1.Introduction

Diabetes mellitus(DM)is a metabolic disorder characterized by hyperglycemia resulting from defects in insulin action,insulin secretion from pancreatic beta cells,or both[1].In addition,DM is a group of diseases characterized by chronic hyperglycemia due to deficiency of insulin action,a common basis of diabetes that leads to characteristic abnormalities in the metabolism of carbohydrate,lipid,and protein[2].The total number of diabetic patients worldwide was estimated to increase from 171 million in the year 2000 to 366 million in 2030[3],although the latter level was already attained in 2011 according to the International Diabetes Federation.A major part of this increase occurred in Asia,mainly China and India[4].A popular theory on meal-induced insulin secretion(the“incretin effect”)states that glucose or any other drug is more effective on the pancreatic cells when administered orally than when given through intravenous or subcutaneous injections[5].The World Health Organization(WHO)recommends plant-based drugs as an alternative medicine[6].Renewed attention to alternative medicines and natural therapies has raised researchers'interest in traditional herbal medicine.Because of their perceived effectiveness,with minimal side effects and relatively low costs,herbal drugs are prescribed widely,even when the contents of their biologically active constituents are unknown[7].Hence,people are seeking traditional medicines for the management of DM.

Flavonoids are naturally occurring compounds widely distributed as secondary metabolites in the plant kingdom.They are recognized for having beneficial clinical properties,such as anti inflammatory[8],cardioprotective[9],antiviral,antibacterial,and anticancer activities[10].Quercetin is one of the flavonoids found in the fruits of Medicinal Plants,such as Phyllanthus emblica and Vaccinium oxycoccos.We have observed that the tribal people of Pachamalai hills use Amla fruits(P.emblica)as a traditional medicine for diabetes.P.emblica is referenced in “Rasayana,”a branch of the 5000-year-old Indian medical system “Ayurveda,”which focuses on enhancing good health,preventing diseases by boosting the immune system,as well as rejuvenating and revitalizing the body and mind[11].It is still used extensively not only in India,but also in Iran,Iraq,Thailand,China,Italy,Germany,and other countries as a laxative,diuretic,astringent,and antiemetic.It is also used to treat other ailments,including anemia,jaundice,and tumors[12].

Computational biology and bioinformatics play an important role in drug design and screening.Molecular docking of a drug molecule with its target molecule can provide vital information about the drug-receptor binding and affinity.Bioinformatics and molecular docking studies helped us determine the efficacy of quercetin,found in P.emblica,in the treatment of DM.These computational results motivated us to further the study by purifying quercetin from the extract of P.emblica fruit.We then conducted in vivo studies in an animal model of diabetes with the purified quercetin.

2.Materials and methods

2.1.Computational tools and database source(ligand and protein)

This study was carried out using the Schrödinger software suite.Maestro(version 10.2)of the Schrödinger suite contains programs such as ligprep,sitemap,grid generation,and glide XP dock[13].Suitable ligands were retrieved from the ChemSpider database[14].These ligand molecules were converted to 3D structures in the Schrödinger suite.Protein molecules of glycogen phosphorylase(PDB:1NOI)and peroxisome proliferator-activated receptor gamma(PPAR-γ,PDB:3G9E)were retrieved from the protein data bank[15].

2.2.Protein preparation

The protein for docking was prepared using the protein preparation wizard of the Schrödinger suite.The missing side chains,back chains,and residues were updated.Occasional water molecules present in the crystal structure,owing to the prevailing conditions at the time of crystallization,may prove to be problematic;any such water molecules were removed in the protein preparation process.The removal of water molecules increases the entropy,but it is offset by an accompanying loss in enthalpy.

