A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications
Identifieur interne : 000B22 ( Pmc/Corpus ); précédent : 000B21; suivant : 000B23A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications
Auteurs : Bochuan Yuan ; Rui Yang ; Yongsheng Ma ; Shan Zhou ; Xiaodong Zhang ; Ying LiuSource :
- Pharmaceutical Biology [ 1388-0209 ] ; 2016.
Abstract
Url:
DOI: 10.1080/13880209.2016.1262433
PubMed: 27951737
PubMed Central: 6130612
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PMC:6130612Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications</title><author><name sortKey="Yuan, Bochuan" sort="Yuan, Bochuan" uniqKey="Yuan B" first="Bochuan" last="Yuan">Bochuan Yuan</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Yang, Rui" sort="Yang, Rui" uniqKey="Yang R" first="Rui" last="Yang">Rui Yang</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Ma, Yongsheng" sort="Ma, Yongsheng" uniqKey="Ma Y" first="Yongsheng" last="Ma">Yongsheng Ma</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Zhou, Shan" sort="Zhou, Shan" uniqKey="Zhou S" first="Shan" last="Zhou">Shan Zhou</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Xiaodong" sort="Zhang, Xiaodong" uniqKey="Zhang X" first="Xiaodong" last="Zhang">Xiaodong Zhang</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Liu, Ying" sort="Liu, Ying" uniqKey="Liu Y" first="Ying" last="Liu">Ying Liu</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27951737</idno><idno type="pmc">6130612</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130612</idno><idno type="RBID">PMC:6130612</idno><idno type="doi">10.1080/13880209.2016.1262433</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000B22</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B22</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications</title><author><name sortKey="Yuan, Bochuan" sort="Yuan, Bochuan" uniqKey="Yuan B" first="Bochuan" last="Yuan">Bochuan Yuan</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Yang, Rui" sort="Yang, Rui" uniqKey="Yang R" first="Rui" last="Yang">Rui Yang</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Ma, Yongsheng" sort="Ma, Yongsheng" uniqKey="Ma Y" first="Yongsheng" last="Ma">Yongsheng Ma</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Zhou, Shan" sort="Zhou, Shan" uniqKey="Zhou S" first="Shan" last="Zhou">Shan Zhou</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Xiaodong" sort="Zhang, Xiaodong" uniqKey="Zhang X" first="Xiaodong" last="Zhang">Xiaodong Zhang</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author><author><name sortKey="Liu, Ying" sort="Liu, Ying" uniqKey="Liu Y" first="Ying" last="Liu">Ying Liu</name><affiliation><nlm:aff id="AF0001"></nlm:aff></affiliation></author></analytic><series><title level="j">Pharmaceutical Biology</title><idno type="ISSN">1388-0209</idno><idno type="eISSN">1744-5116</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p><bold>Context:</bold> Radix Bupleuri has been used in traditional Chinese medicine for over 2000 years with functions of relieving exterior syndrome, clearing heat, regulating liver-<italic>qi</italic>, and lifting yang-<italic>qi</italic>. More natural active compounds, especially saikosaponins, have been isolated from Radix Bupleuri, which possess various valuable pharmacological activities.</p><p><bold>Objective:</bold> To summarize the current knowledge on pharmacological activities, mechanisms and applications of extracts and saikosaponins isolated from Radix Bupleuri, and obtain new insights for further research and development of Radix Bupleuri.</p><p><bold>Methods:</bold> PubMed, Web of Science, Science Direct, Research Gate, Academic Journals and Google Scholar were used as information sources through the inclusion of the search terms ‘Radix Bupleuri’, ‘<italic>Bupleurum</italic>’, ‘saikosaponins’, ‘Radix Bupleuri preparation’, and their combinations, mainly from the year 2008 to 2016 without language restriction. Clinical preparations containing Radix Bupleuri were collected from official website of China Food and Drug Administration (CFDA).</p><p><bold>Results and conclusion:</bold> 296 papers were searched and 128 papers were reviewed. A broad spectrum of <italic>in vitro</italic> and <italic>in vivo</italic> research has proved that Radix Bupleuri extracts, saikosaponin a, saikosaponin d, saikosaponin c, and saikosaponin b<sub>2</sub>, exhibit evident anti-inflammatory, antitumor, antiviral, anti-allergic, immunoregulation, and neuroregulation activities mainly through NF-<italic>κ</italic>B, MAPK or other pathways. 15 clinical preparations approved by CFDA remarkably broaden the application of Radix Bupleuri. The main side effect of Radix Bupleuri is liver damage when the dosage is excess, which indicates that the maximum tolerated dose is critical for clinical use of Radix Bupleuri extract and purified compounds.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ashour, Ml" uniqKey="Ashour M">ML Ashour</name></author><author><name sortKey="El Readi, M" uniqKey="El Readi M">M El-Readi</name></author><author><name sortKey="Youns, M" uniqKey="Youns M">M Youns</name></author><author><name sortKey="Mulyaningsih, S" uniqKey="Mulyaningsih S">S Mulyaningsih</name></author><author><name sortKey="Sporer, F" uniqKey="Sporer F">F Sporer</name></author><author><name sortKey="Efferth, T" uniqKey="Efferth T">T Efferth</name></author><author><name sortKey="Wink, M" uniqKey="Wink M">M. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Pharm Biol</journal-id><journal-id journal-id-type="iso-abbrev">Pharm Biol</journal-id><journal-id journal-id-type="publisher-id">IPHB</journal-id><journal-id journal-id-type="publisher-id">iphb20</journal-id><journal-title-group><journal-title>Pharmaceutical Biology</journal-title></journal-title-group><issn pub-type="ppub">1388-0209</issn><issn pub-type="epub">1744-5116</issn><publisher><publisher-name>Taylor & Francis</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27951737</article-id><article-id pub-id-type="pmc">6130612</article-id><article-id pub-id-type="doi">10.1080/13880209.2016.1262433</article-id><article-id pub-id-type="publisher-id">1262433</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Article</subject></subj-group></article-categories><title-group><article-title>A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications</article-title><alt-title alt-title-type="running-authors">B. Yuan et al.</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Yuan</surname><given-names>Bochuan</given-names></name><xref ref-type="aff" rid="AF0001"></xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Rui</given-names></name><xref ref-type="aff" rid="AF0001"></xref></contrib><contrib contrib-type="author"><name><surname>Ma</surname><given-names>Yongsheng</given-names></name><xref ref-type="aff" rid="AF0001"></xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Shan</given-names></name><xref ref-type="aff" rid="AF0001"></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Xiaodong</given-names></name><xref ref-type="aff" rid="AF0001"></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Ying</given-names></name><xref ref-type="aff" rid="AF0001"></xref><xref ref-type="corresp" rid="AN0001"></xref></contrib><aff id="AF0001"><institution>School of Chinese Pharmacy, Beijing University of Chinese Medicine</institution>, Beijing,<country>China</country></aff></contrib-group><author-notes><corresp id="AN0001">CONTACT <addr-line>Ying Liu</addr-line><email>liuyliwd@sina.com</email><institution>School of Chinese Pharmacy, Beijing University of Chinese Medicine</institution>, <addr-line>Wangjing Zhonghuan South Street, Chaoyang District</addr-line>, Beijing100102, <country>China</country></corresp></author-notes><pub-date pub-type="collection"><year>2017</year></pub-date><pub-date pub-type="epub"><day>12</day><month>12</month><year>2016</year></pub-date><volume>55</volume><issue>1</issue><fpage seq="81">620</fpage><lpage>635</lpage><history><date date-type="received"><day>13</day><month>6</month><year>2016</year></date><date date-type="rev-recd"><day>08</day><month>9</month><year>2016</year></date><date date-type="accepted"><day>15</day><month>11</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>The Author(s).</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="iphb-55-1262433.pdf"></self-uri><abstract><title>Abstract</title><p><bold>Context:</bold> Radix Bupleuri has been used in traditional Chinese medicine for over 2000 years with functions of relieving exterior syndrome, clearing heat, regulating liver-<italic>qi</italic>, and lifting yang-<italic>qi</italic>. More natural active compounds, especially saikosaponins, have been isolated from Radix Bupleuri, which possess various valuable pharmacological activities.</p><p><bold>Objective:</bold> To summarize the current knowledge on pharmacological activities, mechanisms and applications of extracts and saikosaponins isolated from Radix Bupleuri, and obtain new insights for further research and development of Radix Bupleuri.</p><p><bold>Methods:</bold> PubMed, Web of Science, Science Direct, Research Gate, Academic Journals and Google Scholar were used as information sources through the inclusion of the search terms ‘Radix Bupleuri’, ‘<italic>Bupleurum</italic>’, ‘saikosaponins’, ‘Radix Bupleuri preparation’, and their combinations, mainly from the year 2008 to 2016 without language restriction. Clinical preparations containing Radix Bupleuri were collected from official website of China Food and Drug Administration (CFDA).</p><p><bold>Results and conclusion:</bold> 296 papers were searched and 128 papers were reviewed. A broad spectrum of <italic>in vitro</italic> and <italic>in vivo</italic> research has proved that Radix Bupleuri extracts, saikosaponin a, saikosaponin d, saikosaponin c, and saikosaponin b<sub>2</sub>, exhibit evident anti-inflammatory, antitumor, antiviral, anti-allergic, immunoregulation, and neuroregulation activities mainly through NF-<italic>κ</italic>B, MAPK or other pathways. 15 clinical preparations approved by CFDA remarkably broaden the application of Radix Bupleuri. The main side effect of Radix Bupleuri is liver damage when the dosage is excess, which indicates that the maximum tolerated dose is critical for clinical use of Radix Bupleuri extract and purified compounds.</p></abstract><kwd-group kwd-group-type="author"><title>Keywords</title><kwd>Radix Bupleuri</kwd><kwd>saikosaponins</kwd><kwd>anti-inflammatory</kwd><kwd>antitumor</kwd><kwd>neuroregulation</kwd></kwd-group><counts><page-count count="16"></page-count><word-count count="11862"></word-count></counts></article-meta></front><body><sec id="s0001"><title>Introduction</title><p>With a 2000-year medicinal history, Radix Bupleuri (<italic>Chai Hu</italic> in Chinese) is believed to be one of the most important herbal medicines in China. The earliest record about Radix Bupleuri in China appeared in <italic>Shen Nong Ben Cao Jing</italic>, the first Chinese medical book, since then, Radix Bupleuri has been widely used in traditional Chinese medicine (TCM) for its effects of relieving exterior syndrome, clearing heat, regulating the liver-<italic>qi</italic>, and lifting yang-<italic>qi</italic> (Sen <xref rid="CIT0076" ref-type="bibr">1959</xref>). It has been used in many traditional Chinese prescriptions, such as <italic>Xiao Chai Hu Tang</italic> and <italic>Chai Hu Shu Gan Yin</italic> to treat cold and liver diseases (Chen et al. <xref rid="CIT0013" ref-type="bibr">2011</xref>). The roots are usually the medicinal parts of Radix Bupleuri, and which is often processed into pieces for easy use (<xref ref-type="fig" rid="F0001">Figure 1</xref>).</p><fig id="F0001" orientation="portrait" position="float"><label>Figure 1.</label><caption><p>Radix Bupleuri (a) and its pieces (b).