• <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 ?

    Mechanisms of Dihuang (Rehmanniae Radix) in treating diabetic nephropathy complicated with depression based on network pharmacology

    2022-07-02 07:46:26LEIXingCHENQingyoWANGXiopingXUJieGAOYzhenLINQiohongYEZuwenZHANGJieynSIQinWANGFng
    Digital Chinese Medicine 2022年2期
    關(guān)鍵詞:要訣證治神農(nóng)本草經(jīng)

    LEI Xing,CHEN Qingyo,WANG Xioping,XU Jie,GAO Yzhen,LIN Qiohong,YE Zuwen,ZHANG Jieyn,SI Qin*,WANG Fng*

    a. Key Laboratory of Modern Traditional Chinese Medicine Preparation,Ministry of Education,Jiangxi University of Chinese Medicine,Nanchang,Jiangxi 330004,China

    b. Pharmacy Department,Zhangzhou Health Vocational College,Zhangzhou,F(xiàn)ujian 363000,China

    c. School of Agro-Industry,Mae Fah Luang University,Muang,Chiang Rai 57100,Thailand

    ABSTRACT Objective To predict the molecular mechanism of Dihuang (Rehmanniae Radix) in the treatment of diabetic nephropathy (DN) complicated with depression based on network pharmacology.Methods The components of Dihuang (Rehmanniae Radix) were identified from the Integrated Pharmacology-based Research Platform of Traditional Chinese Medicine (TCMIP),Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP),and relevant literature. The component targets were detected by combining the SwissTarget-Prediction and PubChem databases. Disease targets were collected from the Therapeutic Target Database (TTD),DisGeNET,and Ensembl databases with “diabetic nephropathy” and“depression” as keywords. The disease-component targets were mapped using Venny 2.1.0 to obtain potential targets. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and Cytoscape 3.7.2. The co-expression genes of the key targets were collected based on the COXPRESdb 7.3. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed for potential targets using R language. Target-component docking was verified and evaluated using Discovery Studio 4.5.Results According to the databases and literature reports,Dihuang (Rehmanniae Radix) contained 65 active components,and had 155 related targets for the treatment of DN complicated with depression. PPI screening showed that the key targets included serine/threonine protein kinase 1 (AKT1),signal transducer and activator transcription 3 (STAT3),interleukin 6(IL-6),mitogen-activated protein kinase 1 (MAPK1),and vascular endothelial growth factor A(VEGFA),etc. GO enrichment analysis mainly involved biological processes,such as lipid metabolism,protein secretion regulation,cell homeostasis,and phosphatidylinositol 3 kinase activity. KEGG pathway enrichment analysis included the role of the AGE-RAGE signaling pathway in diabetic complements,insulin resistance (IR),neurotrophin signal path,Toll-like receptor signaling pathway,relaxin signaling pathway,epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs),etc. Molecular docking showed that the target had high affinity for stachyose,manninotriose,verbascose,nigerose,etc.Conclusion Based on network parmacology,this study preliminarily predict the effects of Dihuang (Rehmanniae Radix) in treating DN complicated with depression by regulating inflammation,glucose metabolism,nution nerve,etc.

    Keywords Dihuang (Rehmanniae Radix) Diabetic nephropathy Depression Network pharmacology Molecular docking Simultaneous treatment of different diseases True deficiency with false excess patterns Inflammation

    1 Introduction

    Dihuang (Rehmanniae Radix) is the fresh or dry root tuber ofRehmannia glutinosaLibosch.[1],which was first recorded inShennong's Classic of Materia Medica(Shen Nong Ben Cao Jing,《神農(nóng)本草經(jīng)》) and was listed as the top grade[2].Famous Doctors(Ming Yi,《名醫(yī)》)says: “Dihuang (Rehmanniae Radix) is found earlier in Xianyang,with the better in yellow earth. Roots are picked and dried in the shade on February 8 of the lunar calendar”; it is mainly distributed in Henan,Hebei,Shandong,Shanxi,etc.,withRehmannia glutinosafrom Huaiqing House (the present Jiaozuo in Henan Province)as the most valuable[3].Compendium of Materia Medica(Ben Cao Gang Mu,《本草綱目》) records: “Dihuang(Rehmanniae Radix),which is planted with yellow earth in Jiangsu and Zhejiang,appears good but shows mild effects due to southern Yang Qi,Huai Dihuang (Rehmanniae Radix from the ancient Huaiqing House),appears coarse with knots but shows strong effects due to the northern pure Yin Qi”[4]. The medicinal history of China has reported freshRehmannia glutinosa,rawRehmannia glutinosa,and preparedRehmannia glutinosa[5-8]. Extensive research has been recently conducted on the components of Dihuang (Rehmanniae Radix),which mainly include iridoids,saccharides,glycosides,amino acids,etc. Dihuang (Rehmanniae Radix) has the effects of clearing heat and cooling blood,nourishing Yin and tonifying the kidney,and reinforcing essence and supplementing marrow. It has beneficial effects on improving glucose and lipid metabolism,improving vascular endothelial function,reducing oxidative stress in cells,increasing immunity,and inhibiting inflammatory factors[3,9-11].

