ABSTRACT
The physiologic properties of glucagon‐like peptide 1 (GLP‐1) make it a potent candidate drug target in the treatment of type 2 diabetes mellitus (T2DM). GLP‐1 is capable of regulating the ...blood glucose level by insulin secretion after administration of oral glucose. The advantages of GLP‐1 for the avoidance of hypoglycemia and the control of body weight are attractive despite its poor stability. The clinical efficacies of long‐acting GLP‐1 derivatives strongly support discovery pursuits aimed at identifying and developing orally active, small‐molecule GLP‐1 receptor (GLP‐1R) agonists. The purpose of this study was to identify and characterize a novel oral agonist of GLP‐1R (i.e., myricetin). The insulinotropic characterization of myricetin was performed in isolated islets and in Wistar rats. Long‐term oral administration of myricetin demonstrated glucoregulatory activity. The data in this study suggest that myricetin might be a potential drug candidate for the treatment of T2DM as a GLP‐1R agonist. Further structural modifications on myricetin might improve its pharmacology and pharmacokinetics.—Li, Y., Zheng, X., Yi, X., Liu, C., Kong, D., Zhang, J., Gong, M. Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist. FASEB J. 31, 2603–2611 (2017). www.fasebj.org
The challenge of effectively delivering therapeutic agents to the brain has created an entire field of active research devoted to overcoming the blood brain barrier (BBB) and efficiently delivering ...drugs to the brain. Angiopep-2 can trigger transcytosis and traverse the BBB by recognizing low-density lipoprotein related protein-1 (LRP-1) expressed on the brain capillary endothelial cells. Here, we designed a novel strategy for the delivery of drugs to the brain. The novel drug delivery system was a combination of a receptor-targeting ligand, such as low-density lipoprotein related protein 1, and a cell-penetrating peptide (CPP). It was hypothesized that this conjugate will enhance the delivery of associated therapeutic cargo across the BBB and increase the permeability of a solid tumor. Our findings indicate that the combination of these two agents in a delivery vehicle significantly improved translocation of small molecules (paclitaxel) into the brain compared to the vehicle treatment, which contained only receptor-targeting ligand. The application of this strategy could potentially expand the horizons for the treatment of central nervous system disorders.
This paper reviews the current knowledge on plutonium (Pu) isotopic composition (the atom or activity ratios) and activity concentrations of 238Pu, 239Pu, 240Pu, and 241Pu resulting from the ...Fukushima Daiichi Nuclear Power Plant (FDNPP) accident in 2011. In this critical review, we document the characteristic values of Pu atom or activity ratios (fingerprints) and present their spatial distributions around the FDNPP site. Based on multiple Pu fingerprints (238Pu/239+240Pu activity ratio, 240Pu/239Pu atom ratio, and 241Pu/239Pu atom ratio), we clarify that Pu contamination from the FDNPP accident occurred in a restricted terrestrial area, while Pu in the Northwest Pacific Ocean is still predominately sourced from the Pacific Proving Grounds (PPG) and global fallout. Using a simple two end–member mixing model, we calculate average contributions of Pu from the FDNPP accident of 13 ± 20% (n = 180) in soil samples, 55 ± 32% (n = 38) in leaf litter samples, and 67 ± 26% (n = 129) in air dust/black substances. In the marine environment, the PPG source average contributions are 45 ± 15% (n = 76) in seawater and 42 ± 12% (n = 48) in sediments. The spatial distributions of Pu atom or activity ratios based on existing studies suggest that: 1) in the terrestrial region investigated 80 km northwest of the FDNPP site, the Pu contamination is mainly observed in an area within a 50 km distance, and 2) in the terrestrial region investigated 60 km southwest of the FDNPP site, the Pu contamination is mainly observed in an area within a 30 km distance. Studies of Cs-bearing radioactive particles indicate that Pu occurs as Pu oxide, and the fuel fragments containing Pu that were released from the reactors to the surrounding environment are associated with micron-scale Cs-bearing radioactive particles. We note that the fractionation between Pu and other radionuclides occurred after release. These new findings about the Pu fingerprints around the FDNPP site will help researchers to establish a reference background database for future environmental risk assessment and geochemical study there.