</p></caption><graphic content-type="color" xlink:href="IPHB_A_1262433_F0001_C"></graphic></fig><p><italic>Bupleurum chinense</italic> DC. (Apiaceae) and <italic>Bupleurum scorzonerifolium</italic> Willd. are defined as the original plants of Radix Bupleuri in <italic>Chinese Pharmacopeia</italic> (National Pharmacopoeia Committee <xref rid="CIT0072" ref-type="bibr">2010</xref>). In fact, many other <italic>Bupleurum</italic> species are also used as Radix Bupleuri in East Asia, such as <italic>Bupleurum falcatum</italic> L., which is officially listed in <italic>Japanese Pharmacopeia</italic> (Saiko in Japanese) (Japanese Pharmacopoeia Editorial Board <xref rid="CIT0037" ref-type="bibr">2011</xref>), and <italic>Bupleurum yinchowense</italic> Shan and Li, which is recorded in some provincial <italic>Pharmacopeia</italic> of China (The Inner Mongolia Autonomous Region Health Department <xref rid="CIT0080" ref-type="bibr">1988</xref>; Food and Drug Administration of Gansu Province <xref rid="CIT0023" ref-type="bibr">2008</xref>). These <italic>Bupleurum</italic> medicinal plants are widely distributed in the northern hemisphere (Judd <xref rid="CIT0039" ref-type="bibr">2008</xref>), and also commonly used in Eurasia and North Africa for their medicinal properties (Mabberley <xref rid="CIT0069" ref-type="bibr">2008</xref>). As shown in <xref ref-type="fig" rid="F0002">Figure 2</xref>, they are perennial herbs with compound umbels, yellowish or rarely purplish bisexual flowers, containing five stamens, cremocarps, and simple, long, slender leaves (<xref ref-type="fig" rid="F0002">Figure 2</xref>).</p><fig id="F0002" orientation="portrait" position="float"><label>Figure 2.</label><caption><p><italic>Bupleurum chinense</italic> DC. (a) Shows the compound umbels and simple, long, slender leaves, (b) shows the yellowish bisexual flowers of compound umbels.</p></caption><graphic content-type="color" xlink:href="IPHB_A_1262433_F0002_C"></graphic></fig><p>With the development of modern pharmacology, many valuable and important activities of Radix Bupleuri have been discovered, such as anti-inflammatory (Xie et al. <xref rid="CIT0104" ref-type="bibr">2012</xref>), antitumor (Liu & Li <xref rid="CIT0062" ref-type="bibr">2014</xref>), antidepressant (Jin et al. <xref rid="CIT0038" ref-type="bibr">2013</xref>), antiviral (Chiang et al. <xref rid="CIT0018" ref-type="bibr">2003</xref>), hepatoprotection (Wang et al. <xref rid="CIT0086" ref-type="bibr">2013a</xref>), immunoregulation (Ying et al. <xref rid="CIT0110" ref-type="bibr">2014</xref>), and neuromodulation activities (Zhou et al. <xref rid="CIT0123" ref-type="bibr">2014</xref>). All of these potent effects are due to its various secondary metabolites, especially saikosaponins, the content of which is up to 7% of the total dry weight of Radix Bupleuri roots (Ashour & Wink <xref rid="CIT0003" ref-type="bibr">2011</xref>). To date, over 100 glycosylated oleanane-type saponins have been isolated and identified from Radix Bupleuri (Pistelli et al. <xref rid="CIT0075" ref-type="bibr">1993</xref>; Ebata et al. <xref rid="CIT0022" ref-type="bibr">1996</xref>), and some of them have been demonstrated possessing bioactive properties both <italic>in vitro</italic> and <italic>in vivo</italic>. Therefore, reviewing and summarizing the pharmacological activities and mechanisms of saikosaponins from Radix Bupleuri is meaningful and important to obtain new insights for further research and development of Radix Bupleuri. In addition, since extracts are the main source of Chinese patent medicines containing Radix Bupleuri, their pharmacological properties and mechanisms are also summarized. Moreover, the applications and toxicity studies are discussed to provide a basis for further studies concerning the safety and efficacy of Radix Bupleuri.</p><p>In this paper, six main databases, PubMed, Web of Science, Science Direct, Research Gate, Academic Journals, and Google Scholar were used as information sources through the inclusion of the search terms ‘Radix Bupleuri’, ‘<italic>Bupleurum</italic>’, ‘saikosaponins’, ‘Radix Bupleuri preparation’, and their combinations, mainly from the year 2008 to 2016 without language restriction. As a result, we searched 296 papers and a total of 128 references were included in the present work.</p></sec><sec id="s0002"><title>Purified saikosaponins from Radix Bupleuri</title><p>In recent years, over 100 different triterpenoid saponins have been isolated from Radix Bupleuri, among them saikosaponin a (SSa), saikosaponin d (SSd), saikosaponin c (SSc) and saikosaponin b<sub>2</sub> (SSb<sub>2</sub>) (<xref ref-type="fig" rid="F0003">Figure 3</xref>) are believed to be responsible for the most pharmacological activites of Radix Bupleuri (Liu et al. <xref rid="CIT0061" ref-type="bibr">2002</xref>; Huang et al. <xref rid="CIT0033" ref-type="bibr">2013</xref>). Saikosaponins are oleanane type triterpenoid saponins and divided into seven types according to different aglycones. SSa, SSd and SSc are epoxy-ether saikosaponins (type I), while SSb<sub>2</sub>, with a different aglycone, is heterocyclic diene saikosaponin (type II) (Lin et al. <xref rid="CIT0057" ref-type="bibr">2013</xref>).</p><fig id="F0003" orientation="portrait" position="float"><label>Figure 3.</label><caption><p>The structures of SSa, SSd, SSc and SSb<sub>2</sub>.</p></caption><graphic content-type="black-white" xlink:href="IPHB_A_1262433_F0003_B"></graphic></fig></sec><sec id="s0003"><title>SSa</title><p>SSa, one of the most important active saikosaponins in Radix Bupleuri (Liang et al. <xref rid="CIT0055" ref-type="bibr">2014</xref>), plays a significant role in anti-inflammatory (Wu et al. <xref rid="CIT0100" ref-type="bibr">2008</xref>, <xref rid="CIT0101" ref-type="bibr">2010</xref>; Han et al. <xref rid="CIT0025" ref-type="bibr">2011</xref>; Lu et al. <xref rid="CIT0065" ref-type="bibr">2012b</xref>; Chen et al. <xref rid="CIT0008" ref-type="bibr">2013b</xref>; Wang et al. <xref rid="CIT0086" ref-type="bibr">2013b</xref>; Zhu et al. <xref rid="CIT0124" ref-type="bibr">2013</xref>; Fu et al. <xref rid="CIT0024" ref-type="bibr">2015</xref>; Kim et al. <xref rid="CIT0043" ref-type="bibr">2015</xref>; Zhao et al. <xref rid="CIT0117" ref-type="bibr">2015a</xref>; Zhou et al. <xref rid="CIT0121" ref-type="bibr">2015</xref>), antitumor (Tsai et al. <xref rid="CIT0082" ref-type="bibr">2002</xref>; Wang et al. <xref rid="CIT0089" ref-type="bibr">2010a</xref>, <xref rid="CIT0085" ref-type="bibr">2010b</xref>), antiviral (Cheng et al. <xref rid="CIT0015" ref-type="bibr">2006</xref>; Chen et al. <xref rid="CIT0007" ref-type="bibr">2015</xref>), neuromodulation (Yu et al. <xref rid="CIT0114" ref-type="bibr">2012</xref>; Xie et al. <xref rid="CIT0106" ref-type="bibr">2013</xref>; Yoon et al. <xref rid="CIT0111" ref-type="bibr">2012</xref>, <xref rid="CIT0112" ref-type="bibr">2013</xref>; Zhou et al. <xref rid="CIT0123" ref-type="bibr">2014</xref>), and immunoregulation (Sun et al. <xref rid="CIT0079" ref-type="bibr">2009</xref>) activities. The various pharmacological activities, mechanisms, models and applications of SSa are given in <xref rid="t0001" ref-type="table">Table 1</xref>.</p><table-wrap id="t0001" orientation="portrait" position="float"><label>Table 1.</label><caption><p>The various pharmacological activities, mechanisms, models, and applications of SSa.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col></colgroup><thead><tr><th align="left">Pharmacologicalactivities of SSa</th><th align="center">Tissue</th><th align="center">Models/cells</th><th align="center"><italic>In vivo</italic>/<italic>vitro</italic></th><th align="center">Mechanisms</th><th align="center">Applications</th><th align="center">References</th></tr></thead><tbody valign="top"><tr><td align="left">Anti-inflammatory activity</td><td align="left">Adipocytes</td><td align="left">3T3-L1</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa inhibits the expression of inflammatory associated genes and is a potent inhibitor of NF-<italic>κ</italic>B activation.</td><td align="left">Obesity-associated inflammation</td><td align="left">(Kim et al. <xref ref-type="bibr" rid="CIT0043">2015</xref>)</td></tr><tr><td align="left"> </td><td align="left">Ileum</td><td align="left">Male Wistar rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSa suppresses the production of TNF-<italic>α</italic> and IL-6 and inhibits the nucleotide-binding oligomerization domain 2 (NOD2)/NF-<italic>κ</italic>B signalling pathway.</td><td align="left">Sepsis</td><td align="left">(Zhao et al. <xref ref-type="bibr" rid="CIT0117">2015a</xref>)</td></tr><tr><td align="left"> </td><td align="left">Liver</td><td align="left">LX-2</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa down-regulates BMP-4 expression and inhibits hepatic stellate cell activation.</td><td align="left">Liver fibrosis</td><td align="left">(Wang et al. <xref ref-type="bibr" rid="CIT0086">2013b</xref>)</td></tr><tr><td align="left"> </td><td align="left">Macrophages</td><td align="left">RAW 264.7</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa regulates inflammatory mediators and suppresses the MAPK and NF-<italic>κ</italic>B signalling pathways.</td><td align="left">Lipopolysaccharide (LPS) -induced inflammation</td><td align="left">(Zhu et al. <xref ref-type="bibr" rid="CIT0124">2013</xref>)</td></tr><tr><td align="left"> </td><td align="left">Macrophages</td><td align="left">RAW264.7</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa inhibits receptor activator of the nuclear factor-<italic>κ</italic>Bligand (RANKL)-induced I<italic>κ</italic>B<italic>α</italic> phosphorylation, p65phosphorylation and NF-κB luciferase activity</td><td align="left">Osteoporosis</td><td align="left">(Zhou et al. <xref ref-type="bibr" rid="CIT0121">2015</xref>)</td></tr><tr><td align="left"> </td><td align="left">Vascular tissue</td><td align="left">HUVECs</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa dose-dependently inhibits the production of ROS,TNF-<italic>α</italic>, IL-8, COX-2 and iNOS in LPS-stimulated HUVECs.</td><td align="left">Oxidative damage</td><td align="left">(Fu et al. <xref ref-type="bibr" rid="CIT0024">2015</xref>)</td></tr><tr><td align="left"> </td><td align="left">Liver</td><td align="left">HSC-T6</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa decreases the expressions of ERK1/2, PDGFR, TGF-<italic>β</italic>1R, <italic>α</italic>-smooth muscle actin, and connective tissue growth factor to inhibit proliferation and activation of HSCs.</td><td align="left">Liver inflammation and fibrogenesis</td><td align="left">(Chen et al. <xref ref-type="bibr" rid="CIT0008">2013b</xref>)</td></tr><tr><td align="left"> </td><td align="left">Macrophages</td><td align="left">RAW264.7</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa inhibits the activation of NF-<italic>κ</italic>B, iNOS, COX-2 and pro-inflammatory cytokines TNF-<italic>α</italic> and IL-6.</td><td align="left">LPS-induced inflammation</td><td align="left">(Lu et al. <xref ref-type="bibr" rid="CIT0065">2012a</xref>)</td></tr><tr><td align="left"> </td><td align="left">Inflammatory tissue</td><td align="left">HMC-1</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa decreases the expression of IL-6, IL-1β and TNF-<italic>α</italic> and suppresses NF-<italic>κ</italic>B signal pathway.</td><td align="left">Anti-inflammation</td><td align="left">(Han et al. <xref ref-type="bibr" rid="CIT0025">2011</xref>)</td></tr><tr><td align="left"> </td><td align="left">Liver</td><td align="left">Sprague-Dawley rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSa inhibits the expression of hepatic proinflammatory cytokines and NF-<italic>κ</italic>B signal pathway and increases the expression of anti-inflammatory cytokine IL-10.</td><td align="left">Inhibition of liver injury</td><td align="left">(Wu et al. <xref ref-type="bibr" rid="CIT0100">2008</xref>, <xref ref-type="bibr" rid="CIT0101">2010</xref>)</td></tr><tr><td align="left"> </td><td align="left">Human monocytic leukemia cells</td><td align="left">THP-1</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa inhibits oxLDL-induced activation of AKT and NF-kappaB, assembly of NLRP3 inflammasome and production of pro-inflammatory cytokines.