High-Throughput Screening to Identify Plant Derived Human LDH-A Inhibitors
Identifieur interne : 000A56 ( Pmc/Corpus ); précédent : 000A55; suivant : 000A57High-Throughput Screening to Identify Plant Derived Human LDH-A Inhibitors
Auteurs : S. Deiab ; E. Mazzio ; S. Messeha ; N. Mack ; K. F. A. SolimanSource :
- European journal of medicinal plants [ 2231-0894 ] ; 2013.
Abstract
Lactate dehydrogenase (LDH)-A is highly expressed in diverse human malignant tumors, parallel to aggressive metastatic disease, resistance to radiation/chemotherapy and clinically poor outcome. Although this enzyme constitutes a plausible target in treatment of advanced cancer, there are few known LDH-A inhibitors.
In this work, we utilized a high-throughput enzyme micro-array format to screen and evaluate > 900 commonly used medicinal plant extracts (0.00001-.5
The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis- MALDI
Of the natural extracts tested, the lowest IC50s [<0.001 mg/ml] were obtained by: Chinese Gallnut (
These findings reflect relative potency by rank of commonly used herbs and plants that contain human LDH-A inhibitory properties. Future research will be required to isolate chemical constituents within these plants responsible for LDH-A inhibition and investigate potential therapeutic application.
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PubMed: 24478981
PubMed Central: 3903096
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">High-Throughput Screening to Identify Plant Derived Human LDH-A Inhibitors</title><author><name sortKey="Deiab, S" sort="Deiab, S" uniqKey="Deiab S" first="S." last="Deiab">S. Deiab</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author><author><name sortKey="Mazzio, E" sort="Mazzio, E" uniqKey="Mazzio E" first="E." last="Mazzio">E. Mazzio</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author><author><name sortKey="Messeha, S" sort="Messeha, S" uniqKey="Messeha S" first="S." last="Messeha">S. Messeha</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author><author><name sortKey="Mack, N" sort="Mack, N" uniqKey="Mack N" first="N." last="Mack">N. Mack</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author><author><name sortKey="Soliman, K F A" sort="Soliman, K F A" uniqKey="Soliman K" first="K. F. A." last="Soliman">K. F. A. Soliman</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24478981</idno><idno type="pmc">3903096</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903096</idno><idno type="RBID">PMC:3903096</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000A56</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A56</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">High-Throughput Screening to Identify Plant Derived Human LDH-A Inhibitors</title><author><name sortKey="Deiab, S" sort="Deiab, S" uniqKey="Deiab S" first="S." last="Deiab">S. Deiab</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author><author><name sortKey="Mazzio, E" sort="Mazzio, E" uniqKey="Mazzio E" first="E." last="Mazzio">E. Mazzio</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author><author><name sortKey="Messeha, S" sort="Messeha, S" uniqKey="Messeha S" first="S." last="Messeha">S. Messeha</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author><author><name sortKey="Mack, N" sort="Mack, N" uniqKey="Mack N" first="N." last="Mack">N. Mack</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author><author><name sortKey="Soliman, K F A" sort="Soliman, K F A" uniqKey="Soliman K" first="K. F. A." last="Soliman">K. F. A. Soliman</name><affiliation><nlm:aff id="A1">College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</nlm:aff></affiliation></author></analytic><series><title level="j">European journal of medicinal plants</title><idno type="eISSN">2231-0894</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Aims</title><p id="P1">Lactate dehydrogenase (LDH)-A is highly expressed in diverse human malignant tumors, parallel to aggressive metastatic disease, resistance to radiation/chemotherapy and clinically poor outcome. Although this enzyme constitutes a plausible target in treatment of advanced cancer, there are few known LDH-A inhibitors.</p></sec><sec id="S2"><title>Study Design</title><p id="P2">In this work, we utilized a high-throughput enzyme micro-array format to screen and evaluate > 900 commonly used medicinal plant extracts (0.00001-.5 <italic>mg/ml</italic>) for capacity to inhibit activity of recombinant full length human LDHA; EC .<italic>1.1.1.27</italic>.</p></sec><sec id="S3"><title>Methodology</title><p id="P3">The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis- MALDI<italic>-TOF-</italic>MS/MS, enzyme activity was validated by oxidation of NADH (500μM) and kinetic inhibition established in the presence of a known inhibitor (Oxalic Acid).</p></sec><sec id="S4"><title>Results</title><p id="P4">Of the natural extracts tested, the lowest IC<sub>50</sub>s [<0.001 mg/ml] were obtained by: Chinese Gallnut (<italic>Melaphis chinensis gallnut)</italic>, Bladderwrack (<italic>Fucus vesiculosus)</italic>, Kelp (<italic>Laminaria Japonica</italic>) and Babul (<italic>Acacia Arabica)</italic>. Forty-six additional herbs contained significant LDH-A inhibitory properties with IC<sub>50</sub>s [<0.07 mg/ml], some of which have common names of Arjun, Pipsissewa, Cinnamon, Pink Rose Buds/Petals, Wintergreen, Cat’s Claw, Witch Hazel Root and Rhodiola Root.</p></sec><sec id="S5"><title>Conclusion</title><p id="P5">These findings reflect relative potency by rank of commonly used herbs and plants that contain human LDH-A inhibitory properties. 