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<document id="BF489C28E068A43AD8220D4007F8E420" ID-DOI="10.1016/j.phytochem.2022.113204" ID-ISSN="1873-3700" ID-Zenodo-Dep="8235444" IM.bibliography_approvedBy="carolina" IM.illustrations_approvedBy="carolina" IM.materialsCitations_approvedBy="felipe" IM.metadata_approvedBy="felipe" IM.tables_approvedBy="carolina" IM.taxonomicNames_approvedBy="carolina" IM.treatments_approvedBy="carolina" checkinTime="1691690424832" checkinUser="felipe" docAuthor="Ding, Min, Wu, Sheng-Li, Hu, Jing, He, Xiao-Feng, Huang, Xiao-Yan, Li, Tian-Ze, Ma, Yun-Bao, Zhang, Xue-Mei &amp; Geng, Chang-An" docDate="2022" docId="038C87CEFFEDEF73FCBFFC8FBFA6FA0E" docLanguage="en" docName="Phytochemistry.199.113204.pdf" docOrigin="Phytochemistry (113204) 199" docSource="http://dx.doi.org/10.1016/j.phytochem.2022.113204" docStyle="DocumentStyle:F36D69FC8B198FBE91029DF9C24697D3.5:Phytochemistry.2020-.journal_article" docStyleId="F36D69FC8B198FBE91029DF9C24697D3" docStyleName="Phytochemistry.2020-.journal_article" docStyleVersion="5" docTitle="Amomum villosum" docType="treatment" docVersion="1" lastPageNumber="4" masterDocId="FFB5FFB6FFEFEF70FF8DFFC5BC1DFFAA" masterDocTitle="Norlignans as potent GLP- 1 secretagogues from the fruits of Amomum villosum" masterLastPageNumber="8" masterPageNumber="1" pageNumber="3" updateTime="1692302591890" updateUser="carolina">
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<mods:title id="6680D8E4FA0BFD0BEB922501836A7A43">Norlignans as potent GLP- 1 secretagogues from the fruits of Amomum villosum</mods:title>
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<mods:namePart id="B7E1E07776BB787146281332FACFA977">Ding, Min</mods:namePart>
<mods:affiliation id="A089FB0AD585B48089A70BED8E0B0600">* &amp; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan Key Laboratory of &amp; University of Chinese Academy of Sciences, Beijing, 100049, Peoples Republic of China</mods:affiliation>
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<mods:namePart id="5E37017E84A6622797CD28099AE83B0C">Li, Tian-Ze</mods:namePart>
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<emphasis id="B951EACAFFEDEF72FCBFFC8FB907FCF7" bold="true" box="[818,1306,842,862]" italics="true" pageId="2" pageNumber="3">
2.3. Antidiabetic effects of
<taxonomicName id="4C254D5BFFEDEF72FBA6FC8FB88DFCF7" ID-CoL="CWRL" authority="(Amomi Fructus)" baseAuthorityName="Amomi Fructus" box="[1067,1168,842,861]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="2" pageNumber="3" phylum="Tracheophyta" rank="species" species="villosum">A. villosum</taxonomicName>
on db/db mice
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<paragraph id="8B9A36D8FFEDEF73FCDCFC47BD1DFAB2" blockId="2.[818,1488,898,1364]" lastBlockId="3.[100,770,1146,1304]" lastPageId="3" lastPageNumber="4" pageId="2" pageNumber="3">
The antidiabetic effects of
<taxonomicName id="4C254D5BFFEDEF72FBCBFC47B8B5FC3F" box="[1094,1192,898,917]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="2" pageNumber="3" phylum="Tracheophyta" rank="species" species="villosum">
<emphasis id="B951EACAFFEDEF72FBCBFC47B8B5FC3F" bold="true" box="[1094,1192,898,917]" italics="true" pageId="2" pageNumber="3">A. villosum</emphasis>
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were assayed on
<emphasis id="B951EACAFFEDEF72FAC5FC47B963FC3F" bold="true" box="[1352,1406,898,917]" italics="true" pageId="2" pageNumber="3">db/db</emphasis>
mice for the amelioration of random blood glucose, fasting blood glucose, plasma insulin and leptin levels, oral glucose tolerance, and insulin tolerance (
<figureCitation id="131E2A5DFFEDEF72FCB7FC13BF73FC43" box="[826,878,982,1001]" captionStart="Fig" captionStartId="5.[100,130,1439,1456]" captionTargetBox="[188,1398,150,1409]" captionTargetId="figure-410@5.[187,1400,148,1411]" captionTargetPageId="5" captionText="Fig. 5. Antidiabetic effects of A. villosum on db/db mice, (AE) random blood glucose (04 weeks), (F) fasting blood glucose (4th week), (G) plasma insulin level, (H) plasma leptin level, (I) OGTT, (J) ITT, (K) food intake, and (L) body weight. Data were presented as mean ±SDs (n =8). *p &lt;0.05, **p &lt;0.01 vs Vehicle, ##p &lt;0.01, ###p &lt;0.001, ####p &lt;0.0001 vs Lean." figureDoi="http://doi.org/10.5281/zenodo.8235449" httpUri="https://zenodo.org/record/8235449/files/figure.png" pageId="2" pageNumber="3">Fig. 5</figureCitation>
). The