</td><td align="left">Atherosclerosis</td><td align="left">(He et al. <xref ref-type="bibr" rid="CIT0027">2016</xref>)</td></tr><tr><td align="left">Neuroregulation</td><td align="left">Hippocampal tissue</td><td align="left">Sprague-Dawley rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSa inhibits NMDA receptor current and persistent sodium current.</td><td align="left">Epilepsy</td><td align="left">(Yu et al. <xref ref-type="bibr" rid="CIT0114">2012</xref>)</td></tr><tr><td align="left"> </td><td align="left">CA1 neurons</td><td align="left">Sprague-Dawley rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSa exerts selectively enhancing effects on I A.</td><td align="left">Epilepsy</td><td align="left">(Xie et al. <xref ref-type="bibr" rid="CIT0106">2013</xref>)</td></tr><tr><td align="left"> </td><td align="left">Spinal cord tissues</td><td align="left">Chronic constriction injury rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSa inhibits the activation of p38 MAPK and NF-<italic>κ</italic>B signalling pathways in spinal cord.</td><td align="left">Chronic constriction injury</td><td align="left">(Zhou et al. <xref ref-type="bibr" rid="CIT0123">2014</xref>)</td></tr><tr><td align="left"> </td><td align="left">Hippocampus</td><td align="left">Sprague-Dawley rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSa attenuates cocaine-reinforced behaviour throughactivation of GABA(B) receptors.</td><td align="left">Morphine-reinforced behaviour</td><td align="left">(Yoon et al. <xref ref-type="bibr" rid="CIT0111">2012</xref>, <xref ref-type="bibr" rid="CIT0112">2013</xref>)</td></tr><tr><td align="left"> </td><td align="left">Nervous tissue</td><td align="left">Sprague-Dawley rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSa counteracts the inflammatory response and neurological function deficits via an anti-inflammatory response and inhibition of the MAPK signalling pathway.</td><td align="left">Nerve injury</td><td align="left">(Mao et al. <xref ref-type="bibr" rid="CIT0127">2016</xref>)</td></tr><tr><td align="left"> </td><td align="left">Nervous tissue</td><td align="left">Sprague-Dawley rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSa inhibits this addiction by regulating GABA(B) receptor system.</td><td align="left">Drug addiction</td><td align="left">(Maccioni et al. <xref ref-type="bibr" rid="CIT0126">2016</xref>)</td></tr><tr><td align="left">Antitumor activity</td><td align="left">Different cancer cells</td><td align="left">A549, SKOV3, HeLa and Siha</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa sensitizes cancer cells to cisplatin through ROS -mediated apoptosis.</td><td align="left">Cancer cell cytotoxicity</td><td align="left">(Wang et al. <xref ref-type="bibr" rid="CIT0089">2010a</xref>)</td></tr><tr><td align="left"> </td><td align="left">Glioma</td><td align="left">C6 glioma cells</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa enhances the enzymatic activities of GS and CNP.</td><td align="left">C6 glioma cells proliferation</td><td align="left">(Tsai et al. <xref ref-type="bibr" rid="CIT0082">2002</xref>)</td></tr><tr><td align="left">Antiviral activity</td><td align="left">Human fetal lung fibroblasts</td><td align="left">Human coronavirus 229E</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa intervenes in the early stage of viral replication, such as absorption and penetration.</td><td align="left">Coronavirus infection</td><td align="left">(Cheng et al. <xref ref-type="bibr" rid="CIT0015">2006</xref>)</td></tr><tr><td align="left"> </td><td align="left">Lung tissue</td><td align="left">Influenza A virus infected A549</td><td align="left"><italic>In vitro</italic></td><td align="left">SSa attenuates viral replication, aberrant pro-inflammatory cytokine production and lung histopathology.</td><td align="left">Pathological influenza virus infections</td><td align="left">(Chen et al. <xref ref-type="bibr" rid="CIT0007">2015</xref>)</td></tr><tr><td align="left">Immunoregulation</td><td align="left">Lymphoid tissue</td><td align="left">Sprague-Dawley rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSa inhibits the proliferation and activation of T cells and causes the G0/G1 arrest as well as the induction of apoptosis via mitochondrial pathway.</td><td align="left">Inflammatory andautoimmune diseases</td><td align="left">(Sun et al. <xref ref-type="bibr" rid="CIT0079">2009</xref>)</td></tr></tbody></table></table-wrap><sec id="s0004"><title>Anti-inflammatory activity</title><p>Among all of the pharmacological activities of SSa, the most important one is anti-inflammatory activity. SSa develops its anti-inflammatory activity mainly by inhibiting some inflammation-associated cytokines, proteins and enzymes, and regulating inflammation-related signal pathways, such as nuclear factor-κB (NF-κB) pathway and mitogen-activated protein kinase (MAPK) pathway. In order to better explain the molecular mechanisms of the anti-inflammatory activity of SSa, <xref ref-type="fig" rid="F0004">Figures 4(a,b)</xref> are provided to describe its NF-κB pathway and MAPK pathway.</p><fig id="F0004" orientation="portrait" position="float"><label>Figure 4.</label><caption><p>The molecular mechanisms of the anti-inflammatory activity of SSa. (a) shows the NF-<italic>κ</italic>B pathway, (b) shows the MAPK pathway.</p></caption><graphic content-type="color" xlink:href="IPHB_A_1262433_F0004_C"></graphic></fig><p>In general, SSa inhibits the expression of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α), transforming growth factor-β1R (TGF-β1R), interleukin 1β (IL-1β), IL-6, and IL-8, and increases the expression of anti-inflammatory cytokine TGF-β1 and IL-10 (Wu et al. <xref rid="CIT0100" ref-type="bibr">2008</xref>, <xref rid="CIT0101" ref-type="bibr">2010</xref>; Han et al. <xref rid="CIT0025" ref-type="bibr">2011</xref>; Lu et al. <xref rid="CIT0065" ref-type="bibr">2012a</xref>; Zhu et al. <xref rid="CIT0124" ref-type="bibr">2013</xref>; Fu et al. <xref rid="CIT0024" ref-type="bibr">2015</xref>; Kim et al. <xref rid="CIT0043" ref-type="bibr">2015</xref>; Zhao et al. <xref rid="CIT0117" ref-type="bibr">2015a</xref>). SSa exerts inhibiting effect on inflammatory associated proteins and enzymes, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) (Lu et al. <xref rid="CIT0065" ref-type="bibr">2012b</xref>; Zhu et al. <xref rid="CIT0124" ref-type="bibr">2013</xref>; Fu et al. <xref rid="CIT0024" ref-type="bibr">2015</xref>; Kim et al. <xref rid="CIT0043" ref-type="bibr">2015</xref>), extracellular matrix-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) (Chen et al. <xref rid="CIT0008" ref-type="bibr">2013b</xref>; Zhu et al. <xref rid="CIT0124" ref-type="bibr">2013</xref>; Zhou et al. <xref rid="CIT0121" ref-type="bibr">2015</xref>), and it also suppresses particular proteins, bone morphogenetic protein 4 (BMP-4) (Wang et al. <xref rid="CIT0086" ref-type="bibr">2013b</xref>), platelet-derived growth factor receptor 1 (PDGFR1) (Chen et al. <xref rid="CIT0008" ref-type="bibr">2013b</xref>) and toll-like receptor 4 (TLR4) (Fu et al. <xref rid="CIT0024" ref-type="bibr">2015</xref>) to exert particular effects (Wang et al. <xref rid="CIT0086" ref-type="bibr">2013b</xref>).</p><p>NF-<italic>κ</italic>B pathway is an important signal pathway in inflammatory process (Bannon et al. <xref rid="CIT0004" ref-type="bibr">2015</xref>). SSa attenuates inflammation mainly by inhibiting the activation of NF-<italic>κ</italic>B pathway (Wu et al. <xref rid="CIT0100" ref-type="bibr">2008</xref>, <xref rid="CIT0101" ref-type="bibr">2010</xref>; Han et al. <xref rid="CIT0025" ref-type="bibr">2011</xref>; Lu et al. <xref rid="CIT0065" ref-type="bibr">2012a</xref>; Kim et al. <xref rid="CIT0043" ref-type="bibr">2015</xref>; Zhao et al. <xref rid="CIT0117" ref-type="bibr">2015a</xref>; Zhou et al. <xref rid="CIT0121" ref-type="bibr">2015</xref>). As shown in <xref ref-type="fig" rid="F0004">Figure 4(a)</xref>, these inhibition effects are mainly reflected in two ways. One is inhibitory effects on phosphorylation of kinases, including I<italic>κ</italic>B<italic>α</italic>, p65 (Zhu et al. <xref rid="CIT0124" ref-type="bibr">2013</xref>; Kim et al. <xref rid="CIT0043" ref-type="bibr">2015</xref>; Zhou et al. <xref rid="CIT0121" ref-type="bibr">2015</xref>), p38 (Han et al. <xref rid="CIT0025" ref-type="bibr">2011</xref>; Chen et al. <xref rid="CIT0008" ref-type="bibr">2013b</xref>; Zhou et al. <xref rid="CIT0121" ref-type="bibr">2015</xref>), JNK (Zhu et al. <xref rid="CIT0124" ref-type="bibr">2013</xref>; Zhou et al. <xref rid="CIT0121" ref-type="bibr">2015</xref>), and Akt (He et al. <xref rid="CIT0027" ref-type="bibr">2016</xref>), and the other is blocking translocation of nuclear factors, including NF-<italic>κ</italic>B (Lu et al. <xref rid="CIT0065" ref-type="bibr">2012a</xref>; Zhu et al. <xref rid="CIT0124" ref-type="bibr">2013</xref>; Kim et al. <xref rid="CIT0043" ref-type="bibr">2015</xref>) and NF-<italic>κ</italic>B/Rel A(Han et al. <xref rid="CIT0025" ref-type="bibr">2011</xref>). The above two inhibition effects are marked by triangle in <xref ref-type="fig" rid="F0004">Figure 4(a)</xref>.</p><p>As shown in <xref ref-type="fig" rid="F0004">Figure 4(b)</xref>, SSa also has an inhibiting effect on MAPK pathway. It downregulates the phosphorylation of three key kinase, p38 MAPK, c-JNK, and ERK 1/2, which are located in the downstream of MAPK pathway and marked by triangle symbol in <xref ref-type="fig" rid="F0004">Figure 4(b)</xref>.</p><p>For studying the anti-inflammatory activity of SSa, it has been applied to mouse macrophage cells RAW264.7 (Zhou et al. <xref rid="CIT0121" ref-type="bibr">2015</xref>), human umbilical vein endothelial cells (HUVECs) (Fu et al. <xref rid="CIT0024" ref-type="bibr">2015</xref>), mouse embryonic fibroblasts 3T3-L1 (Kim et al. <xref rid="CIT0043" ref-type="bibr">2015</xref>), hepatic stellate cells (HSCs) (Chen et al. <xref rid="CIT0008" ref-type="bibr">2013b</xref>), and human mast cells (HMCs) (Han et al. <xref rid="CIT0025" ref-type="bibr">2011</xref>) <italic>in vitro</italic>, and has been applied to the livers of Sprague-Dawley rats (Wu et al. <xref rid="CIT0101" ref-type="bibr">2010</xref>) and Wistar rats (Zhao et al. <xref rid="CIT0117" ref-type="bibr">2015a</xref>) <italic>in vivo</italic>.</p></sec><sec id="s0005"><title>Neuroregulation activity</title><p>SSa plays a significant role on neuroregulation. It exerts antiepileptic mainly by inhibiting <italic>N</italic>-methyl-<sc>D</sc>-aspartic acid (NMDA) receptor current, persistent sodium current (Yu et al. <xref rid="CIT0114" ref-type="bibr">2012</xref>) and inactivating K<sup>+ </sup>current (Xie et al. <xref rid="CIT0106" ref-type="bibr">2013</xref>). It inhibits the activation of p38 MAPK, NF-<italic>κ</italic>B signaling pathways to attenuate neuropathic pain (Zhou et al. <xref rid="CIT0123" ref-type="bibr">2014</xref>), and activates <italic>γ</italic>-aminobutyric acid (GABA) receptor B to attenuate cocaine-reinforced behavior (Yoon et al. <xref rid="CIT0111" ref-type="bibr">2012</xref>, <xref rid="CIT0112" ref-type="bibr">2013</xref>) and drug addiction (Maccioni et al. <xref rid="CIT0126" ref-type="bibr">2016</xref>). It also counteracts the inflammatory response and neurological function deficits via an anti-inflammatory response and inhibition of the MAPK signaling pathway to ease nerve injury (Mao et al. <xref rid="CIT0127" ref-type="bibr">2016</xref>). SSa has been applied to the hippocamp, CA1 neurons, and spinal cord tissues of Sprague-Dawley rats (Mao et al. <xref rid="CIT0127" ref-type="bibr">2016</xref>; Maccioni et al. <xref rid="CIT0126" ref-type="bibr">2016</xref>; Yu et al. <xref rid="CIT0114" ref-type="bibr">2012</xref>; Xie et al. <xref rid="CIT0106" ref-type="bibr">2013</xref>; Yoon et al. <xref rid="CIT0111" ref-type="bibr">2012</xref>, <xref rid="CIT0112" ref-type="bibr">2013</xref>), and chronic constriction injury rats (Zhou et al. <xref rid="CIT0123" ref-type="bibr">2014</xref>) <italic>in vivo</italic>, which determined its potential application in epilepsy, chronic constriction injury, nerve injury, and drug addiction.