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article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101583475</journal-id><journal-id journal-id-type="pubmed-jr-id">40208</journal-id><journal-id journal-id-type="nlm-ta">European J Med Plants</journal-id><journal-id journal-id-type="iso-abbrev">European J Med Plants</journal-id><journal-title-group><journal-title>European journal of medicinal plants</journal-title></journal-title-group><issn pub-type="epub">2231-0894</issn></journal-meta><article-meta><article-id pub-id-type="pmid">24478981</article-id><article-id pub-id-type="pmc">3903096</article-id><article-id pub-id-type="manuscript">NIHMS543685</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>High-Throughput Screening to Identify Plant Derived Human LDH-A Inhibitors</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Deiab</surname><given-names>S.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mazzio</surname><given-names>E.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Messeha</surname><given-names>S.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mack</surname><given-names>N.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Soliman</surname><given-names>K. F. A.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN1" ref-type="author-notes">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA</aff><author-notes><corresp id="FN1"><label>*</label>Corresponding author: <email>karam.soliman@famu.edu</email>;</corresp></author-notes><pub-date pub-type="nihms-submitted"><day>6</day><month>1</month><year>2014</year></pub-date><pub-date pub-type="epub"><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>27</day><month>1</month><year>2014</year></pub-date><volume>3</volume><issue>4</issue><fpage>603</fpage><lpage>615</lpage><permissions><copyright-statement>© 2013 Deiab et al.;</copyright-statement><copyright-year>2013</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/3.0"><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/3.0">http://creativecommons.org/licenses/by/3.0</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><sec id="S1"><title>Aims</title><p id="P1">Lactate dehydrogenase (LDH)-A is highly expressed in diverse human malignant tumors, parallel to aggressive metastatic disease, resistance to radiation/chemotherapy and clinically poor outcome. Although this enzyme constitutes a plausible target in treatment of advanced cancer, there are few known LDH-A inhibitors.</p></sec><sec id="S2"><title>Study Design</title><p id="P2">In this work, we utilized a high-throughput enzyme micro-array format to screen and evaluate > 900 commonly used medicinal plant extracts (0.00001-.5 <italic>mg/ml</italic>) for capacity to inhibit activity of recombinant full length human LDHA; EC .<italic>1.1.1.27</italic>.</p></sec><sec id="S3"><title>Methodology</title><p id="P3">The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis- MALDI<italic>-TOF-</italic>MS/MS, enzyme activity was validated by oxidation of NADH (500μM) and kinetic inhibition established in the presence of a known inhibitor (Oxalic Acid).</p></sec><sec id="S4"><title>Results</title><p id="P4">Of the natural extracts tested, the lowest IC<sub>50</sub>s [<0.001 mg/ml] were obtained by: Chinese Gallnut (<italic>Melaphis chinensis gallnut)</italic>, Bladderwrack (<italic>Fucus vesiculosus)</italic>, Kelp (<italic>Laminaria Japonica</italic>) and Babul (<italic>Acacia Arabica)</italic>. Forty-six additional herbs contained significant LDH-A inhibitory properties with IC<sub>50</sub>s [<0.07 mg/ml], some of which have common names of Arjun, Pipsissewa, Cinnamon, Pink Rose Buds/Petals, Wintergreen, Cat’s Claw, Witch Hazel Root and Rhodiola Root.</p></sec><sec id="S5"><title>Conclusion</title><p id="P5">These findings reflect relative potency by rank of commonly used herbs and plants that contain human LDH-A inhibitory properties. Future research will be required to isolate chemical constituents within these plants responsible for LDH-A inhibition and investigate potential therapeutic application.</p></sec></abstract><kwd-group><kwd>Lactic acid</kwd><kwd>Warburg</kwd><kwd>LDH-A</kwd><kwd>inhibitor</kwd><kwd>herbs</kwd><kwd>medicinal plants</kwd></kwd-group></article-meta></front><body><sec id="S6"><title>1. INTRODUCTION</title><p id="P6">Human lactate dehydrogenase is a tetrameric enzyme [<xref rid="R1" ref-type="bibr">1</xref>] highly expressed in smooth muscle. The LDH subtype A is up-regulated in diverse tumor tissues [<xref rid="R2" ref-type="bibr">2</xref>] including lung [<xref rid="R3" ref-type="bibr">3</xref>], pheochromocytoma, paraganglioma [<xref rid="R4" ref-type="bibr">4</xref>], esophageal squamous cell carcinoma [<xref rid="R5" ref-type="bibr">5</xref>], breast [<xref rid="R6" ref-type="bibr">6</xref>], endometrial adenocarcinoma, ovarian cystadenocarcinoma [<xref rid="R7" ref-type="bibr">7</xref>], hereditary leiomyomatosis renal carcinoma [<xref rid="R8" ref-type="bibr">8</xref>] and colon carcinoma [<xref rid="R9" ref-type="bibr">9</xref>–<xref rid="R11" ref-type="bibr">11</xref>]. Unlike normal differentiated cells where lactate accumulation occurs anaerobically, cancer cells readily convert glucose into lactate aerobically, a phenomenon termed the Warburg effect [<xref rid="R12" ref-type="bibr">12</xref>]. Elevated protein expression or enzyme function of LDH–A is a contributor to not only accumulated lactate, but also aggressive tumor growth [<xref rid="R13" ref-type="bibr">13</xref>], advanced progression [<xref rid="R14" ref-type="bibr">14</xref>], metastasis [<xref rid="R15" ref-type="bibr">15</xref>–<xref rid="R17" ref-type="bibr">17</xref>], acidity [<xref rid="R18" ref-type="bibr">18</xref>], and subsequent resistance to radiation and chemotherapy [<xref rid="R19" ref-type="bibr">19</xref>–<xref rid="R22" ref-type="bibr">22</xref>]. LDH–A knockdown, or lowering the functional capacity of LDH-A can suppress tumor growth and metastasis [<xref rid="R23" ref-type="bibr">23</xref>], indicating that this enzyme could serve as a novel targeted cancer therapy strategy. In this study, we elucidate LDH–A inhibitory effects of commonly used medicinal herbal extracts rom around the world.