• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    A Network Pharmacology Analysis of Cang Fu Dao Tan Formula for the Treatment of Obese Polycystic Ovary Syndrome

    2020-11-03 03:12:04CAIMengChengJINYongShengYUChoQinCHENGWen
    Digital Chinese Medicine 2020年3期
    關(guān)鍵詞:天南星香附枳殼

    CAI Meng-Cheng,JIN Yong-Sheng,YU Cho-Qin,CHENG Wen

    a.Basic Medical School,Navy Military Medical University,Shanghai 200433,China

    b.Department of Pharmacy,Navy Military Medical University,Shanghai 200433,China

    c.Department of Traditional Chinese Medicine,Navy Military Medical University,Shanghai 200433,China

    Keywords

    Cang Fu Dao Tan Formula(CFDTF)

    Polycystic ovary syndrome(PCOS)

    Network pharmacology

    Quercetin

    AGE-RAGE signaling pathway

    ABSTRACT

    Objective To explore the potential molecular targets of Cang Fu Dao Tan Formula(CFDTF)in the treatment of obese polycystic ovary syndrome(PCOS)using network pharmacology and bioinformatic approaches.

    Methods The potential blood-entry active compounds and targets of CFDTF were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),and obese PCOS related gene targets were retrieved from GeneCard databases.A protein-protein interaction(PPI)network of CFDTF component-targets and obese PCOS diseasetargets was constructed using STRING.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis of the intersection network were conducted using a Bioconductor database.

    Results In total,114 active compounds were screened according to oral bioavailability(OB)and drug similarity(DL),and 328 targets related to these constituents were obtained.Further,2 559 target genes directly related to obese PCOS were obtained from the GeneCard databases,and 82 genes were obtained from the intersection of the component-target and disease-target PPI network.These genes were mainly involved in response to steroid hormones,nutrient levels and lipopolysaccharide as well as in other biological processes.Their molecular functions were mainly related to nuclear receptor activity,phosphatase binding and cytokine activity,and they were enriched in the cytoplasm,cell membrane and membrane region.

    Conclusions CFDTF consists of 114 active compounds that are responsible for its pharmacodynamic effects.It mainly regulates the AGE-RAGE signaling pathway in diabetic complications,bladder cancer,and hepatitis B and in other signaling networks.These findings provide certain theoretical and scientific basis for the treatment of obese PCOS with Chinese medicine.

    1 Introduction

    Polycystic ovary syndrome(PCOS)is a common endocrine and metabolic disorder in women.Its main clinical manifestations are menstrual disorders,infertility,hirsutism,obesity and metabolic syndrome.A recent research shows that its incidence varies in different regions and ethnic groups,but its incidence rate is generally about 5% - 10%[1].It seriously affects patients’quality of life and financially burdens families and the society.Presently,its pathogenesis is unclear,and it is clinically treated using ethinylestradiol cyproterone(Diane-35),clomiphene,metformin and other drugs.Although these drugs have curative effects,their side effects cannot be avoided.

    Cang Fu Dao Tan Formula(CFDTF)contains eight main components,which has been clinically used for 300 years with exact curative effect and has good clinical effect against PCOS[2],including Atractylodis Rhizoma(Cang Zhu,蒼術(shù)),Cyperi Rhizoma(Xiang Fu,香附),Arisaematis Rhizoma(Tian Nan Xing,天南星),Citri Reticulatae Pericarpium(Chen Pi,陳皮),Aurantii Fructus(Zhi Qiao,枳殼),Poria(Fu Ling,茯苓),Glycyrrhizae Radix Et Rhizoma(Gan Cao,甘草)and Zingiberis Rhizoma Recens(Sheng Jiang,生姜).CFDTF is mainly used in treating phlegm associated with stasis of moisture.Previous studies have proven that CFDTF could activate Qi and reduce phlegm in rats[3-5].However,its complexity has brought about certain difficulties in the systematic study of its pharmacodynamic substance basis and mechanism.

    Chinese herb is the material basis of treating diseases in traditional Chinese medicine(TCM),which has multi-target,multi-link and multi-effect characteristics.The development of TCM is limited by its unclear mechanism.Network pharmacology is a new subject that integrates system biology and pharmacology in recent years,and it analyses biological information to reveal the interaction mechanism between drugs and diseases from micro levels.In this study,we excavated the main active compounds and targets of CFDTF and used network pharmacology and bioinformatics to predict its key genes in the treatment of obese PCOS.Moreover,we analyzed the functional enrichment of these genes and studied the key protein-protein interaction(PPI)network,so as to provide clues for the clinical prevention and treatment of obese PCOS,and provide a scientific basis for the promotion and application of TCM or integrated TCM and western medicine in the treatment of obese PCOS.

