Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic ß-Cell Proliferation Through the CPEB1/CDKN1B Pathway.

Pancreatic ß-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in ß-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed that miR-455 overexpression facilitated ß-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory ß-cell expansion. Mechanistically, our results revealed that increased miR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly(A) tail and the subsequent translation of Cdkn1b mRNA, reducing the CDKN1B expression level and finally promoting ß-cell proliferation. Taken together, our results show that the miR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of ß-cells to meet metabolic demand during obesity.

The long non-coding RNA ßFaar regulates islet ß-cell function and survival during obesity in mice.

Despite obesity being a predisposing factor for pancreatic ß-cell dysfunction and loss, the mechanisms underlying its negative effect on insulin-secreting cells remain poorly understood. In this study, we identify an islet-enriched long non-coding RNA (lncRNA), which we name ß-cell function and apoptosis regulator (ßFaar). ßFaar is dramatically downregulated in the islets of the obese mice, and a low level of ßFaar is necessary for the development of obesity-associated ß-cell dysfunction and apoptosis. Mechanistically, ßFaar promote the synthesis and secretion of insulin by upregulating islet-specific genes Ins2, NeuroD1, and Creb1 through sponging miR-138-5p. In addition, using quantitative mass spectrometry, we identify TRAF3IP2 and SMURF1 as interacting proteins that are specifically associated with ßFaar. We demonstrate that SMURF1 ubiquitin ligase activity is essential for TRAF3IP2 ubiquitination and activation of NF-κB-mediate ß-cell apoptosis. Our experiments provide direct evidence that dysregulated ßFaar contributes to the development of obesity-induced ß-cell injury and apoptosis.

RNase H amplified RNA probe and graphene oxide system for highly sensitive detection of (CAG)n DNA repeat sequences.

Huntington's disease is a chronic progressive neurodegeneration which is caused by CAG repeat sequences expanding in the huntingtin gene. There is currently no disease-modifying treatment for the disease, and its progression can only be slowed down before the onset of symptoms. A novel fluorescent platform which contains an RNA probe and graphene oxide for detection of the biomarker of Huntington's disease, CAG repeat sequences, was constructed in this investigation. In addition, RNase H was employed in the fluorescent system to enhance the sensitivity of the detection capability. The fluorescent signal was increased through the cyclic amplified reaction, which results from RNase H, specifically digestion of the RNA strand in the complement of the RNA-DNA duplex. The designed measurement method can detect CAG repeat sequences with a detection limit of 108 pM (R2 = 0.968) under which we optimized assay conditions. Furthermore, the detection limit is approximately 18 times lower than the traditional DNA and graphene oxide detection method without assistance of RNase H. Additionally, the probing platform also shows stronger ability to discriminate between the fluorescence of the target sequence and that of other non-target sequences. The results of our studies demonstrate that the RNase H amplified RNA probe and graphene oxide system exhibited excellent sensitivity and selectivity to the target of CAG repeats sequences.

A graphene oxide fluorescent sensing platform for sensitive and specific detecting biomarker of radiation-resistant nasopharyngeal carcinoma.

Since microRNA-205 (miR-205) is predictive biomarkers for radiation-resistant of nasopharyngeal carcinoma, monitoring of the dynamic variation of miR-205 is of great interest for developing a personalized strategy for the treatment of NPC. Herein, a method for detection of miR-205 was designed based on graphene oxide (GO) and fluorescent probe. The method was successfully used to sensitively and selectively assay miR-205 in aqueous solution, and a low limit of detection of 1.18 nM was obtained in the range 0-300 nM and R2 = 0.990. In addition, the designed platform is specific in that it can distinguish the target miRNA from non-target miRNAs, and even the sequences with single base, double base and three base mismatches. Considering the simplicity and superior sensitivity, it has great potential for clinical application in determining biomarker of radiation-resistant nasopharyngeal carcinoma.