Beneficial Effects of Milk-Derived Extracellular Vesicles on Liver Fibrosis Progression by Inhibiting Hepatic Stellate Cell Activation.

Liver fibrosis is the consequence of various chronic liver diseases, resulting in accumulation of extracellular matrix, following the activation and proliferation of hepatic stellate cells (HSCs). Based on the milk-derived extracellular vesicles' (MDEs') characteristics and biological proprieties, we investigate whether MDEs may regulate fibrotic progression by inhibiting HSCs' activation via the MDEs' miRNA content. In order to study this question, we examined the effect of human and cow MDEs on HSCs isolated from murine livers, on activation, proliferation and their proteins' expression. We have shown that MDEs are able to enter into HSCs in vitro and into the livers in vivo. MDEs inhibited HSCs' proliferation following stimulation with PDGF. Moreover, in vivo treatment with MDEs resulted in an increase of in miRNA-148 and Let7a expression in HSCs. In contrast, treatment with MDEs reduced the expression of miR-21 in HSCs. In addition, MDEs regulate HSC activation, as was shown by downregulation of collagen I expression and alpha smooth muscle actin, and upregulation of PPARγ. MDEs carrying beneficial miRNAs can be a nontoxic natural target for treatment of liver cirrhosis.

Oxytocin Regulates the Expression of Selected Colostrum-derived microRNAs.

OBJECTIVE: The highly expressed microRNAs (miRNAs) in milk are known as beneficial miRNAs, such as mir148a-3p, which is related to immune system development and disease prevention. There is a need to study their expression and secretion regulatory mechanism in breast milk. We hypothesize that oxytocin can be involved in the regulation of expression and secretion of milk-derived miRNAs. METHODS: Initially, oxytocin's effect on miRNA expression in human mammary cells was analyzed. Secondly, the expression of selected miRNAs in mothers' colostrum treated or not with oxytocin before, during, or after labor was compared. MiRNA expression was analyzed by quantitative real-time PCR. RESULTS: The expression of miR-148a was significantly upregulated, and miR-320 downregulated in oxytocin-treated mammary cells as well as their secreted extracellular vesicles to the media, compared with untreated cells. MiR-148a was found to be upregulated, and miR-320 was downregulated in the human colostrum of exogenous oxytocin-treated mothers. Moreover, miR-320 was highly expressed compared with miR-148a in the colostrum of mothers that did not receive exogenous oxytocin. In contrast, in the milk of mothers who received exogenous oxytocin, the expression of miRNA-148-3p was highly expressed compared with miR-320. CONCLUSIONS: This study shows that oxytocin modulates the expression of main milk-derived miRNAs. Our findings provide a novel insight into oxytocin's role in milk composition by regulating miRNA expression. Our results implicate that oxytocin increases miRNA expression in mammary epithelial cells and human milk, affecting human milk composition and may contribute to further infant health.

Cow and Human Milk-Derived Exosomes Ameliorate Colitis in DSS Murine Model.

The aim of this study was to investigate the therapeutic effect of cow and human milk derived exosomes (MDEs) on colitis. We used gavage administration of fluorescent labeled MDEs to track their localization patterns in vivo and studied their therapeutic effect on colitis in a dextran sulfate sodium (DSS)-induced colitis model. MDEs attenuated the severity of colitis induced by DSS and statistically reduced the histopathological scoring grade and shortening of the colon. Likewise, treatment with MDEs reduced the expression of interleukin 6 and tumor necrosis factor-α. Moreover, miRNAs highly expressed in milk, such as miRNA-320, 375, and Let-7, were found to be more abundant in the colon of MDE-treated mice compared with untreated mice; contrastingly, the expression of their target genes, mainly DNA methyltransferase 1 (DNMT1) and DNMT3 were downregulated. Furthermore, the level of TGF-ß was upregulated in the colon of MDE-treated mice. We demonstrated that MDEs have a therapeutic and anti-inflammatory effect on colitis, involving several complementary pathways in its mechanism of action. The therapeutic effects of MDEs might have implications for the possible addition of MDEs as a nutrient in enteral nutrition formulas for patients with inflammatory bowel disease.

Molecular Evolution of the Glutathione S-Transferase Family in the Bemisia tabaci Species Complex.

The glutathione S-transferase (GST) family plays an important role in the adaptation of herbivorous insects to new host plants and other environmental constrains. The family codes for enzymes that neutralize reactive oxygen species and phytotoxins through the conjugation of reduced glutathione. Here, we studied the molecular evolution of the GST family in Bemisia tabaci, a complex of >35 sibling species, differing in their geographic and host ranges. We tested if some enzymes evolved different functionality, by comparing their sequences in six species, representing five of the six major genetic clades in the complex. Comparisons of the nonsynonymous to synonymous substitution ratios detected positive selection events in 11 codons of 5 cytosolic GSTs. Ten of them are located in the periphery of the GST dimer, suggesting a putative involvement in interactions with other proteins. Modeling the tertiary structure of orthologous enzymes, identified additional 19 mutations in 9 GSTs, likely affecting the enzymes' functionality. Most of the mutation events were found in the environmentally responsive classes Delta and Sigma, indicating a slightly different delta/sigma tool box in each species. At a broader genomic perspective, our analyses indicated a significant expansion of the Delta GST class in B. tabaci and a general association between the diet breadth of hemipteran species and their total number of GST genes. We raise the possibility that at least some of the identified changes improve the fitness of the B. tabaci species carrying them, leading to their better adaptation to specific environments.