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Original Article
Network pharmacology-based study of the protective mechanism of conciliatory anti-allergic decoction on asthma
Xiaobo Xuana,1, Ziyan Suna,1, Chenhuan Yub, Jian Chena, Mei Chena, Qili Wanga, Lan Lia,
Corresponding author
lilan99hz@163.com

Corresponding author.
a The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310006, China
b Experimental Animal centre, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, 310013, China
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">The ingredient-target network of CAD&#46; The blue node represents the target&#44; and diamond nodes with different colors represent active ingredients from different herbs of CAD&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Asthma is a common chronic respiratory disease especially endemic among children&#46; According to the epidemiological survey by the World Health Organization in 2015&#44; there were approximately 334 million people &#40;4&#46;9&#37; of the world&#39;s population&#41; suffering from asthma&#44; and 250&#44;000 people die of asthma prematurely each year&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> Recent years have witnessed a rising tendency of the morbidity and mortality of asthma worldwide&#44; which poses a serious threat to human health and medical resources&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">2&#44;3</span></a> Studies have shown that many risk factors&#44; including genetic susceptibility&#44; allergens&#44; air pollution&#44; climate change&#44; and respiratory virus infection are closely related to asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> The pathogenesis of asthma is complex and has not been clearly elucidated&#44; but the airway inflammation&#44; accompanied by airway hyperresponsiveness and airway remodeling&#44; are well-acknowledged characteristics of asthma&#46; In the allergic reaction of asthma&#44; allergens or pathogens that enter through body surfaces &#40;e&#46;g&#46;&#44; the skin or lungs&#41; are phagocytized by antigen-presenting cells&#44; such as dendritic cells&#44; which come to mature with the help of different cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> Th2 cells can produce pro-inflammatory cytokines&#44; including IL4&#44; IL5&#44; and IL13 to exert their effects on many other cell types&#44; including B cells&#44; eosinophils&#44; mast cells&#44; epithelial cells&#44; and airway goblet cells&#44; and can also induce immunoglobulin E &#40;IgE&#41; production by B cells&#44; resulting in the regulation of inflammation in asthma&#46; Some drugs such as glucocorticoids&#44; &#946;2 receptor agonists&#44; anti-cholinergic drugs&#44; theophylline and leukotriene receptor antagonists&#44; have also been approved for asthma treatment&#59; however&#44; the side effects and acquired resistance limit their clinical application&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">6&#8211;8</span></a> Thus&#44; developing more safe and effective drugs for asthma therapy remains urgent and crucial&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Over thousands of years&#44; traditional Chinese medicine has provided excellent therapeutic effects for asthma treatment in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a> Traditional Chinese medicine possesses the advantages of &#8220;simple&#44; convenient&#44; economic&#44; effective and individualized therapy&#8221;&#44; which is in good accordance with the concept of modern medicine&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> Conciliatory anti-allergic decoction &#40;CAD&#41;&#44; a modified decoction comprising 10 herbs originating from the classical formula Xiao Chai Hu Tang by the well-known Chinese physician Zhang Zhongjing&#44; has been widely used for asthma treatment in hospitals&#46; Our former clinical research revealed that CAD can effectively reduce the frequency of asthma attacks and respiratory tract infection in children with asthma&#44; enhance the immune function and anti-allergic ability of respiratory mucosa&#44; and alleviate airway inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> However&#44; the therapeutic mechanism of CAD in asthma still remains unclear&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Our current study was designed to explore the anti-asthma mechanisms of CAD&#46; Network pharmacology study was applied in this work since it can provide a novel strategy to uncover the bioactive ingredients and underlying mechanisms of CAD from a systemic and holistic perspective&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> With the approach of network pharmacology&#44; the active ingredients and related targets relevant to asthma were screened out&#44; an ingredients-targets network and a protein&#8211;protein interaction &#40;PPI&#41; network were constructed&#44; gene functional enrichment analysis&#44; and molecular docking of the targets were conducted to clarify the pharmacological mechanisms of the targets and ingredients in CAD&#46; Furthermore&#44; animal experiments were also performed to validate the pharmacological mechanisms of CAD in an asthma mouse model&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Screening of the active ingredients of CAD</span><p id="par0020" class="elsevierStylePara elsevierViewall">The CAD is composed of ten traditional Chinese herbs&#44; including <span class="elsevierStyleItalic">Radix Bupleuri</span> &#40;Chinese pinyin name Chaihu&#41;&#44; <span class="elsevierStyleItalic">Scutellariae Radix</span> &#40;Chinese pinyin name Huangqin&#41;&#44; <span class="elsevierStyleItalic">Pseudostellariae Radix</span> &#40;Chinese pinyin name Taizishen&#41;&#44; <span class="elsevierStyleItalic">Arum Ternatum Thunb&#46;</span> &#40;Chinese pinyin name Banxia&#41;&#44; <span class="elsevierStyleItalic">Radix Salviae</span> &#40;Chinese pinyin name Danshen&#41;&#44; <span class="elsevierStyleItalic">Ephedra Herba</span> &#40;Chinese pinyin name Mahuang&#41;&#44; <span class="elsevierStyleItalic">Fritillariae Thunbrgii Bulbus</span> &#40;Chinese pinyin name Zhebeimu&#41;&#44; <span class="elsevierStyleItalic">Farfarae Flos</span> &#40;Chinese