</p></sec><sec id="S7"><title>2. METHODOLOGY</title><p id="P7">Hanks Balanced Salt Solution, (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES), iodoacetamide, DL-Dithiothreitol (DTT), ethanol, 96 well plates, general reagents and supplies were all purchased from Sigma Scientific (Sigma, St Louis MO), LDH-A was purchased from Abcam (Cambridge, MA). Natural products were provided by Frontier Natural Products Co-op (Norway, IA), Montery Bay Spice Company (Watsonville, CA), Mountain Rose Herbs (Eugene, OR), Mayway Traditional Chinese Herbs (Oakland, California), Kalyx Natural Marketplace (Camden, NY), Futureceuticals (Momence, IL), organic fruit vegetable markets and Florida Food Products Inc. (Eustis, FL).</p><sec id="S8"><title>2.1 Herbal Extraction</title><p id="P8">Plant and herbal extracts were macerated, diced, chopped and homogenized in 100% ethanol at 50mg/ml. Samples were placed on a rocker shaker for 24 hours and stored in air tight containers at −20°C in the dark. All serial dilutions were made using a diluent consisting of HBSS with 10mM HEPES adjusted to a pH 7.4.</p></sec><sec id="S9"><title>2.2 MALDI MS/MS Protein Identification</title><p id="P9">Recombinant full length Human LDHA (amino acids 1–332) with N terminal His tag; 352 amino acids with tag, MW 38.8 kDa: Enzyme Commission (EC) Number 1.1.1.27 (BRENDA | IUBMB) (Abcam, Cambridge, MA) was utilized. The protein was validated by proteomic analysis using Matrix Assisted Laser Desorption Ionization (MALDI) Mass Spec (MS/MS) and analyzed by Mascot ID. Briefly, pure enzyme was solubilized, denatured and subjected to 1 D SDS page gel electrophoresis using a 5–20% Tris-HCL gradient gel with a running buffer 25 mM Tris, 192 mM glycine, 0.1% SDS at 200 V for 35 minutes. High intensity bands for LDH-A at 38 KD were visualized with G-Biosciences’ LabSafe GEL Blue<sup>™</sup> stain, then excised, followed by in gel digestion of peptides with trypsin, followed by reduction/alkylation with DTT and iodoacetamide, respectively. Samples were analyzed using MALDI MS/MS (Applied Biosystems) and protein sequence identified by Mascot analysis.</p></sec><sec id="S10"><title>2.3 LDH-A Activity</title><p id="P10">A continuous LDH-A assay was used to conduct high-throughput screening (HTS). Briefly, a buffer consisted of HBSS + calcium and magnesium pH adjusted to 7.0. LDH-A enzyme (final concentration .02 Units/ml) was added to treatments of tier one, with concentrations of .5 mg/ml. After addition of β-Nicotinamide Adenine Dinucleotide, Reduced Form Solution (β-NADH) (final working concentration of 500μM) a pre-reading @ 340nm was established and the reaction was started with a solution of substrate pyruvate (final concentration = 3mM).</p></sec><sec id="S11"><title>2.4 High Throughput Design</title><p id="P11">A rapid screening model was used based on works previously described [<xref rid="R24" ref-type="bibr">24</xref>]. An enzyme micro-array format was adapted to where a 96 well plate contained a known concentration of enzyme, and treatments of equal concentration dissolved in buffered HBSS and β-NADH. After addition of the substrate (pyruvate) a curve for time dependent NADH oxidation was monitored continuously over 75 minutes @340nm. A first tier investigation was established at a final working concentration of 0.5 mg/ml for each herbal extract. All compounds that inhibited LDH-A with in the first tier screen below 50% of control, were then placed in a second tier (final concentration = 0.25 mg/ml), third tier (final concentration =0.1 mg/ml) and fourth tier (final concentrations with extended range at 0.006, 0.03 and 0.16 mg/ml). Extracts were ranked for potency, and the most potent were further evaluated over a minimum of 6 concentrations from 1mg/ml to less than 0.00001 mg/ml to establish an IC<sub>50</sub>. The enzyme micro-array format was rapid, reproducible and repeatedly corroborated by a four-tier evaluation process.</p></sec><sec id="S12"><title>2.5 Data Analysis</title><p id="P12">Statistical analysis was performed using Graph Pad Prism (version 3.0; Graph Pad Software Inc. San Diego, CA, USA) with significance of difference between the groups assessed using a one-way ANOVA, followed by Tukey post hoc means comparison test, a two way ANOVA or Student’s t test. IC<sub>50</sub>s were determined by regression analysis using Origin Software (OriginLab, Northampton, MA).</p></sec></sec><sec id="S13"><title>3. RESULTS AND DISCUSSION</title><p id="P13">Method validation was established by monitoring continuous NADH oxidation initiated by addition of the substrate pyruvic acid (3mM) in the presence of varying enzyme concentration/time (<xref rid="F1" ref-type="fig">Fig. 1a</xref>)</p><p id="P14">A screening validation process was established using 0.02 U/ml LDH-A over 75 minutes (<xref rid="F1" ref-type="fig">Fig. 1b</xref>) ± a known inhibitor; oxalic acid (<xref rid="F1" ref-type="fig">Fig. 1c</xref>). The data shows a slow but steady rate of reaction, resulting in time dependent O.D. decay over 65–70 minutes with high signal/noise ratio.