles

Somiya

Yoshioka²,

Ochiya³

2018

J of Extracellular Vesicle

206

168

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“…61 Similarly to human breast feeding, the consumption of raw bovine milk is also associated with decreased risk of allergy and asthma, 62 and it cannot be excluded that bovine miRNAs are implicated in these phenomena. A recent study proved that bovine milk-derived miRNAs can be absorbed and appear in human blood after milk consumption, 63 but this finding is also debated. 64,65 The bovine milk-derived xeno-miRNA, miR-29b which is identical to its human counterpart, 66 has been shown to raise the expression of the runt related transcription factor 2 (RUNX2) in human blood peripheral mononuclear cells.…”

Section: Dietary Xeno-mirna In Inter-species Communicationmentioning

confidence: 99%

“…64,65 The bovine milk-derived xeno-miRNA, miR-29b which is identical to its human counterpart, 66 has been shown to raise the expression of the runt related transcription factor 2 (RUNX2) in human blood peripheral mononuclear cells. 63 As RUNX2 is involved in the regulation of bone homeostasis by inducing osteoblasts and inhibiting the osteoclast differentiation in the host, the ingested bovine miR-29b xeno-miRNA might be hypothesized to induce bone mineralization. 67,68 Milk consumption might thus promote bone mineralization not only as a classical source of dietary calcium, but even via its miRNA content.…”

Section: Dietary Xeno-mirna In Inter-species Communicationmentioning

confidence: 99%

Potential relevance of microRNAs in inter-species epigenetic communication, and implications for disease pathogenesis

et al. 2016

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MicroRNAs are short non-protein coding RNA molecules involved in the epigenetic regulation of gene expression. Recently, extracellular microRNAs have been described in body fluids that might enable epigenetic communication between distant tissues. Being highly conserved molecules, exogenous xenomicroRNAs from different species could affect gene expression in the host even in a cross-kingdom fashion. Several data underline the relevance of microRNA-mediated communication between virus and host, and there are some experimental data showing that plant-or animal-derived dietary microRNAs might have gene expression modulating activity in humans. Milk-derived microRNAs might be involved in the "epigenetic priming" of the baby. Exogenous microRNAs might be hypothesized to be implicated in disease pathogenesis, e.g. in tumors. Major questions remain to be addressed including the amount of xeno-microRNAs needed for biological action or routes for microRNA delivery. In this brief review, experimental data and hypotheses on the potential pathogenic inter-species relevance of microRNA are presented.Abbreviations: AGO2, Argonaute-2 protein; dsRNA, double stranded RNA; FoxO1, forkhead box class O1A; FOXP3, forkhead box P3; HDL, high density lipoprotein; LDL, low density lipoprotein; LDLRAP1, low-density lipoprotein receptor adapter protein 1; miRNA, miR, microRNA; mTORC1, mechanistic target of rapamycin complex 1; premiRNA, precursor microRNA; pri-miRNA, primary microRNA; RISC, RNA-induced silencing complex; RUNX2, runt related transcription factor 2; siRNA, small interfering RNA; TCF7, transcription factor 7; TLR, Toll-like receptor; Treg, regulatory T-cell; ZEB1, zinc finger E-box binding homeobox 1

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“…Focusing on mammals exposed to plants and milk (Dickinson et al 2013;Snow et al 2013;Witwer et al 2013;Baier et al 2014;Tosar et al 2015), experimental results and current understanding of RNA stability, transport, and function do not appear to be consistent with proposed forms of cross-kingdom communication. In many cases, presumably positive ncRNA findings were shown to result from, e.g., sample contaminations or artefacts caused by technical limitations of the applied technologies (Witwer 2015).…”

Section: Kenneth W Witwer Johns Hopkins University School Of Medicimentioning

confidence: 99%

Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop

Aigner¹,

Buesen²,

Gant³

et al. 2016

Regulatory Toxicology and Pharmacology

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The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that the abundance of data obtained from ncRNA expression profiling requires careful evaluation to determine the utility of specific ncRNAs for regulatory toxicology. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify candidate ncRNAs for further assessment as potential biomarkers of toxicity and areas of toxicology where ncRNA expression profiling can address prevailing scientific deficiencies.(2) Develop consensus on how to conduct and report ncRNA expression profiling in a toxicological context to support applicability for regulatory decision-making. (3) Conduct experimental projects to evaluate the toxicological relevance of the expression profiles of selected ncRNAs. As necessary, retrospective analyses (e.g. from surplus samples from control groups from regulatory studies) can be supplemented with new (90-day) rat oral toxicity studies. These projects should aim at establishing physiological ncRNA expression profiles including the biological variability of healthy individuals. To substantiate the relevance of key ncRNAs for cell homeostasis or pathogenesis, molecular events should be linked with substance-induced apical effects in a dose-dependent manner. Applying a holistic approach, knowledge on ncRNAs, and relevant information from 'omics and epigenetics technologies, should be integrated into adverse outcome pathways to improve the understanding of the functional roles of ncRNAs within a regulatory context.

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MicroRNAs Are Absorbed in Biologically Meaningful Amounts from Nutritionally Relevant Doses of Cow Milk and Affect Gene Expression in Peripheral Blood Mononuclear Cells, HEK-293 Kidney Cell Cultures, and Mouse Livers

Abstract: We conclude that miRNAs in milk are bioactive food compounds that regulate human genes.

Cited by 386 publications

References 41 publications

Biocompatibility of highly purified bovine milk‐derived extracellular vesicles

Biocompatibility of highly purified bovine milk‐derived extracellular vesicles

Potential relevance of microRNAs in inter-species epigenetic communication, and implications for disease pathogenesis

Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop

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