    Diabetic nephropathy (DN) is a microvascular complication with high incidence in patients with diabetes mellitus (DM),and is categorized as “diabetes” “edema”“clearance” and “fatigue” in traditional Chinese medicine (TCM)[12]. According to the epidemiological prediction,approximately 592 million patients will be diagnosed with DM worldwide in 2035[13],and approximately one third of the patients with diabetes will develop DN[14,15]. In the past 30 years,the incidence of DN in China has increased from 2.7% to 35.2%[16],and it has become the primary cause of end-stage renal injury[17]. Depression is a mental disorder characterized by obvious and lasting mental symptoms,which is categorized as“depression” “dirty mania” and “l(fā)ily disease” in TCM.The occurrence of DN is closely related to depression[18].According to the statistics,the risk of diabetes in patients with depression is two times higher than that in healthy people[19],and the detection rate of DN complicated with depression is 53%[20]. Compared with a single disease,comorbidity is rarely studied. The impacts of DN and depression are superimposed,and the disease recognition and treatment rates are low,which greatly increases the mortality and disability rates[21]. At present,the therapeutic effect of western medicine is still not ideal. In contrast,the multi-target,multi-level,and multi-axis therapeutic characteristics of Chinese medicines,and the feasibility of comprehensive intervention make it the key researching area[22]. DN complicated with depression is closely related to a decrease in glomerular filtration rate,insulin resistance (IR),neuroendocrine dysfunction,and inflammation[23,24]. Heary and lasting depression aggravates DN,accelerates the disease process,and increases the mortality[25]. Professor RUAN Shiyi,a master of TCM,once thought that the source of depression lied in the kidney based on the theory of “heart-liver-kidney integration”,and that depression could be treated by “nourishing Yin and tonifying the kidney”[26]. Dihuang (Rehmanniae Radix) is one of the core drugs in the Baihe Dihuang Decoction (百合地黃湯),a classic antidepressant prescription. Dihuang (Rehmanniae Radix) mainly lowers apoptosis and neuronal damage to exert antidepressant effects by regulating neurotransmitters and their receptors,attenuating inflammation,and improving metabolism[27-29]. TCM formulae,such as Liuwei Dihuang Pill (六味地黃丸),are commonly used in clinical practice to treat DN,improve the disorders of glucose and lipid metabolism,and lower the level of nuclear factor-κB (NF-κB) and cell adhesion factor-1 to reduce urinary protein excretion and alleviate renal inflammatory reactions[30,31]. Therefore,TCM compounds are clinically used to manage comorbidity with psychotherapy[32,33]. At present,the mechanism of Dihuang (Rehmanniae Radix) in treating DN complicated with depression is not fully understood. This study aims to preliminarily predict the mechanism of Dihuang (Rehmanniae Radix) in treating DN complicated with depression based on network pharmacology. Figure 1 shows the overall design of this study.

    2 Methods

    2.1 Collecting and screening disease targets

    “Diabetic nephropathy” and “depression” were utilized as keywords to search in Therapeutic Target Database(TTD) (http://db.idrblab.net/ttd/),DisGeNET database(https://www.disgenet.org/search),and Ensembl database (https://uswest.ensembl.org/index.html).

    Figure 1 Research process of Dihuang (Rehmanniae Radix) in treating DN complicated with depression

    2.2 Collecting and screening the components of Dihuang(Rehmanniae Radix)

    The components of Dihuang (Rehmanniae Radix) were collected from the Integrated Pharmacology-based Research Platform of Traditional Chinese Medicine(TCMIP) 2.0 (http://www.tcmip.cn/TCMIP/index.php/Home/),and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP)(http://tcmspw.com/tcmsp.php). Considering that some active components were not included in the database,relevant literature on Dihuang (Rehmanniae Radix) in the last five years was retrieved to supplement.

    2.3 Screening and predicting potential component targets of Dihuang (Rehmanniae Radix)

    Based on the active components collected above,the relevant component targets of Dihuang (Rehmanniae Radix) were collected from the TCMIP 2.0,TCMSP,Pub-Chem (https://pubchem.ncbi.nlm.nih.gov/),and Swiss-TargetPrediction (http://swisstargetprediction.ch/) databases. Venny 2.1.0 (https://bioinfogp.cnb.csic.es/tools/venenny/index.html) was used to map the components and disease targets.

    2.4 Protein-protein interaction (PPI) network analysis

    The information on intersection targets was imported into the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database (https://string-db.org/). The screening index was set as confidence ≥ 0.700.The data were updated and saved in “.tsv” format. The information of node #1 and node #2,and the combined score were imported into Cytoscape 3.7.2. The network targets were topologically analyzed,and the targets with a degree value greater than two times the median were selected as key targets. COXPRESdb 7.3 database(https://coxpresdb.jp/) was used to search for genes strongly expressed at the key targets.

    2.5 Pathway enrichment analysis

    Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were carried out to identify the potential targets of Dihuang(Rehmanniae Radix) in treating DN complicated with depression using R language (clusterProfiler package). The relationship between the top 20 KEGG pathways and the active components and the potential targets of Dihuang(Rehmanniae Radix) was visualized using Cytoscape 3.7.2 software.

    2.6 Molecular docking

    The molecular docking software,Discovery Studio 4.5,was used to verify the docking of the top five targets of degree in topological analysis. Using the RCSB Protein Data Bank (PDB) database (http://www.rcsb.org/) and the DrugBank database (https://www.drugbank.com/),the target protein structure was screened as the counter receptor,and the listed drugs were selected as positive controls according to the target protein. In this study,valsartan and fluoxetine were selected as positive drugs for DN and depression[34,35]. The two dimensional (2D)chemical structure of TCM components,valsartan,and fluoxetine,were obtained from PubChem (https://pubchem.ncbi.nlm.nih.gov/) database. The larger the docking score,the more stable the binding.

    3 Results

    3.1 Screening key targets

    Based on TCMIP 2.0,TCMSP database,and literature reports,65 active components of Dihuang (Rehmanniae Radix) were identified. From the collected targets in the database,703 active component targets of Dihuang(Rehmanniae Radix),1 297 DN-related targets,and 1 735 depression-related targets were identified. Venny 2.1.0 tool was used to map Dihuang (Rehmanniae Radix) components,DN,and depression targets. A total of 155 potential targets were obtained by intersection (Figure 2),which showed that Dihuang (Rehmanniae Radix) treats DN and depression through the same mechanism.