</p><p id="P15">Although the enzyme used in this screening, was described as a recombinant full length Human LDHA (amino acids 1–332) with N terminal His tag; 352 amino acids with tag, MW 38.8 kDa: Enzyme Commission (EC) Number 1.1.1.27 (BRENDA | IUBMB) (Abcam, Cambridge, MA), we confirmed the identity of the enzyme using Matrix Assisted Laser Desorption Ionisation (MALDI) Mass Spec (MS/MS) and analysis by Mascot ID (<xref rid="F2" ref-type="fig">Fig. 2</xref>). <xref rid="F2" ref-type="fig">Fig. 2</xref> (Top panel) shows the 1 D SDS page gel electrophoresis of the purified enzyme at three concentrations (right), along with a molecular marker standard (left). The gel band was excised, digested and analyzed by MSMS for peptide sequence and protein identify (Bottom Panel). The data showed a positive hit for human LDH-A with a 95% confidence interval for peptide/sequence mass.</p><p id="P16">A high throughput enzyme micro-array model was used in this work. Over 900 extracts of equal concentration (0.5 mg/ml) were dissolved in buffered HBSS and incubated with the enzyme, for 5 minutes prior to start of the reaction. After addition of the substrate, a curve for time dependent product formation was monitored continuously over 75 minutes. <xref rid="F3" ref-type="fig">Fig. 3</xref> represents the 75 minute reading taken from the original screening with values for each compound sorted according to inhibitory potency. Of the initially tested extracts, only 115 inhibited LDH-A within the first tier below 50% of control, denoted by red dotted line --- (<xref rid="F3" ref-type="fig">Fig. 3</xref>). These plant extracts were then subject to a second tier screenings (final concentration = 0.25 mg/ml), third tier screenings (final concentration =0.1 mg/ml) and fourth tier screenings (final concentrations with extended range at 0.006 to 0.16 mg/ml) to which regression analysis was used to calculate IC<sub>50</sub>s.</p><p id="P17">Of the 115 retested, 46 extracts showed an IC<sub>50</sub> <0.077 mg/ml <xref rid="T1" ref-type="table">Table 1</xref> as listed by potency rank. Full inhibitory dose response curves are shown for the top four inhibitors (<xref rid="F4" ref-type="fig">Fig. 4</xref>).</p><p id="P18"><xref rid="T1" ref-type="table">Table 1</xref> Human LDH-A inhibitors by potency. Extract IC<sub>50</sub>s are listed by both mg/ml and μg/ml for inhibiting NADH oxidation on .02U/ml of LDHA.</p></sec><sec id="S14"><title>4. DISCUSSION</title><p id="P19">In this HTS study, we investigated the ethanol extract of 905 natural products to identify those with human LDH-A inhibitor properties. Our results show Melaphis chinensis gallnut, also known as Rhus chinensis (RC) nut, to be the most potent and within a therapeutic range. Rhus chinensis belongs to family Anacardiaceae and genus Rhus. This family, consists of 250 species found in China [<xref rid="R25" ref-type="bibr">25</xref>] and many other locations around the world. Numerous traditional Chinese herbalists recommend RC for ailments such as chronic cough due to lung deficiency, chronic diarrhea and for clearing toxins. Unfortunately, these claims are not based on scientific grounds, yet the interest in this herb continues to increase for its numerous scientifically based findings. There is an abundance of research on the biological and pharmacological benefits of RC. For example, it was shown to be very effective in harmful intestinal and periodontal bacterial growth inhibition by a mechanism mediated in parts by its constituent’s gallic acid and gallotaninns [<xref rid="R26" ref-type="bibr">26</xref>–<xref rid="R28" ref-type="bibr">28</xref>]. As an antiviral, RC ethyl acetate extract has inhibitory effects against hepatitis carcinoma virus [<xref rid="R29" ref-type="bibr">29</xref>,<xref rid="R30" ref-type="bibr">30</xref>] and severe acute respiratory syndrome corona virus [<xref rid="R30" ref-type="bibr">30</xref>]. Penta-1,2,3,4,6-O-galloyl-β-D-glucose (PGG) isolated from RC shows promising hepatoprotective properties [<xref rid="R31" ref-type="bibr">31</xref>] and the anticancer effects of RC are believed to involve inhibition of dcd25A phosphotase activity [<xref rid="R32" ref-type="bibr">32</xref>] or gallic acid as one of the bioactive components in RC [<xref rid="R26" ref-type="bibr">26</xref>,<xref rid="R33" ref-type="bibr">33</xref>,<xref rid="R34" ref-type="bibr">34</xref>] which directly induces apoptosis in prostate cancer cells [<xref rid="R35" ref-type="bibr">35</xref>]. PGG was also shown by Huh et al, to be a constituent in RC with ability to inhibit angiogenesis and stimulate apoptosis [<xref rid="R36" ref-type="bibr">36</xref>]. In addition, PGG reduced cancer cell viability [<xref rid="R37" ref-type="bibr">37</xref>] as well as suppressed prostate cancer, bone metastasis [<xref rid="R38" ref-type="bibr">38</xref>] and caused cell cycle arrest at the G1 phase [<xref rid="R39" ref-type="bibr">39</xref>].