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Characterization and Biological Function of Milk-Derived miRNAs

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (1 June 2023) | Viewed by 11330

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Special Issue Editor

Dr. Regina Golan-Gerstl

E-Mail Website1 Website2
Guest Editor

Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem 9112001, Israel
Interests: milk and breastfeeding; miRNA; extracellular vesicles; exosomes; colitis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Milk represents a complex and dynamic signaling system that transmits nutritional, hormonal, and molecular elements from mothers to their infants during a sensitive window of post-natal development. In the last years, new components have been identified in milk: microRNAs (miRNAs). The beneficial effects of milk on health may be associated in part with its peculiar components, among others miRNAs are found in high concentrations in all mammalian milk. Milk miRNAs are present in both the skim and fat fractions of human milk. In the skim fraction, miRNAs are carried by extracellular vesicles such as exosomes.

While miRNAs are important regulatory elements, and their profile expression was characterized in different mammalian milk almost nothing is known about their effect on infant health and development. Furthermore, more studies are needed to characterize the variation and dynamics of miRNA content within milk over time, or how they are affected by maternal environments. MiRNA activity in breast milk is likely influenced by the overall ecosystem of the early environment, including maternal characteristics, behaviors, and health. Alteration of milk miRNA profiles may have important cascading effects on the offspring. Understanding the health implications of miRNA content in milk produced by mothers on infants may ultimately be important for improving the health of future generations and potentially contribute to the discovery of a new aspect of the beneficial effects of milk on gut maturation, immune system development, and the prevention of metabolic disorders. In this regard, we invite investigators to contribute original research articles and review articles that will stimulate the continuing efforts to understand the biological effect of milk-derived miRNAs.The topics of this Special Issue include miRNA expression and its biological function in all mammalian milk and the different layers of the milk.

As the Guest Editor of this Special Issue, I hope that the collection of articles will be useful references for teaching and research to stimulate discussion and to open up new researches in the area of milk-derived miRNAs.

Dr. Regina Golan-Gerstl
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

milk-derived miRNAs
milk-derived extracellular vesicles
exosomes
colitis
nutritional elements

Published Papers (5 papers)

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Research

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19 pages, 7688 KiB

Open AccessArticle

Influence of Estrus on Dairy Cow Milk Exosomal miRNAs and Their Role in Hormone Secretion by Granulosa Cells

by Wenju Liu, Chao Du, Liangkang Nan, Chunfang Li, Haitong Wang, Yikai Fan, Ao Zhou and Shujun Zhang

Int. J. Mol. Sci. 2023, 24(11), 9608; https://doi.org/10.3390/ijms24119608 - 01 Jun 2023

Cited by 3 | Viewed by 1520

Abstract

Estrus is crucial for cow fertility in modern dairy farms, but almost 50% of cows do not show the behavioral signs of estrus due to silent estrus and lack of suitable and high-accuracy methods to detect estrus. MiRNA and exosomes play essential roles in reproductive function and may be developed as novel biomarkers in estrus detection. Thus, we analyzed the miRNA expression patterns in milk exosomes during estrus and the effect of milk exosomes on hormone secretion in cultured bovine granulosa cells in vitro. We found that the number of exosomes and the exosome protein concentration in estrous cow milk were significantly lower than in non-estrous cow milk. Moreover, 133 differentially expressed exosomal miRNAs were identified in estrous cow milk vs. non-estrous cow milk. Functional enrichment analyses indicated that exosomal miRNAs were involved in reproduction and hormone-synthesis-related pathways, such as cholesterol metabolism, FoxO signaling pathway, Hippo signaling pathway, mTOR signaling pathway, steroid hormone biosynthesis, Wnt signaling pathway and GnRH signaling pathway. Consistent with the enrichment signaling pathways, exosomes derived from estrous and non-estrous cow milk both could promote the secretion of estradiol and progesterone in cultured bovine granulosa cells. Furthermore, genes related to hormonal synthesis (CYP19A1, CYP11A1, HSD3B1 and RUNX2) were up-regulated after exosome treatment, while exosomes inhibited the expression of StAR. Moreover, estrous and non-estrous cow-milk-derived exosomes both could increase the expression of bcl2 and decrease the expression of p53, and did not influence the expression of caspase-3. To our knowledge, this is the first study to investigate exosomal miRNA expression patterns during dairy cow estrus and the role of exosomes in hormone secretion by bovine granulosa cells. Our findings provide a theoretical basis for further investigating milk-derived exosomes and exosomal miRNA effects on ovary function and reproduction. Moreover, bovine milk exosomes may have effects on the ovaries of human consumers of pasteurized cow milk. These differential miRNAs might provide candidate biomarkers for the diagnosis of dairy cow estrus and will assist in developing new therapeutic targets for cow infertility. Full article