<emphasis id="B951EACAFFEDEF72FC24FC13BFC2FC43" bold="true" box="[937,991,982,1001]" italics="true" pageId="2" pageNumber="3">db/db</emphasis>
mice were orally administrated with metformin (
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/kg) and
<taxonomicName id="4C254D5BFFEDEF72FC29FC37B81BFBAE" box="[932,1030,1009,1029]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="2" pageNumber="3" phylum="Tracheophyta" rank="species" species="villosum">
<emphasis id="B951EACAFFEDEF72FC29FC37B81BFBAE" bold="true" box="[932,1030,1009,1029]" italics="true" pageId="2" pageNumber="3">A. villosum</emphasis>
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(400 and
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/kg) daily for four weeks. At the fourth week, the random blood glucose of the
<taxonomicName id="4C254D5BFFEDEF72FB66FBCBB952FB8A" box="[1259,1359,1037,1057]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="2" pageNumber="3" phylum="Tracheophyta" rank="species" species="villosum">
<emphasis id="B951EACAFFEDEF72FB66FBCBB952FB8A" bold="true" box="[1259,1359,1037,1057]" italics="true" pageId="2" pageNumber="3">A. villosum</emphasis>
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(
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/kg) group was obviously decreased, which was equivalent to the positive control, metformin (
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/kg) at the same dose. Whereas, the highdose group (
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/kg) showed no significant variation compared with the vehicle group, although the random blood glucose maintained the decreased tendency. Different from metformin,
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<emphasis id="B951EACAFFEDEF72FA93FB5CB99EFB06" bold="true" box="[1310,1411,1177,1196]" italics="true" pageId="2" pageNumber="3">A. villosum</emphasis>
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did not influence the fasting blood glucose at the tested doses of 400 and
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/kg. At the fourth week, both the plasma insulin and leptin levels in
<emphasis id="B951EACAFFEDEF72FCBFFB29BF7AFB55" bold="true" box="[818,871,1260,1279]" italics="true" pageId="2" pageNumber="3">db/db</emphasis>
mice were obviously increased by metformin (
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/kg), whereas
<taxonomicName id="4C254D5BFFEDEF72FC0BFACCBFF7FAB1" box="[902,1002,1288,1308]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="2" pageNumber="3" phylum="Tracheophyta" rank="species" species="villosum">
<emphasis id="B951EACAFFEDEF72FC0BFACCBFF7FAB1" bold="true" box="[902,1002,1288,1308]" italics="true" pageId="2" pageNumber="3">A. villosum</emphasis>
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only in
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/kg dosage showed a promotion in insulin levels. Besides,
<taxonomicName id="4C254D5BFFEDEF72FB9AFAE0B862FA9D" box="[1047,1151,1316,1336]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="2" pageNumber="3" phylum="Tracheophyta" rank="species" species="villosum">
<emphasis id="B951EACAFFEDEF72FB9AFAE0B862FA9D" bold="true" box="[1047,1151,1316,1336]" italics="true" pageId="2" pageNumber="3">A. villosum</emphasis>
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had little influence on the blood glucose in oral glucose tolerance test (OGTT) and insulin tolerance test (ITT), as well as the body weight and food intake during the four-week treatment. As a comparison, metformin (
<quantity id="4CDD9B3DFFECEF73FE52FB53BE34FB03" box="[479,553,1174,1193]" metricMagnitude="-4" metricUnit="kg" metricValue="2.0" pageId="3" pageNumber="4" unit="mg" value="200.0">200 mg</quantity>
/kg) could alleviate the blood glucose in OGTT and ITT tests. This study suggested that
<taxonomicName id="4C254D5BFFECEF73FFE9FB08BCD4FB4A" box="[100,201,1229,1248]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="3" pageNumber="4" phylum="Tracheophyta" rank="species" species="villosum">
<emphasis id="B951EACAFFECEF73FFE9FB08BCD4FB4A" bold="true" box="[100,201,1229,1248]" italics="true" pageId="3" pageNumber="4">A. villosum</emphasis>
</taxonomicName>
showed hypoglycemic effects on
<emphasis id="B951EACAFFECEF73FD83FB08BE59FB4A" bold="true" box="[526,580,1229,1248]" italics="true" pageId="3" pageNumber="4">db/db</emphasis>
mice by promoting insulin secretion, which might have a different mechanism of action with metformin.