</p></sec><sec id="S15"><title>5. CONCLUSION</title><p id="P20">The findings in this study, while broad show that a number of natural products have the ability to inhibit LDH-A, which may adversely affect cancer cell survival. We present evidence for LDH-A inhibitory properties of a number of commonly used herbs and spices with previously reported anti-cancer properties including bladderwrack [<xref rid="R40" ref-type="bibr">40</xref>], kelp [<xref rid="R41" ref-type="bibr">41</xref>], cinnamon [<xref rid="R42" ref-type="bibr">42</xref>], cats claw bark [<xref rid="R43" ref-type="bibr">43</xref>], arjun [<xref rid="R44" ref-type="bibr">44</xref>], polygonum multiflorum [<xref rid="R45" ref-type="bibr">45</xref>] and witch hazel [<xref rid="R46" ref-type="bibr">46</xref>]. Future research will be required to evaluate if LDH-A inhibition is a contributing factor to tumoricidal or anti-proliferative properties of these herbs on diverse human cancer cells.</p></sec></body><back><ack id="S16"><p>This research was supported by a grant from NIH NCRR RCMI program (G12RR 03020) and the National Institute on Minority Health and Health Disparities, NIH (8G12MD007582-28 and 1P20 MD006738-01).</p></ack><fn-group><fn id="FN2" fn-type="con"><p><bold>Authors’ contributions</bold></p><p>This work was carried out in collaboration between all authors. Author SD prepared the extracts, performed the preliminary screening and wrote the discussion and introduction. Authors EM, SM and NM corroborated screening results, established enzyme kinetics, inhibitor controls and protein identification validation. Author KFAS was involved with planning studies, drafting manuscript and overseeing research. 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Human LDH-A Activity-time and enzyme concentration dependent NADH oxidation in the presence of 3mM pyruvate. The data represent μM NADH reduced from 0–75 minutes (incubation at RT) and are presented as the Mean ± S.E.M, n=4. Significance of difference for product formation between Time <sub>0</sub> vs Time <sub>15 – 75 minutes</sub> were determined using a two-way ANOVA.* p< 0.05</p><p>Fig. 1b. <italic>Human</italic> LDH Activity at .02 Units/ml with time dependent NADH oxidation in the presence of 3mM pyurvate. The data represent μM NADH and are presented as the Mean ± S.E.M, n=4. Significance of difference for product formation between Time <sub>0</sub> vs Time <sub>75 minutes</sub> was determined using a one-way ANOVA followed by a Tukey post hoc test. * p<0 .05</p><p>Fig. 1c. Human LDH Activity – Inhibitor Control. The data represent % Enzyme Activity @ 75 Minutes and are presented as the Mean ± S.E.M, n=4. Significance of difference for enzyme activity between the control and oxalic acid (0.9–11.3 mM) was determined using a one-way ANOVA followed by a Tukey post hoc test. * p<0 .05</p></caption><graphic xlink:href="nihms543685f1a"></graphic><graphic xlink:href="nihms543685f1b"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Fig. 2</label><caption><p>Mascot results for protein identification by peptide mass fingerprinting of Human LDH-A tryptic digest analyzed by MALDI-TOF/TOF-MS</p></caption><graphic xlink:href="nihms543685f2"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Fig. 3</label><caption><p>A high-throughput enzyme experimental micro-array design. 905 extracts were evaluated for capacity to inhibit <italic>Human</italic> LDH-A. A first tier screening was conducted at a final working concentration of 0.5 mg/ml for each herbal extract. Enzyme activity was continuously monitored over a 75 min period. Extracts demonstrating an IC<sub>50</sub> <0.5 mg/ml (red dotted line -----) were screened through subsequent tier evaluations</p></caption><graphic xlink:href="nihms543685f3"></graphic></fig><fig id="F4" orientation="portrait" position="float"><label>Fig. 4</label><caption><p>Most Potent Herbal Extract Inhibitors of <italic>Human</italic> LDH-A activity. The data represent LDH-A activity as % control in the presence or absence of extracts and are presented as Mean ± S.E.M., n=4. IC<sub>50</sub> concentrations were established from a sigmoidal fit dose-response equation and significance of difference between the controls vs. treatment was determined using a one-way ANOVA followed by a Tukey post hoc test. * p<0.05</p></caption><graphic xlink:href="nihms543685f4"></graphic></fig><table-wrap id="T1" position="float" orientation="landscape"><label>Table 1</label><caption><p>Natural source aqueous extracts with human LDH-A inhibitory potency by rank</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="bottom" align="right" rowspan="1" colspan="1">Rank</th><th valign="bottom" align="center" rowspan="1" colspan="1">ID No.</th><th valign="bottom" align="left" rowspan="1" colspan="1">Common ± Chinese Name</th><th valign="bottom" align="left" rowspan="1" colspan="1"><italic>Scientific Name</italic></th><th valign="bottom" align="center" rowspan="1" colspan="1">IC 50 mg/ml</th><th valign="bottom" align="center" rowspan="1" colspan="1">IC 50 μg/ml</th></tr></thead><tbody><tr><td align="right" valign="top" rowspan="1" colspan="1">1</td><td align="center" valign="top" rowspan="1" colspan="1">M22</td><td align="left" valign="top" rowspan="1" colspan="1">Wu Bei Zi</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Melaphis chinensis gallnut</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00009</td><td align="center" valign="top" rowspan="1" colspan="1">0.09</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">4</td><td align="center" valign="top" rowspan="1" colspan="1">B53</td><td align="left" valign="top" rowspan="1" colspan="1">Babul Chall Bark</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Acacia arabica</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00075</td><td align="center" valign="top" rowspan="1" colspan="1">0.75</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">2</td><td