(This article belongs to the Special Issue Characterization and Biological Function of Milk-Derived miRNAs)

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12 pages, 1043 KiB

Open AccessArticle

Variation of miRNA Content in Cow Raw Milk Depending on the Dairy Production System

by Loubna Abou el qassim, Sandrine Le Guillou and Luis J. Royo

Int. J. Mol. Sci. 2022, 23(19), 11681; https://doi.org/10.3390/ijms231911681 - 02 Oct 2022

Cited by 4 | Viewed by 1455

Abstract

Pasture-based milk presents several advantages over milk from intensive industrial farming in terms of human health, the environment, animal welfare, and social aspects. This highlights the need for reliable methods to differentiate milk according to its origin on the market. Here, we explored whether miRNA profiles could serve as a marker of milk production systems. We compared levels of previously described miRNAs in milk from four production systems (altogether 112 milk samples): grazing, zero grazing, grass silage or corn silage. Total RNA was extracted from the fat phase, and miRNAs levels were quantified by real-time quantitative PCR. The levels of the miRNAs bta-miR-155 and bta-miR-103 were higher in the grazing system than in corn silage farms. The levels of bta-miR-532, bta-miR-103 and bta-miR-7863 showed differences between different farm managements. The miRNAs bta-miR-155 and bta-miR-103 were predicted to participate in common functions related to fat metabolism and fatty acid elongation. All four differentially expressed miRNAs were predicted to participate in transport, cell differentiation, and metabolism. These results suggest that the dairy production system influences the levels of some miRNAs in milk fat, and that bta-miR-155 and bta-miR-103 may be potential biomarkers to identify milk from pasture-managed systems. Full article

(This article belongs to the Special Issue Characterization and Biological Function of Milk-Derived miRNAs)

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15 pages, 1516 KiB

Open AccessArticle

Characterization of miRNAs in Milk Small Extracellular Vesicles from Enzootic Bovine Leukosis Cattle

by Fumi Tsukada, Shigeo Takashima, Yoshiko Wakihara, Yuji O. Kamatari, Kaori Shimizu, Ayaka Okada and Yasuo Inoshima

Int. J. Mol. Sci. 2022, 23(18), 10782; https://doi.org/10.3390/ijms231810782 - 15 Sep 2022

Cited by 11 | Viewed by 1658

Abstract

Enzootic bovine leukosis (EBL) is a B-cell lymphosarcoma caused by the bovine leukemia virus (BLV). Most BLV-infected cattle show no clinical signs and only some develop EBL. The pathogenesis of EBL remains unclear and there are no methods for predicting EBL before its onset. Previously, it was reported that miRNA profiles in milk small extracellular vesicles (sEVs) were affected in cattle in the late stage of BLV infection. It raised a possibility that miRNA profile in milk sEVs from EBL cattle could be also affected. To characterize the difference in milk of EBL cattle and healthy cattle, we examined the miRNA profiles in milk sEVs from four EBL and BLV-uninfected cattle each using microarray analysis. Among the detected miRNAs, three miRNAs—bta-miR-1246, hsa-miR-1290, and hsa-miR-424-5p—which were detectable using quantitative real-time PCR (qPCR) and are associated with cancers in humans—were selected as biomarker candidates for EBL. To evaluate the utility of these miRNAs as biomarkers for EBL, their levels were measured using milk that was freshly collected from 13 EBL and seven BLV-uninfected cattle. bta-miR-1246 and hsa-miR-424-5p, but not hsa-miR-1290, were detected using qPCR and their levels in milk sEVs from EBL cattle were significantly higher than those in BLV-uninfected cattle. bta-miR-1246 and hsa-miR-424-5p in sEVs may promote metastasis by targeting tumor suppressor genes, resulting in increased amounts in milk sEVs in EBL cattle. These results suggest that bta-miR-1246 and hsa-miR-424-5p levels in milk sEVs could serve as biomarkers for EBL. Full article

