Antidiabetic activity and molecular docking of fructooligosaccharides produced by Aureobasidium pullulans in poloxamer-407-induced T2DM rats

This study evaluated the beneficial effects of fructooligosaccharide (FOS) intake from Aureobasidium pullulans using poloxamer-407 (PX-407) induced type 2 diabetes mellitus (T2DM) in rat. Administration of FOS enhanced enzymatic activities of catalase and glutathione reductase in a dose-dependent manner. Significant reduction in fasting plasma triacylglycerol and very low-density lipoprotein level coupled with slight increase in fasting plasma insulin level was observed. Significant decrease in severe glucosuria, proteinuria, blood creatinine, urea and advanced glycation end products was also observed. Supplementation of FOS increased glucagon like peptide-1 content as well as Bifidobacteria and Lactobacilli populations in the caecum. Molecular docking by Gold and Glide software revealed that three sugar types present in the FOS (1-kestose, nystose, and 1-β-fructofuranosyl nystose) are potent dipeptidyl peptidase-IV inhibitors as well as peroxisome proliferator-activated receptor-gamma agonists. This work indicates that FOS can be positioned as a nutraceutical product, beneficial in diabetes-associated metabolic abnormalities.     

Atomic model of the recognition site of the American cockroach pheromone receptor

All the minimum-energy conformations (MECs) of two sex pheromones of the American cockroach,Periplaneta americana, and their 11 structural analogs (seven agonists, two antagonists, and two inactive compounds) were calculated using the molecular mechanics method. The MECs of the analogs were compared with the most populated MECs of the pheromones. The MECs most common in all the ligands were assumed to represent the bioactive conformations. An atomic model complementary to the bioactive conformation of one of the pheromones, periplanone B, was constructed. The model incorporates five groups capable of forming H bonds with oxygen atoms of the ligands and a set of hydrogen atoms contributing to nonbonded interactions with the ligands. Using this model, the energies of ligand-receptor complexes were calculated. For a group of mimics, the activities predicted from the calculated energies of ligand-receptor interactions were in reasonable agreement with the experimentally observed activities. The sites of the receptor model essential for the receptor activation were specified.     

Hedgehog Pathway Agonism: Therapeutic Potential and Small‐Molecule Development

The Hedgehog (Hh) pathway is a developmental signaling pathway that plays multiple roles during embryonic development and in adult tissues. Constitutive Hh signaling has been linked to the development and progression of several forms of cancer, and the application of small‐molecule pathway inhibitors as anticancer chemotherapeutics is well studied and clearly defined. Activation of the Hh pathway as a therapeutic strategy for a variety of degenerative or ischemic disorders has also been proposed; however, the development of small‐molecule Hh agonists has received less attention. The goal of this review is to highlight the recent evidence supporting the therapeutic potential of Hh pathway activators and to provide a comprehensive overview of small‐molecule pathway agonists.     

超高效液相色谱-线性离子阱同时检测动物源性样品中7种β2-受体激动剂

目的建立测定动物源性样品中马布特罗、塞曼特罗、莱克多巴胺、克伦特罗、沙丁胺醇、特布他林、苯氧丙酚胺等7种β2-受体激动剂残留量的超高效液相色谱-串联质谱(UHPLC-MS/MS)的分析方法和阳性样品确证方法。方法动物源性样品经乙酸铵缓冲溶液酶解提取,用阳离子交换柱净化,以流动相A:1 mmol/L乙酸铵-0.1%甲酸水、流动相B:1 mmol/L乙酸铵-0.1%甲酸乙腈水(90∶10,V/V),经Agilent C18色谱柱(2.1 mm×50 mm,1.8μm)分离,阳性样品通过QTrap四级杆质谱仪的增强型子离子扫描模式作进一步确证。本研究同时考察了7种β2-受体激动剂的基质效应。结果动物源性样品中β2-受体激动剂残留量的检测存在较强的基质效应。7种β2-受体激动剂在0.25~50 ng/g浓度范围内,呈良好线性,线性相关系数r0.99,加标回收率为86.6%~108.7%,方法检出限为0.1~0.5 ng/g。结论该方法采用了内标法定量以减小基质效应带来的定量误差,检出限较低、定量准确、仪器分析时间短,可用于检测动物源性样品样中β2-受体激动剂的残留量,同时对阳性样品作进一步确证。     

Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists

Retinoic-acid-related orphan receptor γt (RORγt) inverse agonists could be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1 a with a flexible linear linker as a novel RORγt inverse agonist. A U-shaped conformation in the complex structure of 1 a with RORγt protein was confirmed. Further improvement of the pharmacokinetic (PK) profiles was required because of the low drug exposure in mice upon oral administration (mouse AUC of 1 a : 27 ng ⋅ h ⋅ mL⁻¹ at 1 mg ⋅ kg⁻¹, p.o.). To improve the PK profiles, conformationally constrained U-shaped scaffolds were investigated. As a result, morpholine analogues with improved PK profiles and high potency were successfully identified. The substituent at the N1 position of the quinazoline moiety was also modified, leading to an enhancement of reporter activity. Consequently, compound 43 (N²-(3-chloro-4-cyanophenyl)-N⁴-(3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)morpholine-2,4-dicarboxamide) exhibited improved drug exposure (mouse AUC: 1289 ng ⋅ h ⋅ mL⁻¹ at 1 mg ⋅ kg⁻¹, p.o.). In addition, suppression of IL-17A gene expression by IL-23 stimulation in a mouse pharmacodynamics model was observed for 43 . The conformation of 43 with RORγt protein was also confirmed as U-shape by X-ray co-crystal structure analysis. The key interaction that boosts potency is also discussed.