</p></sec><sec id="s0006"><title>Anti-tumor activity</title><p>SSa exhibits antitumor activity <italic>in vitro</italic> by sensitizing cancer cells to cisplatin, such as human lung adenocarcinoma cells A549, ovarian cancer cells SKOV3, and cervix cancer cells Hela and Siha, through reactive oxygen species (ROS)-mediated apoptosis (Wang et al. <xref rid="CIT0089" ref-type="bibr">2010a</xref>) and enhancing the enzymatic activities of glutamine synthetase (GS) and 2′,3′-cyclic nucleotide 3′-phosphohydrolase (CNP) in rat C6 glioma cells (Tsai et al. <xref rid="CIT0082" ref-type="bibr">2002</xref>). Thus, the combination of SSa with cisplatin could be an effective therapeutic strategy against cancer.</p></sec><sec id="s0007"><title>Antiviral activity</title><p>SSa has generally inhibitory effects against human coronavirus 229E (Cheng et al. <xref rid="CIT0015" ref-type="bibr">2006</xref>) and influenza A virus (Chen et al. <xref rid="CIT0007" ref-type="bibr">2015</xref>). It exerts antiviral activity mainly through interference in the early stage of viral replication, such as absorption and penetration (Chen et al. <xref rid="CIT0007" ref-type="bibr">2015</xref>), and attenuating aberrant pro-inflammatory cytokine production (Cheng et al. <xref rid="CIT0015" ref-type="bibr">2006</xref>). These two viruses are cultured in human cells, human fetal lung fibroblasts MRC-5 and A549 cells, respectively.</p></sec><sec id="s0008"><title>Immunoregulation activity</title><p>SSa inhibits the proliferation and activation of T cells and causes the G0/G1 cells arrest as well as the induction of apoptosis via mitochondrial pathway to exhibit its immunoregulation effect in Sprague-Dawley rats (Sun et al. <xref rid="CIT0079" ref-type="bibr">2009</xref>). This may herald a novel approach for further studies of SSa as a candidate for the treatment of autoimmune diseases.</p></sec></sec><sec id="s0009"><title>SSd</title><p>SSd is the epimer of SSa, they have the same basal structure. So, it has some similar pharmacological activities with SSa, such as anti-inflammatory (Lu et al. <xref rid="CIT0065" ref-type="bibr">2012b</xref>), antitumor (Chen et al. <xref rid="CIT0008" ref-type="bibr">2013a</xref>), and immunoregulation activities (Sun et al. <xref rid="CIT0079" ref-type="bibr">2009</xref>; Ying et al. <xref rid="CIT0110" ref-type="bibr">2014</xref>). However, SSd also possesses some specific pharmacological activities, such as anti-allergic (Hao et al. <xref rid="CIT0026" ref-type="bibr">2012</xref>) and anti-apoptosis activities (Li et al. <xref rid="CIT0052" ref-type="bibr">2014b</xref>). The various pharmacological activities, mechanisms, models and applications of SSd are listed in <xref rid="t0002" ref-type="table">Table 2</xref>.</p><table-wrap id="t0002" orientation="portrait" position="float"><label>Table 2.</label><caption><p>The various pharmacological activities, mechanisms, models, and applications of SSd.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col></colgroup><thead><tr><th align="left">Pharmacological activities of SSd</th><th align="center">Tissue</th><th align="center">Models/cells</th><th align="center"><italic>In vivo</italic>/<italic>vitro</italic></th><th align="center">Mechanisms</th><th align="center">Applications</th><th align="center">References</th></tr></thead><tbody valign="top"><tr><td align="left">Antitumor activity</td><td align="left">Liver</td><td align="left">Sprague Dawley rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSd inhibits the activation of CCAAT/enhancer binding protein <italic>β</italic> (C/EBP<italic>β</italic>) and COX-2.</td><td align="left">Human hepatocellular carcinoma</td><td align="left">(Lu et al. <xref ref-type="bibr" rid="CIT0065">2012b</xref>)</td></tr><tr><td align="left"> </td><td align="left">Thyroid</td><td align="left">ARO, 8305C, SW1736</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd promotes cell apoptosis and induced G1-phase cell cycle arrest.</td><td align="left">Human undifferentiated thyroid carcinoma</td><td align="left">(Liu & Li <xref ref-type="bibr" rid="CIT0062">2014</xref>)</td></tr><tr><td align="left"> </td><td align="left">Liver</td><td align="left">SMMC7721</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd suppresses the expression of COX-2 through the p-STAT3/hypoxia inducible factor-1<italic>α</italic> (HIF-1α) pathway.</td><td align="left">Human hepatocellular carcinoma</td><td align="left">(He et al. <xref ref-type="bibr" rid="CIT0028">2014</xref>)</td></tr><tr><td align="left"> </td><td align="left">Prostate carcinoma cells</td><td align="left">DU145</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd has effects on induction of apoptosis and cell cycle arrest at G0/G1 phase.</td><td align="left">Prostate carcinoma</td><td align="left">(Yao et al. <xref ref-type="bibr" rid="CIT0109">2014</xref>)</td></tr><tr><td align="left"> </td><td align="left">Different cancer cells</td><td align="left">HeLa, HepG2</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd suppresses TNF-<italic>α</italic>-induced NF-<italic>κ</italic>B activation and its target genes expression to inhibit cancer cell proliferation, invasion, angiogenesis and survival.</td><td align="left">As a combined adjuvant remedy with TNF- α for cancer patients</td><td align="left">(Wong et al. <xref ref-type="bibr" rid="CIT0093">2013a</xref>)</td></tr><tr><td align="left"> </td><td align="left">Lung carcinoma</td><td align="left">A549</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd induces apoptosis and blocked cell cycle progression by activating Fas/FasL pathway in the G1 phase in A549 cells.</td><td align="left">Human non-small cell lung cancer</td><td align="left">(Hsu et al. <xref ref-type="bibr" rid="CIT0029">2004a</xref>)</td></tr><tr><td align="left"> </td><td align="left">Liver</td><td align="left">HepG2, 2.2.15</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd induces the apoptosis through the activation of caspases-3 and caspases-7.</td><td align="left">Human hepatocellular carcinoma</td><td align="left">(Chiang et al. <xref ref-type="bibr" rid="CIT0018">2003</xref>)</td></tr><tr><td align="left"> </td><td align="left">Liver</td><td align="left">Hep3B</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd induces apoptosis in Hep3B cells through the caspase-3 -independent pathways.</td><td align="left">Human hepatocellular carcinoma</td><td align="left">Zhou <xref ref-type="bibr" rid="CIT0122">2003</xref></td></tr><tr><td align="left"> </td><td align="left">Breast carcinomas tissue</td><td align="left">MCF-7</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd activates oestrogen response element (ERE)-luciferase activity via the ER <italic>α</italic>-mediated pathway.</td><td align="left">Acting as a weak phytoestrogen.</td><td align="left">(Wang et al. <xref ref-type="bibr" rid="CIT0089">2010a</xref>)</td></tr><tr><td align="left"> </td><td align="left">Liver</td><td align="left">SMMC-7721, HepG2</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd has a radiosensitizing effect on hepatoma cells under hypoxic conditions by inhibiting HIF-1<italic>α</italic> expression.</td><td align="left">Radiotherapy sensitizer in hepatoma radiotherapy</td><td align="left">(Wang et al. <xref ref-type="bibr" rid="CIT0084">2014a, </xref><xref ref-type="bibr" rid="CIT0085">2014b</xref>)</td></tr><tr><td align="left"> </td><td align="left">Different cancer cells</td><td align="left">HeLa, MCF-7</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd induces autophagy through the formation of autophagosomes by inhibiting SERCA.</td><td align="left">Apoptosis-resistant cancer cells</td><td align="left">(Wong et al. <xref ref-type="bibr" rid="CIT0094">2013b</xref>)</td></tr><tr><td align="left">Anti-inflammatory activity</td><td align="left">Inflammatory tissue</td><td align="left">RAW264.7</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd has inhibitory effects on NF-<italic>κ</italic>B activation and iNOS, COX-2 and pro-inflammatory cytokines including TNF-<italic>α</italic> and IL-6.</td><td align="left">LPS-induced inflammation</td><td align="left">(Lu et al. <xref ref-type="bibr" rid="CIT0065">2012a</xref>)</td></tr><tr><td align="left"> </td><td align="left">Hepatic stellate cells</td><td align="left">HSC-T6</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd decreases the expressions of extracellular matrix-regulated kinase 1/2 (ERK1/2), PDGFR, TGF-<italic>β</italic>1R, <italic>α</italic>-smooth muscle actin, TGF-<italic>β</italic>1 and connective tissue growth factor.</td><td align="left">Liver inflammation and fibrogenesis</td><td align="left">(Chen et al. <xref ref-type="bibr" rid="CIT0008">2013a</xref>)</td></tr><tr><td align="left"> </td><td align="left">Human acute monocytic leukaemia cells</td><td align="left">THP-1</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd inhibits selectin-mediated cell adhesion.</td><td align="left">L-selectin-mediated cell adhesion</td><td align="left">(Jang et al. <xref ref-type="bibr" rid="CIT0036">2014</xref>)</td></tr><tr><td align="left"> </td><td align="left">Liver</td><td align="left">C57/BL6 rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSd down-regulates NF-<italic>κ</italic>B and STAT3-mediated inflammatory signal pathway.</td><td align="left">Hepatotoxicity and liver injury</td><td align="left">(Liu et al. <xref ref-type="bibr" rid="CIT0059">2014a</xref>)</td></tr><tr><td align="left"> </td><td align="left">Liver</td><td align="left">Hepatic fibrosis rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSd down-regulates liver TNF-<italic>α</italic>, IL-6 and NF-<italic>κ</italic>B p65 expression and increases I<italic>κ</italic>B-<italic>α</italic> activity.</td><td align="left">Hepatic fibrosis</td><td align="left">(Dang et al. <xref ref-type="bibr" rid="CIT0020">2007</xref>)</td></tr><tr><td align="left"> </td><td align="left">Kidney</td><td align="left">LLC-PK1</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd increases the activity and expression of anti-oxidant enzymes (SOD, CAT, GPx) and HSP72.</td><td align="left">Oxidative damage in the kidney</td><td align="left">(Zhang et al. <xref ref-type="bibr" rid="CIT0115">2014</xref>)</td></tr><tr><td align="left"> </td><td align="left">Nervous tissue</td><td align="left">C6 rat glioma cells</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd possesses a dual effect: an inhibition of PGE2 production without a direct inhibition of cyclooxygenase activity and an elevation of [Ca<sup>2+</sup>]i.</td><td align="left">Inflammation in C6 rat glioma cells</td><td align="left">(Kodama et al. <xref ref-type="bibr" rid="CIT0044">2003</xref>)</td></tr><tr><td align="left"> </td><td align="left">Lung</td><td align="left">VILI rats</td><td align="left"><italic>In vivo</italic></td><td align="left">SSd decreases the expression of pro-inflammatory cytokines including MIP-2, IL-6 and TNF-<italic>α</italic> and elevates the expression of anti-inflammatory mediators, such as TGF-<italic>β</italic>1 and IL-10.</td><td align="left">Lung injury</td><td align="left">(Wang et al. <xref ref-type="bibr" rid="CIT0087">2015</xref>)</td></tr><tr><td align="left"> </td><td align="left">Renal tubular epithelial cells</td><td align="left">NRK-52E</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd attenuates oxidative injury via upregulation of SirT<sub>3</sub>.</td><td align="left">High glucose induced kidney injury</td><td align="left">(Zhao et al. <xref ref-type="bibr" rid="CIT0117">2015b</xref>)</td></tr><tr><td align="left"> </td><td align="left">Kidney</td><td align="left">HK-2</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd represses ROS-mediated activation of MAPK and NF-<italic>κ</italic>B signal pathways.