pinyin name Kuandonghua&#41;&#44; <span class="elsevierStyleItalic">Cicadae Periostracum</span> &#40;Chinese pinyin name Chantui&#41;&#44; and <span class="elsevierStyleItalic">Licorice</span> &#40;Chinese pinyin name Gancao&#41;&#46; The ingredient information of these ten herbs was searched from the TCMSP database &#40;<a href="http://ibts.hkbu.edu.hk/LSP/tcmsp.php">http&#58;&#47;&#47;ibts&#46;hkbu&#46;edu&#46;hk&#47;LSP&#47;tcmsp&#46;php</a>&#41;&#46; Data on the molecule name&#44; 2D structure&#44; Pubchem ID&#44; pharmacological and molecular properties of the ingredients could all be obtained from that database&#46; The ADME system parameters were used as the criteria to select the candidate active ingredients in each herb with oral bioavailability &#40;OB&#41; &#8805;30&#44; drug-likeness &#40;DL&#41; &#8805;0&#46;18 and half-life &#40;HL&#41; &#8805;4 based on the suggestion by the TCMSP database&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Prediction and screening of candidate targets</span><p id="par0025" class="elsevierStylePara elsevierViewall">The targets linked to the active ingredients in CAD were searched and predicted from the TCMSP database and STITCH database &#40;<a href="http://stitch.embl.de/">http&#58;&#47;&#47;stitch&#46;embl&#46;de&#47;</a>&#44; ver&#46; 5&#46;0&#41; with the &#8216;Homo sapiens&#8217; species setting&#46; The targets related to asthma were identified from the TTD &#40;<a href="http://bidd.nus.edu.sg/group/cjttd/">http&#58;&#47;&#47;bidd&#46;nus&#46;edu&#46;sg&#47;group&#47;cjttd&#47;</a>&#41;&#44; OMIM &#40;<a href="http://www.omim.org/">http&#58;&#47;&#47;www&#46;omim&#46;org&#47;</a>&#41;&#44; and PharmGKB &#40;<a href="https://www.pharmgkb.org/">https&#58;&#47;&#47;www&#46;pharmgkb&#46;org&#47;</a>&#41; databases with &#8216;asthma&#8217; as the input keyword&#46; The target gene information&#44; including IDs and names&#44; was confirmed and standardized using UniProt &#40;<a href="http://www.uniprot.org/">http&#58;&#47;&#47;www&#46;uniprot&#46;org&#47;</a>&#41; and duplicate targets were removed to obtain drug-related targets and disease-related targets&#44; respectively&#46; The Venny diagram online tool &#40;<a href="http://bioinfogp.cnb.csic.es/tools/venny/">http&#58;&#47;&#47;bioinfogp&#46;cnb&#46;csic&#46;es&#47;tools&#47;venny&#47;</a>&#41; was employed to screen the overlapped targets between ingredients and diseases&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protein&#8211;protein interaction &#40;PPI&#41; and gene functional enrichment analysis of the targets</span><p id="par0030" class="elsevierStylePara elsevierViewall">The STRING database &#40;<a href="https://string-db.org/">https&#58;&#47;&#47;string-db&#46;org&#47;</a>&#41; was used to explore the interactions&#44; and the hub gene targets among the candidate targets were screened with the &#8216;Homo sapiens&#8217; species setting&#46; The interaction data obtained from STRING were imported into Cytoscape software to construct the PPI network&#44; and the topological properties of the network were analyzed with the plugin tool &#8220;Network analyzer&#8221;&#46; For the candidate targets&#44; the Cytoscape software plugin tool Clue GO was applied to perform the biological process and KEGG pathway enrichment analysis with terms&#44; and <span class="elsevierStyleItalic">P</span> value &#60;0&#46;05 was set as the significance criterion for the terms&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Molecular docking</span><p id="par0035" class="elsevierStylePara elsevierViewall">The crystal structure of the target protein was obtained from the Protein Data Bank &#40;<a href="http://www.rcsb.org/">http&#58;&#47;&#47;www&#46;rcsb&#46;org&#47;</a>&#41;&#44; and the 2D structure of the compound was downloaded from the PubChem database &#40;<a href="https://pubchem.ncbi.nlm.nih.gov/">https&#58;&#47;&#47;pubchem&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;</a>&#41;&#46; The docking exercise was conducted with the systemDock online tool &#40;<a href="http://systemsdock.unit.oist.jp/iddp/home/index">http&#58;&#47;&#47;systemsdock&#46;unit&#46;oist&#46;jp&#47;iddp&#47;home&#47;index</a>&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Network construction</span><p id="par0040" class="elsevierStylePara elsevierViewall">The ingredient-target network and target-related pathway network were constructed by the Cytoscape software and analyzed with the plugin tool &#8220;Network analyzer&#8221; to obtain the topological properties of the network&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Pharmacological verification</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Animals</span><p id="par0045" class="elsevierStylePara elsevierViewall">BALB&#47;c mice weighting 18&#8211;20<span class="elsevierStyleHsp" style=""></span>g were purchased from the Centre of Experimental Animals at the Shanghai SLAC Laboratory Animal Co&#46; Ltd&#46; &#40;Shanghai&#44; China&#41;&#46; The animal experiments were approved by the Ethics Committee of Zhejiang Traditional Chinese Medicine University &#40;Hangzhou&#44; China&#41;&#44; and all animal procedures were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals&#46; The mice were housed for a week at standard room temperature &#40;20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>&#176;C&#41; and relative humidity &#40;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#37;&#41; under a 12<span class="elsevierStyleHsp" style=""></span>h light&#47;dark cycle&#44; with free access to water and food&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Experimental design and drug administration</span><p id="par0050" class="elsevierStylePara elsevierViewall">A total of 60 BALB&#47;c mice were randomly divided into six groups &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; as follows&#58; control group&#59; ovalbumin &#40;OVA&#41; group&#59; OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>low CAD group &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#59; OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>medium CAD group &#40;20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#59; OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>high