align="center" valign="top" rowspan="1" colspan="1">F17</td><td align="left" valign="top" rowspan="1" colspan="1">Bladderwrack</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Fucus vesiculosus</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00100</td><td align="center" valign="top" rowspan="1" colspan="1">1.00</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">3</td><td align="center" valign="top" rowspan="1" colspan="1">K06</td><td align="left" valign="top" rowspan="1" colspan="1">Kelp Powder</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Laminaria Japonica</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00134</td><td align="center" valign="top" rowspan="1" colspan="1">1.34</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">5</td><td align="center" valign="top" rowspan="1" colspan="1">B13</td><td align="left" valign="top" rowspan="1" colspan="1">Bayberry Root bark</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Morella cerifera</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00158</td><td align="center" valign="top" rowspan="1" colspan="1">1.58</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">6</td><td align="center" valign="top" rowspan="1" colspan="1">C8</td><td align="left" valign="top" rowspan="1" colspan="1">CraneSbill Root</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Geranium maculatum</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00173</td><td align="center" valign="top" rowspan="1" colspan="1">1.73</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">7</td><td align="center" valign="top" rowspan="1" colspan="1">A78</td><td align="left" valign="top" rowspan="1" colspan="1">Arjun</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Terminalia arjuna</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00183</td><td align="center" valign="top" rowspan="1" colspan="1">1.83</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">8</td><td align="center" valign="top" rowspan="1" colspan="1">P54</td><td align="left" valign="top" rowspan="1" colspan="1">Ye Jiao Ten</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Polygonum multiflorum vine</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00288</td><td align="center" valign="top" rowspan="1" colspan="1">2.88</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">9</td><td align="center" valign="top" rowspan="1" colspan="1">P56</td><td align="left" valign="top" rowspan="1" colspan="1">Mu Dan Pi</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Paeonia suffructicose root - bark</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00298</td><td align="center" valign="top" rowspan="1" colspan="1">2.98</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">10</td><td align="center" valign="top" rowspan="1" colspan="1">W2</td><td align="left" valign="top" rowspan="1" colspan="1">Witch Hazel Root</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Hamamelis virginiana</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00321</td><td align="center" valign="top" rowspan="1" colspan="1">3.21</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">11</td><td align="center" valign="top" rowspan="1" colspan="1">P82</td><td align="left" valign="top" rowspan="1" colspan="1">Pipsissewa</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Chimaphila umbellata</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00410</td><td align="center" valign="top" rowspan="1" colspan="1">4.10</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">12</td><td align="center" valign="top" rowspan="1" colspan="1">C82</td><td align="left" valign="top" rowspan="1" colspan="1">Cinnamon powder</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Cinnamon powder</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00434</td><td align="center" valign="top" rowspan="1" colspan="1">4.34</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">13</td><td align="center" valign="top" rowspan="1" colspan="1">R19</td><td align="left" valign="top" rowspan="1" colspan="1">Rose Buds and Petals Pink</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Rosa Rugosa Flower</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00478</td><td align="center" valign="top" rowspan="1" colspan="1">4.78</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">14</td><td align="center" valign="top" rowspan="1" colspan="1">C10</td><td align="left" valign="top" rowspan="1" colspan="1">Cat Claw Bark</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Uncaria tomentosa</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00483</td><td align="center" valign="top" rowspan="1" colspan="1">4.83</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">15</td><td align="center" valign="top" rowspan="1" colspan="1">D10</td><td align="left" valign="top" rowspan="1" colspan="1">Dryopteris Male Fern Rhizome</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Dryopteris crassirhizoma</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00636</td><td align="center" valign="top" rowspan="1" colspan="1">6.36</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">16</td><td align="center" valign="top" rowspan="1" colspan="1">R25</td><td align="left" valign="top" rowspan="1" colspan="1">Rhodiola Root</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Rhodiola kirilowii</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00809</td><td align="center" valign="top" rowspan="1" colspan="1">8.09</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">17</td><td