</paragraph>
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<paragraph id="8B9A36D8FFEDEF72FDBBF869BFE0F817" blockId="2.[566,1021,1964,1981]" box="[566,1021,1964,1981]" pageId="2" pageNumber="3">
<emphasis id="B951EACAFFEDEF72FDBBF869BE6DF817" bold="true" box="[566,624,1964,1981]" pageId="2" pageNumber="3">Fig. 2.</emphasis>
Key 2D NMR correlations of compounds
<emphasis id="B951EACAFFEDEF72FC55F869BFE5F817" bold="true" box="[984,1016,1964,1981]" pageId="2" pageNumber="3">14</emphasis>
.
</paragraph>
</caption>
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<paragraph id="8B9A36D8FFECEF73FDE8FB85BFD3FBFA" blockId="3.[613,974,1088,1105]" box="[613,974,1088,1105]" pageId="3" pageNumber="4">
<emphasis id="B951EACAFFECEF73FDE8FB85BE83FBFB" bold="true" box="[613,670,1088,1105]" pageId="3" pageNumber="4">Fig. 3.</emphasis>
Chiral analysis of compounds
<emphasis id="B951EACAFFECEF73FC24FB85BFD4FBFB" bold="true" box="[937,969,1088,1105]" pageId="3" pageNumber="4">14</emphasis>
.
</paragraph>
</caption>
<paragraph id="8B9A36D8FFECEF73FFE9FA86BDCCFAFC" blockId="3.[100,465,1347,1366]" box="[100,465,1347,1366]" pageId="3" pageNumber="4">
<heading id="D0D281B4FFECEF73FFE9FA86BDCCFAFC" bold="true" box="[100,465,1347,1366]" fontSize="36" level="1" pageId="3" pageNumber="4" reason="1">
<emphasis id="B951EACAFFECEF73FFE9FA86BDCCFAFC" bold="true" box="[100,465,1347,1366]" italics="true" pageId="3" pageNumber="4">2.4. GLP-1 secretion stimulative activity</emphasis>
</heading>
</paragraph>
<paragraph id="8B9A36D8FFECEF73FF09FABEBDC4F8E6" blockId="3.[100,770,1403,1869]" pageId="3" pageNumber="4">
The EtOH extract and EtOAc fraction of
<taxonomicName id="4C254D5BFFECEF73FE70FABEBE7DFA24" box="[509,608,1403,1422]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="3" pageNumber="4" phylum="Tracheophyta" rank="species" species="villosum">
<emphasis id="B951EACAFFECEF73FE70FABEBE7DFA24" bold="true" box="[509,608,1403,1422]" italics="true" pageId="3" pageNumber="4">A. villosum</emphasis>
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were assayed for their stimulative effects on GLP-1 secretion in STC-1 cells (
<figureCitation id="131E2A5DFFECEF73FD0EFA52BEAAFA00" box="[643,695,1431,1450]" captionStart="Fig" captionStartId="6.[100,130,575,592]" captionTargetBox="[108,766,150,544]" captionTargetId="figure-858@6.[106,767,148,547]" captionTargetPageId="6" captionText="Fig. 6. The stimulation of fractions and compounds on GLP-1 secretion. Oleoylethanolamide (OEA) was used as positive control. Data were expressed as mean ± SD (n = 3). **p &lt;0.01, ***p &lt;0.001." figureDoi="http://doi.org/10.5281/zenodo.8235451" httpUri="https://zenodo.org/record/8235451/files/figure.png" pageId="3" pageNumber="4">Fig. 6</figureCitation>
). At the concentration of 50.0
<emphasis id="B951EACAFFECEF73FEB7FA76BD58FA62" bold="true" box="[314,325,1459,1480]" italics="true" pageId="3" pageNumber="4">μ</emphasis>
g/mL, the EtOH extract could stimulate GLP-1 secretion by 100.1%. After extracted with EtOAc, the obtained EtOAc part showed higher activity with promotion rates of 156.2% (25.0
<emphasis id="B951EACAFFECEF73FD6CFA2FBEF1FA55" bold="true" box="[737,748,1514,1535]" italics="true" pageId="3" pageNumber="4">μ</emphasis>
g/ mL) and 273.9% (50.0
<emphasis id="B951EACAFFECEF73FECDF9C3BD56F9B1" bold="true" box="[320,331,1542,1563]" italics="true" pageId="3" pageNumber="4">μ</emphasis>
g/mL). Compounds
<emphasis id="B951EACAFFECEF73FD8AF9C3BE36F9B3" bold="true" box="[519,555,1542,1562]" pageId="3" pageNumber="4">14</emphasis>
were assayed for their GLP-1 stimulative effects at concentrations of 12.5 and 25.0