CAD group &#40;40<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#59; and OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>dexamethasone &#40;Dex&#41; group &#40;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#46; The OVA-induced asthma mouse model was established as previously published with slight modifications&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> Briefly&#44; the mice were sensitized by intraperitoneal injection of 2<span class="elsevierStyleHsp" style=""></span>mg&#47;ml OVA&#47;Al&#40;OH&#41;<span class="elsevierStyleInf">3</span> gel in a total volume of 0&#46;5<span class="elsevierStyleHsp" style=""></span>ml or saline in the control group on days 1 and intraperitoneal injection of 0&#46;2<span class="elsevierStyleHsp" style=""></span>ml on day 13 to enhance sensitization&#46; From day 23&#44; the mice were then challenged by intranasal inhalations with OVA &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#41; or PBS aerosol challenges for 30<span class="elsevierStyleHsp" style=""></span>min three times a week for 8 weeks&#46; CAD &#40;10&#44; 20&#44; 40<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; or Dex was administered intragastrically 1<span class="elsevierStyleHsp" style=""></span>h prior to OVA challenge&#46; The control and OVA groups received PBS on the same schedule with the same volume&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">ELISA assay</span><p id="par0055" class="elsevierStylePara elsevierViewall">Twenty-four hours after the last OVA challenge&#44; the mice were anesthetized with an inhalation of diethyl ether and sacrificed by exsanguination&#46; Bronchoalveolar lavage fluid &#40;BALF&#41; was obtained by intratracheal instillation&#44; and the lungs were lavaged three times with 0&#46;8<span class="elsevierStyleHsp" style=""></span>ml of sterile PBS&#46; The BALF from each sample was centrifuged&#44; and supernatants were stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C for subsequent analysis&#46; The levels of TNF-&#945;&#44; IL4&#44; IL5&#44; IL10&#44; and IL13 in BALF were measured by ELISA kits according to the manufacturer&#39;s instructions&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">HE staining and AB-PAS staining</span><p id="par0060" class="elsevierStylePara elsevierViewall">Lung tissues from each group were collected and fixed in 10&#37; buffered formalin for 24<span class="elsevierStyleHsp" style=""></span>h&#44; dehydrated&#44; embedded in paraffin&#44; and then cut into approximately 3-&#956;m tissue sections&#46; Subsequently&#44; the tissue sections were stained with hematoxylin and eosin &#40;H&#38;E&#41; to evaluate the degree of peribronchial and perivascular inflammation&#44; and stained with Alcian blue-periodic acid Schiff &#40;AB-PAS&#41; to identify goblet cells in the epithelium and measure mucus production&#44; respectively&#46; The degree of peribronchial inflammation was scored in a blinded manner according to the following criteria&#58; 0&#44; no cells&#59; 1&#44; a few cells&#59; 2&#44; a ring of cells one cell layer deep&#59; 3&#44; a ring of cells two to four cells deep&#59; and 4&#44; a ring of cells of more than four cells deep&#46; The degree of mucus production and goblet cell hyperplasia in the airway epithelium were also quantified in a blinded manner using a five-point scoring system&#58; 0&#44; no goblet cells&#59; 1&#44; 25&#37;&#59; 2&#44; 25&#8211;50&#37;&#59; 3&#44; 50&#8211;75&#37;&#59; and 4&#44; 75&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">The experimental data are presented as the mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation &#40;SD&#41;&#46; Differences between groups were analyzed using one-way analysis of variance &#40;ANOVA&#41; followed by Bonferroni&#39;s test&#46; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered to be significant&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Active ingredients and candidate targets in CAD</span><p id="par0070" class="elsevierStylePara elsevierViewall">A total of 77 active ingredients were screened from the TCMSP database according to the ADME criteria&#44; with six compounds in <span class="elsevierStyleItalic">Radix Bupleuri</span>&#44; 13 compounds in <span class="elsevierStyleItalic">Scutellariae Radix</span>&#44; three compounds in <span class="elsevierStyleItalic">Pseudostellariae Radix</span>&#44; five compounds in <span class="elsevierStyleItalic">Arum Ternatum Thunb&#46;</span>&#44; 27 compounds <span class="elsevierStyleItalic">Radix Salviae</span>&#44; nine compounds in <span class="elsevierStyleItalic">Ephedra Herba</span>&#44; one compound in <span class="elsevierStyleItalic">Fritillariae Thunbrgii Bulbus</span>&#44; four compounds in <span class="elsevierStyleItalic">Farfarae Flos</span>&#44; two compounds in <span class="elsevierStyleItalic">Cicadae Periostracum</span>&#44; and 27 compounds in <span class="elsevierStyleItalic">Licorice</span>&#46; Although the ingredients in CAD are complex&#44; some compounds were repeated among the herbs&#44; like quercetin&#44; kaempferol&#44; stigmasterol&#44; beta-sitosterol&#44; luteolin&#44; acacetin&#44; naringenin&#44; and baicalin&#44; which exist in more than two herbs of CAD&#46; Based on the DrugBank and STITCH databases&#44; a total of 392 proteins were linked to the 77 identified ingredients&#44; thus forming an ingredient-related target network &#40;see <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Based on the TTD&#44; OMIM&#44; and PharmGKB databases&#44; a total of 345 proteins were identified to be related to asthma in the asthma target network&#46; According to the Venny diagram&#44; 48 proteins were found to be overlapped in the two networks and thus concluded as CAD ingredient-related targets for asthma treatment&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Ingredient-target network of CAD for asthma treatment</span><p id="par0075" class="elsevierStylePara elsevierViewall">The ingredient-target network of CAD for asthma treatment was visualized by Cytoscape and is shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46; There were 147 nodes and 666 edges in the network&#46; 48 