2.2.1.Validation of binding site

高折射率电介质元件相对于x和y轴倾斜45°，这可以引起对沿x或y方向偏振的入射波的线偏振转换，即，反射波的偏振角度相对于入射波被旋转90°。以y方向极化的入射场为例，该场可以分解为两个分量，分别沿ϕ=45°和135°极化，如图2。图3和4绘制了它们反射波的振幅和相位，在53到70 GHz的频段范围内两个正交极化之间实现了全反射和180°的相位差。因此，y方向偏振入射场下，反射的两个分量形成了x方向偏振反射场，如图2所示。图5表示电介质超表面的偏振转换效率，定义为|Ecross|2/（|Ecross|2+|Eco|2）。很明显，转换效率在53到70 GHz之间保持在0.93以上。

2.2.2.Grid generation

Grid generation is very important for fixing the target site of protein molecules.The phytocompounds or commercial drugs were docked with the target in order to determine the docking parameters with the help of Grid-based ligand docking.A grid box was generated for docking the ligand at the centroid of the target site[16].

2.3.Ligand preparation

The ligand preparation was performed using the LigPrep(2.2)module[17].The drawn ligand was geometry optimized via the Optimized Potentials for Liquid Simulations 2005(OPLS2005)force field.LigPrep is a utility in the Schrödinger suite for the purpose of combining tools to generate 3D structures from 1D(Smiles)and 2D(SDF)representations,which probes tautomers and stereoisomers for geometric minimization of ligands.

2.4.Molecular docking

Molecular docking was performed in the form of flexible docking for the prediction of binding affinity,ligand efficiency,and inhibitory constant.All the ligands were docked with the target active site using Glide Xtra precision(XP).Active compounds will only have positioning that avoids penalties and receives favorable scores for accurate hydrophobic contacts between the protein and ligand.

2.5.Plant material

The fruits of P.emblica were collected from the Pachamalai hills during January 2016.The plant was authenticated by taxonomists in the Rapinat herbarium,St.Josephs College,Trichy,India.A voucher specimen(PHC1125)of the plant material was deposited at the Pushpam Herbarium Cabinet,Department of Botany,A.V.V.M Sri Pushpam College(Autonomous),Poondi,Thanjavur,India.

2.6.Extract preparation

Fresh fruits were washed under running water,cleaned,and air-dried at 35°C.After drying,the fruit was ground to powder and kept dry in an air tight container until extraction.This powder,dissolved in methanol,served as the extract tested in this study.

2.7.Phytocompound isolation

Methanolic fruit extract of P.emblica was chromatographed on a silica gel column.Solvent mixtures of increasing polarity composed of methanol and chloroform(methanol up to 90%)were used for elution,and the fractions were collected.The purity of all the fractions collected was determined by thin layer chromatography on silica gel with methanol and petroleum ether(90:10,v/v)as the mobile phase.Spots were visualized by spraying the plates with 20%antimony chloride in chloroform.The column fractions that showed a single spot of the same Rf value were pooled.

The electrostatic energy of the binding interface is important for protein-ligand complex formation.The major electrostatic interactions include hydrogen bonds(both from side chains and back bones),salt bridges,and π-π stacking.Hydrogen bonding is one of the most important interactions for biological macromolecular interactions,crucial for conferring stability to protein molecules and selected protein-ligand interactions.

2.8.Experimental animals

Albino Wister male rats(7–8 weeks old,weighing 150–200 g)were purchased from the GSA Animal Farm,Mayiladuthurai,Tamil Nadu,India.The animals were fed with standard pellet diet(Chakan Oil Mills,Sangli)and water ad libitum.Ethical clearance was obtained from the Institutional Animal Ethics Committee and the experiments were conducted according to the Indian National Science Academy guidelines for the use and care of experimental animals(CPCSEA/265).

2.9.Induction of diabetes and treatments

Streptozotocin(STZ)was dissolved freshly in 100 mM citrate buffer(pH 4.5)and the calculated amount(60 mg/kg)of the solution was injected intraperitoneally to overnight-fasted rats.Blood glucose was checked 48 h later and animals showing blood glucose values greater than 250 mg/dL were deemed diabetic and included in the experiments.Experimental rats were divided into six groups(one normal control group and five diabetic groups)with six animals per group.Treatments were given orally,once a day,in the following manner:

采用排放绩效标准作为反映火电机组发电过程中兼顾能源利用效率与污染物排放控制的综合指标，根据火电机组发电量来计算其污染物许可排放量，使所有火电企业遵循同等的环境管理要求，在大气污染物总量控制方面不仅可以有效促进火电行业的清洁化发展，还可以提高发电效率。由此，实施统一的基于产出的排放绩效标准，一方面在环境管理政策方面操作简单而公平，另一方面为火电企业提供有效的竞争机制，促进火电行业的绿色持续发展。

Group II:Diabetes(STZ-injected rats);

Group III:Diabetes(STZ-injected rats)treated with 25 mg/kg

body weight quercetin;

教师教学理念陈旧、方法单一、内容枯燥 教师已从传统教学中的主体转为主导地位，而课堂教学是教师“传道、授业、解惑”的途径之一，但部分教师教学模式僵化、教学方法单一、教学理念陈旧，教学中存在“一言堂”、照本宣科，课堂教学不灵活，方法不适用于所授科目，课堂教学内容枯燥，课堂氛围不活跃。学生上课时感觉到枯燥无味，就会通过使用手机来打发时间[7]。

Group IV:Diabetes(STZ-injected rats)treated with 50 mg/kg

Group V:Diabetes(STZ-injected rats)treated with 75 mg/kg

body weight quercetin;

After termination of the experiment and euthanasia of the rats,the livers were subjected to histopathological studies.They were cut into small species(1 mm×1 mm×1 mm),preserved7 in 10%formaldehyde in saline for 48 h,dehydrated by treating successively with increasing concentrations of ethyl alcohol(50%,80%,95%,and 100%),cleared in xylene,and embedded in paraffin.Samples were cut into ultrathin sections with an ultramicrotome,stained with hematoxylin and eosin dye,and mounted in neutral deparaffinated xylene(DPX)medium for microscopic observation of cells.The sections were examined for necrosis,fatty changes,hyaline degeneration,and ballooning degeneration.

Group VI:Diabetes(STZ-injected rats)treated with 10 mg/kg

body weight metformin;

重庆市的地质灾害有滑坡、崩塌、泥石流、地面塌陷等，其中以滑坡、崩塌为主，泥石流分布较少。重庆市近年来通过地质灾害排查，市境内现有地质灾害点16076个，其中泥石流329个，占灾害点总数的2.04%[1]。主要分布三峡库区及非库区的渝东南、渝中地区。近年来，重庆市发生泥石流灾害以1986年、1987年、1998年、2006年、2014年、2016年发生的泥石流灾害损失严重[2]。重庆地区以稀性、小型泥石流为主，但其形成的危害也不容忽视。

Quercetin and metformin were orally administered daily for 28 days.Body weights and blood glucose levels of overnight-fasted rats were measured weekly.At the end of the experimental period,the animals were fasted overnight and blood samples were collected for various biochemical estimations.

2.10.Biochemical determinations

The serum was separated by centrifugation of the blood samples at 3000g for 10 min in a microcentrifuge.Then,biochemical parameters,such as blood glucose,triglycerides(TG),high-density lipoprotein(HDL),low-density lipoprotein(LDL),total cholesterol(TC),and very-low-density lipoprotein(VLDL),were determined.The hepatic glycogen levels were measured as per the method described by Kemp and Kits Van Hejnijen[18].

2.11.Histopathological study

body weight quercetin;

2.12.Statistical analysis

All the data were statistically evaluated and the significance of various treatments was calculated.Results are expressed as means±standard error(S.E)and comparisons among the groups were made by analysis of variance(ANOVA),followed by Student's ttests.A value of P＜0.01 was considered significant.

3.Results and discussion

3.1.Validation of binding sites

Ligand binding site validation was performed for all binding sites in the target molecule and the binding cavity was chosen based on the site score(Table 1).The 3D structure of the target molecule is shown in Fig.1A and the active site is shown in Fig.1B.

3.2.Molecular docking

3.2.1.Glycogen phosphorylase(GP)protein

Molecular docking studies clearly revealed that quercetin has a higher docking score with GP than does any other ligand.Inhibition of glycogenolysis has been proposed as a therapeutic strategy for the treatment of type 2 diabetes.GP catalyzes the first step in glycogen degradation as the rate limiting enzyme.It is expected that inhibition of GP will inhibit glycogenolysis,reduce hepatic glucose production,and lower blood glucose,thereby providing a potential new treatment for type 2 diabetes[19–21].