•We clarify Pu source in a Fukushima restricted terrestrial area and northwest Pacific Ocean after 10 years of the accident.•In the northwest of the FDNPP site (<80 km), Pu contamination is mainly observed within 50 km distance.•In the southwest of the FDNPP site (<60 km), Pu contamination is mainly observed within 30 km distance.•Fukushima accident contributed Pu ∼13% in soils, ∼55% in litters and ∼67% in air dust, respectively.•Pacific Proving Grounds contributed Pu ∼45% in seawater and ∼42% in sediments.
Siamese networks have been extensively studied in recent years. Most of the previous research focuses on improving accuracy, while merely a few recognize the necessity of reducing parameter ...redundancy and computation load. Even less work has been done to optimize the runtime memory cost when designing networks, making the Siamese-network-based tracker difficult to deploy on edge devices. In this paper, we present SiamMixer, a lightweight and hardware-friendly visual object-tracking network. It uses patch-by-patch inference to reduce memory use in shallow layers, where each small image region is processed individually. It merges and globally encodes feature maps in deep layers to enhance accuracy. Benefiting from these techniques, SiamMixer demonstrates a comparable accuracy to other large trackers with only 286 kB parameters and 196 kB extra memory use for feature maps. Additionally, we verify the impact of various activation functions and replace all activation functions with ReLU in SiamMixer. This reduces the cost when deploying on mobile devices.
With the development of artificial intelligence research, the convolutional neural networks (CNN) triumphantly continue to conquer diverse visual tasks, with lots of technical and practical problems ...emerging. When the detection networks need to meet the high-speed processing requirement and the low power consumption constraint in edge computing, dedicated circuits and algorithm optimization are necessary. In this brief, we propose a non-maximum suppression (NMS) coprocessor that cooperated with a Vision Processor (VP) to speed up the detection. It contains a parallel process unit and dynamic memory management to accelerate NMS processing. Meanwhile, the software workflow provides a comprehensive method to convert the one-stage detection network to our processor in a post-training manner. The experimental results show that our co-design solution reaches 166 FPS to run a MobileNet-SSD, promising to deploy in edge-computing scenarios. Moreover, the detection accuracy on the Airbus dataset is 88.6%, favorable in practical applications.
Foot ulceration is a major cause of morbidity in patients with diabetes, and abnormal peripheral neuropathy often results in hospitalization. Up-regulation of matrix metalloproteinases and ...down-regulation of tissue inhibitor of metalloproteinase 1 are noted to be distinctive biological functions of diabetic dermal fibroblasts. The aim of this study was to evaluate the biological effects of modified retinoids on diabetic fibroblasts. Myricetin, a natural compound, balances the TIMP1/MMP ratio and oxidative stress in diabetic fibroblasts. Our results indicate that myricetin significantly ameliorates the effects of diabetes on dermal fibroblasts. In addition, we found that the oxidative stress imbalance induced by a high glucose concentration plays an important role in the changes to dermal fibroblasts that occur in diabetes. Our findings support the hypothesis that myricetin has the potential to repair faulty skin function arising from diabetes.
FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged ...fragments for FXIa inhibitors’ lead discovery. After replacing the (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamide moiety in compound 3 with 5-(3-chlorophenyl)-1H-pyrazole-3-carboxamide, we traveled from FXIa inhibitor3 to a scaffold that fused the privileged fragments into a pharmacophore for FXIa inhibitors. Subsequently, we synthesized and assessed the FXIa inhibitory potency of a series of 5-phenyl-1H-pyrazole-3-carboxamide derivatives with different P1, P1′ and P2′moiety. Finally, the SAR of them was systematically investigated to afford the lead compound 7za (FXIa Ki = 90.37 nM, 1.5× aPTT in rabbit plasma = 43.33μM) which exhibited good in vitro inhibitory potency against FXIa and excellent in vitro coagulation activities. Furthermore, the binding mode of 7za with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of 7za makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making 7za binds to FXIa in a highly efficient manner.