blue elliptic nodes represent 48 targets&#44; and diamond nodes with different kinds of colors represent ingredients in different herbs&#46; The six compounds in <span class="elsevierStyleItalic">Radix Bupleuri</span> targeted 33 proteins in the network&#44; 13 compounds in <span class="elsevierStyleItalic">Scutellariae Radix</span> targeted 26 proteins in the network&#44; three compounds in <span class="elsevierStyleItalic">Pseudostellariae Radix</span> targeted 21 proteins in the network&#44; five compounds in <span class="elsevierStyleItalic">Arum Ternatum Thunb&#46;</span> targeted 23 proteins in the network&#44; 27 compounds in <span class="elsevierStyleItalic">Radix Salviae</span> targeted 29 proteins in the network&#44; nine compounds in <span class="elsevierStyleItalic">Ephedra Herba</span> targeted 33 proteins in the network&#44; one compound in <span class="elsevierStyleItalic">Fritillariae Thunbrgii Bulbus</span> targeted nine proteins in the network&#44; four compounds in <span class="elsevierStyleItalic">Farfarae Flos</span> targeted 28 proteins in the network&#44; two compounds in <span class="elsevierStyleItalic">Cicadae Periostracum</span> targeted six proteins in the network&#44; and 27 compounds in <span class="elsevierStyleItalic">Licorice</span> targeted 33 proteins in the network&#46; Quercetin had the highest degree with 20 proteins targeted&#44; followed by kaempferol with 12 targets&#44; wogonin with 10 targets&#44; stigmasterol&#44; luteolin&#44; beta-sitosterol and acacetin with nine targets&#44; etc&#46; The ingredient-target network has properties of complex ingredients&#44; multiple targets&#44; and close interactions between ingredients and targets&#44; thus forming a network for asthma treatment&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Gene Ontology enrichment analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">With the Cytoscape software plugin tool Clue GO&#44; gene functional enrichment analysis was performed &#40;see <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>a&#41;&#46; Each node represents a biological process term&#44; and node size represents term enrichment significance&#46; Different colors represent different clusters&#46; Gene biological process analysis showed that these 48 targets were enriched in 225 significant terms of biological process&#44; and these biological process terms also interact closely with each other and are assigned in several clusters&#44; thus forming a complex and compact network&#46; The top 20 terms with their respective <span class="elsevierStyleItalic">P</span> values are also presented&#46; These targets were mainly enriched in biological processes including cytokine production involved in immune response&#44; the positive regulation of inflammatory response&#44; regulation of IL12 production&#44; IL8 production&#44; the positive regulation of receptor signaling pathway via JAK-STAT&#44; the regulation of TNF superfamily cytokine production&#44; endothelial cell apoptotic process&#44; nitric oxide metabolic&#47;biosynthetic process&#44; etc&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Potential target-related pathway analysis</span><p id="par0085" class="elsevierStylePara elsevierViewall">KEGG pathway analysis of the targets was also conducted&#44; and the results are shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>b&#46; KEGG pathway network showed that these targets were significantly enriched in 40 pathway terms&#44; which were assigned into five clusters and interacted closely with each other&#46; The significant pathways that these targets were enriched in mainly include the asthma pathway&#44; IL17 signaling pathway&#44; T cell receptor signaling pathway&#44; TNF signaling pathway&#44; Th1 and Th2 cell differentiation&#44; JAK-STAT signaling pathway&#44; HIF-1 signaling pathway&#44; NF-&#954;B signaling pathway&#44; etc&#46; The pathway analysis results also demonstrated that each target was involved in several pathways&#44; and accordingly&#44; each pathway was enriched with several targets&#44; thus forming a multiple target&#8211;multiple pathway network that directly or indirectly affects the occurrence and progression of asthma&#46; Among these pathways&#44; the asthma pathway was directly related to asthma&#44; and five out of the 48 targets &#40;TNF&#44; IL4&#44; IL5&#44; IL10&#44; IL13&#41; were involved in this pathway with a term <span class="elsevierStyleItalic">P</span> value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;16E&#8722;06 &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>b&#41;&#44; indicating that CAD might interact with these targets&#44; thus directly influencing the asthma pathway to play a protective role for asthma treatment&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">PPI network analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">The PPI network is presented in <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>a&#44; there were 48 nodes and 285 edges in the network with a medium degree of six for each node&#46; The network topological properties of the targets&#44; such as degree&#44; and closeness centrality were also analyzed according to the &#8220;Network analyzer&#8221; tool in Cytoscape&#46; The node size and color of each target were positively related to the node degree&#46; TNF &#40;degree<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>29&#41;&#44; PTGS2 &#40;degree<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>29&#41;&#44; IL10 &#40;degree<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26&#41;&#44; TLR4 &#40;degree<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#41;&#44; IL4 &#40;degree<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41;&#44; CCL2 &#40;degree<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>23&#41;&#44; IFNG &#40;degree<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>21&#41;&#44; and TLR2 &#40;degree<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>21&#41; were selected as the important targets from the PPI network with degree &#62;20&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Molecular docking of the ingredients binding to asthma pathway related targets</span><p