MicroRNA-146a Mimics Reduce the Peripheral Neuropathy in Type 2 Diabetic Mice

Liu, Xian Shuang; Fan, Baoyan; Szalad, Alexandra; Jia, Longfei; Wang, Lei; Wang, Xinli; Pan, Wanlong; Zhang, Li; Zhang, Ruilan; Hu, Jiani; Zhang, Xiao Ming; Chopp, Michael; Zhang, Zheng Gang

doi:10.2337/db16-1182

Cited by 101 publications

(103 citation statements)

References 47 publications

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“…In addition, miR-146a is consistently dysregulated in T1DM patients ( 49 ). In mice with T2DM, miR-146a mimics significantly ameliorated peripheral neuropathy, principally by suppressing the expression of hyperglycemia-induced proinflammatory genes ( 50 ). Moreover, miR-146a is reportedly involved in high-glucose-induced endothelial inflammation, which suggests that it may be a novel therapeutic target for diabetic vascular disease ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Exosomes Derived From Mesenchymal Stromal Cells Pretreated With Advanced Glycation End Product-Bovine Serum Albumin Inhibit Calcification of Vascular Smooth Muscle Cells

Wang

Zhu

et al. 2018

Front. Endocrinol.

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Background: The osteogenic differentiation of vascular smooth muscle cell (VSMCs) is important for the development of vascular calcification (VC), particularly in diabetes. Exosomes derived from Mesenchymal Stromal Cells (MSCs) are effective against cardiovascular diseases, yet their role in VC remains unclear. Advanced glycation end products (AGEs) inhibit bone marrow stromal cell osteogenesis by targeting osteogenesis-associated genes. Thus, we investigated the role of exosomes derived from MSCs pretreated with AGEs-BSA in VC and its potential mechanisms.Methods: Primary VSMCs and MSCs were isolated from the aorta and bone marrow of Sprague-Dawley rats, respectively. VSMCs were cultured with AGEs-BSA to induce osteogenic differentiation. Exosomes were harvested from MSCs by ultracentrifugation. MSCs and VSMCs were cocultured in Transwells, and exosomes were added to VSMC culture medium to assess their effects on osteogenic differentiation. Double luciferase reporter assay was applied to confirm that miR-146a directly targets the 3' UTR of the thioredoxin-interacting protein (TXNIP) gene.Results: Pretreatment of VSMCs with AGEs-BSA increased the expression of thioredoxin-interacting protein (TXNIP) by inhibiting that of miR-146a, resulting in enhanced ROS production and VSMC calcification. By contrast, the expression of miR-146a in MSCs was increased by AGEs-BSA treatment. Thus, miR-146a was transferred from AGEs-BSA-pretreated or miR-146a-transfected MSCs to VSMCs via exosomes. After coculture with miR-146a-containing exosomes, the AGEs-BSA-mediated increase in VSMC calcification was diminished, accompanied by decreased TXNIP expression and ROS production. Furthermore, TXNIP overexpression counteracted the anti-calcification effects of MSC-derived miR-146a-containing exosomes. In addition, TXNIP was identified as a target gene of miR-146a, and the results of double luciferase reporter assay confirmed that TXNIP was the direct target gene of miR-146a.Conclusions: Exosomes secreted by MSCs pretreated with AGEs-BSA contained a high level of miR-146a, which was transferred to VSMCs and inhibited AGEs-BSA-induced calcification in a TXNIP-dependent manner. Thus, miR-146a-containing exosomes may be a potential therapeutic target for VC.

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Section: Discussionmentioning

confidence: 99%

Exosomes Derived From Mesenchymal Stromal Cells Pretreated With Advanced Glycation End Product-Bovine Serum Albumin Inhibit Calcification of Vascular Smooth Muscle Cells

Wang

Zhu

et al. 2018

Front. Endocrinol.

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“…Recent papers have linked miRNA expression with the pathogenesis of DPN. For instance, miR-146a overexpression was able to inhibit DPN progression through increasing neurological function and reducing inflammatory response [15]. Likewise, miR-25 acted as a protective gene in DPN to reduce the generation of ROS [16].…”

Section: Introductionmentioning

confidence: 99%

Notoginsenoside R1 alleviates high glucose-evoked damage in RSC96 cells through down-regulation of miR-503

Wang

Hao

2019

Artificial Cells, Nanomedicine, and Biotechnology

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Notoginsenoside R1 (NGR1) is a major bioactive ingredient of Radix notoginseng that has promise in treating several diabetes-related diseases, like diabetic nephropathy and diabetic cardiomyopathy. This work is designed to explore if NGR1 has potential in treating diabetic peripheral neuropathy (DPN). A cell model of DPN was made by stimulating RSC96 cells with high glucose. The effects of NGR1 preconditioning were examined by conducting CCK-8 assay, flow cytometry, ROS assay and Western blot. The downstream effector and signalling of NGR1 were then explored by qRT-PCR and Western blot. High glucose incubation led to cell viability loss, apoptosis facilitation, caspase-3 and PARP cleavage, and ROS generation of RSC96 cells. Meanwhile, expression of NGF and BDNF was declined by high glucose. Preconditioning NGR1 significantly protected RSC96 cells against high glucose-evoked damage. And NGR1 prevented high glucose-induced expression of miR-503. The beneficial functions of NGR1 towards high glucose-injured RSC96 cells were impeded by miR-503 overexpression. Further, NGR1 activated PI3K/AKT and b-catenin signalling through a miR-503-dependent way. This paper illustrated the neuroprotective and neurotrophic function of NGR1 in RSC96 cells. The beneficial function may due to its regulation on miR-503 expression and the downstream signalling such as PI3K/AKT and b-catenin.