    2 Materials and Methods

    2.1 Database

    The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP,version 2.3,http://lsp.nwu.edu.cn/tcmsp.php)contains large data on formulas and their herbal compounds.We retrieved the compounds and protein targets of CFDTF from TCMSP for further analysis.STRING(version 11.0,https://stringdb.org/)is a functional protein association network.Cytoscape(version 3.6.1,https://cytoscape.org/)is a social network analysis and visualization tool.GeneCard(version 4.5.0,http://www.genecards.org/)and Bioconductor(version 3.6.0,http://www.bioconductor.org)are databases[6].

    2.2 Screening the active components and predicting the targets of CFDTF

    We entered “cangzhu” “xiangfu” “tiannanxing”“chenpi” “fuling” “zhiqiao” “gancao” and“shengjiang” in the herb name field.All chemical compounds data of CFDTF were searched in the TCMSP database based on absorption,distribution,metabolism and excretion parameters,and the possible active compounds were screened according to the principles of oral bioavailability(OB)≥ 30%and drug similarity(DL)≥ 0.18.The “related targets”module in the TCMSP database was used to predict the target of the active compounds in CFDTF,and Cytoscape software was used to construct the active compound-target network of CFDTF.In the network,nodes represented the molecules and target proteins,and edges represented the interaction between components and targets.

    2.3 Retrieval of known genes specifically associated with obese PCOS

    “Obese polycystic ovary syndrome” or “obese PCOS”were used as keywords to retrieve known gene targets related to obese PCOS from GeneCard disease databases.

    2.4 Gene target analysis of CFDTF in the treatment of obese PCOS

    The effective components of drugs exert their effects in the body by directly acting on the target or indirectly acting on other targets.Various complex signal networks regulate the occurrence and prevention of diseases.There are interactions among different signal pathways and signal transduction between upstream and downstream targets.The direct and indirect regulatory relationship between target and target can be clearly displayed by constructing a PPI network.The active compound targets and obese PCOS disease targets of CFDTF were imported into STRING for PPI network drawing.The above two PPI networks were fused by Cytoscape software,and the intersection network was extracted.The direct or indirect targets of CFDTF for obese PCOS treatment were then obtained.

    2.5 Gene Ontology(GO)and pathway enrichment analysis of CFDTF in the treatment of obese PCOS

    GO is a common method for annotating genes and their expression products.It is mainly divided into three parts:biological process(BP),cell component(CC)and molecular function(MF).We can understand the biological functions,ways or cell localization of drug targets through GO analysis,which can help investigators explore new research directions.Kyoto Encyclopedia of Genes and Genomes(KEGG)can analyze the signaling pathways of drug targets(or differentially expressed genes)in order to understand the signaling pathways that have significantly changed in the course of disease,which is of great significance in exploring the mechanism of action of CFDTF in the treatment of obese PCOS.In this study,R software was used to analyze the GO and KEGG pathway enrichment of CFDTF on the direct or indirect targets of obese PCOS.P<0.05 and FDR<0.05 were set as the critical values of significant gene enrichment.Term and- Log10Pwere used to plot.

    3 Results

    3.1 Screening of bioactive components from CFDTF

    In total,670 chemical constituents of CFDTF were retrieved and screened according to OB and DL.Among them,354 components were OB ≥ 30%,328 were DL ≥ 0.18,and 142 were OB ≥ 30% and DL ≥0.18(Figure 1).After further searching and pairing analysis,114 blood-entry active compounds with corresponding targets were screened out from CFDTF.Glycyrol,citromitin,7,2',4'-trihydroxy-5-methoxy-3-arylcoumarin,licopyranocoumarin and shinpterocarpin had the highest OB values,and(-)-medicocarpin,kanzonol F,xambioona,isoglycyrol and dehydroeburicoic acid had the highest DL values(Table 1).

    3.2 Targets retrieval results related to obese PCOS and their representation on a Venn map

    2 559 targets were retrieved from GeneCard databases.To draw a Venn map,they were inputted into the R software,along with 229 drug composition targets and 159 common targets were obtained after their intersection(Figure 2).

    3.3 Prediction of action targets of CFDTF and visual analysis of bioactive compound-target network

    The TCMSP database was used to retrieve the targets of CFDTF’s active compounds.After eliminating the repetitive targets,159 predictive genes were obtained.Cytoscape 3.6.1 was used to visualize the active compound-targets network and draw the network diagram.As shown in Figure 3,there were 1 207 correlations between the active compounds of CFDTF and their corresponding targets.Among all the chemical compounds,quercetin had the highest number of targets(102),and among all the targets,PTGS2 was most acted upon(99 chemical components acted on it)(Table 2).

    3.4 Construction of a PPI network of target genes for CFDTF in the treatment of obese PCOS

    A PPI network(Figure 4)was constructed using string software.The species selected wereHomo sapienswith confidence > 0.99.There are 82 nodes and 204

    edges in the PPI notework,nodes representing targets and edges representing PPI.According to the degree of nodes,the graph of 18 key nodes such as AKT1,JUN and STAT3,was drawn by STRING statistical function(Table 3).Among all the targets,AKT1 had the most targets,reaching 102.