    Figure 2 Potential targets of Dihuang (Rehmanniae Radix) in treating DN complicated with depression

    3.2 Analysis of intersection targets PPI and co-expression gene network

    A total of 155 potential targets were imported into the STRING database combined with the Cytoscape 3.7.2,33 key targets were screened with degree values greater than two times the median (degree > 16). As shown in Table 1,the top five were serine/threonine protein kinase 1(AKT1),signal transducer and activator transcription 3(STAT3),interleukin-6 (IL-6),mitogen-activated protein kinase 1 (MAPK1),and vascular endothelial growth factor A (VEGFA). PPI network is shown in Figure 3. The co-expression genes of the 33 key targets were searched using the COXPRESdb 7.3 database. The first three strongly expressed genes were selected,and 47 co-expressed genes were obtained,which were introduced into Cytoscape 3.7.2. With the help of 12 network structures (e.g. MCC,DMNC,MNC,and degree in the plug-in cytoHubba and the weighted algorithm between nodes),the top five hub genes (key genes) were identified,namely tumor necrosis factor (TNF),matrix metalloproteinase-2 (MMP2),chemokine ligand 3 (CCL3),macrophage inflammatory protein 1β(CCL4),and type III collagen (COL3A1).

    Figure 3 PPI network of Dihuang (Rehmanniae Radix) in treating DN complicated with depression

    Table 1 Key target information in PPI network

    3.3 GO and KEGG pathway enrichment analysis

    To further explore the mechanism of Dihuang (Rehmanniae Radix) in treating DN complicated with depression,gene annotation and pathway analysis of mapping targets were carried out using R language. GO function enrichment analysis showed enrichment of 2 581 items (P<0.05),including 2 365 biological processes (BP),namely the regulation of lipid metabolism,protein secretion,cell homeostasis,response to oxygen level,smooth muscle cell proliferation,etc. A total of 151 molecular functions(MF) were identified,including protein serine/threonine kinase activity,protein phosphatase binding,transmembrane receptor protein tyrosine kinase activity,nuclear receptor transcription coactivator activity,phosphatidylinositol 3 kinase activity (PI3K),etc. A total of 65 cell components (CC) were identified. They were related to glutamatergic synapses,phosphatidylinositol 3 kinase complexes,nuclear transcription factor complexes,secretory granule lumens,etc. The top 20 pathways based on these three aspects were selected for the graphic display (Figure 4). These results showed that the active components of Dihuang (Rehmanniae Radix) could play a therapeutic role in DN complicated with depression by regulating various biological pathways.

    A total of 171 entries were obtained by enrichment analysis of KEGG pathway (P< 0.05). The enriched pathways included AGE-RAGE signaling pathway,IR,Toll-like receptor signaling,neurotrophic factor signaling pathway,C-type lectin receptor signaling pathway,chalasin signaling pathway,epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs),endocrine resistance,TNF signaling pathway,HIF-1 signaling pathway,apoptosis,etc. The KEGG Mapper tool[36]was used to integrate the screened important pathways with key targets,including oxidative stress,glucose metabolism,apoptosis,inflammatory reactions,etc. (Figure 5). According to thePvalue,the top 20 pathways were plotted with the corresponding component-target-pathway diagram (Figure 6). From the component-target-pathway diagram,we found class I phosphatidylinositol 3-kinase (PIK3CA),AKT1,phosphatidylinositol 4,5-diphosphate 3-kinase catalytic subunit delta (PIK3CD),protein kinase Cα(PRKCA),MAPK1,phosphatidylinositol 3-kinase catalytic subunitβ(PIK3CB),mitogen-activated protein kinase 3(MAPK3),etc. appear frequently. On analyzing the component-target-pathway diagram,it was found that,among the active components of Dihuang (Rehmanniae Radix),one active component could act on multiple targets at the same time,and one target also corresponded to a variety of active components. This proves that the active components of Dihuang (Rehmanniae Radix)could play a therapeutic role in multiple components and targets,and the possible relationship among Chinese medicines,diseases,and targets can be effectively predicted. In addition,the complex network diagram indirectly reflected the complexity of the interactions between drugs. Figure 6 shows 52 targets related to the active components of Dihuang (Rehmanniae Radix) and 75 potential targets in the top 20 pathways. Targets with higher frequencies were directly or indirectly involved in the AGE-RAGE signaling pathway in diabetic complications,the TNF signaling pathway,and the HIF-1 signaling pathway. Among them,the AGE-RAGE signaling pathway in diabetic complications involves the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway,which is a key pathway affecting insulin-mediated hypoglycemic effects and is abnormally regulated in patients with DN. IR can induce mitochondrial dysfunction and various neurotransmitters,and aggravate neuronal damage. Improving IR can reverse the depression-like behavior in rats with DN[22]. Thus,modulation of this pathway has a positive impact on treating DN complicated with depression.

    Figure 4 GO functional enrichment analysis of potential targets of Dihuang (Rehmanniae Radix) in treating DN completed with depression

    Figure 5 Path map of Dihuang (Rehmanniae Radix) in treating DN complicated with depression

    Figure 6 Component-target-pathway map of Dihuang (Rehmanniae Radix) in treating DN complicated with depression DH represents Dihuang (Rehmanniae Radix).

    3.4 Molecular docking results

    Based on the top five targets in the PPI network,the corresponding target protein receptors were downloaded from the RCSB PDB database: AKT1 (PDB ID 2GHG),STAT3 (PDB ID 5AX3),IL-6 (PDB ID 4QIL),MAPK1 (PDB ID 60PI),and VEGFA (PDB ID 4ZFF). The targets were verified with the positive drugs valsartan and fluoxetine,and the corresponding Chinese medicine components.The docking results are presented in Table 2. The higher the docking fraction,the better the binding activity between the target protein and the effective chemical components,and the closer it is to the docking value of the positive drugs. Stachyose,maninotriose,verbasose,and nigerose exhibited higher affinities in the docking process.