The fruit of P.emblica,contains quercetin and gallic acid also.The computational approach used involved docking of the ligands(quercetin and gallic acid)to form a complex with GP and PPAR-γ.Computational studies showed that quercetin interacts with GP residues GLY177,TRP173,THR85,and THR219(Fig.2A).The backbones of GLY177 and TRP173 formed hydrogen bonds with the ligand OH groups,while the side chains of THR85 and THR219 formed hydrogen bonds.These interactions are represented as two types of arrows from protein to ligand;the first is a solid blue line(H-bond backbone)and the other is a dotted blue line(H-bond side chain)(Fig.2B).In addition,another ligand molecule,gallic acid,has the second docking score of-6.48347(Table 2).The docked molecule interacts with GP residues ILE166,ARG40,ASN178,and TRP173(Fig.3A).The backbones of ILE166 and TRP173 residues form hydrogen bonds with the ligand OH groups,while the side chains of ARG40 and ASN173 form hydrogen bonds with the ligand OH groups(Fig.3B).According to the report by Paramaguru et al.[22],quercetin interacts more favorably with GP than gallic acid affinity.They also suggest that quercetin has potent antihyperglycemic drug properties[22].

3.2.2.PPAR-γprotein

2016年10月，阿里巴巴整合优酷土豆、阿里影业、阿里音乐、阿里体育、阿里游戏等业务，成立阿里巴巴文化娱乐集团（即阿里大文娱），由俞永福出任首任董事长，杨伟东担任大优酷事业群总裁。而“终于可以休个假”的古永锵，变成了阿里大文娱战略投资委员会主席。

The other protein molecule,PPAR-γ,was docked with the two phytocompounds(quercetin and gallic acid)and one synthetic ligand,metformin.The 3D structure of the PPAR-γbinding cavity is represented in Fig.4,and the site scores are displayed in Table 3.In this docking analysis,the interactions between protein and ligands were examined.The results show that quercetin is the best ligand and a potentially potent inhibitor for PPAR-γ.The docking scores are listed in Table 4.Quercetin interacts with PPAR-γamino acid residue TYR473(Fig.5A).The side chain of TYR473 forms a hydrogen bond with the OH group of quercetin(Fig.5B).The docking score of the other phytocompound,gallic acid,is lower than that of quercetin,but it also has good binding affinity(Fig.6).

（1）通过前期调研和数据分析汇总，确定了建筑信息模型的基础数据、信息的定义方法、定义规则、扩展等基本方法；建立了底层核心标准数据信息库、基础数学库、二维及三维几何核心造型库；基于BIM技术数据需求建立了底层数据框架；建立了基于BIM 的核心数据平台基本框架，为后续的软件研发确立了基本体系框架。

Metformin has the lowest docking score when compared with that of the phytocompounds.Metformin interacts with PPAR-γ amino acid residues SER42 and GLU291(Fig.7A).The backbone of SER342 formed a hydrogen bond with the ligand NH group.The side chain of GLU291 formed hydrogen bonds with the ligand NH/NH2groups(Fig.7B).

According to reports,commercial antidiabetic drugs stimulate insulin production from the pancreas,with the other treatment being insulin injection.Various synthetic diabetes drugs are available on the market,including the insulin secretagogues,sulfonylurea and meglitinides.Several insulin sensitizers,such as biguanides,thiazolidinediones,and metformin,as well asα-glycosidase inhibitors(e.g.,acarbose)are also available.These medications have many side-effects such as hypoglycemia,idiosyncratic liver cell injury,lactic acidosis,digestive discomfort,permanent neurological def i cit,headache,dizziness,and even death[23,24].As mentioned previously,these drugs are often expensive[25]

3.3.Isolation of the phytocompound

The potential phytocompound was isolated from P.emblica fruit extracts.The identity of the purified sample was elucidated by13C NMR,1H NMR,mass spectroscopy,and UV absorption spectroscopy.The functional groups of quercetin were analyzed by Fourier-transform infrared(FTIR)spectroscopy.