</td><td align="left">DDP-induced kidney injury</td><td align="left">(Ma et al. <xref ref-type="bibr" rid="CIT0068">2015</xref>)</td></tr><tr><td align="left">Immunoregulation</td><td align="left">Lymphoid tissue</td><td align="left">Mouse T cells</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd inhibits the T cell proliferation and activation through the NF-<italic>κ</italic>B, NF-AT and AP-1 signal pathways, and it also inhibits the cytokine secretion and IL-2 receptor expression.</td><td align="left">T cell-mediated autoimmune conditions</td><td align="left">(Wong et al. <xref ref-type="bibr" rid="CIT0095">2009</xref>)</td></tr><tr><td align="left"> </td><td align="left">Monocyte-derived dendritic cells</td><td align="left">DCs</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd reduces the differentiation of human DCs and promotes DCs maturation and increases the function of mature DCs.</td><td align="left">Condylomata acuminata</td><td align="left">(Ying et al. <xref ref-type="bibr" rid="CIT0110">2014</xref>)</td></tr><tr><td align="left">Anti-allergic activity</td><td align="left">Lymphoid tissue</td><td align="left">Rat basophilic leukemia-2H3 cells</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd suppresses the intracellular calcium mobilization and tyrosine phosphorylation, thereby prevents gene activation of Cdc42 and c-Fos.</td><td align="left">Soybean allergy</td><td align="left">(Hao et al. <xref ref-type="bibr" rid="CIT0026">2012</xref>)</td></tr><tr><td align="left">Neuroregulation</td><td align="left">Neuronal cells</td><td align="left">PC12</td><td align="left"><italic>In vitro</italic></td><td align="left">SSd regulates mitochondrial and nuclear GR translocation, partial reversal of mitochondrial dysfunction, inhibition of the mitochondrial apoptotic pathway, and selective activation of the GR-dependent survival pathway.</td><td align="left">Against corticosterone-induced apoptosis</td><td align="left">(Li et al. <xref ref-type="bibr" rid="CIT0052">2014b</xref>)</td></tr><tr><td align="left"> </td><td align="left">Neuronal cells</td><td align="left">PC12</td><td align="left"><italic>In vitro</italic></td><td align="left">SSD reduces PC12 cells apoptosis by removing ROS and blocking MAPK-dependent oxidative damage.</td><td align="left">Neuronal oxidative stress</td><td align="left">(Lin et al. <xref ref-type="bibr" rid="CIT0058">2016</xref>)</td></tr></tbody></table></table-wrap><sec id="s0010"><title>Antitumor activity</title><p>The most important pharmacological activity of SSd is antitumor activity. In order to better explain this important activity, <xref ref-type="fig" rid="F0005">Figure 5</xref> is provided to describe its molecular mechanisms. SSd exhibits the antitumor activity mainly through activation and inhibition, which are marked by rectangle and triangle in <xref ref-type="fig" rid="F0005">Figure 5</xref>, respectively. First, SSd increases the expression of p53 and Bax (Liu & Li <xref rid="CIT0062" ref-type="bibr">2014</xref>; Wang et al. <xref rid="CIT0084" ref-type="bibr">2014a, </xref><xref rid="CIT0085" ref-type="bibr">2014b</xref>; Yao et al. <xref rid="CIT0109" ref-type="bibr">2014</xref>), activates caspases apoptosis pathway, including the activation of caspases-3 and caspases-7 (Chiang et al. <xref rid="CIT0018" ref-type="bibr">2003</xref>; Chou et al. <xref rid="CIT0019" ref-type="bibr">2003</xref>) and the Fas/FasL apoptotic system (Hsu et al. <xref rid="CIT0029" ref-type="bibr">2004a</xref>) in several cancer cell lines <italic>in vitro</italic>, which are marked by rectangle in <xref ref-type="fig" rid="F0005">Figure 5</xref>. Second, SSd decreases the expression of B cell lymphoma 2 (Bcl-2) family proteins (Liu & Li <xref rid="CIT0062" ref-type="bibr">2014</xref>; Wang et al. <xref rid="CIT0084" ref-type="bibr">2014a, </xref><xref rid="CIT0085" ref-type="bibr">2014b</xref>; Yao et al. <xref rid="CIT0109" ref-type="bibr">2014</xref>), suppresses the expression of COX-2, which has been shown to be involved in carcinogenesis (Lu et al. <xref rid="CIT0065" ref-type="bibr">2012b</xref>; He et al. <xref rid="CIT0028" ref-type="bibr">2014</xref>), and also potentiates TNF-<italic>α</italic>-mediated cell death via suppression of TNF-<italic>α</italic>-induced NF-<italic>κ</italic>B activation (Wong et al. <xref rid="CIT0093" ref-type="bibr">2013a</xref>), which are marked by triangle in <xref ref-type="fig" rid="F0005">Figure 5</xref>. Besides, SSd also suppresses MCF-7 cells proliferation through the estrogenic effect of SSd by the estrogen receptor (Wang et al. <xref rid="CIT0089" ref-type="bibr">2010a</xref>, <xref rid="CIT0085" ref-type="bibr">2010b</xref>), and induces autophagy of apoptosis-resistant cancer cells through the formation of autophagosomes by inhibiting sarcoplasmic/endoplasmic reticulum Ca<sup>2+ </sup>ATPase pump (SERCA) (Wong et al. <xref rid="CIT0094" ref-type="bibr">2013b</xref>).</p><fig id="F0005" orientation="portrait" position="float"><label>Figure 5.</label><caption><p>The molecular mechanisms of the anti-tumor activity of SSd.</p></caption><graphic content-type="color" xlink:href="IPHB_A_1262433_F0005_C"></graphic></fig><p>To date, SSd has been applied in human hepatoma cells HepG2, Hep3B (Chou et al. <xref rid="CIT0019" ref-type="bibr">2003</xref>), SMMC7721 (He et al. <xref rid="CIT0028" ref-type="bibr">2014</xref>), and 2.2.15 cells (Chiang et al. <xref rid="CIT0018" ref-type="bibr">2003</xref>), anaplastic thyroid cancers cells ARO, 8305C, and SW1736 (Liu & Li <xref rid="CIT0062" ref-type="bibr">2014</xref>), prostate carcinoma cells DU145 (Yao et al. <xref rid="CIT0109" ref-type="bibr">2014</xref>), lung cancer cells A549 (Hsu et al. <xref rid="CIT0029" ref-type="bibr">2004a</xref>), cervical carcinoma cells Hela (Wong et al. <xref rid="CIT0093" ref-type="bibr">2013a, </xref><xref rid="CIT0094" ref-type="bibr">2013b</xref>), and breast carcinoma cells MCF-7 (Wang et al. <xref rid="CIT0090" ref-type="bibr">2010b</xref>) <italic>in vitro</italic>, and applied in diethylinitrosamine (DEN)-treated Sprague Dawley rats <italic>in vivo</italic> (Lu et al. <xref rid="CIT0065" ref-type="bibr">2012b</xref>), and which indicates its potential in treatment of cancer.</p></sec><sec id="s0011"><title>Anti-inflammatory activity</title><p>SSd also possesses an evident anti-inflammatory activity, and the mechanisms are similar to SSa, as shown in <xref ref-type="fig" rid="F0004">Figure 4(a)</xref>. On the cytokines level, SSd suppresses pro-inflammatory cytokines including TNF-α, IL-6, macrophage inflammatory protein-2 (MIP-2), and elevates the expression of anti-inflammatory cytokines, such as TGF-β1 and IL-10 (Lu et al. <xref rid="CIT0065" ref-type="bibr">2012a</xref>; Ma et al. <xref rid="CIT0068" ref-type="bibr">2015</xref>; Wang et al. <xref rid="CIT0087" ref-type="bibr">2015</xref>). On the level of proteins and enzymes, it inhibits the activity and expression of iNOS, COX-2, ERK1/2, PDGFR, α-smooth muscle actin, NF-<italic>κ</italic>B, and signal transducer and activator of transcription 3 (STAT3) (Chen et al. <xref rid="CIT0008" ref-type="bibr">2013a</xref>; Liu et al. <xref rid="CIT0059" ref-type="bibr">2014a</xref>), and increases the activity and expression of inhibitor of nuclear factor of <italic>κ</italic>B-<italic>α</italic> (I<italic>κ</italic>B-<italic>α</italic>) (Dang et al. <xref rid="CIT0020" ref-type="bibr">2007</xref>), SirT3 (Zhao L et al. <xref rid="CIT0119" ref-type="bibr">2015</xref>), anti-oxidant enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and heat shock protein (HSP) 72 (Zhang et al. <xref rid="CIT0115" ref-type="bibr">2014</xref>). Furthermore, SSd also exhibits its particular anti-inflammatory pattern by inhibiting selectin-mediated cell adhesion (Jang et al. <xref rid="CIT0036" ref-type="bibr">2014</xref>), and possessing a dual effect, an inhibition of prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) production without a direct inhibition of cyclooxygenase activity and an elevation of Ca<sup>2+</sup> (Kodama et al. <xref rid="CIT0044" ref-type="bibr">2003</xref>).</p><p>According to the above reports, SSa and SSd are very similar in mechanisms of anti-inflammation, however, there are still several different points, which are listed in <xref rid="t0003" ref-type="table">Table 3</xref>. SSa is able to inhibit phosphorylation of three key kinase in MAPK pathway, which was not reported in researches of SSd. While SSd is able to restrain selectin-mediated cell adhesion, PGE<sub>2</sub> production, and elevate the Ca<sup>2+ </sup>level intracellular, which were not reported in researches of SSa</p><table-wrap id="t0003" orientation="portrait" position="float"><label>Table 3.</label><caption><p>The similarities and differences of SSa and SSd in mechanisms of anti-inflammation.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col></colgroup><thead><tr><th align="left">The possible mechanisms of anti-inflammation</th><th align="center">SSa</th><th align="center">SSd</th></tr></thead><tbody valign="top"><tr><td align="left">Inhibiting pro-inflammatory cytokines and promoting anti-inflammatory cytokines</td><td align="left">✓</td><td align="left">✓</td></tr><tr><td align="left">Inhibiting activity of enzymes associated with inflammation</td><td align="left">✓</td><td align="left">✓</td></tr><tr><td align="left">Inhibiting activation of NF-κB pathway</td><td align="left">✓</td><td align="left">✓</td></tr><tr><td align="left">Inhibiting activation of MAPK pathway</td><td align="left">✓</td><td align="left">✗</td></tr><tr><td align="left">Inhibiting selectin-mediated cell adhesion</td><td align="left">✗</td><td align="left">✓</td></tr><tr><td align="left">Inhibiting PGE2 production and elevating Ca<sup>2+</sup> level intracellular</td><td align="left">✗</td><td align="left">✓</td></tr></tbody></table></table-wrap><p>For a better understanding of SSd’s anti-inflammatory activity, it has been applied to mouse leukaemic monocyte macrophage macroph RAW264.7 (Lu et al. <xref rid="CIT0065" ref-type="bibr">2012a</xref>), hepatic stellate cells HSC-T6 (Chen et al. <xref rid="CIT0008" ref-type="bibr">2013a</xref>), human acute monocytic leukemia cells THP-1 (Jang et al. <xref rid="CIT0036" ref-type="bibr">2014</xref>), pig kidney proximal tubular cells LLC-PK1 (Zhang et al. <xref rid="CIT0115" ref-type="bibr">2014</xref>), C6 rat glioma cells (Kodama et al. <xref rid="CIT0044" ref-type="bibr">2003</xref>), renal tubular epithelial cells NRK-52E (Zhao et al. <xref rid="CIT0117" ref-type="bibr">2015b</xref>), and HK-2 (Ma et al. <xref rid="CIT0068" ref-type="bibr">2015</xref>) <italic>in vitro</italic>, and acetaminophen-induced hepatotoxicity C57/BL6 rats (Liu et al. <xref rid="CIT0059" ref-type="bibr">2014a</xref>), hepatic fibrosis model rats (Dang et al. <xref rid="CIT0020" ref-type="bibr">2007</xref>), and ventilator-induced lung injury (VILI) rats (Wang et al. <xref rid="CIT0087" ref-type="bibr">2015</xref>) <italic>in vivo</italic>, which determined its potential application for treating hepatitis, pneumonia, nephritis and other inflammation.</p></sec><sec id="s0012"><title>Immunoregulation activity</title><p>SSd plays its immunoregulation role by regulating the NF-<italic>κ</italic>B, nuclear factor-AT (NF-AT), and activator protein 1 (AP-1) signal pathways to inhibit T cell proliferation and activation (Wong et al. <xref rid="CIT0095" ref-type="bibr">2009</xref>). It has been applied to condylomata acuminate, a disease caused by human papilloma virus (HPV), by reducing the differentiation of human monocyte-derived dendritic cells (DCs) and promoting DCs maturation and increasing the function of mature DCs (Ying et al. <xref rid="CIT0110" ref-type="bibr">2014</xref>).