Treatment with AICAR inhibits blastocyst development, trophectoderm differentiation and tight junction formation and function in mice

Calder, Michele D.; Edwards, Nicole; Betts, Dean H.; Watson, Andrew J.

doi:10.1093/molehr/gax050

Cited by 16 publications

(17 citation statements)

References 63 publications

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“…It is shown in previous studies that AMPK facilitates the assembly of tight junctions in epithelial cells ( Calder et al, 2017 ; Prasad et al, 2017 ; Rowart et al, 2017 ; Wang et al, 2017 ). Here we observed the distribution of ZO-1, claudin-1 and occludin in the presence or absence of metformin (30 μM) in Caco2 cells after 2.5% DSS treatment for 48 h with immunofluorescence staining and confocal microscopy.…”

Section: Resultsmentioning

confidence: 93%

Activating AMPK to Restore Tight Junction Assembly in Intestinal Epithelium and to Attenuate Experimental Colitis by Metformin

et al. 2018

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Adenosine monophosphate-activated protein kinase (AMPK), a crucial molecule in energy metabolism, is reported to play a potential role in gut epithelial differentiation and barrier function recently; however, its performance and mechanisms in the pathological process of inflammatory bowel diseases remain unidentified. In this study, we have found that the phosphorylation of AMPK in colonic tissues is negatively correlated with severity of disease during the initiation and development of experimental colitis induced by dextran sulfate sodium. Activation of AMPK by metformin significantly controls the progression of colitis, which is associated with the maintenance of tight junction in colonic epithelium in mice. Moreover, our in vitro data in colonic epithelial Caco2 cells shows that metformin promotes expression and assembly of tight junctions via an AMPK-dependent way. Overall, our results suggested that activating AMPK by a clinically safe drug metformin could be a beneficial choice for colitis treatment.

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Section: Resultsmentioning

confidence: 93%

Activating AMPK to Restore Tight Junction Assembly in Intestinal Epithelium and to Attenuate Experimental Colitis by Metformin

et al. 2018

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“…Consistent with the aforementioned studies, we also discovered that cell adhesion-related genes, including CDH1, were up-regulated by KDM6A overexpression in bovine embryos. Importantly, during preimplantation embryo development, adherens and tight junctions coordinately establish the first internal cavity of the embryo to transform the morula into a blastocyst (54); perturbation of these junctions leads to defects in blastocyst formation (55)(56)(57). These results provide a basis for investigating the mechanism of the first cell fate determination during embryonic development in mammals.…”

Section: Discussionmentioning

confidence: 96%

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

et al. 2019

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Aberrant epigenetic reprogramming is a major factor of developmental failure of cloned embryos. Histone H3 lysine 27 trimethylation (H3K27me3), a histone mark for transcriptional repression, plays important roles in mammalian embryonic development and induced pluripotent stem cell (iPSC) generation. The global loss of H3K27me3 marks may facilitate iPSC generation in mice and humans. However, the H3K27me3 level and its role in bovine somatic cell nuclear transfer (SCNT) reprogramming remain poorly understood. Here, we show that SCNT embryos exhibit global H3K27me3 hypermethylation from the 2‐ to 8‐cell stage and that its removal by ectopically expressed H3K27me3 lysine demethylase (KDM)6A greatly improves nuclear reprogramming efficiency. In contrast, H3K27me3 reduction by H3K27me3 methylase enhancer of zeste 2 polycomb repressive complex knockdown or donor cell treatment with the enhancer of zeste 2 polycomb repressive complex—selective inhibitor GSK343 suppressed blastocyst formation by SCNT embryos. KDM6A overexpression enhanced the transcription of genes involved in cell adhesion and cellular metabolism and X‐linked genes. Furthermore, we identified methyl‐CpG‐binding domain protein 3‐like 2, which was reactivated by KDM6A, as a factor that is required for effective reprogramming in bovines. These results show that H3K27me3 functions as an epigenetic barrier and that KDM6A overexpression improves SCNT efficiency by facilitating transcriptional reprogramming.—Zhou, C., Wang, Y., Zhang, J., Su, J., An, Q., Liu, X., Zhang, M., Wang, Y., Liu, J., Zhang, Y. H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency. FASEB J. 33, 4638–4652 (2019). http://www.fasebj.org

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“…Mouse embryos exposed to metformin from the 2-cell to the blastocyst stage in vitro are smaller in size with lower cell numbers ( 55 ). The cell-to cell contact with trophectoderm was also altered because of an increase in tight junction permeability ( 55 ).…”

Section: Metformin's Potential Impact On Infertilitymentioning

confidence: 99%

Metformin in Reproductive Biology

et al. 2018

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Initially produced in Europe in 1958, metformin is still one of the most widely prescribed drugs to treat type II diabetes and other comorbidities associated with insulin resistance. Metformin has been shown to improve fertility outcomes in females with insulin resistance associated with polycystic ovary syndrome (PCOS) and in obese males with reduced fertility. Metformin treatment reinstates menstrual cyclicity, decreases the incidence of cesareans, and limits the number of premature births. Notably, metformin reduces steroid levels in conditions associated with hyperandrogenism (e.g., PCOS and precocious puberty) in females and improves fertility of adult men with metabolic syndrome through increased testosterone production. While the therapeutical use of metformin is considered to be safe, in the last 10 years some epidemiological studies have described phenotypic differences after prenatal exposure to metformin. The goals of this review are to briefly summarize the current knowledge on metformin focusing on its effects on the female and male reproductive organs, safety concerns, including the potential for modulating fetal imprinting via epigenetics.

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Treatment with AICAR inhibits blastocyst development, trophectoderm differentiation and tight junction formation and function in mice

Abstract: Canadian Institutes of Health Research (CIHR) operating funds. There are no competing interests.

Cited by 16 publications

References 63 publications

Activating AMPK to Restore Tight Junction Assembly in Intestinal Epithelium and to Attenuate Experimental Colitis by Metformin

Activating AMPK to Restore Tight Junction Assembly in Intestinal Epithelium and to Attenuate Experimental Colitis by Metformin

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

Metformin in Reproductive Biology

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