Effectiveness of Nateglinide on In Vitro Insulin Secretion from Rat Pancreatic Islets Desensitized to Sulfonylureas

Chronic exposure of pancreatic islets to sulfonylureas (SUs) is known to impair the ability of islets to respond to subsequent acute stimulation by SUs or glucose. Nateglinide (NAT) is a novel insulinotropic agent with a primarily site of action at β-cell KATP channels, which is common to the structurally diverse drugs like repaglinide (REP) and the SUs. Earlier studies on the kinetics, glucosedependence and sensitivity to metabolic inhibitors of the interaction between NAT and KATP channels suggested a distinct signaling pathways with NAT compared to REP, glyburide (GLY) or glimepiride (GLI). To obtain further evidence for this concept, the present study compared the insulin secretion in vitro from rat islets stimulated acutely by NAT, GLY, GLI or REP at equipotent concentrations during 1-hr static incubation following overnight treatment with GLY or tolbutamide (TOL). The islets fully retained the responsiveness to NAT stimulation after prolonged pretreatment with both SUs, while their acute response to REP, GLY, and GLI was markedly attenuated, confirming the desensitization of islets. The insulinotropic efficacy of NAT in islets desensitized to SUs may result from a distinct receptor/effector mechanism, which contributes to the unique pharmacological profile of NAT

Glucose-dependent and Glucose-sensitizing Insulinotropic Effect of Nateglinide: Comparison to Sulfonylureas and Repaglinide

Nateglinide, a novel D-phenylalanine derivative, stimulates insulin release via closure of KATP channels in pancreatic β-cell, a primary mechanism of action it shares with sulfonylureas (SUs) and repaglinide. This study investigated (1) the influence of ambient glucose levels on the insulinotropic effects of nateglinide, glyburide and repaglinide, and (2) the influence of the antidiabetic agents on glucose-stimulated insulin secretion (GSIS) in vitro from isolated rat islets. The EC50 of nateglinide to stimulate insulin secretion was 14 μM in the presence of 3mM glucose and was reduced by 6-fold in 8mM glucose and by 16-fold in 16mM glucose, indicating a glucose-dependent insulinotropic effect. The actions of glyburide and repaglinide failed to demonstrate such a glucose concentration-dependent sensitization. When tested at fixed and equipotent concentrations (~2x EC50 in the presence of 8mM glucose) nateglinide and repaglinide shifted the EC50s for GSIS to the left by 1.7mM suggesting an enhancement of islet glucose sensitivity, while glimepiride and glyburide caused, respectively, no change and a right shift of the EC50. These data demonstrate that despite a common basic mechanism of action, the insulinotropic effects of different agents can be influenced differentially by ambient glucose and can differentially influence the islet responsiveness to glucose. Further, the present findings suggest that nateglinide may exert a more physiologic effect on insulin secretion than comparator agents and thereby have less propensity to elicit hypoglycemia in vivo

Identification and comprehensive analyses of the CBL and CIPK gene families in wheat (Triticum aestivum L.)

The interaction analysis of wheat TaCBL and TaCIPK proteins were performed by Y2H method. (PDF 191 kb

A model for soil moisture dynamics estimation based on artificial neural network

Research on soil moisture estimation models can effectively improve the growth environment of crops. In this paper, the author studied the artificial neural network and variation pattern of soil moisture. Then, application of the model for water diversion estimation was explored based on artificial neural network. On this basis, an optimization algorithm was presented to simulate water diversion. Furthermore, a model for remote sensing of soil moisture dynamics was applied to artificial neural network. It has been proven that the research can optimize the application of the proposed model, laying a solid foundation for future study

Greenhouse gas emissions associated with urban water infrastructure:What we have learnt from China's practice