(This article belongs to the Special Issue Characterization and Biological Function of Milk-Derived miRNAs)

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17 pages, 1926 KiB

Open AccessArticle

Breast Milk MicroRNAs Related to Leptin and Adiponectin Function Can Be Modulated by Maternal Diet and Influence Offspring Phenotype in Rats

by Marta Alonso-Bernáldez, Antoni Asensio, Andreu Palou-March, Juana Sánchez, Andreu Palou, Francisca Serra and Mariona Palou

Int. J. Mol. Sci. 2022, 23(13), 7237; https://doi.org/10.3390/ijms23137237 - 29 Jun 2022

Cited by 4 | Viewed by 2181

Abstract

There is evidence of the role of milk components in the metabolic programming of offspring. Here, we aimed to investigate the effects of a diet during lactation on breast milk leptin, adiponectin, and related miRNAs’ expression, and their impact on dams and their offspring. Dams were fed a control diet (controls) or a diet enriched with oleic acid, betaine, and leucine (TX) throughout lactation. A TX diet promoted higher leptin at lactation day (LD) five and lower adiponectin on LD15 (vs. controls) in milk, resulting in increased leptin to adiponectin (L/A) ratio throughout lactation. Moreover, TX diet reduced milk levels of miR-27a, miR-103, miR-200a, and miR-222. Concerning TX offspring, higher body fat was early observed and maintained into adult life, accompanied by higher HOMA-IR than controls at three months of age. Offspring body fat content in adulthood correlated positively with milk L/A ratio at LD15 and negatively with miRNAs modulated by the TX diet. In conclusion, maternal diet during lactation can modulate leptin and adiponectin interplay with miRNAs in milk, setting up the metabolic programming of the offspring. Better knowledge about the influence of diet on this process is necessary to promote a healthy adult life in the progeny. Full article

(This article belongs to the Special Issue Characterization and Biological Function of Milk-Derived miRNAs)

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Review

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56 pages, 5837 KiB

Open AccessReview

Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

by Bodo C. Melnik and Gerd Schmitz

Int. J. Mol. Sci. 2022, 23(19), 11503; https://doi.org/10.3390/ijms231911503 - 29 Sep 2022

Cited by 8 | Viewed by 3768

Abstract

Pancreatic β cell expansion and functional maturation during the birth-to-weaning period is driven by epigenetic programs primarily triggered by growth factors, hormones, and nutrients provided by human milk. As shown recently, exosomes derived from various origins interact with β cells. This review elucidates the potential role of milk-derived exosomes (MEX) and their microRNAs (miRs) on pancreatic β cell programming during the postnatal period of lactation as well as during continuous cow milk exposure of adult humans to bovine MEX. Mechanistic evidence suggests that MEX miRs stimulate mTORC1/c-MYC-dependent postnatal β cell proliferation and glycolysis, but attenuate β cell differentiation, mitochondrial function, and insulin synthesis and secretion. MEX miR content is negatively affected by maternal obesity, gestational diabetes, psychological stress, caesarean delivery, and is completely absent in infant formula. Weaning-related disappearance of MEX miRs may be the critical event switching β cells from proliferation to TGF-β/AMPK-mediated cell differentiation, whereas continued exposure of adult humans to bovine MEX miRs via intake of pasteurized cow milk may reverse β cell differentiation, promoting β cell de-differentiation. Whereas MEX miR signaling supports postnatal β cell proliferation (diabetes prevention), persistent bovine MEX exposure after the lactation period may de-differentiate β cells back to the postnatal phenotype (diabetes induction). Full article

(This article belongs to the Special Issue Characterization and Biological Function of Milk-Derived miRNAs)

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