</p></sec><sec id="s0013"><title>Anti-allergic activity</title><p>β-Conglycinin has been identified as a potential diagnostic marker for severe basophil-dependent allergic reactions to soybean. SSd possesses anti-allergic activity by inhibiting β-conglycinin-induced rat basophilic leukemia-2H3 cell degranulation and suppressing critical incidents in the signal transduction pathway (Hao et al. <xref rid="CIT0026" ref-type="bibr">2012</xref>), Hence it could become an effective herbal therapy for alleviating soybean allergy.</p></sec><sec id="s0014"><title>Neuroregulation activity</title><p>Neuronal oxidative stress injury has been proven to be associated with many neurodegenerative diseases. SSd exerts neuroregulation activity on neuronal PC12 cells by inhibiting the translocation of the glucocorticoid receptor (GR) to the mitochondria, restoring mitochondrial function, down-regulating the expression of pro-apoptotic-related signalling events and up-regulating anti-apoptotic-related signalling events (Li et al. <xref rid="CIT0052" ref-type="bibr">2014b</xref>). In H<sub>2</sub>O<sub>2</sub>-induced oxidative stress PC12 cells, SSd effectively decreases oxidative stress injury by blocking H<sub>2</sub>O<sub>2</sub>-induced phosphorylation of ERK, JNK, and p38MAPK to exert neuroregulation activity (Lin et al. <xref rid="CIT0058" ref-type="bibr">2016</xref>). Thus, SSd treatment is an effective method for treating neurodegenerative diseases.</p></sec></sec><sec id="s0015"><title>SSc</title><p>SSc has the same basal structure with SSa and SSd. They are epoxy-ether saikosaponins belonging to type I saikosaponins (Shin et al. <xref rid="CIT0077" ref-type="bibr">2015</xref>). However, the pharmacological activities of SSc are far weaker than SSa and SSd. To date, reports about pharmacological activities of SSc are very limited. SSc exerts anti-apoptotic effects on HUVECs by suppressing caspase-3 activation and subsequent degradation of focal adhesion kinase (FAK) and other cell adhesion signals, which is similar to SSa (Lee et al. <xref rid="CIT0051" ref-type="bibr">2014</xref>). Thus, it will be a promising therapeutic candidate for the treatment of vascular endothelial cell injury and cellular dysfunction. Besides, SSc completely prevents the development of nephritis (Chen et al. <xref rid="CIT0010" ref-type="bibr">2008</xref>), but the mechanism of this activity is still unclear. In addition, SSc exhibits antiviral activity by inhibiting hepatitis B virus (HBV) DNA replication (Chiang et al. <xref rid="CIT0018" ref-type="bibr">2003</xref>).</p></sec><sec id="s0016"><title>SSb<sub>2</sub></title><p>SSb<sub>2</sub> has a different basic structure compared to SSa, SSd, and SSc. SSb<sub>2</sub> is a type II saikosaponin, and it is not considered as a main active compound in Radix Bupleuri. However, SSb<sub>2</sub> has fairly inhibitory effects against corona virus and hepatitis C virus (HCV). It mainly interferes with the early stages of viral replication, such as absorption and penetration of the virus (Cheng et al. <xref rid="CIT0015" ref-type="bibr">2006</xref>). SSb<sub>2</sub> potently inhibits HCV infection at non-cytotoxic concentrations through efficient inhibition on early HCV entry, including neutralization of virus particles, preventing viral attachment, and inhibiting viral entry/fusion (Lin et al. <xref rid="CIT0056" ref-type="bibr">2014</xref>).</p></sec><sec id="s0017"><title>Radix Bupleuri extracts</title><p>Many <italic>Bupleurum</italic> medicinal plants are used as Radix Bupleuri. The pharmacological activities of extracts from seven <italic>Bupleurum</italic> species, <italic>B. chinense</italic> (Wen et al. <xref rid="CIT0092" ref-type="bibr">2011</xref>), <italic>B. falcatum</italic> (Lee et al. <xref rid="CIT0047" ref-type="bibr">2012a</xref>), <italic>Bupleurum marginatum</italic> Wall. ex DC. (Ashour et al. <xref rid="CIT0002" ref-type="bibr">2014</xref>), <italic>B. yinchowense</italic> (Li et al. <xref rid="CIT0053" ref-type="bibr">2013</xref>), <italic>Bupleurum kaoi</italic> L. (Hsu et al. <xref rid="CIT0029" ref-type="bibr">2004a</xref>, <xref rid="CIT0030" ref-type="bibr">2004b</xref>), <italic>B. scorzonerifolium</italic> (Cheng et al. <xref rid="CIT0017" ref-type="bibr">2005</xref>), and <italic>Bupleurum longiradiatum</italic> Turcz. (You et al. <xref rid="CIT0113" ref-type="bibr">2002</xref>), are given in <xref rid="t0004" ref-type="table">Table 4</xref>. They have been demonstrated to possess antitumor (Cheng et al. <xref rid="CIT0016" ref-type="bibr">2003</xref>, <xref rid="CIT0017" ref-type="bibr">2005</xref>; Hsu et al. <xref rid="CIT0029" ref-type="bibr">2004a, </xref><xref rid="CIT0030" ref-type="bibr">2004b</xref>; Chen et al. <xref rid="CIT0014" ref-type="bibr">2005</xref>; Kang et al. <xref rid="CIT0040" ref-type="bibr">2008</xref>; Ashour et al. <xref rid="CIT0002" ref-type="bibr">2014</xref>), antiviral (Wen et al. <xref rid="CIT0092" ref-type="bibr">2011</xref>), anti-inflammatory (Lee et al. <xref rid="CIT0048" ref-type="bibr">2010</xref>; Nakahara et al. <xref rid="CIT0071" ref-type="bibr">2011</xref>), anti-hyperthyroidism (Kim et al. <xref rid="CIT0041" ref-type="bibr">2012b</xref>) and neuroregulation effects (Xie et al. <xref rid="CIT0105" ref-type="bibr">2006</xref>; Lee et al. <xref rid="CIT0046" ref-type="bibr">2009</xref>, <xref rid="CIT0047" ref-type="bibr">2012b</xref>; Li et al. <xref rid="CIT0053" ref-type="bibr">2013</xref>; Liu et al. <xref rid="CIT0059" ref-type="bibr">2014b</xref>).</p><table-wrap id="t0004" orientation="portrait" position="float"><label>Table 4.</label><caption><p>The pharmacological activities and mechanisms of extracts from different <italic>Bupleurum</italic> species.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col></colgroup><thead><tr><th align="left">Species</th><th align="center">Extractive fractions</th><th align="center">Extraction method</th><th align="center">Activities</th><th align="center">Mechanisms</th><th align="center">References</th></tr></thead><tbody valign="top"><tr><td align="left"><italic>B. chinenes</italic></td><td align="left">Aqueous extracts</td><td align="left">Water decoction, 3 h</td><td align="left">Antitumor activity</td><td align="left">Enhancing 5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cells and protecting normal blood lymphocytes.</td><td align="left">(Kang et al. <xref ref-type="bibr" rid="CIT0040">2008</xref>)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">Water decoction, 3 h</td><td align="left">Antiviral activity</td><td align="left">Suppressing the effect on regulated activation normal T-cell expressed (RANTES) secretion.</td><td align="left">(Wen et al. <xref ref-type="bibr" rid="CIT0092">2011</xref>)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">Water decoction, 3 h</td><td align="left">Affect drug distribution</td><td align="left">Inhibiting the activity of β-glucuronidase.</td><td align="left">(Chen et al. <xref ref-type="bibr" rid="CIT0012">2014</xref>)</td></tr><tr><td align="left"> </td><td align="left">Methanol TSS extracts</td><td align="left">Methanol, reflux, 4 h</td><td rowspan="2" align="left">Neuroregulation</td><td align="left">Suppressing the abnormal activation of hippocampal astrocyte through inhibiting the overexpression of glial fibrillary acidic protein.</td><td align="left">(Xie et al. <xref ref-type="bibr" rid="CIT0105">2006</xref>)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">95% methanol 5% pyridine, reflux, 4 h</td><td align="left">TSS antagonizes the reserpine-induced akinesia, and ptosis in mice.</td><td align="left">(Liu et al. <xref ref-type="bibr" rid="CIT0059">2014a</xref>)</td></tr><tr><td align="left"><italic>B. falcatum</italic></td><td align="left">Ethanol extracts</td><td align="left">70% ethanol, reflux, 6 h</td><td align="left">Anti-inflammatory activity</td><td align="left">Inhibiting the expression and activation of both metal matrix proteinase (MMP)-2 and MMP-9 after spinal cord injury (SCI) and the mRNA expressions of TNF-<italic>α</italic>, IL-1<italic>β</italic>, COX-2, and iNOS.</td><td align="left">(Lee et al. <xref ref-type="bibr" rid="CIT0048">2010</xref>)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">80% ethanol, reflux, 6 h</td><td align="left">Anti-depressant activity</td><td align="left">Reducing depression and anxiety-like behaviors, possibly through central adrenergic mechanism.</td><td align="left">(Lee et al. <xref ref-type="bibr" rid="CIT0047">2012a</xref>)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">80% ethanol, reflux, 6h</td><td align="left">Memory improvement</td><td align="left">Attenuating IMO stress-induced loss of cholinergic immunoreactivity in the hippocampus.</td><td align="left">(Lee et al. <xref ref-type="bibr" rid="CIT0046">2009</xref>)</td></tr><tr><td align="left"> </td><td align="left">Methanol extracts</td><td align="left">Methanol, reflux, 4 h</td><td align="left">Anti-depressant activity</td><td align="left">The mechanism of this activity involves the serotonergic and noradrenergic systems.</td><td align="left">(Kwon et al. <xref ref-type="bibr" rid="CIT0045">2010</xref>)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">Methanol, reflux, 4 h</td><td align="left">Anti-inflammatory activity</td><td align="left">Decreasing the content of alanine transaminase (ALT) in blood serum of the liver injury rats.</td><td align="left">(Nakahara et al. <xref ref-type="bibr" rid="CIT0071">2011</xref>)</td></tr><tr><td align="left"> </td><td align="left">Aqueous extracts</td><td align="left">Water decoction, 3 h</td><td align="left">Anti-hyperthyroidism</td><td align="left">Attenuating LT4-induced hyperthyroidisms and normalizing LT4-induced liver oxidative stresses and reducing liver and epididymal fat pad changes.</td><td align="left">(Kim et al. <xref ref-type="bibr" rid="CIT0041">2012b</xref>)</td></tr><tr><td rowspan="2" align="left"><italic>B. scorzonerifolium</italic></td><td rowspan="2" align="left">Acetone extracts</td><td align="left">Acetone, reflux, 4 h</td><td rowspan="2" align="left">Antitumor activity</td><td align="left">Inducing tubulin polymerization, and activates caspase-3 and caspase-9 in A549 cells, and these effects are related to ERK 1/2 activation and the apoptosis.</td><td align="left">(Chen et al. <xref ref-type="bibr" rid="CIT0014">2005</xref>; Cheng et al. <xref ref-type="bibr" rid="CIT0017">2005</xref>)</td></tr><tr><td align="left">Acetone, reflux, 4 h</td><td align="left">Inhibiting telomerase activity and activation of apoptosis.</td><td align="left">(Cheng et al. <xref ref-type="bibr" rid="CIT0016">2003</xref>)</td></tr><tr><td align="left"><italic>B. marginatum</italic></td><td align="left">Methanol extracts</td><td align="left">Methanol, reflux, 6 h</td><td align="left">Anti-infective and antitumor activities</td><td align="left">Methanol extracts show a significant anti-trypanosomal activity and moderate activity against <italic>Streptococcus pyogenes</italic> and have the cytotoxicity inducing apoptosis.</td><td align="left">(Ashour et al. <xref ref-type="bibr" rid="CIT0002">2014</xref>)</td></tr><tr><td align="left"><italic>B. longiradiatum</italic></td><td align="left">Ethyl acetate extracts</td><td align="left">Ethyl acetate, reflux, 4 h</td><td align="left">Antiangiogenic activity</td><td align="left">It has an inhibitory effect on the tube-like formation of HUVECs.</td><td align="left">(You et al. <xref ref-type="bibr" rid="CIT0113">2002</xref>)</td></tr><tr><td align="left"><italic>B. yinchowense</italic></td><td align="left">Ethanol TSS extracts</td><td align="left">60% ethanol 0.5% ammonia reflux, 6 h</td><td align="left">Neuroregulation</td><td align="left">The neuroprotective mechanism relates with inhibiting the ER stress and the mitochondrial apoptotic pathways.</td><td align="left">(Li et al. <xref ref-type="bibr" rid="CIT0053">2013</xref>)</td></tr><tr><td rowspan="2" align="left"><italic>B. kaoi</italic></td><td rowspan="2" align="left">Methanol TSS extracts</td><td align="left">Methanol, reflux, 4 h</td><td rowspan="2" align="left">Antitumor activity</td><td align="left">The activity of the Fas/Fas ligand apoptotic system participates in the antiproliferative activity of TSS in A549 cells.