Suppression of milk-derived miR-148a caused by stress plays a role in the decrease in intestinal ZO-1 expression in infants

Chiba, Takeshi; Takaguri, Akira; Kooka, Aya; Kowatari, Kiyoko; Yoshizawa, Megumi; Fukushi, Yukiharu; Hongo, Fuminori; Sato, Hideki; Fujisawa, Miho; Wada, Shinichiro; Maeda, Tomoji

doi:10.1016/j.clnu.2022.10.004

Cited by 10 publications

(4 citation statements)

References 32 publications

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“…11) Recently, we reported that the milk-derived miRNA miR-148a, which is abundantly present in breast milk, is associated with the development of intestinal barrier function via increased ZO-1 expression in infants. 12) These results suggest that HMEs enhance intestinal barrier function and may protect infants from intestinal injury, such as NEC. However, the mechanism underlying the HME-mediated induction of TJ proteins in human intestinal epithelial cells remains unknown.…”

Section: Introductionmentioning

confidence: 83%

Human Milk Exosomes Induce ZO-1 Expression <i>via</i> Inhibition of REDD1 Expression in Human Intestinal Epithelial Cells

Chiba

Maeda

2023

Biological & Pharmaceutical Bulletin

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Human milk exosomes (HMEs) enhance intestinal barrier function and contribute to an improvement in inflammation and mucosal injury, such as necrotizing enteritis (NEC), in infants. Here, we aimed to elucidate the intracellular factors involved in HME-induced expression of zonula occludens-1 (ZO-1), a tight junction protein, in Caco-2 human intestinal epithelial cells. HME treatment for 72 h significantly increased transepithelial electrical resistance in these cells. The mean ZO-1 protein levels in cells treated with HME for 72 h were significantly higher than those in the control cells. The mRNA and protein levels of regulated in development and DNA damage response 1 (REDD1) in HME-treated cells were significantly lower than those in the control cells. Although HME treatment did not increase the mechanistic target of rapamycin (mTOR) level in Caco-2 cells, it significantly increased the phosphorylated mTOR (p-mTOR) level and p-mTOR/ mTOR ratio. The ZO-1 protein levels in cells treated with an inducer of REDD1, cobalt chloride (CoCl 2 ) alone were significantly lower than those in the control cells. However, ZO-1 protein levels in cells co-treated with HME and CoCl 2 were significantly higher than those in cells treated with CoCl 2 alone. Additionally, REDD1 protein levels in cells treated with CoCl 2 alone were significantly higher than those in the control cells. However, REDD1 protein levels in cells co-treated with HME and CoCl 2 were significantly lower than those in cells treated with CoCl 2 alone. This HME-mediated effect may contribute to the development of barrier function in the infant intestine and protect infants from diseases. Key words exosome, breast milk, tight junction, regulated in development and DNA damage response 1, zonula occludens-1

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Section: Introductionmentioning

confidence: 83%

Human Milk Exosomes Induce ZO-1 Expression <i>via</i> Inhibition of REDD1 Expression in Human Intestinal Epithelial Cells

Chiba

Maeda

2023

Biological & Pharmaceutical Bulletin

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“…Milk, mammary epithelium, lung tissue, and whole blood samples were collected from the mice after exposure to CS on day 11 postpartum. Milk was collected as described previously [ 27 , 28 ]. After milk collection, mammary epithelial and lung tissues were collected from the mice and frozen in liquid nitrogen.…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative polymerase chain reaction (PCR) analysis of miRNA expression in milk, mammary epithelium, lung tissue, and cultured cells was performed as previously described [ 27 , 28 ]. Briefly, total RNA was extracted to evaluate miRNA expression using the miRNeasy Serum/Mini Kit (Qiagen, Hilden, Germany) or the miRNeasy Mini Kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

Smoking-induced suppression of β-casein in milk is associated with an increase in miR-210-5p expression in mammary epithelia

Chiba,

Takaguri,

Mikuma

et al. 2024

Biochemistry and Biophysics Reports

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“…As a result, Figure 2C showed that top 5 highest abundance HMEV-miRs may exhibit physiologic functions involving transcriptional regulation, cell growth and development, and immunomodulation. Noted that miR-148a is the most abundance HMEV-derived microRNA, 11,58 influencing various functions, including DNA methylation through DNA methyltransferase 1, 59 cell and tissue development, 60 inflammation, 61,62 and neuroprotection. 63,64 Also, miR-146a-5p is known to regulate type I interferon signaling 65,66 and involved in cellular responses upon viral infection.…”

Section: Relative Protein Intensitiesmentioning

confidence: 99%

Prenatal SARS-CoV-2 infection alters postpartum human milk-derived extracellular vesicles

Cetinkaya

Zhang

Kuhnell

et al. 2023

Preprint

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Human milk-derived extracellular vesicles (HMEVs) are crucial functional components in breast milk, contributing to infant health and development. Maternal conditions could affect HMEV cargos; however, the impact of SARS-CoV-2 infection on HMEVs remains unknown. This study evaluated the influence of SARS-CoV-2 infection during pregnancy on postpartum HMEV molecules. Milk samples (9 prenatal SARS-CoV-2 vs. 9 controls) were retrieved from the IMPRINT birth cohort. After defatting and casein micelle disaggregation, 1 mL milk was subjected to a sequential process of centrifugation, ultrafiltration, and qEV-size exclusion chromatography. Particle and protein characterizations were performed following the MISEV2018 guidelines. EV lysates were analyzed through proteomics and miRNA sequencing, while the intact EVs were biotinylated for surfaceomic analysis. Multi-Omics was employed to predict HMEV functions associated with prenatal SARS-CoV-2 infection. Demographic data between the prenatal SARS-CoV-2 and control groups were similar. The median duration from maternal SARS-CoV-2 test positivity to milk collection was 3 months (range: 1-6 months). Transmission electron microscopy showed the cup-shaped nanoparticles. Nanoparticle tracking analysis demonstrated particle diameters of <200 nm and yields of >1e11 particles from 1 mL milk. Western immunoblots detected ALIX, CD9 and HSP70, supporting the presence of HMEVs in the isolates. Thousands of HMEV cargos and hundreds of surface proteins were identified and compared. Multi-Omics predicted that mothers with prenatal SARS-CoV-2 infection produced HMEVs with enhanced functionalities involving metabolic reprogramming and mucosal tissue development, while mitigating inflammation and lower EV transmigration potential. Our findings suggest that SARS-CoV-2 infection during pregnancy boosts mucosal site-specific functions of HMEVs, potentially protecting infants against viral infections. Further prospective studies should be pursued to reevaluate the short- and long-term benefits of breastfeeding in the post-COVID era.

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Suppression of milk-derived miR-148a caused by stress plays a role in the decrease in intestinal ZO-1 expression in infants

Cited by 10 publications

References 32 publications

Human Milk Exosomes Induce ZO-1 Expression <i>via</i> Inhibition of REDD1 Expression in Human Intestinal Epithelial Cells

Human Milk Exosomes Induce ZO-1 Expression <i>via</i> Inhibition of REDD1 Expression in Human Intestinal Epithelial Cells

Smoking-induced suppression of β-casein in milk is associated with an increase in miR-210-5p expression in mammary epithelia

Prenatal SARS-CoV-2 infection alters postpartum human milk-derived extracellular vesicles

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