    Table 1 Bioactive compounds of CFDTF screened by ADME parameters

    Table 1 Continued

    Table 1 Continued

    Table 1 Continued

    Table 1 Continued

    3.5 Analysis of GO function enrichment of CFDTF in the treatment of obese PCOS

    The mechanism of CFDTF in the treatment of obese PCOS mainly involved response to steroid hormone,nutrient levels,lipopolysaccharide,antibiotic,metal ion,alcohol,acid chemical,oxidative stress,nutrient,oxygen levels and other biological processes.The molecular functions included nuclear receptor activity,phosphatase binding,cytokine activity,cytokine receptor binding,steroid hormone receptor activity,protein phosphatase binding,nuclear hormone receptor binding,protease binding,MAP kinase activity and hormone receptor binding.It was enriched in the intracellular region,membrane raft,membrane microdomain,membrane region,caveola,plasma membrane raft,nuclear chromatin,vesicle lumen,cytoplasmic vesicle lumen,nuclear transcription factor complex and nuclear receptor activity(Figure 5).

    Table 2 Network of main compound-targets and their topological properties

    3.6 Analysis of KEGG pathway enrichment of CFDTF in the treatment of obese PCOS

    As depicted in Figure 6,the molecular mechanism of CFDTF in the treatment of obese PCOS mainly involved the following 20 key signaling pathways:AGE-RAGE signaling pathway in diabetic complications,bladder cancer,hepatitis B,fluid shear stress and atherosclerosis,Kaposi sarcomaassociated heobese herpesvirus infection,endocrine resistance,prostate cancer,proteoglycans in cancer,pancreatic cancer,non-small cell lung cancer,EGFR tyrosine kinase inhibitor resistance,IL-17 signaling pathway,HIF-1 signaling pathway,hepatitis C,human cytomegalovirus infection,TNF signaling pathway,colorectal cancer,VEGF signaling pathway,relaxin signaling pathway and platinum drug resistance.

    Table 3 Key targets of the PPI network

    4 Discussion

    PCOS is a common endocrine and metabolic disorder in women.Its etiology is closely related to hereditary,environmental and organismal factors.Its pathogenesis is the inability to select the dominant follicles in polycystic ovary.This phenomenon stops the growth of most follicles and causes them to get together,leading to anovulation[7].Besides its association with endocrine dysfunction regulated by the hypothalamus-pituitary-ovary axis,it also causes compensatory hyperinsulinemia in patients[8].Modern medicine,which only treats symptoms and ignores the root of the disease,focuses on weight loss,androgen reduction and ovulation induction.

    PCOS is associated with “oligomenorrhea” “l(fā)ate menstruation” “metrorrhagia” “amenorrhea” and“infertility” in TCM,which are closely related to the dysfunction of the spleen,liver and kidney,and its etiologies are closely related to dampness,phlegm and blood stasis.As the spleen,liver and kidney govern transport essence,dispersing emotion,store essence,respectively,their dysfunction obstructs the normal transport of Qi,blood and body fluid,causing them to stagnate and block the Chong and Ren two collateral channels,which leads to the development of PCOS[9].Clinically,PCOS patients mainly show phlegm associated with stasis of moisture syndrome,which is principally treated by invigorating spleen to dissipate phlegm.Modern medicine believes that insulin resistance caused by intestinal flora imbalance is an important mechanism of PCOS.The functions of intestinal flora,including enhancing immunity and promoting digestion,absorption and excretion,are similar to those of the spleen,which resist external evils and transports water and grain essence.Phlegm dampness caused by spleen dysfunction is an important basis of PCOS.In addition,phlegm dampness patients showed metabolic disorder and hyperinflammation,which coincided with the understanding of PCOS in modern medicine.Although modern research shows that CFDTF can significantly regulate the intestinal flora,metabolism of glucose and lipid,and rate of ovulation and pregnancy,its mechanism is still unclear[10-12].