id="par0095" class="elsevierStylePara elsevierViewall">Since the KEGG pathway analysis revealed that CAD&#39;s ingredient-related targets were involved in the asthma pathway&#44; we used molecular docking analysis to validate the binding property of the asthma-related targets TNF&#44; IL4&#44; IL5&#44; IL10&#44; IL13 and the linked active ingredients with docking score&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>b&#44; TNF native ligand had a docking score of 4&#46;79&#44; while stigmasterol&#44; kaempferol&#44; quercetin&#44; luteolin&#44; and cryptotanshinone in CAD that targeted TNF all had higher scores than that of the native ligand&#44; which suggested that these active ingredients possess ideal interactions with TNF&#46; The docking results of all five targets are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; It can be concluded that the majority of the ingredients have a higher score than the native ligand for the corresponding targets&#44; which indicates that the ingredients in CAD can closely interact with the predicted targets and can thus influence asthma-related pathways&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Effects of CAD on the histological changes in OVA-induced asthmatic mice lungs</span><p id="par0100" class="elsevierStylePara elsevierViewall">To evaluate the therapeutic effect of CAD&#44; histological studies of the lung tissues in different groups were performed&#46; Compared with the control group&#44; it can be observed that there was abundant inflammatory cell invasion into the peribronchial and perivascular areas in OVA-induced asthma mouse lung tissues stained by HE &#40;see <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>a&#41;&#46; When CAD or Dex was administered at different doses&#44; the inflammatory cell invasion was markedly attenuated&#44; especially in the high CAD group and Dex group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; AB-PAS staining was used to evaluate the presence of goblet cell hyperplasia and mucus secretion&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>b&#44; the overexpression of goblet cell hyperplasia and mucus oversecretion can be observed in the bronchial airways of OVA group lung tissues&#46; CAD in high doses &#40;40<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; and Dex can efficiently alleviate goblet cell hyperplasia and mucus secretion compared with the asthma model group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Effect of CAD on TNF-&#945;&#44; IL4&#44; IL5&#44; IL10&#44; and IL13 levels in BALF</span><p id="par0105" class="elsevierStylePara elsevierViewall">The levels of TNF-&#945;&#44; IL4&#44; IL5&#44; IL10&#44; and IL13 in BALF were detected with ELISA and the results are shown in <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>c&#46; Compared to that in the normal control group&#44; the levels of TNF-&#945;&#44; IL4&#44; IL5&#44; IL10&#44; and IL13 in the OVA-induced asthma group were significantly elevated &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; After administration of CAD at different doses&#44; the levels of these pro-inflammatory cytokines decreased to varying degrees&#46; For TNF-&#945;&#44; CAD &#40;40<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; or Dex could significantly reduce the level of TNF-&#945; in BALF &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#44; the same trend was also observed for IL4&#46; For IL5 and IL13&#44; the administration of 20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg CAD reduced the levels in BALF &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; and with 40<span class="elsevierStyleHsp" style=""></span>mg&#47;kg CAD or Dex&#44; the levels decreased significantly &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; For IL10&#44; the changes in level among the experiment groups were not significant&#46;</p></span></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">Asthma is a chronic inflammatory disease of the airway with high morbidity and mortality globally&#46; Numerous traditional Chinese medicines have excellent therapeutic effects for asthma&#44; including CAD&#46; Compared with the well-applied treatments in the clinic&#44; the pharmacological mechanisms of CAD have not been researched clearly&#46; In the present study&#44; we applied network pharmacology to explore the anti-asthma mechanisms of CAD&#46; A total of 77 active ingredients and 48 asthma-related targets of CAD were identified from the databases&#46; Ingredient-target network and PPI network revealed that these ingredients and targets interact closely with each other&#46; Pathway enrichment analysis also showed that these targets were directly or indirectly involved in asthma-related pathways&#46; The molecular docking exercise showed that the majority of the active ingredients have a higher binding score than the native ligand binding to the corresponding targets&#46; In the OVA-induced asthma mouse model&#44; CAD administration efficiently attenuated airway inflammation and mucus production&#44; and the expression of the hub targets were also decreased with CAD treatment&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">CAD comprises 10 herbs&#44; Radix Bupleuri&#44; Scutellariae Radix&#44; Pseudostellariae Radix&#44; Arum Ternatum Thunb&#46;&#44; Radix Salviae&#44; Ephedra Herba&#44; Fritillariae Thunbrgii Bulbus&#44; Farfarae Flos&#44; Cicadae Periostracum&#44; and Licorice&#46; Most of these herbs have been proven to have anti-inflammatory and anti-allergic activities&#44; due to the complex active compounds in these herbs&#46; Quercetin&#44; one the most important ingredients&#44; was found in four herbs of CAD with 20 targets&#59; it was reported to regulate Th1&#47;Th2 balance in asthma&#44; reduce the level of IL4&#44; and increase the level of IFN-&#947;&#44; and restrain antigen-specific IgE antibody formation&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a> Kaempferol&#44; identified in four out of the ten herbs of CAD&#44; was reported to suppress eosinophil infiltration and airway inflammation in airway epithelial cells and in mice with allergic asthma by disturbing NF-&#954;B signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> Baicalin&#44; screened from Radix Bupleuri&#44; Arum Ternatum Thunb&#46;&#44; and Radix Salviae&#44; was reported to inhibit airway remodeling in asthmatic mice by decreasing the expression of TGF-&#946;1&#44; IL13&#44; and VEGF and inhibiting the activation of the extracellular signal-regulated kinase pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> Stigmasterol in CAD was also reported with significant anti-asthmatic properties and had suppressive effects on the key features of allergen-induced asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a> Wogonin identified from Scutellariae Radix attenuated OVA-induced airway inflammation in a mouse model of asthma via the suppression of IL4&#47;STAT6 signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a> These studies demonstrated that the major active ingredients identified from CAD were efficient for asthma treatment and accordingly confirmed the therapeutic effect of CAD&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The pathway enrichment analysis in the present study revealed that TNF&#44; IL4&#44; IL5&#44; IL10&#44; IL13 were directly enriched in the asthma pathway&#46; And several targets including TNF&#44; PTGS2&#44; IL10&#44; TLR4&#44; IL4&#44; CCL2&#44; IFN-&#947;&#44; and TLR2 were also regarded as important targets according to their topological properties in the PPI network&#46; TNF-&#945; and IFN-&#947; belong to Th1 cell cytokines&#44; IL4&#44; IL5&#44; and IL13 belong to Th2 cell cytokines&#44; and the imbalance of Th1&#47;Th2 cells is related to the pathogenesis of asthma&#46; TNF-&#945;&#44; the most studied pro-inflammatory cytokine of the TNF family&#44; is produced by several pro-inflammatory cells &#40;mainly macrophages&#44; but also monocytes&#44; dendritic cells&#44; B-cells&#44; CD4&#43; cells&#44; neutrophils&#44; mast cells and eosinophils&#41; and is known to be crucial in the pathogenesis of asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> Its elevated expression can be involved in the development and progression of airway pathology in asthma&#44; and has recently been highlighted as potentially important for asthma&#46; The development of neutralizing biological agents against TNF-&#945; is also a therapeutic strategy for asthma with improvement in lung function&#44; airway hyper-responsiveness and quality-of-life in patients&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> The administration of IFN-&#947; has the ability to elevate airway hyper-responsiveness via the up-regulation of neurokinin A&#47;neurokinin-2 receptor signaling in severe asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The Th2 cytokines including IL4&#44; IL5&#44; and IL13 are critical in the pathogenesis of asthma&#44; since they contribute to hallmarks of this disease&#44; including airway inflammation&#44; airway eosinophilia&#44; increased mucus production&#44; goblet cell hyperplasia&#44; production of allergen-specific IgE and development of airway hyper-responsiveness&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a> IL4 plays a key role in inducing T cell polarization into Th2 cells&#44; and the subsequent generation of IL4&#44; IL5&#44; and IL13 by Th2 cells&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> IL5 can induce eosinophilia in lung tissues during asthma via the production of eotaxins to activate the recruitment of eosinophils to the lung tissues&#46; Similar to IL4 and sharing the same signaling pathways&#44; IL13 and its receptor IL13R&#945;1 can be detected in eosinophils&#44; B cells&#44; macrophages&#44; smooth muscle cells&#44; lung epithelial cells&#44; airway goblet cells&#44; and endothelial cells&#46; Antagonists targeting at IL4&#44; IL5&#44; and IL13 have also been developed as a therapeutic strategy in asthma&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">24&#44;25</span></a> The active ingredients&#44; including quercetin&#44; kaempferol&#44; stigmasterol&#44; luteolin&#44; and cryptotanshinone in CAD&#44; were identified to target TNF&#44; IL4&#44; IL5&#44; IL10&#44; and IL13&#44; and the molecular docking also proved the ideal binding score between these cytokines and active ingredients&#46; In the asthma mouse model of our study&#44; elevated levels of these Th1 and Th2 cytokines were also detected&#44; and the CAD-treated group showed a significant decrease in cytokines expression in a dose-dependent manner&#46; It can be indicated that CAD efficiently targets Th1 and Th2 cell cytokines&#44; maintains Th1&#47;Th2 balance&#44; and inhibits the asthma pathway&#44; thus exerting curative effects on asthma&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In the pathogenesis of asthma&#44; except for the central role of Th2 cells cytokines &#40;IL4&#44; IL5&#44; IL10&#44; IL13&#41;&#44; or Th1 cells cytokines &#40;TNF-&#945;&#44; IFN-&#947;&#41;&#44; the signaling pathways involved with various targets are also vitally important&#46; The NF-&#954;B signaling pathway is one of the most important cellular signal transduction pathways that is essential for apoptosis&#44; tumorigenesis&#44; inflammation&#44; viral infections&#44; and various autoimmune diseases&#46; The expression of the NF-&#954;B signaling pathway can be abnormally activated in asthma&#44; thus regulating many downstream targets and the secretion of pro-inflammatory cytokines to accelerate the progression of asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a> Studies have found that airway inflammation can be alleviated via inhibition of the NF-&#954;B pathway in asthma&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">27&#44;28</span></a> The differentiation of Th1 and Th2 cells from naive T cells occurs primarily via the JAK&#47;STAT signaling pathway&#46; IFN-&#947;-induced JAK&#47;STAT signaling pathway is reported to be responsible for glucocorticoid insensitive in airway epithelial cells&#44; and this steroid responsiveness of insensitive can be restored by the transfection of cells with siRNA-STAT1&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In conclusion&#44; the protective effect and underlying mechanism of CAD on asthma was explored in the