3.3.1.Structural determination and characterization

Group I:Normal control(without any drug treatment);

where σ(x, y, z) was the canal conductivity. ρ(x, y) was the fixed charges density in the depopulated region, the mobile charges density in the conductive channel region at a point(x, y, z) for an n-channel transistor was given by −ρ(x, y):

入库河道生态建设中应根据河道变化趋势，综合考虑河道纵向和横向的特点以及防洪、供水、灌溉、发电等方面要求，因势利导整治建设。在保证河道防洪、结构稳定的前提下，以提高水质、保持水土和营造良好的生态系统为目标。

Different spectral analysis techniques were used to interpret the structure of the purified molecule.Precisely,the FTIR spectrum revealed peaks at 709 cm-1(C-H rocking),1549 cm-1(C-C stretching(Ar)),1709 cm-1(C-O stretching),3502 cm-1(O–H stretching(bending)),3066 cm-1(C-H stretching(Ar)),and 3640 cm-1(H-O stretching–free OH group present)(Fig.S1 and Table5).1H NMR revealed the aromaticC-H proton at δ7.00–7.24(S)-Ar(Fig.S1A),13C NMR revealed a carbonyl(C=O)atδ170,C–H carbon atδ112,tertiary cation atδ124,C–OH atδ136,and C–OH(L)at δ147(Fig.S1B).Mass spectroscopy revealed the molecular ion peak of the compound at 302(m+).The mass spectroscopy indicates the base is obtained at 115.The identified product is accomplished by determination of elemental physical constants(Fig.S1C).UV absorption spectroscopy was used to identify the presence of the conjugatedπe.As shown in Fig.S1D,Peak I is the conjugatedπe at 285 nm,and Peak II is the enone with external conjugated group at 356 nm(Fig.S1D).The product was yellow colored,with an attached chromophoric=O ring in the compound(Fig.8).

3.3.2.Product characterization

After separating the extract by column chromatography,preliminary screening of the various fractions was accomplished by a thin layer chromatographic technique.However,different spectral analyses(i.e.,FTIR,1H NMR,13C NMR,mass spectroscopy,and UV absorption)helped confirm that the compound was2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H- chromen-4-one(quercetin).Its molecular formula is C15H10O7and its molecular weight is 302.235.The compound is yellow crystalline,with a melting point of 316°C.It is insoluble in water but soluble in methanol(Table 6).In computer modeling,the structure of the compound,2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one,strongly suggested its usefulness as an antidiabetic,so we tested it in an STZ-induced diabetic rat model.

Binding site validation plays a vital role in molecular docking.Site validation analysis displays ligand-binding locations,amino acid residues,and site scores.The site map of the entire protein molecule is generated by validating the binding sites using the site map generation tool in Maestro version 10.2 of the Schrödinger suite.Once the site map was generated,we chose only one binding site based on the site score.The binding site of the largest volume was taken for grid generation.