</td><td align="left">(Hsu et al. <xref ref-type="bibr" rid="CIT0030">2004b</xref>)</td></tr><tr><td align="left">Methanol, reflux, 4 h</td><td align="left">Extracts from <italic>B. kaoi</italic> show potent antiproliferative effects on human A375.S2 melanoma cells.</td><td align="left">(Hu et al. <xref ref-type="bibr" rid="CIT0031">2016</xref>)</td></tr></tbody></table></table-wrap><p>Five kinds of extraction agents, water, methanol, ethanol, acetone and ethyl acetate, have been used to extract effective fractions from Radix Bupleuri. Aqueous extracts of Radix Bupleuri are obtained by boiling at 80 °C for 3 h, and then evaporating and lyophilizing (Kang et al. <xref rid="CIT0040" ref-type="bibr">2008</xref>; Wen et al. <xref rid="CIT0092" ref-type="bibr">2011</xref>; Kim et al. <xref rid="CIT0041" ref-type="bibr">2012b</xref>; Chen et al. <xref rid="CIT0012" ref-type="bibr">2014</xref>). The method to obtain methanol, ethanol, acetone and ethyl acetate extracts is reflux extraction (You et al. <xref rid="CIT0113" ref-type="bibr">2002</xref>; Cheng et al. <xref rid="CIT0017" ref-type="bibr">2005</xref>; Lee et al. <xref rid="CIT0048" ref-type="bibr">2010</xref>; Liu et al. <xref rid="CIT0059" ref-type="bibr">2014a</xref>). To obtain methanol extracts, Radix Bupleuri is extracted twice by 100% methanol or 95% methanol with 5% pyridine at 70 °C for 4 h (Xie et al. <xref rid="CIT0105" ref-type="bibr">2006</xref>; Kwon et al. <xref rid="CIT0045" ref-type="bibr">2010</xref>; Nakahara et al. <xref rid="CIT0071" ref-type="bibr">2011</xref>; Liu et al. <xref rid="CIT0059" ref-type="bibr">2014a</xref>; Ashour et al. <xref rid="CIT0002" ref-type="bibr">2014</xref>). To obtain ethanol extracts, Radix Bupleuri is extracted twice by 60% (Li et al. <xref rid="CIT0053" ref-type="bibr">2013</xref>), 70% (Lee et al. <xref rid="CIT0048" ref-type="bibr">2010</xref>) or 80% ethanol (Lee et al. <xref rid="CIT0047" ref-type="bibr">2012a</xref>) at room temperature for 6 h. To obtain acetone and ethyl acetate extracts, Radix Bupleuri is extracted three times by 100% acetone and 100% ethyl acetate at room temperature for 4 h (You et al. <xref rid="CIT0113" ref-type="bibr">2002</xref>; Cheng et al. <xref rid="CIT0017" ref-type="bibr">2005</xref>).</p><p>The pharmacological activities of extracts from <italic>B. chinense</italic> and <italic>B. falcatum</italic> have relative in-depth studies. The aqueous extracts of <italic>B. chinense</italic> possess three activities, antitumor activity on HepG2 hepatoma cells (Kang et al. <xref rid="CIT0040" ref-type="bibr">2008</xref>), antiviral activity on H1N1-infected A549 cells (Wen et al. <xref rid="CIT0092" ref-type="bibr">2011</xref>), and an activity to affect drug distribution (Chen et al. <xref rid="CIT0012" ref-type="bibr">2014</xref>). Methanol total saikosaponins (TSS) extracts of <italic>B. chinense</italic> have a neuroregulation effect (Xie et al. <xref rid="CIT0105" ref-type="bibr">2006</xref>; Liu et al. <xref rid="CIT0059" ref-type="bibr">2014a</xref>). In chronic kindling rats induced by pentetrazole (PTZ), TSS of <italic>B. chinense</italic> inhibit glial fibrillary acidic protein (GFAP) over-expression and suppress the abnormal activation of hippocampal astrocyte (Xie et al. <xref rid="CIT0105" ref-type="bibr">2006</xref>). Anti-depressant activity of TSS is investigated by tail suspension test, forced swimming test, and reserpine antagonism test in mice, which demonstrate that it shortens the immobility time of mice in the tail suspension test in a somewhat dose-dependent manner (Liu et al. <xref rid="CIT0059" ref-type="bibr">2014a</xref>).</p><p>Both ethanol extracts and methanol extracts of <italic>B. falcatum</italic> have an anti-inflammatory effect (Lee et al. <xref rid="CIT0048" ref-type="bibr">2010</xref>; Nakahara et al. <xref rid="CIT0071" ref-type="bibr">2011</xref>) with similar mechanisms to SSa. They also possess an anti-depressant activity possibly through central adrenergic mechanism (Kwon et al. <xref rid="CIT0045" ref-type="bibr">2010</xref>; Lee et al. <xref rid="CIT0047" ref-type="bibr">2012a</xref>). Besides, the ethanol extracts of <italic>B. falcatum</italic> has its specific memory improvement activity by attenuating immobilization (IMO) stress-induced loss of cholinergic immunoreactivity in the hippocampus (Lee et al. <xref rid="CIT0046" ref-type="bibr">2009</xref>). The aqueous extracts of <italic>B. falcatum</italic> has an anti-hyperthyroidism activity by attenuating leukotriene-4 (LT4)-induced hyperthyroidisms, normalizing LT4-induced liver oxidative stresses and reducing liver and epididymal fat pad changes (Kim et al. <xref rid="CIT0041" ref-type="bibr">2012b</xref>).</p><p>The acetone extracts of <italic>B. scorzonerifolium</italic> exerts stronger antitumor activity on A549 cells mainly through inducing tubulin polymerization (Chen et al. <xref rid="CIT0014" ref-type="bibr">2005</xref>), activating caspase-3 and caspase-9 (Cheng et al. <xref rid="CIT0017" ref-type="bibr">2005</xref>), and inhibiting telomerase activity and activation of apoptosis (Cheng et al. <xref rid="CIT0016" ref-type="bibr">2003</xref>). Methanol extracts of <italic>B. marginatum</italic> and <italic>B. kaoi</italic> have an antitumor activity by inducing apoptosis (Ashour et al. <xref rid="CIT0002" ref-type="bibr">2014</xref>) and activating the Fas/Fas ligand apoptotic system respectively (Hsu et al. <xref rid="CIT0030" ref-type="bibr">2004b</xref>), and extracts of <italic>B. kaoi</italic> have antitumor activity on human A375.S2 melanoma cells by inhibiting phosphorylation of JNK, p38 and p53, decreasing level of cytochrome c (Hu et al. <xref rid="CIT0031" ref-type="bibr">2016</xref>). What’s more, the ethanol TSS extracts of <italic>B. yinchowense</italic> show antidepressant activity by inhibiting the estrogen receptor (ER) stress and the mitochondrial apoptotic pathways (Li et al. <xref rid="CIT0053" ref-type="bibr">2013</xref>), and the ethyl acetate extracts of <italic>B. longiradiatum</italic> exhibit an antiangiogenic activity by inhibiting the tube-like formation of HUVECs (You et al. <xref rid="CIT0113" ref-type="bibr">2002</xref>).</p></sec><sec id="s0018"><title>Applications of Radix Bupleuri in TCM</title><p>Radix Bupleuri has been used for more than 2000 years in China since its first record in <italic>Shen Nong Ben Cao Jing</italic> (Xie et al. <xref rid="CIT0103" ref-type="bibr">2009</xref>). And now, it is officially listed in <italic>Chinese Pharmacopeia</italic>. In TCM, Radix Bupleuri is mainly used to treat liver diseases, alleviate cold fever, chills, chest pain, regulate menstruation, and improve uterine prolapsed (Zhou <xref rid="CIT0122" ref-type="bibr">2003</xref>). In particular, Radix Bupleuri also plays a significant role in the treatment of malaria (Xue et al. <xref rid="CIT0107" ref-type="bibr">1996</xref>). Importantly, Radix Bupleuri is usually used as monarch drug in many traditional Chinese prescriptions.</p><p>To date, Radix Bupleuri has been used in about 150 traditional Chinese prescriptions. Among them, <italic>Xiao Chai Hu Tang</italic>, <italic>Chai Hu Gui Zhi Tang</italic>, and <italic>Xiao Yao San</italic> are very famous in TCM. <italic>Xiao Chai Hu</italic> decoction, including Radix Bupleuri, pinellia (the tuber of <italic>Pinellia ternata</italic> (Thunb.) Breit., <italic>Banxia</italic> in Chinese) and skullcap (the root of <italic>Scutellaria baicalensis</italic> Georgi, <italic>Huangqin</italic> in Chinese), is used to treat malaria and jaundice. When Radix Bupleuri combines with cassia twig (the twig of <italic>Cinnamomum cassia</italic> Presl, <italic>Guizhi</italic> in Chinese), it is called <italic>Chai Hu Gui Zhi</italic> decoction which is often used for regulating liver-<italic>qi</italic>, clearing heat, and lifting yang <italic>qi</italic>. <italic>Xiao Yao San</italic>, composed of Radix Bupleuri, Poria (<italic>Poria cocos</italic> (Schw.) Wolf), Radix Paeoniae Alba (<italic>Paeonia lactiflora</italic> Pall.), Radix Angelicae Sinensis (<italic>Angelica sinensis</italic> (Oliv.) Diels), Rhizoma Atractylodis Macrocephalae (<italic>Atractylodes macrocephala</italic> Koidz.), Herba Menthae (<italic>Mentha haplocalyx</italic> Briq.), and Rhizoma Zingiberis Recens (<italic>Zingiber officinale</italic> Rosc.), has been widely used in clinic for treating mental disorders, such as depression and irregular menstruation. In addition, combination with ginseng (<italic>Panax ginseng</italic> C.A.Mey.) and Radix Astragali (<italic>Astragalus membranaceus</italic> (Fisch.) Bge.). Radix Bupleuri is also used to treat hemorrhoids, anal and uterine complications, and diarrhea (1998; 1999; World Health Organization <xref rid="CIT0096" ref-type="bibr">1997</xref>). Inspired by the role in regulating metabolism and controlling <italic>Yin</italic>/<italic>Yang</italic> as mentioned in the traditional Chinese medicine, Radix Bupleuri is also widely used in Korea and Japan (Van & Wink <xref rid="CIT0083" ref-type="bibr">2004</xref>; Pan <xref rid="CIT0074" ref-type="bibr">2006</xref>).</p></sec><sec id="s0019"><title>Applications of Radix Bupleuri in modern Chinese medicine</title><p>With the development of TCM modernization, more Radix Bupleuri preparations have been developed, such as <italic>Xiao Chai Hu</italic> tablets, <italic>Chai Hu</italic> dripping pills, <italic>Chai Hu</italic> injection and <italic>Chai Hu Shu Gan</italic> pills (Li et al. <xref rid="CIT0052" ref-type="bibr">2014a</xref>). The preparations from Radix Bupleuri approved by CFDA from June 2010 to October 2015 are given in <xref rid="t0005" ref-type="table">Table 5</xref>. Among them, <italic>Chai Hu</italic> injection is the first successful traditional Chinese medicine injection having been used in clinic since 1940s, which is widely used to treat fever caused by influenza or common cold and malaria (Zuo et al. <xref rid="CIT0125" ref-type="bibr">2013</xref>). Moreover, some new dosage forms of Radix Bupleuri have been prepared. A nasal temperature-sensitive <italic>in situ</italic> gel system is developed, which is more effective for the treatment of fever than the traditional nasal spray (Chen et al. <xref rid="CIT0006" ref-type="bibr">2010</xref>). Another benefit of this novel <italic>in situ</italic> gel is that it exhibits more noticeable antipyretic effects and remains much more time (Cao et al. <xref rid="CIT0005" ref-type="bibr">2007</xref>). Besides, the Radix Bupleuri suppositoria is very suitable for kids without pain (Wang & Chen <xref rid="CIT0088" ref-type="bibr">2003</xref>).</p><table-wrap id="t0005" orientation="portrait" position="float"><label>Table 5.</label><caption><p>The preparations from Bupleuri Radix approved by CFDA.