align="center" valign="top" rowspan="1" colspan="1">T30</td><td align="left" valign="top" rowspan="1" colspan="1">Turkey Rhubarb</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Rheum palmatum</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.00958</td><td align="center" valign="top" rowspan="1" colspan="1">9.58</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">18</td><td align="center" valign="top" rowspan="1" colspan="1">G26</td><td align="left" valign="top" rowspan="1" colspan="1">Wintergreen</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Gaultheria procumbens</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.01086</td><td align="center" valign="top" rowspan="1" colspan="1">10.86</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">19</td><td align="center" valign="top" rowspan="1" colspan="1">XT76</td><td align="left" valign="top" rowspan="1" colspan="1">Longon Peel</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Dimocarpus longan</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.01195</td><td align="center" valign="top" rowspan="1" colspan="1">11.95</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">20</td><td align="center" valign="top" rowspan="1" colspan="1">H12</td><td align="left" valign="top" rowspan="1" colspan="1">Gloryvine Stem</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Sargentodoxa cuneata vine</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.01260</td><td align="center" valign="top" rowspan="1" colspan="1">12.60</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">21</td><td align="center" valign="top" rowspan="1" colspan="1">M6</td><td align="left" valign="top" rowspan="1" colspan="1">Meadowsweet Powder</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Filipendula ulmaria</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.01566</td><td align="center" valign="top" rowspan="1" colspan="1">15.66</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">22</td><td align="center" valign="top" rowspan="1" colspan="1">N2</td><td align="left" valign="top" rowspan="1" colspan="1">Neem Leaf</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Azadirachta indica</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.01836</td><td align="center" valign="top" rowspan="1" colspan="1">18.36</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">23</td><td align="center" valign="top" rowspan="1" colspan="1">T25</td><td align="left" valign="top" rowspan="1" colspan="1">Sang Ji Sheng</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Taxillus chinensis stem & leaf</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.02060</td><td align="center" valign="top" rowspan="1" colspan="1">20.60</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">24</td><td align="center" valign="top" rowspan="1" colspan="1">C32</td><td align="left" valign="top" rowspan="1" colspan="1">Cynomorium songaricum</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Cynomorium songaricum</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.02150</td><td align="center" valign="top" rowspan="1" colspan="1">21.50</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">25</td><td align="center" valign="top" rowspan="1" colspan="1">P55</td><td align="left" valign="top" rowspan="1" colspan="1">Chi Shao</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Paeonia Lactiflora</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.02283</td><td align="center" valign="top" rowspan="1" colspan="1">22.83</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">26</td><td align="center" valign="top" rowspan="1" colspan="1">P83</td><td align="left" valign="top" rowspan="1" colspan="1">Pygeum Bark</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Pygeum africanum</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.02623</td><td align="center" valign="top" rowspan="1" colspan="1">26.23</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">27</td><td align="center" valign="top" rowspan="1" colspan="1">P8</td><td align="left" valign="top" rowspan="1" colspan="1">Hu Zhang</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Polygonum cuspidatum rhizome</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.02842</td><td align="center" valign="top" rowspan="1" colspan="1">28.42</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">28</td><td align="center" valign="top" rowspan="1" colspan="1">XT 8</td><td align="left" valign="top" rowspan="1" colspan="1">Green Tea</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Camellia sinensis</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.02852</td><td align="center" valign="top" rowspan="1" colspan="1">28.52</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">29</td><td align="center" valign="top" rowspan="1" colspan="1">XT91</td><td align="left" valign="top" rowspan="1" colspan="1">Longon stem</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Dimocarpus longan</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.02973</td><td align="center" valign="top" rowspan="1" colspan="1">29.73</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">30</td><td align="center" valign="top" rowspan="1" colspan="1">A1</td><td align="left" valign="top" rowspan="1" colspan="1">Agrimony</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Agrimonia eupatoria</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.03072</td><td align="center" valign="top" rowspan="1" colspan="1">30.72</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">31</td><td