    Table 2 Target docking results of Dihuang (Rehmanniae Radix) in treating DN complicated with depression

    4 Discussion

    In TCM theory,the basic pathogenesis of “diabetes” combined with “depression” is “true deficiency with false excess patterns”. The former is based on deficiency of zang and fu organs,whereas the latter is based on phlegm coagulation,Qi stagnation,and blood stasis[18].Medical Classic based on Confucianism(Ru Men Shi Qin,《儒門事親》) records: “Disease,without controlling sleep or emotion activities,would reoccur even though it's cured for a while”. It indicates that diabetes and depression inreract as both cause and effect,usally occruing together. According to the domestic report,the incidence of diabetes complicated by depression can reach 26% -58%[37].The Key to Syndrome and Treatment(Zheng Zhi Yao Jue,《證治要訣》) records: “For patients withprolonged diabetes,the urine smells sweet instead of unpleasant; without proper treatment,kidney essence would be exausted”. Physicians generally emphasize that the course of DN is long,which easily leads to poor medication compliance,and is then complicated with depression[38]. Dihuang (Rehmanniae Radix) has the effects of clearing heat and cooling blood,nourishing Yin and tonifying the kidney,and reinforcing the essence and supplementing marrow. Clinically,Dihuang (Rehmanniae Radix) is often used to treat DN and depression in TCM. Dihuang (Rehmanniae Radix) can substantially reduce the expression of the growth factor receptor binding protein 10 (GRB 10) and advanced glycation end products receptor (RAGE),improve lipid metabolism,reduce microangiopathy,and interfere with inflammatory reactions,thus treating DN successfully[31]. It can also treat depression by protecting neurons,promoting neuron regeneration,and regulating monoamine neurotransmitter content[27,39].

    This study identified 65 active components of Dihuang (Rehmanniae Radix) corresponding to 703 targets,of which 155 targets were related to DN and depression.PPI analysis of potential targets of Dihuang (Rehmanniae Radix) in treating DN complicated with depression showed that AKT1,STAT3,IL-6,MAPK1,VEGFA,etc. were highly enriched. A total of 47 co-expressed genes were found from the 33 key targets in PPI,and the top five hub genes co-expressed were TNF,MMP2,CCL3,CCL4,and COL3A1. AKT1 is a subtype of protein kinase B,which is a serine/threonine kinase involved in intracellular signal transduction and participates in the signaling pathways of neurotransmitters such as brain-derived neurotrophic factor (BDNF),nerve growth factor (NGF),5-hydroxytryptamine (5-TH),and dopamine (DA). The improvement in patients with depression is positively correlated with the change in AKTI expression[40]. MMP2 can cause anticoagulation system disorder,accelerate renal vascular calcification[41],and target STAT3,IL-6,MAPK1,TNF,CCL3,and CCL4,which can mediate the activation of inflammatory factors,chemokines,and adhesion factors to a certain extent,and then play a proinflammatory role. The inflammatory cytokine IL-6 phosphorylates and activates STAT3,and the target gene of STAT3 overlaps with the target gene of the NF-κB signaling pathway. Monocytes are induced to release chemokines such as CCL3 and CCL4 by activating the NF-κB signaling pathway[42]. Modern molecular biology and genetics research confirmed the relationship between depression and immune system regulation,and research showed that abnormal levels of peripheral proinflammatory factors such as IL-6,IL-1β,and TNF-αwere detected in the sera of patients with depression[43]. Inflammatory reactions can downregulate BDNF expression,damage hippocampal neurons,and induce depression[44]. Inflammation is also an important mechanism for the development of DN[45]. Augmented levels of TNF-αor IL-6 decrease the expression of thrombomodulin(CD141),which inhibits the onset of renal failure caused by anticoagulation[46]. Meanwhile,the migration and release of inflammatory factors accelerate the apoptosis of glomerular endothelial cells,increase the permeability of endothelial cells,cause proteinuria[47],and aggravate the progression of DN. Several targets related to immune system regulation have been elucidated in the present study. In summary,Dihuang (Rehmanniae Radix) can protect the kidney and hippocampus by reducing inflammation.

    GO enrichment analysis showed that Dihuang(Rehmanniae Radix) was mainly involved in regulating lipid metabolism,protein serine/threonine kinase activity,phosphotyrosine residue binding,nuclear receptor transcription coactivator activity,PI3K,protein secretion,and glutamatergic synapses,etc. Depression can increase platelet activation and blood viscosity[48]. Regulating lipid metabolism can inhibit platelet aggregation,reduce blood viscosity,and improve blood circulation of the glomerular capillaries[49],thus affecting the development of DN complicated with depression. Insulin stimulates the phosphorylation of tyrosine residues by activating the insulin receptor (tyrosine kinase receptor),promotes the cellular uptake and utilization of glucose through insulin receptor substrate-1/phosphatidylinositol-3 kinase/glucose transporter 4 (IRS-1/PI3K/GLUT4),and participates in the regulation of blood glucose[50-52].Therefore,the effect of Dihuang (Rehmanniae Radix) on DN complicated with depression is closely related to the regulation of blood glucose. DING et al.[53]reported that glutamate levels and the glutamine/glutamate ratio in depressed mice increased,glutamine levels decreased,and glutamate levels were reversed after administration of antidepressants.