    On screening of active compounds,flavonoids such as quercetin,luteolin,kaempferol,wogonin and naringenin,were identified in the CFDTF.Flavonoids have many pharmacological effects such as antioxidative,anti-inflammatory and fat metabolism regulatory effects[13].A research shows that flavonoids have good effects on PCOS.Epimedium flavonoid can ameliorate hyperandrogenemia,regulate luteinizing hormone and follicle stimulating hormone ratio,increase serum estrogen and improve ovarian function[14].Dodder flavonoid can protect PCOS rats induced with DHEA combined with HCG[15].In GO enrichment analysis,screened compounds demonstrated the correlation with the response to steroid hormone,nutrient levels,lipopolysaccharide and antibiotic.Recent research showed positive correlations between the risk of abnormal glucose metabolism and serum aldosterone,androstenedione,oestrone and other steroid hormone[16].Modern medicine also uses steroids hormone to treat PCOS.Nutritional intervention can regulate the hormone secretion and glucose metabolism level,reduce the weight and insulin resistance,and improve ovarian function and the success rate of ovulation and conception of patients with obese PCOS[17].Furthermore,paradoxical inflammatory responses involving lipopolysaccharide in mononuclear cells of obese women with PCOS are linked to hyperandrogenism[18],which confirms the results of network pharmacology.The KEGG pathway analysis indicated that they focused on the AGE-RAGE signaling pathway in diabetic complications,endocrine resistance,IL-17 signaling pathway,TNF signaling pathway,HIF-1 signaling pathway,etc.Insulin resistance can lead to the increase of ovarian volume and affect ovarian morphology and endocrine function[19].Studies have shown that the AGE-RAGE signaling pathway in insulin resistance was significantly differentially expressed in normal and obese PCOS patients.Regulating AKT may be an effective strategy for the treatment of obese PCOS[20,21],as AKTs have been confirmed to play an important role in granulosa-lutein cell proliferation,and there is reciprocal feedback between AKT and androgen[22].Moreover,studies have shown that the MAPK signaling pathway plays an important role in ovarian granulosa cell proliferation[23].Prolactin is a polypeptide hormone secreted by the pituitary gland that regulates the female reproductive and endocrine system by activating pathways,including the MAPK pathways[24].It has also been reported that MAPK and NF-κB could effectively regulate endocrine and insulin resistance,which was one of the important ways to treat obese PCOS[25-27].Moreover,inflammation triggered by saturated fat ingestion is linked to insulin resistance and hyperandrogenism in PCOS[28].A previous study revealed that hypoxia-inducible factor-1 mediated endothelin-2 signaling plays an important role in ovulation in rats,and indicated that HIF-1 signaling was inhibited in a PCOS rat model by increasing proline hydroxylase activity[29].Network pharmacology analysis results supported the clinical application of CFDTF in PCOS.

    In conclusion,the results of this study indicated that CFDTF contains 114 main components,including quercetin,luteolin,kaempferol,wogonin and naringenin,etc.The mechanism in the treatment of obese PCOS involved regulation of the AGE-RAGE signaling pathway in diabetic complications,endocrine resistance,IL-17 signaling pathway,TNF signaling pathway,HIF-1 signaling pathway,etc.Its key targets included AKT1,JUN,STAT3,CCND1,CDK2,CDKN1A,IL-10,etc.Its pharmacological action showed the characteristics of multi-component,multi-pathway and multi-target.This research is expected to provide a preliminary basis for clinical or basic research on the treatment of obese PCOS with TCM that invigorates spleen to dissipate phlegm,and provide a scientific basis for clinical application of TCM combined therapy in the treatment of obese PCOS.

    Acknowledgements

    We thank for the funding support from the the Scientific Research Projects of Shanghai Science and Technology Commission(No.19401930200).

    Competing Interests

    The authors declare no conflict of interest.