Municipal water and wastewater services have complicated sources of greenhouse gas (GHG) emissions, and quantifying their roles is critical for tackling global environmental challenges. In this study we provide a systematic review of the state-of-the-art on GHG emission characterizations of China's urban water infrastructure with the aim of shedding light on global implications for sustainable development. We started by synthesizing a framework on GHG emissions associated with water and wastewater infrastructure. Then we analyzed the different sources of GHG emissions in drinking water and wastewater treatment systems. In drinking water services, electricity consumption is the largest source of GHG emissions. A particular concern in China is the common use of secondary pumping for high-rise buildings. Optimized pressure management with an efficient pumping system should be prioritized. In wastewater services, non-CO 2 emissions such as methane (CH 4) and nitrous oxide (N 2O) emissions are substantial, but vary greatly depending on regional and technological differences. Further research directions may include GHG inventory development for urban water systems at the plant level, quantifications of GHG emissions from sewer systems, emission reduction measures via water reclamation, renewable energy recovery, energy efficiency improvement, cost–benefit analyses, and characterizations of Scope 3 emissions. This article is categorized under: Engineering Water &gt; Sustainable Engineering of Water Science of Water &gt; Water and Environmental Change Engineering Water &gt; Planning Water. </p

Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis

<p>Abstract</p> <p>Background</p> <p>In addition to its essential role in ribonucleotide reduction, ribonucleotide reductase (RNR) small subunit, RRM2, has been known to play a critical role in determining tumor malignancy. Overexpression of RRM2 significantly enhances the invasive and metastatic potential of tumor. Angiogenesis is critical to tumor malignancy; it plays an essential role in tumor growth and metastasis. It is important to investigate whether the angiogenic potential of tumor is affected by RRM2.</p> <p>Results</p> <p>We examined the expression of antiangiogenic thrombospondin-1 (TSP-1) and proangiogenic vascular endothelial growth factor (VEGF) in two RRM2-overexpressing KB cells: KB-M2-D and KB-HURs. We found that TSP-1 was significantly decreased in both KB-M2-D and KB-HURs cells compared to the parental KB and mock transfected KB-V. Simultaneously, RRM2-overexpressing KB cells showed increased production of VEGF mRNA and protein. In contrast, attenuating RRM2 expression via siRNA resulted in a significant increased TSP-1 expression in both KB and LNCaP cells; while the expression of VEGF by the two cells was significantly decreased under both normoxia and hypoxia. In comparison with KB-V, overexpression of RRM2 had no significant effect on proliferation in vitro, but it dramatically accelerated in vivo subcutaneous growth of KB-M2-D. KB-M2-D possessed more angiogenic potential than KB-V, as shown in vitro by its increased chemotaxis for endothelial cells and in vivo by the generation of more vascularized tumor xenografts.</p> <p>Conclusion</p> <p>These findings suggest a positive role of RRM2 in tumor angiogenesis and growth through regulation of the expression of TSP-1 and VEGF.</p

Analysis of environmental conditions and characteristics of convective system evolution of a Mei-Yu Front heavy rainstorm in southern Jiangsu

Affected by the Mei-Yu Front and the mesoscale vortex on the Mei-Yu Front, a heavy rain event occurred in Suzhou on 6 July, 2020, and caused disasters such as urban waterlogging. In this paper, by using ERA5 reanalysis data from the European Center for Medium-Range Weather Forecasts, as well as various observational data from ground meteorological stations, Doppler weather radar, and wind profile radar, we analyze the weather background, environmental characteristics, convective system evolution, and maintenance mechanism of this heavy rain process. The results show that: (1) The upper westerly trough moved eastward, the cold shear line at the middle and lower levels pressed southward, the convergence of cold and warm air over southern Jiangsu enhanced the convergence at the lower level, the strengthening of the southwest jet at the middle and lower levels and the maintenance of the ground quasi stationary front provided favorable weather background conditions for the heavy rainstorm process. (2) During the strongest rainfall period, the intensity of the radar echo center is 60 dBz and the top height exceeds 14 km. The strong reflectivity factor area corresponds to a differential propagation phase shift of 7°·km-1. The average vertical extension height of the strong echo is below 6 km, making it a typical low center of mass warm area rainfall. (3) The moderate levels of convective availble potential energy, strong vertical wind shear in the middle and lower levels, and convective instability stratification, and the low lifting condensation level over Suzhou provide favorable environmental conditions for the generation of heavy rainstorm. The continuously increasing low-level jet propagates downwards, to forming an superultra low-level jet. The strong convergence and uplift in the jet exitoutflow area, combined with the rising branches of the secondary circulation above the shear line, provide dynamic uplift and triggering conditions for the generation of heavy precipitation. The strong frontogenesis of the Mei-Yu Front in both horizontal and vertical directions enables the maintenance of heavy precipitation