    KEGG pathway enrichment analysis showed that the related component targets of Dihuang (Rehmanniae Radix) were involved in the AGE-RAGE signaling pathway in diabetes complicated with depression,IR,neurotrophic factor signaling pathway,Toll-like receptor signaling,C-lectin receptor signaling pathway,relaxin signaling pathway,EGFR-TKIs,etc. Upregulation of the AGE-RAGE signaling pathway can increase the number of proinflammatory and profibrotic cytokines and activate oxidative stress and apoptosis,leading to renal failure[54]. The combination of AGES and RAGE can activate the PI3K/Akt signaling pathway,which is the key pathway for insulin to regulate blood glucose[55]. Glycolipid accumulation caused by IR can have toxic effects on podocytes and glomerular filtration membrane,and participate in early diabetic kidney damage[52]. Toll-like receptors widely exist on the surface or inside the immune regulatory cells and immune effector cells[56]. Toll-like receptors bind to ligands,activate the nuclear transcription factor NF-κB,and induce an increase in inflammatory factors and chemokines[57]. Meanwhile,podocytes and renal tubular epithelial cells in high glucose environments can accelerate the activation of Toll-like receptors,and aggravate DN-mediated inflammation and renal fibrosis[58,59]. The neurotrophic factor hypothesis is one of the mechanisms that underly the pathogenesis of depression. BDNF is closely related to neuronal growth,apoptosis,human emotions,and cognitive function[60]. EGFRTKIs can regulate cell growth and inhibit intimal hyperplasia[61]. The core targets of these pathways are related to the active components of Dihuang (Rehmanniae Radix),and play an important role in the treatment of DN complicated with depression.

    5 Conclusion

    The active components of Dihuang (Rehmanniae Radix)maybe play a potential therapeutic role in DN complicated with depression by regulating glucose and lipid metabolism,oxidative stress,inflammatory reactions,endothelial cell apoptosis,vascular microcirculation,and nerve nourishment. Based on the complex mechanism of Dihuang (Rehmanniae Radix),the authors will conduct a follow-up study for experimental verification,such as material basis-pharmacodynamic evaluation-metabolomicspathway verification of Dihuang (Rehmanniae Radix).

    Fundings

    National Natural Science Foundation of China(81960714),and Jiangxi University of Chinese Medicine Graduate Innovation Project (JZYC21S52).

    Competing interests

    The authors declare no conflict of interest.