    猜你喜歡
    天南星香附枳殼
    天南星的研究進(jìn)展及其質(zhì)量標(biāo)志物的預(yù)測(cè)分析
    天南星的臨床應(yīng)用及其用量探究
    天南星和虎掌的本草考證
    中草藥天南星的研究進(jìn)展
    清江枳殼高產(chǎn)栽培技術(shù)
    枳殼及其炮制品色差值與化學(xué)成分的相關(guān)性
    中成藥(2017年6期)2017-06-13 07:30:35
    治胃寒痛
    婦女生活(2016年9期)2016-09-08 10:11:48
    枳殼快速切割器
    枳殼快速切割器
    對(duì) 《中國(guó)藥典》2010年版一部含香附制劑質(zhì)量控制的探討
    中成藥(2015年8期)2015-01-18 07:23:17
    国产私拍福利视频在线观看| 精品日产1卡2卡| 色哟哟哟哟哟哟| 国产色婷婷99| 久久人妻av系列| 日本一本二区三区精品| 亚洲av第一区精品v没综合| 精品国产亚洲在线| 看片在线看免费视频| 一级av片app| 亚洲最大成人手机在线| 久久久精品欧美日韩精品| 两个人的视频大全免费| 99久久99久久久精品蜜桃| av专区在线播放| 亚洲av免费高清在线观看| 一区福利在线观看| 中文亚洲av片在线观看爽| 国产大屁股一区二区在线视频| 十八禁人妻一区二区| 一二三四社区在线视频社区8| 亚洲成人精品中文字幕电影| 成人永久免费在线观看视频| 成年免费大片在线观看| 舔av片在线| 日韩欧美三级三区| 久久99热这里只有精品18| avwww免费| 亚洲欧美日韩无卡精品| 欧美不卡视频在线免费观看| 久久久久精品国产欧美久久久| 国产成人影院久久av| 午夜福利在线观看吧| 亚洲国产精品成人综合色| 男女做爰动态图高潮gif福利片| 亚洲精品一区av在线观看| 日本黄色视频三级网站网址| 欧美不卡视频在线免费观看| 欧美日韩瑟瑟在线播放| 中文字幕免费在线视频6| 国产私拍福利视频在线观看| 欧美激情久久久久久爽电影| 乱码一卡2卡4卡精品| 99久久成人亚洲精品观看| 国产大屁股一区二区在线视频| 国产高清三级在线| 成年女人毛片免费观看观看9| 俺也久久电影网| 亚洲五月婷婷丁香| 国产精品自产拍在线观看55亚洲| 精品一区二区免费观看| 搡女人真爽免费视频火全软件 | 亚洲精品一区av在线观看| 国产大屁股一区二区在线视频| 1024手机看黄色片| 亚洲成a人片在线一区二区| 国产麻豆成人av免费视频| a级毛片免费高清观看在线播放| av中文乱码字幕在线| 女同久久另类99精品国产91| 一个人看视频在线观看www免费| 国产探花在线观看一区二区| 蜜桃久久精品国产亚洲av| 国产精品美女特级片免费视频播放器| АⅤ资源中文在线天堂| 久久精品综合一区二区三区| 99热只有精品国产| 一区二区三区高清视频在线| 日韩国内少妇激情av| 国产高清三级在线| 麻豆av噜噜一区二区三区| 18美女黄网站色大片免费观看| 少妇的逼好多水| 欧美bdsm另类| 国内精品美女久久久久久| 日韩国内少妇激情av| 啦啦啦观看免费观看视频高清| 国产麻豆成人av免费视频| 一边摸一边抽搐一进一小说| 国产精品自产拍在线观看55亚洲| 久久久成人免费电影| 自拍偷自拍亚洲精品老妇| 深夜a级毛片| 伦理电影大哥的女人| 国产精品一区二区三区四区免费观看 | 亚洲国产色片| 日日干狠狠操夜夜爽| 日韩欧美免费精品| 色播亚洲综合网| 真人一进一出gif抽搐免费| 桃色一区二区三区在线观看| 国产单亲对白刺激| 欧美国产日韩亚洲一区| 又爽又黄无遮挡网站| 中文字幕精品亚洲无线码一区| 色综合欧美亚洲国产小说| 日本三级黄在线观看| 日本一本二区三区精品| 91在线观看av| 尤物成人国产欧美一区二区三区| 午夜a级毛片| 欧美最新免费一区二区三区 | 天堂网av新在线| 成人性生交大片免费视频hd| 嫁个100分男人电影在线观看| 精品久久久久久久末码| 91久久精品国产一区二区成人| 午夜福利视频1000在线观看| 午夜影院日韩av| 每晚都被弄得嗷嗷叫到高潮| 国产白丝娇喘喷水9色精品| 一本精品99久久精品77| 亚洲成av人片在线播放无| 中文亚洲av片在线观看爽| 中文字幕人成人乱码亚洲影| 九九热线精品视视频播放| av视频在线观看入口| 午夜激情福利司机影院| 国产精品久久电影中文字幕| 看片在线看免费视频| 女同久久另类99精品国产91| 欧美日本亚洲视频在线播放| 一区福利在线观看| 美女黄网站色视频| 欧美一区二区国产精品久久精品| 欧美精品国产亚洲| 99热只有精品国产| 亚洲综合色惰| www.