current study&#46; The multiple active ingredients in CAD&#44; including quercetin&#44; kaempferol&#44; stigmasterol&#44; luteolin&#44; cryptotanshinone&#44; beta-sitosterol&#44; acacetin&#44; naringenin&#44; baicalin and related targets for asthma&#44; mainly including TNF&#44; IL4&#44; IL5&#44; IL10&#44; IL13&#44; and IFN-&#947;&#44; were identified with ideal binding scores by network pharmacology&#46; KEGG pathway analysis revealed that these targets were involved in the asthma pathway&#44; Th1 and Th2 cell differentiation&#44; and signaling pathways correlated with asthma &#40;NF-&#954;B signaling pathway&#44; IL17 signaling pathway&#44; T cell receptor signaling pathway&#44; TNF signaling pathway&#44; JAK-STAT signaling pathway&#44; HIF-1 signaling pathway&#44; etc&#46;&#41;&#46; Animal experiments also proved the therapeutic role of CAD in asthma by attenuating airway inflammation and mucus production and inhibiting the expression of Th1 and Th2 cytokines&#46; Our study looked forward to providing a new perspective for developing traditional Chinese medicine on asthma therapy&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Funding</span><p id="par0140" class="elsevierStylePara elsevierViewall">This work was funded by Zhejiang Provincia Natural Science Foundation of China &#40;grant number LY15H270006&#41;&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span></span>"
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          "identificador" => "xres1387877"
          "titulo" => "Abstract"
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            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Background"
            ]
            1 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Methods"
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            2 => array:2 [
              "identificador" => "abst0015"
              "titulo" => "Results"
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            3 => array:2 [
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              "titulo" => "Conclusion"
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        1 => array:2 [
          "identificador" => "xpalclavsec1273431"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        3 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Materials and methods"
          "secciones" => array:7 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Screening of the active ingredients of CAD"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Prediction and screening of candidate targets"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Protein&#8211;protein interaction &#40;PPI&#41; and gene functional enrichment analysis of the targets"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Molecular docking"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Network construction"
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            5 => array:3 [
              "identificador" => "sec0040"
              "titulo" => "Pharmacological verification"
              "secciones" => array:4 [
                0 => array:2 [
                  "identificador" => "sec0045"
                  "titulo" => "Animals"
                ]
                1 => array:2 [
                  "identificador" => "sec0050"
                  "titulo" => "Experimental design and drug administration"
                ]
                2 => array:2 [
                  "identificador" => "sec0055"
                  "titulo" => "ELISA assay"
                ]
                3 => array:2 [
                  "identificador" => "sec0060"
                  "titulo" => "HE staining and AB-PAS staining"
                ]
              ]
            ]
            6 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Statistical analysis"
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        4 => array:3 [
          "identificador" => "sec0070"
          "titulo" => "Results"
          "secciones" => array:8 [
            0 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Active ingredients and candidate targets in CAD"
            ]
            1 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Ingredient-target network of CAD for asthma treatment"
            ]
            2 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Gene Ontology enrichment analysis"
            ]
            3 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Potential target-related pathway analysis"
            ]
            4 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "PPI network analysis"
            ]
            5 => array:2 [
              "identificador" => "sec0100"
              "titulo" => "Molecular docking of the ingredients binding to asthma pathway related targets"
            ]
            6 => array:2 [
              "identificador" => "sec0105"
              "titulo" => "Effects of CAD on the histological changes in OVA-induced asthmatic mice lungs"
            ]
            7 => array:2 [
              "identificador" => "sec0110"
              "titulo" => "Effect of CAD on TNF-&#945;&#44; IL4&#44; IL5&#44; IL10&#44; and IL13 levels in BALF"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "sec0115"
          "titulo" => "Discussion"
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        6 => array:2 [
          "identificador" => "sec0120"
          "titulo" => "Funding"
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        7 => array:2 [
          "identificador" => "sec0125"
          "titulo" => "Conflict of interest"
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        8 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2019-08-20"
    "fechaAceptado" => "2019-12-23"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1273431"
          "palabras" => array:6 [
            0 => "Asthma"
            1 => "Conciliatory anti-allergic decoction"
            2 => "Active ingredients"
            3 => "Targets"
            4 => "Pro-inflammatory cytokines"
            5 => "Pathways"
          ]
        ]
      ]