    猜你喜歡
    要訣證治神農(nóng)本草經(jīng)
    從《神農(nóng)本草經(jīng)》論述干姜在經(jīng)方中的應(yīng)用
    應(yīng)急救援要訣“少 快 短”
    勞動保護(2018年8期)2018-09-12 01:16:10
    中醫(yī)古籍 “乳癰”證治探析
    《神農(nóng)本草經(jīng)》中與神志相關(guān)的藥物歸類分析——胡隨瑜教授《神農(nóng)本草經(jīng)》講記(四)
    《理虛元鑒》勞嗽證治芻議
    慢性泄瀉證治體會
    從傷寒六經(jīng)論“觀其脈證,知犯何逆,隨證治之”的臨床應(yīng)用
    提升魅力有要訣
    海外英語(2013年11期)2014-02-11 03:21:02
    “四要訣”上好公開課
    摘錄《神農(nóng)本草經(jīng)讀》(二)
    欧美+日韩+精品| 在线观看人妻少妇| 综合色丁香网| 99热国产这里只有精品6| 中国美白少妇内射xxxbb| 久久午夜福利片| 久久ye,这里只有精品| 日本色播在线视频| 欧美人与善性xxx| 亚洲成人一二三区av| av天堂久久9| 精品久久久久久久久亚洲| 全区人妻精品视频| 国产探花极品一区二区| 蜜桃久久精品国产亚洲av| 亚洲四区av| 嫩草影院入口| 精品久久久久久久久av| 久久热精品热| 亚洲国产日韩一区二区| 18禁动态无遮挡网站| 国产精品女同一区二区软件| 伦理电影免费视频| av免费在线看不卡| 亚洲精品日韩在线中文字幕| 成人综合一区亚洲| 亚洲图色成人| 欧美 日韩 精品 国产| 99久国产av精品国产电影| 99九九线精品视频在线观看视频| 国产男人的电影天堂91| 国产精品偷伦视频观看了| 两个人的视频大全免费| www.av在线官网国产| 涩涩av久久男人的天堂| 久久精品国产亚洲av天美| 国产精品一二三区在线看| 毛片一级片免费看久久久久| 亚州av有码| 日韩精品有码人妻一区| 天天躁夜夜躁狠狠久久av| 国产成人精品无人区| 国产欧美亚洲国产| 男人添女人高潮全过程视频| 99热这里只有是精品50| 久久久久久久国产电影| 亚洲精品日本国产第一区| 婷婷色综合www| 人人澡人人妻人| 色婷婷av一区二区三区视频| 永久免费av网站大全| 欧美区成人在线视频| 亚洲无线观看免费| 两个人免费观看高清视频 | 亚洲一区二区三区欧美精品| 亚洲欧美成人综合另类久久久| 我的老师免费观看完整版| 亚洲av二区三区四区| 18+在线观看网站| 久久久久久人妻| 欧美精品亚洲一区二区| 国产视频首页在线观看| 国产午夜精品久久久久久一区二区三区| .国产精品久久| 人妻 亚洲 视频| 国产日韩欧美在线精品| 三上悠亚av全集在线观看 | 中文在线观看免费www的网站| 国产精品熟女久久久久浪| 国产视频首页在线观看| 日韩三级伦理在线观看| 国产成人91sexporn| 国产黄色免费在线视频| 亚洲精品亚洲一区二区| 色网站视频免费| 久久这里有精品视频免费| 久久久精品免费免费高清| 99热这里只有是精品50| 久久久久久久大尺度免费视频| 亚洲国产成人一精品久久久| 国产中年淑女户外野战色| 性色avwww在线观看| 日本爱情动作片www.在线观看| 日本猛色少妇xxxxx猛交久久| √禁漫天堂资源中文www| 久久久久久久久大av| 最新的欧美精品一区二区| 国产熟女午夜一区二区三区 | 国产av码专区亚洲av| 国产有黄有色有爽视频| 国产精品久久久久久久电影| 久久久国产精品麻豆| 欧美变态另类bdsm刘玥| 大又大粗又爽又黄少妇毛片口| 午夜影院在线不卡| 日韩一区二区三区影片| 好男人视频免费观看在线| 久久精品久久精品一区二区三区| 国产亚洲午夜精品一区二区久久| 美女国产视频在线观看| 国产男人的电影天堂91| 久久人人爽人人爽人人片va| 黄片无遮挡物在线观看| kizo精华| 成年人免费黄色播放视频 | 亚洲,欧美,日韩| 亚洲丝袜综合中文字幕| 人妻 亚洲 视频| 国产欧美日韩精品一区二区| 久久久a久久爽久久v久久| 欧美97在线视频| 大又大粗又爽又黄少妇毛片口| 国产色爽女视频免费观看| 91成人精品电影| 亚洲不卡免费看| 91成人精品电影| 久久久久久人妻| 纯流量卡能插随身wifi吗| 久久精品国产亚洲网站| 久久久久网色| 高清欧美精品videossex| 最后的刺客免费高清国语| 成人无遮挡网站| 国产老妇伦熟女老妇高清| 王馨瑶露胸无遮挡在线观看| 91在线精品国自产拍蜜月| 亚洲精品久久午夜乱码| 欧美精品国产亚洲| 国产亚洲午夜精品一区二区久久| 国产男人的电影天堂91| 久久久国产一区二区| 亚洲欧美成人综合另类久久久| 欧美国产精品一级二级三级 | 国产精品蜜桃在线观看| 熟妇人妻不卡中文字幕| 久久精品国产亚洲av天美| 国产精品伦人一区二区| 亚洲人成网站在线播| 99热这里只有是精品在线观看| 日韩 亚洲 欧美在线| 国内少妇人妻偷人精品xxx网站| 大香蕉97超碰在线| 国产精品久久久久久av不卡| 久久久久人妻精品一区果冻| 各种免费的搞黄视频| 婷婷色综合大香蕉| 免费观看a级毛片全部| 国产精品福利在线免费观看| freevideosex欧美| 男人舔奶头视频| 成人黄色视频免费在线看| 国产精品成人在线| 国产午夜精品久久久久久一区二区三区| av播播在线观看一区| 国产真实伦视频高清在线观看| 一区二区三区精品91| 亚洲av.av天堂| av又黄又爽大尺度在线免费看| 国产精品国产三级国产av玫瑰| 一边亲一边摸免费视频| 久久精品久久精品一区二区三区| 久久精品久久精品一区二区三区| 视频中文字幕在线观看| 我要看黄色一级片免费的| 久久久久精品性色| 久久精品国产亚洲av天美| av有码第一页| 99视频精品全部免费 在线| 日本-黄色视频高清免费观看| 22中文网久久字幕| freevideosex欧美| 日韩一本色道免费dvd| 日韩一本色道免费dvd| 日本午夜av视频| 成人国产麻豆网| 色婷婷av一区二区三区视频| 精品一区在线观看国产| 久久国产亚洲av麻豆专区| 最近手机中文字幕大全| 一级毛片我不卡| 热re99久久精品国产66热6| 免费黄网站久久成人精品| 