色视频.com| 日本 av在线| 午夜福利欧美成人| 国产精品一区二区三区四区久久| 偷拍熟女少妇极品色| 91久久精品国产一区二区成人| 高清毛片免费观看视频网站| 在线免费观看不下载黄p国产 | 日韩亚洲欧美综合| 欧美色欧美亚洲另类二区| 国产成人啪精品午夜网站| 最近最新中文字幕大全电影3| 国产av麻豆久久久久久久| 欧美日韩瑟瑟在线播放| 91午夜精品亚洲一区二区三区 | 国产一级毛片七仙女欲春2| 99久久久亚洲精品蜜臀av| 国产精品影院久久| 午夜两性在线视频| 免费看光身美女| 人妻夜夜爽99麻豆av| 亚洲国产精品999在线| 国产91精品成人一区二区三区| 国产av不卡久久| or卡值多少钱| 观看美女的网站| 91在线精品国自产拍蜜月| 中亚洲国语对白在线视频| 男插女下体视频免费在线播放| 午夜老司机福利剧场| 狂野欧美白嫩少妇大欣赏| av在线老鸭窝| 成人高潮视频无遮挡免费网站| 亚洲 欧美 日韩 在线 免费| 国产一区二区在线观看日韩| 18禁黄网站禁片免费观看直播| 日本成人三级电影网站| 熟妇人妻久久中文字幕3abv| 麻豆一二三区av精品| 一个人看的www免费观看视频| 国产高潮美女av| 男人舔女人下体高潮全视频| 国产视频一区二区在线看| 欧美+日韩+精品| 9191精品国产免费久久| 熟妇人妻久久中文字幕3abv| 欧美精品啪啪一区二区三区| 天天一区二区日本电影三级| 国产精品1区2区在线观看.| .国产精品久久| 99久久九九国产精品国产免费| 99久久99久久久精品蜜桃| 少妇的逼水好多| 夜夜躁狠狠躁天天躁| 又黄又爽又刺激的免费视频.| 内地一区二区视频在线| 国产伦精品一区二区三区四那| 成年版毛片免费区| av天堂在线播放| 麻豆国产97在线/欧美| 男女之事视频高清在线观看| 久久天躁狠狠躁夜夜2o2o| 青草久久国产| 校园春色视频在线观看| 免费在线观看亚洲国产| 男插女下体视频免费在线播放| 美女 人体艺术 gogo| 日韩欧美在线二视频| 在线观看舔阴道视频| 亚洲 欧美 日韩 在线 免费| 91午夜精品亚洲一区二区三区 | 天堂网av新在线| 国产亚洲精品综合一区在线观看| 女同久久另类99精品国产91| 亚洲欧美日韩无卡精品| 久久人人爽人人爽人人片va | 有码 亚洲区| 欧美日韩中文字幕国产精品一区二区三区| 亚洲av成人av| 我要搜黄色片| 成年人黄色毛片网站| 桃色一区二区三区在线观看| 91在线观看av| 国产精品亚洲一级av第二区| 国产精品一区二区性色av| 日韩欧美国产一区二区入口| 国产蜜桃级精品一区二区三区| 精品久久久久久久久av| 日韩欧美免费精品| 免费在线观看成人毛片| 国产大屁股一区二区在线视频| 波多野结衣巨乳人妻| 少妇高潮的动态图| 在线十欧美十亚洲十日本专区| 熟女电影av网| 久久精品夜夜夜夜夜久久蜜豆| 舔av片在线| 国产真实乱freesex| 天堂网av新在线| 亚洲中文字幕日韩| 久久久成人免费电影| 丰满乱子伦码专区| 久久久久久国产a免费观看| 亚洲五月婷婷丁香| 蜜桃久久精品国产亚洲av| 美女被艹到高潮喷水动态| 国产熟女xx| 亚洲电影在线观看av| 国产91精品成人一区二区三区| 久久6这里有精品| 国产单亲对白刺激| 亚洲成av人片在线播放无| 特级一级黄色大片| 国产精品乱码一区二三区的特点| 婷婷精品国产亚洲av| 午夜福利在线观看免费完整高清在 | 亚洲七黄色美女视频| 嫁个100分男人电影在线观看| 久久久国产成人免费| 色av中文字幕| 国产伦精品一区二区三区四那| 99久久九九国产精品国产免费| 一进一出抽搐gif免费好疼| 亚洲精品日韩av片在线观看| 色吧在线观看| 久久久久久久午夜电影| 99热6这里只有精品| 日日摸夜夜添夜夜添小说| 国产极品精品免费视频能看的| 亚洲精品亚洲一区二区| 久久国产乱子免费精品| 亚洲,欧美精品.| 午夜亚洲福利在线播放| 日韩 亚洲 欧美在线| 9191精品国产免费久久| 欧美日韩黄片免| 亚洲美女视频黄频| 丝袜美腿在线中文| 国产真实乱freesex| 国产69精品久久久久777片| 国产 一区 欧美 日韩| 欧美日韩瑟瑟在线播放| 成人av一区二区三区在线看| 最新中文字幕久久久久| 久久亚洲真实| 国产aⅴ精品一区二区三区波| 国语自产精品视频在线第100页| 一区福利在线观看| 91久久精品国产一区二区成人| 国产中年淑女户外野战色| 亚洲avbb在线观看| 亚洲欧美日韩高清在线视频| netflix在线观看网站| 91av网一区二区| 成人特级av手机在线观看| 国产精品嫩草影院av在线观看 | 最近中文字幕高清免费大全6 | 亚洲成人久久性| 国内揄拍国产精品人妻在线| 亚洲性夜色夜夜综合| 亚洲最大成人手机在线| 日本三级黄在线观看| 成人精品一区二区免费| 色哟哟哟哟哟哟| 一二三四社区在线视频社区8| 日韩 亚洲 欧美在线| 亚洲在线自拍视频| 国产精品一区二区三区四区免费观看 | 日韩人妻高清精品专区| 波多野结衣高清作品| 国产精华一区二区三区| 亚洲三级黄色毛片| 亚洲国产高清在线一区二区三| 他把我摸到了高潮在线观看| 深爱激情五月婷婷| 午夜激情福利司机影院| 国产熟女xx| 日韩中字成人| 欧美乱妇无乱码| 日韩欧美国产在线观看| 韩国av一区二区三区四区| 久久精品夜夜夜夜夜久久蜜豆| 久久亚洲真实| 观看免费一级毛片| 色哟哟哟哟哟哟| 亚洲精品粉嫩美女一区| 无人区码免费观看不卡| 国产亚洲精品av在线| 久久久久久九九精品二区国产| 久久久成人免费电影| 亚洲av电影在线进入| 精品一区二区三区视频在线| 美女被艹到高潮喷水动态| 国内精品一区二区在线观看| 久久久久久九九精品二区国产| 国产欧美日韩精品亚洲av| 久99久视频精品免费| 久久久久久久久中文| 免费看a级黄色片| 欧美精品国产亚洲| 性插视频无遮挡在线免费观看| 国产成人欧美在线观看| 免费一级毛片在线播放高清视频| 999久久久精品免费观看国产| 国产免费av片在线观看野外av| 亚洲aⅴ乱码一区二区在线播放| 两人在一起打扑克的视频| 成人一区二区视频在线观看| 亚洲中文字幕一区二区三区有码在线看| 国产精品一及| 成人无遮挡网站| 日韩欧美在线二视频| 欧美最新免费一区二区三区 | 亚洲乱码一区二区免费版| 亚洲av成人av| 成人性生交大片免费视频hd| 午夜精品一区二区三区免费看| 国产免费一级a男人的天堂| 麻豆国产97在线/欧美| 午夜激情欧美在线| 在线国产一区二区在线| 亚洲成人免费电影在线观看| 91麻豆精品激情在线观看国产| 亚洲av免费高清在线观看| 精品久久久久久久人妻蜜臀av| 国产免费一级a男人的天堂| 黄片小视频在线播放| 亚洲国产色片| 国产免费男女视频| 国产免费av片在线观看野外av| 97热精品久久久久久| av在线老鸭窝| 人妻夜夜爽99麻豆av| 99在线人妻在线中文字幕| 男女视频在线观看网站免费| 国产精品久久久久久久久免 | 午夜福利高清视频| 午夜福利免费观看在线| 老司机福利观看| 国产精品亚洲一级av第二区| 男人舔女人下体高潮全视频| 免费看美女性在线毛片视频| 国产视频内射| 91狼人影院| 午夜福利18| 91在线精品国自产拍蜜月| 男人狂女人下面高潮的视频| 免费看光身美女| 欧美bdsm另类| 毛片一级片免费看久久久久 | 舔av片在线| 在线看三级毛片| 少妇熟女aⅴ在线视频| 搡女人真爽免费视频火全软件 | 国产人妻一区二区三区在| av在线老鸭窝| 麻豆久久精品国产亚洲av| 国产精品精品国产色婷婷| 欧美高清性xxxxhd video| 免费在线观看影片大全网站| 久久久精品欧美日韩精品| 观看免费一级毛片| 久久久久亚洲av毛片大全| 国产精品久久视频播放| 日日夜夜操网爽| 久久久久久九九精品二区国产| 精品午夜福利在线看| 亚洲成人久久爱视频| 久久精品国产亚洲av涩爱 | 久久精品人妻少妇| 一夜夜www| 99精品在免费线老司机午夜| 欧美在线黄色| 中文字幕精品亚洲无线码一区| 亚洲av五月六月丁香网| 亚洲熟妇熟女久久| 亚洲欧美精品综合久久99| 国产男靠女视频免费网站| 日韩欧美一区二区三区在线观看| 中国美女看黄片| 麻豆一二三区av精品| 在线观看一区二区三区| 最近在线观看免费完整版| 91九色精品人成在线观看| 亚洲激情在线av| 美女 人体艺术 gogo| 日本成人三级电影网站| 男女床上黄色一级片免费看| 91久久精品国产一区二区成人| 校园春色视频在线观看| 在线天堂最新版资源| 久久精品影院6| 少妇人妻精品综合一区二区 | 桃色一区二区三区在线观看| 欧美激情久久久久久爽电影| 久久99热这里只有精品18| 久久久国产成人免费| 日韩欧美在线乱码| 亚洲美女视频黄频| 欧美黄色淫秽网站| 午夜两性在线视频| 最近中文字幕高清免费大全6 | 一夜夜www| 校园春色视频在线观看| 国产视频一区二区在线看| 99在线人妻在线中文字幕| 最新在线观看一区二区三区| 九九在线视频观看精品| 欧美日韩中文字幕国产精品一区二区三区| 日韩欧美在线二视频| 日韩精品青青久久久久久| 久久午夜福利片| 欧美国产日韩亚洲一区| 看十八女毛片水多多多| 久久精品综合一区二区三区| 亚洲avbb在线观看| 身体一侧抽搐| 国产黄色小视频在线观看| 最近最新中文字幕大全电影3| 51午夜福利影视在线观看| 亚洲七黄色美女视频| 级片在线观看| 免费看a级黄色片| 1024手机看黄色片| 又紧又爽又黄一区二区| 黄色视频,在线免费观看| 久久久精品大字幕| 3wmmmm亚洲av在线观看| 欧美xxxx性猛交bbbb| 看十八女毛片水多多多| 亚洲自偷自拍三级| 国产精品亚洲av一区麻豆| 亚洲人成网站在线播放欧美日韩| 琪琪午夜伦伦电影理论片6080| 婷婷丁香在线五月| 三级国产精品欧美在线观看| 免费大片18禁| 亚洲天堂国产精品一区在线| 国产精品影院久久| 国模一区二区三区四区视频| 亚洲av中文字字幕乱码综合| av欧美777| 国产麻豆成人av免费视频| 亚洲精品一卡2卡三卡4卡5卡| 国产精品自产拍在线观看55亚洲| 男女那种视频在线观看| 深夜a级毛片| 国产淫片久久久久久久久 | 99视频精品全部免费 在线| 久久久精品欧美日韩精品| 国产aⅴ精品一区二区三区波| 精品国产三级普通话版| 老司机午夜福利在线观看视频| 精品人妻1区二区| 能在线免费观看的黄片| 亚洲成人免费电影在线观看| 亚洲精华国产精华精| 国产毛片a区久久久久| 我要看日韩黄色一级片| 看片在线看免费视频| 国产成年人精品一区二区| 亚洲天堂国产精品一区在线| 欧美日本亚洲视频在线播放| 男插女下体视频免费在线播放| 亚洲色图av天堂| av视频在线观看入口| 好看av亚洲va欧美ⅴa在| 成年女人永久免费观看视频| 国内精品久久久久精免费| 欧美bdsm另类| 国产日本99.免费观看| 国产视频一区二区在线看| 亚洲黑人精品在线| 91狼人影院| or卡值多少钱| 国产精品人妻久久久久久| 九色成人免费人妻av| 亚洲av成人精品一区久久| 欧美午夜高清在线| 亚洲国产精品久久男人天堂| 精品久久久久久久久亚洲 | 亚洲五月婷婷丁香| 国产精品乱码一区二三区的特点| 天堂动漫精品| 午夜久久久久精精品| 国产精品av视频在线免费观看| 人妻久久中文字幕网| 色在线成人网| 免费在线观看成人毛片| 又粗又爽又猛毛片免费看| 男人和女人高潮做爰伦理| 日本成人三级电影网站| 精品免费久久久久久久清纯| 日韩大尺度精品在线看网址| 男女做爰动态图高潮gif福利片| 成年免费大片在线观看| 1000部很黄的大片| 久久天躁狠狠躁夜夜2o2o| 欧美绝顶高潮抽搐喷水| 久久精品综合一区二区三区| 国产高清三级在线| 国产精品av视频在线免费观看| 亚洲成a人片在线一区二区| 免费在线观看影片大全网站| 欧美成人一区二区免费高清观看| 久久久久久久久久成人| 国产精品日韩av在线免费观看| 日本一本二区三区精品| 国产精品一及| 天堂网av新在线| 天堂动漫精品| 天堂网av新在线| 亚州av有码| 别揉我奶头 嗯啊视频| 丁香欧美五月| 国产日本99.免费观看| 麻豆久久精品国产亚洲av| 97热精品久久久久久| 在线十欧美十亚洲十日本专区| 美女xxoo啪啪120秒动态图 | 国产成+人综合+亚洲专区| 美女xxoo啪啪120秒动态图 | 久久久久久大精品| a级一级毛片免费在线观看| 久久久久久国产a免费观看| 日日夜夜操网爽| 欧美黑人欧美精品刺激| 国产aⅴ精品一区二区三区波| 精华霜和精华液先用哪个| 亚洲一区高清亚洲精品| 午夜影院日韩av| 又爽又黄无遮挡网站| 97人妻精品一区二区三区麻豆| 国产中年淑女户外野战色| 91久久精品电影网| 男人和女人高潮做爰伦理| 日本成人三级电影网站| 欧美xxxx黑人xx丫x性爽| 日本黄色视频三级网站网址| 欧美色视频一区免费| 99久久久亚洲精品蜜臀av| 久久久国产成人免费| 国产高潮美女av| 99在线视频只有这里精品首页| 全区人妻精品视频| 日韩高清综合在线| 欧美日韩综合久久久久久 | 日韩欧美精品v在线| 国产单亲对白刺激| 一级a爱片免费观看的视频| 精品日产1卡2卡| 久久婷婷人人爽人人干人人爱| 黄色丝袜av网址大全| 国产精品免费一区二区三区在线| 欧美潮喷喷水| 欧美性猛交黑人性爽| 中文字幕高清在线视频| 国产国拍精品亚洲av在线观看| 又黄又爽又刺激的免费视频.| 免费电影在线观看免费观看| 乱码一卡2卡4卡精品| 国产精品,欧美在线| 亚洲第一电影网av| 亚洲综合色惰| 国产 一区 欧美 日韩| 久久久久久久久久黄片| 精品久久久久久久久久免费视频| 亚洲精品色激情综合| 日韩大尺度精品在线看网址| 天堂√8在线中文| 国产伦精品一区二区三区四那| 国产一区二区亚洲精品在线观看| 亚洲在线观看片| 天堂动漫精品| 99精品在免费线老司机午夜| 久久久久久国产a免费观看| 亚洲午夜理论影院| 波多野结衣高清作品| 99久久精品一区二区三区| 午夜福利免费观看在线| 色5月婷婷丁香| 欧美成人性av电影在线观看| 成人高潮视频无遮挡免费网站| 亚洲aⅴ乱码一区二区在线播放| 国产精品国产高清国产av| 欧美在线一区亚洲| 亚洲av五月六月丁香网|