align="center" valign="top" rowspan="1" colspan="1">L46</td><td align="left" valign="top" rowspan="1" colspan="1">Linden Leaf</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Tilia europaea</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.03152</td><td align="center" valign="top" rowspan="1" colspan="1">31.52</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">32</td><td align="center" valign="top" rowspan="1" colspan="1">A63</td><td align="left" valign="top" rowspan="1" colspan="1">Sha Ren Guang</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Amomum villosum fruit Shelled</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.04040</td><td align="center" valign="top" rowspan="1" colspan="1">40.40</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">33</td><td align="center" valign="top" rowspan="1" colspan="1">W16</td><td align="left" valign="top" rowspan="1" colspan="1">White Willow Bark</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Salix alba</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.04108</td><td align="center" valign="top" rowspan="1" colspan="1">41.08</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">34</td><td align="center" valign="top" rowspan="1" colspan="1">W15</td><td align="left" valign="top" rowspan="1" colspan="1">White Oak Bark</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Quercus alba</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.04154</td><td align="center" valign="top" rowspan="1" colspan="1">41.54</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">35</td><td align="center" valign="top" rowspan="1" colspan="1">G40</td><td align="left" valign="top" rowspan="1" colspan="1">Guarana Seed</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Paullinia cupana</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.04253</td><td align="center" valign="top" rowspan="1" colspan="1">42.53</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">36</td><td align="center" valign="top" rowspan="1" colspan="1">S11</td><td align="left" valign="top" rowspan="1" colspan="1">St Johns Wort</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>St Johns Wort</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.04408</td><td align="center" valign="top" rowspan="1" colspan="1">44.08</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">37</td><td align="center" valign="top" rowspan="1" colspan="1">L25</td><td align="left" valign="top" rowspan="1" colspan="1">Lychee Pit</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Litchi chinesis seed</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.04592</td><td align="center" valign="top" rowspan="1" colspan="1">45.92</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">38</td><td align="center" valign="top" rowspan="1" colspan="1">H4</td><td align="left" valign="top" rowspan="1" colspan="1">Hawthorne Leaf and Flower</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Crataegus laevigata</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.04790</td><td align="center" valign="top" rowspan="1" colspan="1">47.90</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">39</td><td align="center" valign="top" rowspan="1" colspan="1">P13</td><td align="left" valign="top" rowspan="1" colspan="1">Bian u</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Polygonum aviculare herb</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.05264</td><td align="center" valign="top" rowspan="1" colspan="1">52.64</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">40</td><td align="center" valign="top" rowspan="1" colspan="1">N1</td><td align="left" valign="top" rowspan="1" colspan="1">Nutmeg</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Myristica fragans</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.05811</td><td align="center" valign="top" rowspan="1" colspan="1">58.11</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">41</td><td align="center" valign="top" rowspan="1" colspan="1">S8</td><td align="left" valign="top" rowspan="1" colspan="1">Saw Palmetto Berry</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Serenoa repens</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.06608</td><td align="center" valign="top" rowspan="1" colspan="1">66.08</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">42</td><td align="center" valign="top" rowspan="1" colspan="1">M38</td><td align="left" valign="top" rowspan="1" colspan="1">Maiden Hair Fern</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Adiantum capillus</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.06847</td><td align="center" valign="top" rowspan="1" colspan="1">68.47</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">43</td><td align="center" valign="top" rowspan="1" colspan="1">T4</td><td align="left" valign="top" rowspan="1" colspan="1">Truja twigs, c/s</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Thuja occidentalis Cupressaceae</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.07676</td><td align="center" valign="top" rowspan="1" colspan="1">76.76</td></tr><tr><td align="right" valign="top" rowspan="1" colspan="1">44</td><td align="center" valign="top" rowspan="1" colspan="1">P29</td><td align="left" valign="top" rowspan="1" colspan="1">Wei Ling Cai</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>Potentilla chinensis herb</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.07772</td><td align="center" valign="top" rowspan="1" colspan="1">77.72</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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