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col><col width="80pt" align="left"></col></colgroup><thead><tr><th align="left">Components</th><th align="center">Dosage forms</th><th align="center">China Approved Drug Names (CADN)</th><th align="center">Batch number</th><th align="center">Approval date</th><th align="center">Drug standard code</th></tr></thead><tbody valign="top"><tr><td align="left">Radix Bupleuri extract, poly yamanashi ester-80, sodium chloride</td><td align="left">Injection</td><td align="left"><italic>Chai Hu</italic> Injection</td><td align="left">Z61021126</td><td align="char" char=".">07/2013</td><td align="char" char=".">86902434000703</td></tr><tr><td align="left">Radix Bupleuri dry extract</td><td align="left">Tablet</td><td align="left"><italic>Chai Hu</italic> Cough Tablets</td><td align="left">Z42020845</td><td align="char" char=".">06/2015</td><td align="char" char=".">86901876000227</td></tr><tr><td align="left">Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice and jujube</td><td align="left">Tablet</td><td align="left"><italic>Xiao Chai Hu</italic> Tablets</td><td align="left">Z20023393</td><td align="char" char=".">10/2015</td><td align="char" char=".">86903050000405</td></tr><tr><td align="left">Radix bupleuri, polyethylene glycol</td><td align="left">Dripping Pill</td><td align="left"><italic>Chai Hu</italic> Dripping Pills</td><td align="left">Z20020053</td><td align="char" char=".">07/2015</td><td align="char" char=".">86900941000063</td></tr><tr><td align="left">Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice and jujube</td><td align="left">Decoction Pill</td><td align="left"><italic>Xiao Chai Hu</italic> Decoction Pills</td><td align="left">Z41021830</td><td align="char" char=".">06/2015</td><td align="char" char=".">86903082001340</td></tr><tr><td align="left">Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice, jujube</td><td align="left">Particle</td><td align="left"><italic>Xiao Chai Hu</italic> Particles</td><td align="left">Z34020723</td><td align="char" char=".">05/2015</td><td align="char" char=".">86904366000721</td></tr><tr><td align="left">Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice, jujube</td><td align="left">Capsule</td><td align="left"><italic>Xiao Chai Hu</italic> Capsules</td><td align="left">Z20090882</td><td align="char" char=".">08/2014</td><td align="char" char=".">86904641002884</td></tr><tr><td align="left">Radix Bupleuri, scutellaria, rhubarb, immature bitter orange, pinellia, paeoniae, jujube, ginger</td><td align="left">Particle</td><td align="left"><italic>Da Chai Hu</italic> Particles</td><td align="left">Z20080007</td><td align="char" char=".">02/2013</td><td align="char" char=".">86901622002642</td></tr><tr><td align="left">Radix Bupleuri, tangerine peel, ligustici, rhizoma cyperi, hoveniadulcis, paeoniae, licorice</td><td align="left">Pill</td><td align="left"><italic>Chai Hu Shu Gan</italic> Pills</td><td align="left">Z20073333</td><td align="char" char=".">07/2015</td><td align="char" char=".">86901174000103</td></tr><tr><td align="left">Radix Bupleuri extract</td><td align="left">Oral Liquid</td><td align="left"><italic>Chai Hu</italic> Oral Liquid</td><td align="left">Z20020107</td><td align="char" char=".">06/2010</td><td align="char" char=".">86903099000244</td></tr><tr><td align="left">Radix Bupleuri, sileris, tangerine peel, paeoniae, licorice, ginger</td><td align="left">Particle</td><td align="left"><italic>Zheng Chai Hu Yin</italic> Particles</td><td align="left">Z20003013</td><td align="char" char=".">06/2015</td><td align="char" char=".">86901622002086</td></tr><tr><td align="left">Radix Bupleuri, sileris, tangerine peel, paeoniae, licorice, ginger</td><td align="left">Capsule</td><td align="left"><italic>Zheng Chai Hu Yin</italic> Capsules</td><td align="left">Z20040013</td><td align="char" char=".">07/2015</td><td align="char" char=".">86904398000362</td></tr><tr><td align="left">Radix Bupleuri, sileris, tangerine peel, paeoniae, licorice, ginger</td><td align="left">Mist</td><td align="left"><italic>Zheng Chai Hu Yin</italic> Mixture</td><td align="left">Z20090749</td><td align="char" char=".">06/2014</td><td align="char" char=".">86901622002666</td></tr><tr><td align="left">Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice and jujube</td><td align="left">Effervescent tablet</td><td align="left"><italic>Xiao Chai Hu</italic> Effervescent Tablets</td><td align="left">Z20060458</td><td align="char" char=".">11/2011</td><td align="char" char=".">86900042000085</td></tr><tr><td align="left">Radix Bupleuri extract, acetaminophen</td><td align="left">Injection</td><td align="left">Paracetamol and Bupleurum Injection</td><td align="left">H52020518</td><td align="char" char=".">09/2010</td><td align="char" char=".">86905510000024</td></tr></tbody></table></table-wrap></sec><sec id="s0020"><title>Side effects of Radix Bupleuri</title><p>Radix Bupleuri is not defined as a toxic medicine in many official pharmacopeias, such as <italic>Chinese Pharmacopeia</italic> and <italic>Japanese Pharmacopeia</italic> (National Pharmacopoeia Committee <xref rid="CIT0072" ref-type="bibr">2010</xref>; Japanese Pharmacopoeia Editorial Board <xref rid="CIT0037" ref-type="bibr">2011</xref>). However, in practical use, it exhibits liver, kidney, and blood system toxicity by taking a large dose for a long period, while it shows no side effect without over-dose (Liu et al. <xref rid="CIT0064" ref-type="bibr">2012</xref>). <italic>Chai Hu</italic> injection may cause a hypersensitivity-like response, hypokalemia and renal failure. And one case is reported to die from severe hypersensitivity shock (Wu et al. <xref rid="CIT0102" ref-type="bibr">2014</xref>). So, the safety of Radix Bupleuri preparations is of great concern to us.</p><p>Saikosaponins and essential oils are believed to be the main compounds responsible for side effects of Radix Bupleuri (Liu et al. <xref rid="CIT0064" ref-type="bibr">2012</xref>). Essential oils from <italic>B. chinense</italic> cause hepatic injury when the dosage is about 1.5–3.4 times of the clinical daily dosage of Radix Bupleuri oral liquid (Sun & Yang <xref rid="CIT0078" ref-type="bibr">2011</xref>). Saikosaponins from <italic>B. chinense</italic> induce the hepatoxicity by causing liver cell damage and necrosis administrating continuously to rats for 15 days (Huang et al. <xref rid="CIT0034" ref-type="bibr">2010</xref>). SSd stimulates mitochondrial apoptosis in hepatocytes to exhibit its hepatotoxicity (Chen et al. <xref rid="CIT0008" ref-type="bibr">2013a</xref>).</p><p>Extracts of Radix Bupleuri also show some side effects. Extracts of <italic>B. chinense</italic> induce hepatotoxicity damage through oxidative damage mechanism, and the hepatotoxicity damage caused by the alcohol extracts is more serious than that caused by aqueous extracts (Lv et al. <xref rid="CIT0067" ref-type="bibr">2009</xref>). Furthermore, LD<sub>50</sub> (50% lethal dose) of the aqueous extracts of Radix Bupleuri after single oral treatment in female and male mice are considered to be over 2000 mg/kg (Kim et al. <xref rid="CIT0041" ref-type="bibr">2012a</xref>). In Kampo (Japanese traditional herbal) medicines, studies of some potential interactions between Radix Bupleuri and other drugs are considered, especially in prescriptions containing Radix Bupleuri, such as <italic>Shosaikoto</italic>, <italic>Daisaikoto</italic>, <italic>Saikokeishito</italic>, <italic>Hochuekkito</italic>, <italic>Saibokuto</italic> and <italic>Saireito</italic>. They may lead to anorexia, slight fever, and nausea (Ikegami et al. <xref rid="CIT0035" ref-type="bibr">2006</xref>).</p><p>Among other <italic>Bupleurum</italic> species, <italic>B. longiradiatum</italic> is a toxic herb in <italic>Chinese Pharmacopeia</italic> (National Pharmacopoeia Committee <xref rid="CIT0072" ref-type="bibr">2010</xref>), and it cannot be used as Radix Bupleuri. The main toxic compounds in <italic>B. longiradiatum</italic> are acetyl-bupleurotoxin, bupleurotoxin (Zhao et al. <xref rid="CIT0118" ref-type="bibr">1987</xref>) and polyene acetylene compounds, which are able to cause neurotoxicity (Chen et al. <xref rid="CIT0011" ref-type="bibr">1981</xref>).</p></sec><sec id="s0021"><title>Discussion and perspective</title><p>Saikosaponins, especially SSa and SSd, are the main active compounds in Radix Bupleuri. They are also prescribed as the marker compounds to evaluate the quality of Radix Bupleuri in <italic>Chinese Pharmacopeia</italic> (National Pharmacopoeia Committee <xref rid="CIT0072" ref-type="bibr">2010</xref>). They possess evident anti-inflammatory, antitumor, neuroregulation, hepatoprotection, immunoregulation, antiviral, and antioxidative activities. And what need to emphasize is that SSa has a strongest anti-inflammatory effect, and SSd possesses a strongest antitumor effect compared with other saikosaponins, and both SSb<sub>2</sub> and SSc have a better antiviral activity than SSa and SSd, which proves that the activities of different saikosaponins have some extent tendency. Inspired by this feature, we speculate that purified saikosaponin has more concentrated pharmacological activities than extracts.</p><p>Recently, more preparations containing Radix Bupleuri have been developed, such as <italic>Xiao Chai Hu</italic> tablets, <italic>Chai Hu</italic> dripping pills, <italic>Chai Hu</italic> injection, and <italic>Chai Hu Shu Gan</italic> pills (Li et al. <xref rid="CIT0052" ref-type="bibr">2014a</xref>). In these preparations the extracts of Radix Bupleuri, especially saikosaponins (Hu et al. <xref rid="CIT0032" ref-type="bibr">2011</xref>), are the main composition. Although <italic>B. chinense</italic> and <italic>B. scorzonerifolium</italic> are the only two original plants of Radix Bupleuri in <italic>Chinese Pharmacopeia</italic>, many other <italic>Bupleurum</italic> species are often used as Radix Bupleuri in China. However, the extracts of <italic>B. chinenes</italic>, <italic>B. falcatum</italic>, <italic>B. marginatum</italic>, <italic>B. yinchowense</italic>, <italic>B. kaoi</italic>, <italic>B. scorzonerifolium</italic>, and <italic>B. longiradiatum</italic> possess different pharmacological activities, such as the antitumor and antiviral activities of <italic>B. chinenes</italic> extracts, and the anti-inflammatory, anti-hyperthyroidism and neuroregulation activities of <italic>B. falcatum</italic> extracts. Because the quality, botanic characteristic and property, and pharmacological activities of different <italic>Bupleurum</italic> species are different, the standardization of Bupleuri Radix extracts is vital for the safe use of Radix Bupleuri.</p><p>In addition, there are many other compounds in Radix Bupleuri, such as polysaccharides and essential oils. Polysaccharides in Radix Bupleuri usually exert hepatoprotective and immunoregulation activities. The hepatoprotective effect of Radix Bupleuri polysaccharides is evaluated by measuring aspartate transaminase (AST), alanine transaminase, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) activities in the plasma of mice (Zhao et al. <xref rid="CIT0026" ref-type="bibr">2012</xref>), and Radix Bupleuri polysaccharides inhibits complement activation on both the classical and alternative pathways (DI HY et al. <xref rid="CIT0021" ref-type="bibr">2013</xref>). The essential oils of Radix Bupleuri have strong antimicrobial (Ashour et al. <xref rid="CIT0001" ref-type="bibr">2009</xref>) and antifungal activities (Mohammadi et al. <xref rid="CIT0070" ref-type="bibr">2014</xref>). Besides, Radix Bupleuri also contains a little lignans, which exhibit antitumor (Ou et al. <xref rid="CIT0073" ref-type="bibr">2012</xref>) and hepatoprotective activities (Lee et al. <xref rid="CIT0049" ref-type="bibr">2011</xref>, <xref rid="CIT0047" ref-type="bibr">2012</xref>). Since polysaccharides (Tong et al. <xref rid="CIT0081" ref-type="bibr">2013</xref>; Wu et al. <xref rid="CIT0099" ref-type="bibr">2013</xref>) and essential oils (Liu et al. <xref rid="CIT0060" ref-type="bibr">2009</xref>; Yan et al. <xref rid="CIT0108" ref-type="bibr">2014</xref>) have been found to possess excellent pharmacological activities so far, we suppose that the quality evaluation method should be updated to meet the need of clinical therapy.</p><p>Radix Bupleuri also exhibits some security problems in the clinic. Since ‘<italic>Xiao Chai Hu</italic> Decoction event’ occurred in late 1980s in Japan, the clinical safety of Radix Bupleuri has been considered (Wu et al. <xref rid="CIT0102" ref-type="bibr">2014</xref>). The reasons of toxicity are complex and there is a great individual variation in the susceptibility to Radix Bupleuri. The current researches have shown that the toxicity of Radix Bupleuri mainly associated with dosage and drug administration time (Liu et al. <xref rid="CIT0064" ref-type="bibr">2012</xref>). For example, SSd exhibits antitumor activity on carcinoma cell lines with dose-dependence, but when the dosage of SSd increased to a high level it would exert cytotoxicity (Zhang et al. <xref rid="CIT0116" ref-type="bibr">2015</xref>). 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