3.4.Effect of quercetin on body weight and blood glucose

The experimental animals were treated with various concentrations of the potential lead compound,quercetin.In the present study,this phytocompound was selected via molecular docking analysis.Quercetin was orally administered at different doses(25,50,and 75 mg/kg)in rats with experimentally induced hyperglycemia.The body weights of the rats are shown in Table 7.The baseline weight of the rats at the beginning of the study was similar among all groups.At the end of the treatment(after 4 weeks),the diabetic animals had lost weight due to the catabolism of protein in muscle tissue caused by insulin deficiency[26].However,the quercetin-treated diabetic rats had not lost body weight(Table 7).It is possible that the phytocompound was able to protect the pancreaticβ-cells.Similar results were obtained by another group,and collectively,suggest that quercetin treatment protects against diabetic weight loss[27].The use of medicinal plants is increasing due to the extraction and development of many successful drugs and chemotherapeutic agents from plants and their use as traditional rural herbal remedies[28].STZ causes selective destruction ofβ-cells of the pancreatic islets,which leads to an increase in blood glucose levels.It is evident from the present investigation that STZ administration at a dose of 60 mg/kg causes significant diabetogenic response in the rats(Table 8).Blood glucose levels were measured randomly at baseline and on the 7th,14th,21st,and 28th days of the study.The increased glucose levels in the diabetic control group were found to be significant(P＜0.05)compared to that of the normal control group.The elevated blood glucose levels declined sharply after oral administration of quercetin(25,50,and 75 mg/kg)or metformin(10 mg/kg).When comparisonswere made between baseline and the 28th day in the treated groups,there was a statistically significant(P＜0.01)decline in blood glucose levels.If the decline in blood glucose levels is the only index to be considered,then treatment with quercetin or metformin produced a highly effective antihyperglycemic response in STZ-induced diabetic rats.Considering the relative efficacy,although all tested concentrations of quercetin produced antihyperglycemic activity,quercetin of 75 mg was shown to produce the highest antihyperglycemic activity among all tested agents including metformin(Table 8).The reduction in blood glucose levels is the principal therapeutic goal of diabetes.According to Torres-Piedra et al.[29],quercetin significantly reduced the glucose levels in STZ-induced diabetic rats.The effective control of blood glucose levels by increasing the secretion of insulin and regeneration ofβ-cells in the pancreas is a vital step in preventing cardiovascular and diabetic complications and improving the quality of life in type 2 diabetic patients[30].Based on the results of our experimental analysis,it is now well-established that quercetin is a plant-based natural drug that is sufficiently potent to reduce elevated glucose levels in diabetic rats.

网架结构可分交叉桁架体系和角锥体系两大类。对于平面形状为矩形且跨度超过60 m以上的大跨度屋盖，通常多采用刚度较大且受力均匀的正方四角锥和斜放四角锥网架[6]。高端阀厅柱内净空尺寸为86.5 m×89.5 m，考虑格构柱本体尺寸后，网架平面尺寸初步按照90 m×90 m考虑；阀厅内部不设置竖向支撑结构，网架为周边支撑形式。

3.5.Effect of quercetin on hemoglobin,plasma insulin,and urine sugar

The levels of hemoglobin,plasma insulin,and urine sugar in normal control and quercetin treated diabetic rats were measured.Increased hemoglobin,plasma insulin,and lack of urine sugar were observed in the treated diabetic rats.These values were significantly improved close to normal after treatment with quercetin(25,50,and 75 mg/kg)or metformin(10 mg/kg)(Table 9).The effect of quercetin on glycogen synthase and glycogen phosphorylase activities in the liver of diabetic rats is shown in Table 10.Diabetic rats showed increased activity of glycogen phosphorylase and decreased activity of glycogen synthase.These enzyme activities were significantly(p＜0.05)reverted to near normal levels after treatment with quercetin.In addition,it has been suggested that quercetin can improve insulin signaling and insulin sensitivity in rats with insulin resistance[31].Quercetin could improve fasting hyperglycemia by enhancing insulin sensitivity viaα-glucosidase inhibition and enhanced insulin signaling in diabetic rats[32].

3.6.Effect of quercetin on plasma lipid pro fi les

Diabetic rats showed significant increases in the blood levels of TC,TG,LDL,and VLDL.In contrast,HDL was significantly reduced compared to the values of normal control rats.Regular administration of quercetin for 4 weeks nearly normalized the lipid profiles in the diabetic rats.Oral administration of metformin significantly decreased the blood levels of TC,LDL,and VLDL.However,metformin did not significantly change the blood levels of TG compared to those of the diabetic control rats.In diabetic rats treated with quercetin (75 mg/kg),theblood levelsofTC(24.02%↓),LDL(31.75%↓),and VLDL(48.23%↓)decreased significantly by the end of study(after 28 days);however,the blood level of HDL was significantly increased compared to the value in the diabetic rats(78.88%↑)(Table 11).In diabetes,LDL and VLDL carry cholesterol to the peripheral tissues where it is deposited,while HDL transports cholesterol from peripheral tissues to the liver to facilitate its excretion and metabolism.It has been reported that elevated serum LDL and VLDL are indicative of the atherogenic process[33].As suggested by previous studies,an active phytocompound,such as quercetin,can decrease the levels of cholesterol and LDL in diabetic rats[34].

针对罐顶固定灭火系统泡沫喷射盲区的问题，在罐内浮船上安装自动消防炮，通过电视监控系统对其操作，在最短时间内将大量泡沫喷洒到起火部位且不存有盲区。自动消防炮水平方向可360°旋转，垂直方向有上下45°角的调整空间，从而实现全区域、全方位的泡沫喷射，以及无死角、无盲区监控和灭火[11]。

松弛通常是面团在整形操作后，筋力收紧，如果再进行操作的话，面团收缩变形，不利于整形，因此松弛一定的时间，再进行下一步的操作，时间为5～10 min。中间醒发是相对最后醒发而言的，中间醒发也可以理解是长时间的松弛或者是中种面团的醒发，因为在有些面包品种中，虽然是一次搅拌，可能由于时间的原因经过多次发酵，因此就不好确定哪次的醒发属于中间醒发。最后醒发是烘烤前的最后一步，经过最后醒发的面包即将进入烤箱烘烤。因此了解松弛、中间醒发、最后醒发的特点和目的，就可以调节这几个环节的时间、次数。

3.7.Histopathology observation

Representative histopathological changes in the pancreas are shown in Fig.9.STZ administration elicited severe injury of the

when compared to diabetes group.pancreas,as indicated by decreasing numbers of islet cells and diminishing diameters of the pancreas islets(Fig.9).The islets were smaller in diabetic rats than in normal control rats(Fig.9B).Administration of quercetin(25,50,and 75 mg/kg)or metformin(10 mg/kg)reduced pancreatic injury.The pancreas is a vital organ of metabolism and macronutrients digestion,which also secretes different digestive enzymes and pancreatic hormones[35].Many studies have indicated that quercetin has the capacity to prevent pancreatic injury,promoting regeneration of the pancreatic islets and increasing its ability to maintain normal blood glucose levels in diabetes-induced rats[32,36].

凭借优质产品与专业技术服务，佐敦已正式扎根于装备制造业市场。甘肃省建设投资（控股）集团作为首家使用佐敦E55，E88产品的客户，将其应用于所生产的水泥搅拌车。佐敦还携手博世力士乐、三一重工、上海华建、潍柴动力、中交西筑等多家业内知名企业，在装备制作业领域不断突破，持续为客户提供最卓有成效的涂料解决方案。

4.Conclusion

The present molecular docking analysis showed a better binding affinity and lead docking score to glycogen phosphorylase with quercetin than with gallic acid.Quercetin was isolated from P.emblica fruit extract after the in silicofinding.Different concentrations of quercetin showed remarkable antihyperglycemic effects and potent defense mechanisms in STZ-induced diabetic rats.Metforminis more commonly associated with gastrointestinal side effects than most other antidiabetic drugs.Finally,we conclude that quercetin is a remarkable antihyperglycemic

agent,which can be considered as a potential drug candidate for diabetes mellitus with fewer side effects than metformin.

Conflicts of interest

The authors declare that there are no conflicts of interest.

The authors are grateful to the DST-SERB Major Research Project,New Delhi,India[Project File No.SB/YS/LS-109/2014]for funding this project.We especially express our thanks to the Management of A.V.V.M.Sri Pushpam College(Autonomous),Poondi,and Sharmila Institute of Medicinal Products Research Academy(SIMPRA),Thanjavur,India,for providing necessary facilities and support in carrying out this work.

按照国际《湿地公约》和《中国湿地资源调查与监测技术规程》的湿地分类系统划分，安徽沿淮湿地主要包括河流、湖泊、水田、库塘4个类型,前两类属天然湿地，后两类属人工湿地。另外，还有采煤沉陷区和行蓄洪区两种特有的人工湿地类型。

Appendix A.Supplementary material

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jpha.2017.10.005.

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