精品亚洲乱码少妇综合久久| 国产日韩欧美亚洲二区| 秋霞在线观看毛片| 下体分泌物呈黄色| 久久久久久人妻| 一个人免费看片子| 亚洲av成人精品一区久久| 国产亚洲av片在线观看秒播厂| 国产精品一区二区性色av| 中文字幕亚洲精品专区| 在线亚洲精品国产二区图片欧美 | 亚洲四区av| 免费观看的影片在线观看| 色网站视频免费| 欧美3d第一页| 丝瓜视频免费看黄片| 老熟女久久久| 国产毛片在线视频| 精品酒店卫生间| av天堂中文字幕网| 熟女电影av网| 亚洲精品日韩av片在线观看| 九九久久精品国产亚洲av麻豆| 一区在线观看完整版| 九色成人免费人妻av| 欧美性感艳星| 丰满迷人的少妇在线观看| 亚洲av免费高清在线观看| 久久久久国产精品人妻一区二区| 香蕉精品网在线| 欧美97在线视频| 人妻制服诱惑在线中文字幕| 在线天堂最新版资源| 美女国产视频在线观看| videossex国产| 建设人人有责人人尽责人人享有的| 国产精品伦人一区二区| 国产爽快片一区二区三区| 少妇精品久久久久久久| av在线老鸭窝| 午夜免费男女啪啪视频观看| 日韩熟女老妇一区二区性免费视频| 91精品一卡2卡3卡4卡| 大片电影免费在线观看免费| 亚洲精品aⅴ在线观看| 久久99精品国语久久久| 97超视频在线观看视频| 高清av免费在线| 观看美女的网站| 人妻人人澡人人爽人人| 少妇 在线观看| 国产91av在线免费观看| 色94色欧美一区二区| 精品熟女少妇av免费看| 91aial.com中文字幕在线观看| 国产一区亚洲一区在线观看| 亚洲精品国产色婷婷电影| 亚洲四区av| 黑人巨大精品欧美一区二区蜜桃 | 亚洲欧美成人综合另类久久久| 国产精品一区二区在线不卡| 大片免费播放器 马上看| 日韩亚洲欧美综合| 99热这里只有是精品在线观看| 免费黄频网站在线观看国产| 日韩,欧美,国产一区二区三区| 全区人妻精品视频| 亚洲美女黄色视频免费看| 亚洲精品乱久久久久久| 狂野欧美激情性xxxx在线观看| 91久久精品国产一区二区成人| 久久精品国产亚洲网站| 国产91av在线免费观看| 精品一区二区三卡| 久久女婷五月综合色啪小说| 亚洲精品视频女| 精品熟女少妇av免费看| 视频区图区小说| 18禁在线无遮挡免费观看视频| 国产免费又黄又爽又色| 草草在线视频免费看| 天堂俺去俺来也www色官网| 男女免费视频国产| 亚洲av电影在线观看一区二区三区| 久久精品久久久久久久性| 黄色配什么色好看| 日本免费在线观看一区| 在线观看免费日韩欧美大片 | 久久人人爽人人片av| 国内少妇人妻偷人精品xxx网站| 亚洲国产日韩一区二区| 久久人妻熟女aⅴ| 看十八女毛片水多多多| 中文在线观看免费www的网站| 青春草视频在线免费观看| 免费黄网站久久成人精品| 久久久国产欧美日韩av| 国产精品麻豆人妻色哟哟久久| 国产色爽女视频免费观看| 一级爰片在线观看| 久久久久久久亚洲中文字幕| 国产在线一区二区三区精| 久久久久久久亚洲中文字幕| 免费少妇av软件| 久久这里有精品视频免费| 伊人久久精品亚洲午夜| 高清午夜精品一区二区三区| 久久热精品热| 日韩一本色道免费dvd| 高清在线视频一区二区三区| 能在线免费看毛片的网站| 国内精品宾馆在线| 亚洲人与动物交配视频| a级毛色黄片| 纯流量卡能插随身wifi吗| 久久久a久久爽久久v久久| 国产中年淑女户外野战色| 午夜激情福利司机影院| 中文字幕精品免费在线观看视频 | 又粗又硬又长又爽又黄的视频| 免费不卡的大黄色大毛片视频在线观看| 精品国产乱码久久久久久小说| 又大又黄又爽视频免费| 一级,二级,三级黄色视频| 黄片无遮挡物在线观看| 久久99一区二区三区| 男女啪啪激烈高潮av片| 日韩中字成人| 丰满迷人的少妇在线观看| 亚洲成人手机| 大香蕉97超碰在线| 国内精品宾馆在线| 在现免费观看毛片| 99久久综合免费| 丰满乱子伦码专区| 大片电影免费在线观看免费| 有码 亚洲区| 欧美日韩av久久| 18禁在线无遮挡免费观看视频| 亚洲精品国产成人久久av| 偷拍熟女少妇极品色| 国产精品久久久久久av不卡| 亚洲国产精品成人久久小说| 国产69精品久久久久777片| 色视频在线一区二区三区| 亚洲,一卡二卡三卡| av不卡在线播放| 欧美xxxx性猛交bbbb| 国产无遮挡羞羞视频在线观看| 亚洲国产成人一精品久久久| 丰满乱子伦码专区| 精品少妇久久久久久888优播| 久久精品国产鲁丝片午夜精品| 国产美女午夜福利| 香蕉精品网在线| 又爽又黄a免费视频| 最后的刺客免费高清国语| 久久久久网色| 久久精品久久久久久久性| 久久久久久久大尺度免费视频| 久久97久久精品| 夜夜骑夜夜射夜夜干| 蜜臀久久99精品久久宅男| 婷婷色综合大香蕉| 一边亲一边摸免费视频| 国产综合精华液| 亚洲精品国产av成人精品| 黄色视频在线播放观看不卡| 免费看日本二区| av又黄又爽大尺度在线免费看| 欧美 亚洲 国产 日韩一| 男人舔奶头视频| 人人妻人人澡人人爽人人夜夜| 91精品一卡2卡3卡4卡| 精品一区在线观看国产| 黄色毛片三级朝国网站 | 亚洲精品成人av观看孕妇| 国产一区亚洲一区在线观看| 美女脱内裤让男人舔精品视频| 交换朋友夫妻互换小说| 国产午夜精品久久久久久一区二区三区| 一本色道久久久久久精品综合| 日本av手机在线免费观看| av国产精品久久久久影院| 国产精品熟女久久久久浪| 日本黄色片子视频| 2018国产大陆天天弄谢| 永久免费av网站大全| 99re6热这里在线精品视频| 精品少妇久久久久久888优播| 国产精品一区二区在线不卡| 午夜老司机福利剧场| 国产亚洲一区二区精品| 男人狂女人下面高潮的视频| 特大巨黑吊av在线直播| 涩涩av久久男人的天堂| 国产精品人妻久久久久久| 国产熟女欧美一区二区| 国产黄色免费在线视频| 亚洲怡红院男人天堂| 亚洲情色 制服丝袜| 亚洲精品成人av观看孕妇| 一级毛片aaaaaa免费看小| 亚洲精品日韩在线中文字幕| 99精国产麻豆久久婷婷| 永久网站在线| 日本色播在线视频| 最近最新中文字幕免费大全7| 搡女人真爽免费视频火全软件| 中文字幕久久专区| 亚洲综合精品二区| 高清av免费在线| 一级毛片久久久久久久久女| 人人妻人人添人人爽欧美一区卜| 久久午夜福利片| 久久久久网色| 