► GLP-1 analog (GLP17057) containing an inter-disulfide bond extended its half-life. ► The analog (GLP17057) remained the biological activity of GLP-1. ► GLP17057 showed better glucose tolerance and ...higher HbA
1c reduction than GLP-1 and Exendin-4. ► GLP17057 might be utilized as a long-lasting drug for type 2 diabetes.
The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the therapy of type 2 diabetes. However, the half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. This indicates that the stabilization of GLP-1 is critical for its utility in drug development. In this study, we developed a cluster of GLP-1 mutants containing an inter-disulfide bond that is predicted to increase the half-life of GLP-1 in vivo. Exendin-4 was also mutated with a disulfide bond similar to the GLP-1 analogs. In this study, the binding capacities of the mutants were determined, the stabilities of the mutants were investigated and the physiological functions of the mutants were compared with those of wild-type GLP-1 and exendin-4 in animals. The results indicated that the mutants remarkably raised the half-life in vivo; they also showed better glucose tolerance and higher HbA
1c reduction than GLP-1 and exendin-4 in rodents. These results suggest that GLP-1 and exendin-4 mutants containing disulfide bonds might be utilized as possible potent anti-diabetic drugs in the treatment of type 2 diabetes mellitus.
► Exendin-4/Pp1 complex extended the half-life of exendin-4 in vitro and in vivo. ► Formation of complex remained the biological activity of exendin-4. ► Complex showed better glucose tolerance and ...higher HbA
1c reduction than exendin-4. ► Complex might be utilized as a long-lasting drug for type 2 diabetes.
The multiple physiological characterizations of exendin-4 make it as a promising drug candidate for the therapy of type 2 diabetes. Although the longer biological half-life offered the exendin-4 with excellent therapeutic potentials for the clinical utility of type 2 diabetes than glucagon-like peptide-1, the exendin-4 still did not free from the inconveniently frequent injections. Therefore, there are increasing requirements for the long-acting exendin-4.
Pp1 regard as a novel exendin-4 protecting peptide, which are predicted to have the ability of increasing the stabilization of exendin-4 in vivo. Protecting peptide is able to form stable complex by non-covalent interaction with human exendin-4.
In this study, the stability of the exendin-4/Pp1 complex was investigated, and the physiological functions of it were analyzed. Results indicated that exendin-4/Pp1 complex remarkably raised the stabilization of exendin-4 in vivo; it also showed better glucose tolerance and higher HbA
1c reduction than exendin-4 which was utilized chronically in rodents.
Based upon these results, it is suggested that an exendin-4/Pp1 complex might be utilized as a potent anti-diabetic drug in the treatment of type 2 diabetes mellitus.
► GLP-1 homodimeric analog (hdGLP1G10C) extended the biological half-life of GLP-1. ► hdGLP1G10C remained the biological activity of GLP-1. ► hdGLP1G10C showed better glucose tolerance and higher ...HbA1c reduction than GLP-1. ► hdGLP1G10C might be utilized as a long-lasting drug for type 2 diabetes.
The multiple physiological characterization of glucagon-like peptide-1 (GLP-1) makes it a promising drug candidate for the therapy of type 2 diabetes. However, the half-life of GLP-1 is short in vivo due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. This indicates that the stabilization of GLP-1 is critical for its utility in drug development. In this study, we developed a cluster of GLP-1 homodimeric analogs, which fused the mutated GLP-1 monomer by an intra-disulfide bridge. The stabilities of the GLP-1 homodimeric analogs were investigated and the physiological functions of the analogs were compared with those of wild-type GLP-1 in rats and human serum. Single dose glucose tolerance test was performed to investigate the administration frequency which satisfied the efficient glucose regulatory in rats. Multiple dose glucose tolerance tests were employed also to study the long-acting anti-diabetic activity of GLP-1 homodimeric analog. The results indicated that the GLP-1 homodimeric analog (hdGLP1G10C) remarkably raised the biological half-life of GLP-1; also HDGLP1G10C showed better glucose tolerance and higher HbA1c reduction than GLP-1 in rodents. Based upon the results in this study, it was suggested that hdGLP1G10C prolonged the stability of GLP-1 and retained the biological activity of GLP-1. The improved physiological characterization of hdGLP1G10C makes it as possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus.
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