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“…Changes in miR-146a in diabetic patients and animals were reported in a previous study. Liu et al [25] demonstrated that treatment of diabetic mice with miR-146a mimics robustly reduced diabetic peripheral neuropathy. Then, the target genes of hsa-miR-146a-3p were identified based on the parallel DEmRNAs in the present study.…”

Section: Resultsmentioning

confidence: 99%

Integrated miRNA-mRNA Expression Profile Analysis Reveals a Role of miR-146a-3p/TRAF6 in Plasma from Gestational Diabetes Mellitus Patients

Chen

Yan

2020

Preprint

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BACKGROUND: By utilizing an integrative strategy, we screened noninvasive molecular markers for the early detection of GDM and constructed miRNA-mRNA regulatory networks associated with GDM.METHODS: A total of 3 microarray datasets (GSE98043, GSE19649 and GSE92772) of plasma samples comparing GDM pregnant women and healthy control pregnant women were downloaded from the GEO database. The GEO2R online platform was used to identify the differentially expressed genes (DEmRNAs) and the differentially expressed miRNAs (DEmiRNAs). The target genes of DEmiRNAs were identified using two independent and complementary types of information: computational target predictions and expression relationships. KEGG pathway annotation was performed for target genes and DEmiRNAs. An interaction network was constructed to identify hub genes of GDM. Another dataset (GSE92772) was used to externally verify the predictive ability of the hub genes. Gene set enrichment analysis (GSEA) was performed to explore the biological function of hub genes.RESULTS: A total of 264 DEmiRNAs and 1217 DEmRNAs were identified by comparing the microarray data of serum samples of GDM patients and healthy pregnant women. Hsa-miR-146a-3p ranked first because of its lowest P value and was selected for further analysis. A total of 47 target genes, including TRAF6, were shared between the computational target predictions and DEmRNAs and were identified as target genes of hsa-miR-146a-3p. Enrichment analysis indicated that GDM-related miRNAs were mainly enriched in the glypican pathway, proteoglycan syndecan-mediated signaling events, and syndecan-1-mediated signaling events. In addition, the glypican pathway was also one of the pathways regulated by hsa-miR-146a-3p. The interaction network analysis of DEmRNAs identified TRAF6, CASP8, PTPN6, and CHD3 as hub genes involved in the pathophysiological process of GDM. Next, these 4 hub genes were selected for independent external validation using the GSE19649 dataset. The expression of TRAF6, CASP8 and CHD3 in 8 pairs of GDM blood samples was confirmed to be higher than that in healthy pregnant women blood samples. However, the expression of PTPN6 in the blood samples of GDM patients was similar to that of healthy pregnant women blood samples. The AUC for predicting GDM was 0.813, 0.828, 0.813, and 0.703 for CHD3, PTPN6, and CASP8, respectively. GSEA showed that 9 hallmark gene sets of metabolism processes were enriched in TRAF6 function.CONCLUSIONS: Three hub genes, TRAF6, CASP8, and CHD3, were identified and independently externally validated as potential GDM noninvasive serum markers. Enrichment analysis indicated that GDM-related miRNAs were mainly enriched in the glypican pathway, proteoglycan syndecan-mediated signaling events, and syndecan-1-mediated signaling events. In addition, integrated miRNA-mRNA expression profile analysis showed that miR-146a-3p/TRAF6 might play a central role in the pathogenesis of gestational diabetes mellitus by involving the above pathways.

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MicroRNA-146a Mimics Reduce the Peripheral Neuropathy in Type 2 Diabetic Mice

Cited by 101 publications

References 47 publications

Exosomes Derived From Mesenchymal Stromal Cells Pretreated With Advanced Glycation End Product-Bovine Serum Albumin Inhibit Calcification of Vascular Smooth Muscle Cells

Exosomes Derived From Mesenchymal Stromal Cells Pretreated With Advanced Glycation End Product-Bovine Serum Albumin Inhibit Calcification of Vascular Smooth Muscle Cells

Notoginsenoside R1 alleviates high glucose-evoked damage in RSC96 cells through down-regulation of miR-503

Integrated miRNA-mRNA Expression Profile Analysis Reveals a Role of miR-146a-3p/TRAF6 in Plasma from Gestational Diabetes Mellitus Patients

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