妹子高潮喷水视频| 国产精品99久久99久久久不卡 | 性色av一级| 色婷婷久久久亚洲欧美| 91精品国产九色| 日韩电影二区| 亚洲欧美日韩东京热| 另类亚洲欧美激情| 欧美最新免费一区二区三区| 国产av精品麻豆| 免费看光身美女| 久久女婷五月综合色啪小说| 我的老师免费观看完整版| 国产在线免费精品| 寂寞人妻少妇视频99o| 国产成人精品婷婷| 精品久久久久久久久亚洲| 免费大片黄手机在线观看| 日本免费在线观看一区| 尾随美女入室| 欧美老熟妇乱子伦牲交| 嫩草影院新地址| 欧美xxxx性猛交bbbb| 精品人妻熟女毛片av久久网站| av福利片在线观看| 哪个播放器可以免费观看大片| 最新的欧美精品一区二区| 我的女老师完整版在线观看| 亚洲欧美成人综合另类久久久| 国产精品成人在线| 国产男女内射视频| 老司机影院成人| 久久久久久久大尺度免费视频| 亚洲婷婷狠狠爱综合网| 日韩免费高清中文字幕av| 99热这里只有是精品50| av视频免费观看在线观看| 黄色欧美视频在线观看| 国产午夜精品一二区理论片| 青春草视频在线免费观看| 黄色视频在线播放观看不卡| 日韩一区二区视频免费看| 欧美日韩综合久久久久久| 国产精品麻豆人妻色哟哟久久| 九九爱精品视频在线观看| 在线观看av片永久免费下载| 久久久午夜欧美精品| 99热全是精品| 午夜免费鲁丝| 好男人视频免费观看在线| 日本av免费视频播放| 亚洲国产日韩一区二区| 两个人免费观看高清视频 | 日韩人妻高清精品专区| 久久久久久久久久成人| 亚洲丝袜综合中文字幕| freevideosex欧美| 亚洲欧美精品自产自拍| 2022亚洲国产成人精品| 26uuu在线亚洲综合色| 大片电影免费在线观看免费| 国产精品欧美亚洲77777| 777米奇影视久久| 国产精品成人在线| 久久免费观看电影| 国产亚洲最大av| 3wmmmm亚洲av在线观看| 美女国产视频在线观看| 99热国产这里只有精品6| .国产精品久久| 99热这里只有是精品50| 久久久亚洲精品成人影院| 国产国拍精品亚洲av在线观看| 国产精品嫩草影院av在线观看| 色视频在线一区二区三区| 国产片特级美女逼逼视频| 亚洲国产欧美日韩在线播放 | 我的老师免费观看完整版| 色网站视频免费| 免费人成在线观看视频色| 精品国产一区二区三区久久久樱花| 国产伦精品一区二区三区四那| 99久久综合免费| 国产精品三级大全| 亚洲色图综合在线观看| 97精品久久久久久久久久精品| 久久99蜜桃精品久久| 日韩av在线免费看完整版不卡| 丰满人妻一区二区三区视频av| av国产精品久久久久影院| 夜夜骑夜夜射夜夜干| 精品亚洲成a人片在线观看| 在线观看av片永久免费下载| 久久 成人 亚洲| 国产精品99久久99久久久不卡 | 精品久久久精品久久久| 九九爱精品视频在线观看| 大陆偷拍与自拍| 最近的中文字幕免费完整| 久久99一区二区三区| 国产深夜福利视频在线观看| 国产一区有黄有色的免费视频| 永久网站在线| 久久影院123| 嘟嘟电影网在线观看| 精品少妇内射三级| 亚洲av男天堂| 大片免费播放器 马上看| 久久午夜综合久久蜜桃| 水蜜桃什么品种好| 亚洲国产精品一区三区| 国语对白做爰xxxⅹ性视频网站| tube8黄色片| 蜜桃久久精品国产亚洲av| 在线观看一区二区三区激情| 国产精品伦人一区二区| 观看免费一级毛片| 中文字幕人妻丝袜制服| 欧美少妇被猛烈插入视频| 乱人伦中国视频| 久久毛片免费看一区二区三区| av有码第一页| 免费av中文字幕在线| 国产一区二区三区av在线| 精品少妇久久久久久888优播| 国产精品偷伦视频观看了| 夜夜看夜夜爽夜夜摸| 亚洲,欧美,日韩| 亚洲丝袜综合中文字幕| 亚洲内射少妇av| 麻豆成人午夜福利视频| 26uuu在线亚洲综合色| 久久久久久久久久人人人人人人| 又爽又黄a免费视频| av国产久精品久网站免费入址| 国产日韩欧美在线精品| 久久久久久久亚洲中文字幕| av在线老鸭窝| 永久免费av网站大全| 免费看光身美女| 亚洲av二区三区四区| 久久99精品国语久久久| 亚洲国产精品专区欧美| 国产一区二区三区av在线| 在线看a的网站| av网站免费在线观看视频| av福利片在线| 内射极品少妇av片p| 一区二区av电影网| 菩萨蛮人人尽说江南好唐韦庄| 国内少妇人妻偷人精品xxx网站| 永久免费av网站大全| 国产欧美另类精品又又久久亚洲欧美| av卡一久久| 欧美高清成人免费视频www| 亚洲精品,欧美精品| 青青草视频在线视频观看| 狠狠精品人妻久久久久久综合| 日韩欧美一区视频在线观看 | 欧美日韩综合久久久久久| 交换朋友夫妻互换小说| 亚洲精品乱码久久久久久按摩| 精品熟女少妇av免费看| 久久午夜综合久久蜜桃| 亚洲精品456在线播放app| 国产伦理片在线播放av一区| 两个人的视频大全免费| 中文字幕人妻丝袜制服| av天堂久久9| 国产在视频线精品| 亚洲精品久久久久久婷婷小说| 欧美日韩视频精品一区| 精品国产乱码久久久久久小说| 国产日韩一区二区三区精品不卡 | 免费在线观看成人毛片| 国产91av在线免费观看| 性高湖久久久久久久久免费观看| 美女中出高潮动态图| 性色av一级| 另类亚洲欧美激情| 日韩av在线免费看完整版不卡| 久久久午夜欧美精品| 中国国产av一级| 水蜜桃什么品种好| 午夜福利,免费看| 观看av在线不卡| 日韩亚洲欧美综合| 亚洲精品国产成人久久av| 国产精品久久久久久久久免| 国产成人精品婷婷| 五月玫瑰六月丁香| 精品人妻偷拍中文字幕| 亚洲精品国产色婷婷电影| 在线观看人妻少妇| 黄片无遮挡物在线观看| 亚洲精品日本国产第一区| 亚洲欧美成人精品一区二区| 国模一区二区三区四区视频| 国产一级毛片在线| 久久久久久久大尺度免费视频| 99热这里只有是精品50| 久久毛片免费看一区二区三区| 91精品一卡2卡3卡4卡| 日韩一区二区三区影片| 日韩人妻高清精品专区| 全区人妻精品视频| 精品久久久久久久久av| 成年人午夜在线观看视频| 免费看不卡的av| 国产精品一区二区性色av| 各种免费的搞黄视频| 国产成人91sexporn| 在线观看免费高清a一片| 中文字幕亚洲精品专区| 亚洲av日韩在线播放| 人人妻人人澡人人看| 久久综合国产亚洲精品|