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Dietary Depletion of Milk Exosomes and Their MicroRNA Cargos Elicits a Depletion of miR-200a-3p and Elevated Intestinal Inflammation and Chemokine (C-X-C Motif) Ligand 9 Expression in Mdr1a-/- Mice.

ABSTRACT: Background:Exosomes transfer regulatory microRNAs (miRs) from donor cells to recipient cells. Exosomes and miRs originate from both endogenous synthesis and dietary sources such as milk. miR-200a-3p is a negative regulator of the proinflammatory chemokine (C-X-C motif) ligand 9 (CXCL9). Male Mdr1a-/- mice spontaneously develop clinical signs of inflammatory bowel disease (IBD). Objectives:We assessed whether dietary depletion of exosomes and miRs alters the severity of IBD in Mdr1a-/- mice owing to aberrant regulation of proinflammatory cytokines. Methods:Starting at 5 wk of age, 16 male Mdr1a-/- mice were fed either milk exosome- and RNA-sufficient (ERS) or milk exosome- and RNA-depleted (ERD) diets. The ERD diet is characterized by a near-complete depletion of miRs and a 60% loss of exosome bioavailability compared with ERS. Mice were killed when their weight loss exceeded 15% of peak body weight. Severity of IBD was assessed by histopathological evaluation of cecum. Serum cytokine and chemokine concentrations and mRNA and miR tissue expression were analyzed by multiplex ELISAs, RNA-sequencing analysis, and qRT-PCR, respectively. Results:Stromal collapse, gland hyperplasia, and additive microscopic disease scores were (mean ± SD) 56.7% ± 23.3%, 23.5% ± 11.8%, and 29.6% ± 8.2% lower, respectively, in ceca of ERS mice than of ERD mice (P < 0.05). The serum concentration of CXCL9 was 35.0% ± 31.0% lower in ERS mice than in ERD mice (P < 0.05). Eighty-seven mRNAs were differentially expressed in the ceca from ERS and ERD mice; 16 of these mRNAs are implicated in immune function. The concentrations of 4 and 1 out of 5 miRs assessed (including miR-200a-3p) were ?63% lower in livers and ceca, respectively, from ERD mice than from ERS mice. Conclusions:Milk exosome and miR depletion exacerbates cecal inflammation in Mdr1a-/- mice.

SUBMITTER: Wu D

PROVIDER: S-EPMC7053579 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Dietary Depletion of Milk Exosomes and Their MicroRNA Cargos Elicits a Depletion of miR-200a-3p and Elevated Intestinal Inflammation and Chemokine (C-X-C Motif) Ligand 9 Expression in <i>Mdr1a<sup>-/-</sup></i> Mice.

Wu Di D Kittana Hatem H Shu Jiang J Kachman Stephen D SD Cui Juan J Ramer-Tait Amanda E AE Zempleni Janos J

Current developments in nutrition 20191031 12

<h4>Background</h4>Exosomes transfer regulatory microRNAs (miRs) from donor cells to recipient cells. Exosomes and miRs originate from both endogenous synthesis and dietary sources such as milk. miR-200a-3p is a negative regulator of the proinflammatory chemokine (C-X-C motif) ligand 9 (CXCL9). Male <i>Mdr1a<sup>-/-</sup></i> mice spontaneously develop clinical signs of inflammatory bowel disease (IBD).<h4>Objectives</h4>We assessed whether dietary depletion of exosomes and miRs alters the sever ...[more]

PMID: 32154493

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Project description:Objective:This study was set out to explore the expression and related mechanism of XIST and miR-200a-3p in retinoblastoma (Rb). Patients and Methods:Fifty-four children with Rb who came to our hospital for surgery from January 2018 to September 2019 were collected. In addition, Rb cells and human retinal epithelial cells were purchased. XIST-siRNA (si-XIST), XIST-shRNA (sh-XIST), empty vector plasmid (siRNA-NC), miR-200a-3p-mimics and miR -200a-3p-inhibition were transfected into Y79 cells. The expression of XIST and miR-200a-3p in the samples were determined by qRT-PCR. ?-catenin, cyclin B1, cyclin D1, Bax, Caspase-3, N-cadherin, vimentin, Snail, E-Cadherin and ZO-1 protein levels were measured by WB. MTT, Transwell and flow cytometry were utilized to detect cell proliferation, invasion, and apoptosis, respectively. Results:XIST was highly expressed while miR-200a-3p was lowly expressed in patients' tissues, and the AUC of both was over 0.8. XIST and miR-200a-3p was related to differentiation degree in Rb patients. Y79 cells were selected for transfection. Compared with the siRNA-NC group, XIST was significantly reduced in the siRNA-XIST group, and it was significantly increased in the shRNA-XIST group (P<0.01). The proliferation capacity of siRNA-XIST group was decreased, while that of shRNA-XIST group was up-regulated. The apoptosis rate of siRNA-XIST group was significantly up-regulated, while that of shRNA-XIST group was decreased (P<0.001). The invasive capacity of siRNA-XIST group was decreased, while that of shRNA-XIST group was up-regulated (P<0.001). Silencing XIST and over-expressed miR-200a-3p could inhibit cell epithelial-mesenchymal transition (EMT), proliferation, invasion, and promote apoptosis. WB detection showed that Carboplatin + LncRNA XIST intervention group could more significantly inhibit ?-catenin, cyclin B1, cyclin D1, N-cadherin, vimentin, Snail protein, and promote the up-regulation of Bax, Caspase-3, E-Cadherin and ZO-1 expression. Conclusion:Inhibition of XIST expression can up-regulate miR-200a-3p-mediated PI3K-Akt/MAPK-ERK signaling pathway and affect cell EMT, proliferation, invasion, and apoptosis, which is expected to be a potential therapeutic target for Rb.

Dataset Information

Dietary Depletion of Milk Exosomes and Their MicroRNA Cargos Elicits a Depletion of miR-200a-3p and Elevated Intestinal Inflammation and Chemokine (C-X-C Motif) Ligand 9 Expression in Mdr1a-/- Mice.

Publications

Dietary Depletion of Milk Exosomes and Their MicroRNA Cargos Elicits a Depletion of miR-200a-3p and Elevated Intestinal Inflammation and Chemokine (C-X-C Motif) Ligand 9 Expression in <i>Mdr1a<sup>-/-</sup></i> Mice.

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