Background/Aims: Type 2 Diabetes Mellitus (T2DM) is characterized by insulin resistance (IR), but the underlying molecular mechanisms are incompletely understood. MicroRNAs (miRNAs) have been demonstrated to participate in the signalling pathways relevant to glucose metabolism in IR. The purpose of this study was to test whether the multiple-target anti-miRNA antisense oligonucleotides (MTg-AMO) technology, an innovative miRNA knockdown strategy, can be used to interfere with multiple miRNAs that play critical roles in regulating IR. Methods: An MTg-AMO carrying the antisense sequences targeting miR-106b, miR-27a and miR-30d was constructed (MTg-AMO_106b/27a/30d). Protein levels were determined by Western blot analysis, and transcript levels were detected by real-time RT-PCR (qRT-PCR). Insulin resistance was analysed with glucose consumption and glucose uptake assays. Results: We found that the protein level of glucose transporter 4 (GLUT4), Mitogen-activated protein kinase 14 (MAPK 14), Phosphatidylinositol 3-kinase regulatory subunit beta (PI3K regulatory subunit beta) and mRNA level of Slc2a4 (encode GLUT4), Mapk14 (encode MAPK 14) and Pik3r2 (encode PI3K regulatory subunit beta) were all significantly down-regulated in the skeletal muscle of diabetic rats and in insulin-resistant L6 cells. Overexpression of miR-106b, miR-27a and miR-30d in L6 cells decreased glucose consumption and glucose uptake, and reduced the expression of GLUT4, MAPK 14 and PI3K regulatory subunit beta. Conversely, silencing of endogenous miR-106b, miR-27a and miR-30d in insulin-resistant L6 cells enhanced glucose consumption and glucose uptake, and increased the expression of GLUT4, MAPK 14 and PI3K regulatory subunit beta. MTg-AMO_106b/27a/30d up-regulated the protein levels of GLUT4, MAPK 14 and PI3K regulatory subunit beta, enhanced glucose consumption and glucose uptake. Conclusion: Our data suggested that miR-106b, miR-27a and miR-30d play crucial roles in the regulation of glucose metabolism by targeting the GLUT4 signalling pathway in L6 cells. Moreover, MTg-AMO_106b/27a/30d offers more potent effects than regular singular AMOs.

Interleukin 6 (IL-6) has been shown to be an important regulator of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-6 in the development of diabetic cardiomyopathy and the underlying mechanisms. Cardiac function of IL-6 knockout mice was significantly improved and interstitial fibrosis was apparently alleviated in comparison with wildtype (WT) diabetic mice induced by streptozotocin (STZ). Treatment with IL-6 significantly promoted the proliferation and collagen production of cultured cardiac fibroblasts (CFs). High glucose treatment increased collagen production, which were mitigated in CFs from IL-6 KO mice. Moreover, IL-6 knockout alleviated the up-regulation of TGFβ1 in diabetic hearts of mice and cultured CFs treated with high glucose or IL-6. Furthermore, the expression of miR-29 reduced upon IL-6 treatment, while increased in IL-6 KO hearts. Overexpression of miR-29 blocked the pro-fibrotic effects of IL-6 on cultured CFs. In summary, deletion of IL-6 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The mechanism involves the regulation of IL-6 on TGFβ1 and miR-29 pathway. This study indicates the therapeutic potential of IL-6 suppression on diabetic cardiomyopathy disease associated with fibrosis.

Inhibition of α-glucosidase and α-amylase decreases postprandial blood glucose levels and delays glucose absorption, making it a treatment strategy for type 2 diabetes. This study examined in vivo and in vitro antidiabetic activities of natural prenylchalconaringenins 1 and 2 and prenylnaringenins 3 and 4, found in hops and beer. 3'-Geranylchalconaringenin (2) competitively and irreversibly inhibited α-glucosidase (IC = 1.08 μM) with activity 50-fold higher than that of acarbose (IC = 51.30 μM) and showed moderate inhibitory activity against α-amylase (IC = 20.46 μM). Docking analysis substantiated these findings. In addition, compound 2 suppressed the increase in postprandial blood glucose levels and serum levels of total cholesterol and triglycerides in streptozotocin-induced diabetic mice. Taken together, these results suggest that 2 has dual inhibitory activity against α-glucosidase and α-amylase and alleviates diabetic hyperglycemia and hyperlipidemia, making it a potential functional food ingredient and drug candidate for management of type 2 diabetes.

The IPCC assume a linear relationship between nitrogen (N) application rate and nitrous oxide (N 2 O) emissions in inventory reporting, however, a growing number of studies show a nonlinear relationship under specific soil-climatic conditions. In the North China plain, a global hotspot of N 2 O emissions, covering a land as large as Germany, the correlation between N rate and N 2 O emissions remains unclear. We have therefore specifically investigated the N 2 O response to N applications by conducting field experiments with five N rates, and highfrequency measurements of N 2 O emissions across contrasting climatic years. Our results showed that cumulative and yield-scaled N 2 O emissions both increased exponentially as N applications were raised above the optimum rate in maize (Zea mays L.). In wheat (Triticum aestivum L.) there was a corresponding quadratic increase in N 2 O emissions with the magnitude of the response in 2012−2013 distinctly larger than that in 2013−2014 owing to the effects of extreme snowfall. Existing empirical models (including the IPCC approach) of the N 2 O response to N rate have overestimated N 2 O emissions in the North China plain, even at high N rates. Our study therefore provides a new and robust analysis of the effects of fertilizer rate and climatic conditions on N 2 O emissions.

Oxygen (O2) plays a critical and yet poorly understood role in regulating nitrous oxide (N2O) production in well-structured agricultural soils. We investigated the effects of in situ O2 dynamics on N2O production in a typical intensively managed Chinese cropping system under a range of environmental conditions (temperature, moisture, ammonium, nitrate, dissolved organic carbon, and so forth). Climate and management (fertilization, irrigation, precipitation, and temperature), and their interactions significantly affected soil O2 and N2O concentrations (P < 0.05). Soil O2 concentration was the most significant factor correlating with soil N2O concentration (r = −0.71) when compared with temperature, water-filled pore space, and ammonium concentration (r = 0.30, 0.25, and 0.26, respectively). Soil N2O concentration increased exponentially with decreasing soil O2 concentrations. The exponential model of N treatments and fertilization with irrigation/precipitation events predicted 74–90% and 58% of the variance in soil N2O concentrations, respectively. Our results highlight that the soil O2 status is the proximal, direct, and the most decisive environmental trigger for N2O production, outweighing the effects of other factors and could be a key variable integrating the aggregated effects of various complex interacting variables. This study offers new opportunities for developing more sensitive approaches to predicting and through appropriate management interventions mitigating N2O emissions from agricultural soils.

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Myocardial fibrotic tissue from mouse infarcted heart displayed the expression signature of long non-coding RNAs (lncRNAs) and mRNAs. Fifty-seven differentially expressed lncRNAs and 20 differentially expressed mRNAs were found to be related to 8 signalling pathways involved in the development of cardiac fibrosis.