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    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">This study aimed to explore the underlying anti-asthma pharmacological mechanisms of conciliatory anti-allergic decoction &#40;CAD&#41; with a network pharmacology approach&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Traditional Chinese medicine related databases were utilized to screen the active ingredients of CAD&#46; Targets of CAD for asthma treatment were also identified based on related databases&#46; The protein-protein interaction network&#44; biological function and KEGG pathway enrichment analysis&#44; and molecular docking of the targets were performed&#46; Furthermore&#44; an asthma mouse model experiment involving HE staining&#44; AB-PAS staining&#44; and ELISA was also performed to assess the anti-asthma effect of CAD&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">There were 77 active ingredients in CAD&#44; including quercetin&#44; kaempferol&#44; stigmasterol&#44; luteolin&#44; cryptotanshinone&#44; beta-sitosterol&#44; acacetin&#44; naringenin&#44; baicalin&#44; and 48 related targets for asthma treatment&#44; mainly including TNF&#44; IL4&#44; IL5&#44; IL10&#44; IL13 and IFN-&#947;&#44; were identified with ideal molecular docking binding scores by network pharmacology analysis&#46; KEGG pathway analysis revealed that these targets were directly involved in the asthma pathway&#44; Th1 and Th2 cell differentiation&#44; and signaling pathways correlated with asthma &#40;NF-&#954;B&#44; IL17&#44; T cell receptor&#44; TNF&#44; JAK-STAT signaling pathways&#44; etc&#46;&#41;&#46; Animal experiments also confirmed that CAD could attenuate inflammatory cell invasion&#44; goblet cell hyperplasia and mucus secretion&#46; The levels of the major targets TNF-&#945;&#44; IL4&#44; IL5&#44; and IL13 can also be regulated by CAD in an asthma mouse model&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The anti-asthma mechanism of CAD possibly stemmed from the active ingredients targeting asthma-related targets&#44; which are involved in the asthma pathway and signaling pathways to exhibit therapeutic effects&#46;</p></span>"
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            "titulo" => "Background"
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            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
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            "titulo" => "Conclusion"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Xiaobo Xuan and Ziyan Sun contributed equally to this work&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Candidate target screening in CAD for asthma treatment&#46; CAD&#58; conciliatory anti-allergic decoction&#46;</p>"
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        "etiqueta" => "Figure 2"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">The ingredient-target network of CAD&#46; The blue node represents the target&#44; and diamond nodes with different colors represent active ingredients from different herbs of CAD&#46;</p>"
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        "etiqueta" => "Figure 3"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Gene functional enrichment analysis of the targets&#46; &#40;a&#41; Gene Ontology enrichment analysis&#46; In Gene Ontology enrichment network&#44; each node represents a biological process term&#44; with different colors assigned to different clusters&#46; The top 20 significant terms of biological processes were also presented as a bubble diagram&#46; &#40;b&#41; Target-related KEGG pathway analysis&#46; KEGG pathway network and the enriched pathways bubble diagram of the targets were presented&#59; these targets were enriched in the asthma pathway&#44; and the genes with red color in the asthma pathway represent CAD related targets&#46; The figure of the asthma pathway was downloaded from the KEGG database &#40;<span class="elsevierStyleInterRef" id="intr0005" href="https://www.genome.jp/kegg/">https&#58;&#47;&#47;www&#46;genome&#46;jp&#47;kegg&#47;</span>&#41;&#46;</p>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">&#40;a&#41; PPI network of CAD related targets&#46; The node size and color of each target were positively related to the node degree&#46; &#40;b&#41; Molecular docking exercise of ingredients binding to TNF&#46;</p>"
        ]
      ]
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        "etiqueta" => "Figure 5"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Effect of CAD on OVA-induced asthmatic mice&#46; &#40;a&#41; Effect of CAD on airway inflammation of asthma mice &#40;HE staining&#44; &#215;400&#41;&#59; &#40;b&#41; effect of CAD on mucus hypersecretion of asthma mice &#40;AB-PAS staining&#44; &#215;400&#41;&#59; &#40;c&#41; effect of CAD on TNF-&#945;&#44; IL4&#44; IL5&#44; IL10&#44; and IL13 levels in mice BALF&#46; The data presented are the means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#44; &#42;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 or &#42;&#42;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01 vs&#46; the OVA group&#46; BALF&#58; bronchoalveolar lavage fluid&#46;</p>"
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                  \t\t\t\t">Native ligand&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Stigmasterol&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Kaempferol&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Quercetin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Luteolin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Cryptotanshinone&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Formononetin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Acacetin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#46;08&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Molecular docking of the TNF&#44; IL4&#44; IL5&#44; IL10&#44; IL13 and linked active ingredients&#46;</p>"
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                      "titulo" => "The epidemiology of noncommunicable respiratory disease in sub-Saharan Africa&#44; the Middle East&#44; and North Africa"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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Article information
ISSN: 03010546
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos