MicroRNA-17-92 Regulates Beta-Cell Restoration After Streptozotocin Treatment

Zhang, Jie; Chen, Xiang; Lang, Jiangli; Li, Li; Chen, Fei; Tian, Li; Meng, Yan; Yu, Xijie

doi:10.3389/fendo.2020.00009

Cited by 16 publications

(14 citation statements)

References 69 publications

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“…However, several concerns must be addressed. Previous studies have implicated a role for miR-92a in other pathobiological processes including type 1 diabetes (T1D) ( 90 , 91 ), neurogenesis ( 92 ), cancer ( 25 , 64 , 93 ), as well as TLR ( 94 ) and estrogen receptor signaling ( 95 ). These studies were performed using either the entire miR-17~92 cluster–deficient mice ( 91 , 92 ) or without the use of Mir92a –/– mice or miR-92a inhibitors in vivo ( 90 , 94 , 95 ).…”

Section: Discussionmentioning

confidence: 99%

microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance

Fujiwara¹,

Raheja²,

Garo³

et al. 2022

Journal of Clinical Investigation

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A disequilibrium between immunosuppressive Tregs and inflammatory IL-17–producing Th17 cells is a hallmark of autoimmune diseases, including multiple sclerosis (MS). However, the molecular mechanisms underlying the Treg and Th17 imbalance in CNS autoimmunity remain largely unclear. Identifying the factors that drive this imbalance is of high clinical interest. Here, we report a major disease-promoting role for microRNA-92a (miR-92a) in CNS autoimmunity. miR-92a was elevated in experimental autoimmune encephalomyelitis (EAE), and its loss attenuated EAE. Mechanistically, miR-92a mediated EAE susceptibility in a T cell–intrinsic manner by restricting Treg induction and suppressive capacity, while supporting Th17 responses, by directly repressing the transcription factor Foxo1. Although miR-92a did not directly alter Th1 differentiation, it appeared to indirectly promote Th1 cells by inhibiting Treg responses. Correspondingly, miR-92a inhibitor therapy ameliorated EAE by concomitantly boosting Treg responses and dampening inflammatory T cell responses. Analogous to our findings in mice, miR-92a was elevated in CD4 + T cells from patients with MS, and miR-92a silencing in patients’ T cells promoted Treg development but limited Th17 differentiation. Together, our results demonstrate that miR-92a drives CNS autoimmunity by sustaining the Treg/Th17 imbalance and implicate miR-92a as a potential therapeutic target for MS.

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Section: Discussionmentioning

confidence: 99%

microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance

Fujiwara¹,

Raheja²,

Garo³

et al. 2022

Journal of Clinical Investigation

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“…In the context of insulin resistance, the effect of miR-92a in glucose uptake in insulin target cells such as liver, skeletal muscle or adipocytes has not been reported yet. However, miR-92a is reported to help beta islet cell repair and restoration [ 67 , 68 ]. Hence, the increased level of miR-92a-3p in circulating EVs in GDM indicates the miR-92a-3p might be involved in a protective mechanism to prevent hyperglycaemia by increasing the glucose uptake in skeletal muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus

et al. 2021

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Background Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9–15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile. Methods Discovery: A retrospective, case–control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status (i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM. Results A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p < 0.05) across gestation and 101 miRNAs were significantly changed between NGT and GDM. Analysis of the miRNA changes in NGT and GDM separately identified a total of 256 (NGT-group), and 302 (GDM-group) miRNAs that change across gestation. A multivariate classification model was developed, based on the quantitative expression of EV-associated miRNAs, and the accuracy to correctly assign samples was > 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake. Conclusions During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM.

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“…These outcomes were attributable to reduced β‐cell number and mass and an increased incidence of β‐cell apoptosis. In turn, these deleterious effects were associated with higher levels of PTEN expression, which suppressed PI3K/Akt signaling 68 …”

Section: Modulators Of Pi3k/akt Signaling Are Potential Therapeuticsmentioning

confidence: 99%

Targeting the PI3K/Akt signaling pathway in pancreatic β‐cells to enhance their survival and function: An emerging therapeutic strategy for type 1 diabetes

Camaya

Donnelly

O’Brien

2022

Journal of Diabetes

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Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of the insulin‐producing β‐cells within the pancreas. Islet transplantation represents one cure; however, during islet preparation and post transplantation significant amounts of β‐cell death occur. Therefore, prevention and cure of T1D is dependent upon the preservation of β‐cell function and the prevention of β‐cell death. Phosphoinositide 3‐kinase (PI3K)/Akt signaling represents a promising therapeutic target for T1D due to its pronounced effects on cellular survival, proliferation, and metabolism. A growing amount of evidence indicates that PI3K/Akt signaling is a critical determinant of β‐cell mass and function. Modulation of the PI3K/Akt pathway, directly (via the use of highly specific protein and peptide‐based biologics, excretory/secretory products of parasitic worms, and complex constituents of plant extracts) or indirectly (through microRNA interactions) can regulate the β‐cell processes to ultimately determine the fate of β‐cell mass. An important consideration is the identification of the specific PI3K/Akt pathway modulators that enhance β‐cell function and prevent β‐cell death without inducing excessive β‐cell proliferation, which may carry carcinogenic side effects. Among potential PI3K/Akt pathway agonists, we have identified a novel parasite‐derived protein, termed FhHDM‐1 (Fasciola hepatica helminth defense molecule 1), which efficiently stimulates the PI3K/Akt pathway in β‐cells to enhance function and prevent death without concomitantly inducing proliferation unlike several other identified stimulators of PI3K/Akt signaling . As such, FhHDM‐1 will inform the design of biologics aimed at targeting the PI3K/Akt pathway to prevent/ameliorate not only T1D but also T2D, which is now widely recognized as an inflammatory disease characterized by β‐cell dysfunction and death. This review will explore the modulation of the PI3K/Akt signaling pathway as a novel strategy to enhance β‐cell function and survival.

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MicroRNA-17-92 Regulates Beta-Cell Restoration After Streptozotocin Treatment

Cited by 16 publications

References 69 publications

microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance

microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance

Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus

Targeting the PI3K/Akt signaling pathway in pancreatic β‐cells to enhance their survival and function: An emerging therapeutic strategy for type 1 diabetes

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