<emphasis id="B951EACAFFECEF73FD4FF9E7BED0F99D" bold="true" box="[706,717,1570,1591]" italics="true" pageId="3" pageNumber="4">μ</emphasis>
M, of which amovillosumin A (
<emphasis id="B951EACAFFECEF73FED8F9FBBD7CF9FB" bold="true" box="[341,353,1598,1617]" pageId="3" pageNumber="4">1</emphasis>
) showed the highest activity in stimulating GLP-1 secretion by 166.9% and 375.1%, more potent than the positive control, oleoylethanolamide (OEA, 163.1%, 25.0
<emphasis id="B951EACAFFECEF73FDB3F9B3BE54F921" bold="true" box="[574,585,1654,1675]" italics="true" pageId="3" pageNumber="4">μ</emphasis>
M). Also, amovillosumin B (
<emphasis id="B951EACAFFECEF73FF36F957BCDAF90F" bold="true" box="[187,199,1682,1701]" pageId="3" pageNumber="4">2</emphasis>
) obviously increased the GLP-1 secretion by 62.7% (12.5
<emphasis id="B951EACAFFECEF73FD51F957BEFAF90D" bold="true" box="[732,743,1682,1703]" italics="true" pageId="3" pageNumber="4">μ</emphasis>
M) and 222.7% (25.0
<emphasis id="B951EACAFFECEF73FE96F96BBD3BF969" bold="true" box="[283,294,1710,1731]" italics="true" pageId="3" pageNumber="4">μ</emphasis>
M), comparable to the positive control. Whereas, amovillosumins C (
<emphasis id="B951EACAFFECEF73FE91F90FBD35F977" bold="true" box="[284,296,1738,1757]" pageId="3" pageNumber="4">3</emphasis>
) and D (
<emphasis id="B951EACAFFECEF73FEF2F90FBD96F977" bold="true" box="[383,395,1738,1757]" pageId="3" pageNumber="4">4</emphasis>
) were inactive at the tested concentrations (
<tableCitation id="C6A70363FFECEF73FF2FF923BCF7F953" box="[162,234,1766,1785]" captionStart="Table 3" captionStartId="6.[100,150,703,719]" captionTargetPageId="6" captionText="Table 3 The stimulative effects of fractions and compounds on GLP-1 secretion in STC-1 cells." pageId="3" pageNumber="4">Table 3</tableCitation>
). Compounds
<emphasis id="B951EACAFFECEF73FEFAF923BD87F953" bold="true" box="[375,410,1766,1785]" pageId="3" pageNumber="4">
1
<emphasis id="B951EACAFFECEF73FE0EF92DBD93F953" bold="true" box="[387,398,1768,1785]" italics="true" pageId="3" pageNumber="4"></emphasis>
4
</emphasis>
possessed similar structures with the main difference at two phenyl rings. Thus, the substitution patterns (1
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,3
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- and 3,4,5-subsititution) at phenyl rings might play key roles in maintaining GLP-1 stimulative activity.
</paragraph>
<paragraph id="8B9A36D8FFECEF73FFE9F8B6BCE2F82C" blockId="3.[100,255,1907,1926]" box="[100,255,1907,1926]" pageId="3" pageNumber="4">
<heading id="D0D281B4FFECEF73FFE9F8B6BCE2F82C" bold="true" box="[100,255,1907,1926]" fontSize="36" level="1" pageId="3" pageNumber="4" reason="1">
<emphasis id="B951EACAFFECEF73FFE9F8B6BCE2F82C" bold="true" box="[100,255,1907,1926]" pageId="3" pageNumber="4">3. Conclusions</emphasis>
</heading>
</paragraph>
<paragraph id="8B9A36D8FFECEF73FF09F86EBFA6FA0E" blockId="3.[132,770,1962,1982]" lastBlockId="3.[818,1488,1146,1444]" pageId="3" pageNumber="4">
In this study, the fruits of
<taxonomicName id="4C254D5BFFECEF73FE11F86EBE18F817" box="[412,517,1962,1982]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="3" pageNumber="4" phylum="Tracheophyta" rank="species" species="villosum">
<emphasis id="B951EACAFFECEF73FE11F86EBE18F817" bold="true" box="[412,517,1962,1982]" italics="true" pageId="3" pageNumber="4">A. villosum</emphasis>
</taxonomicName>
were first revealed with hypoglycemic effects on
<emphasis id="B951EACAFFECEF73FBABFBBFB841FB27" bold="true" box="[1062,1116,1146,1165]" italics="true" pageId="3" pageNumber="4">db/db</emphasis>
mice by promoting insulin secretion. Guided by GLP-1 secretion assay, four new norlignans, amovillosumins AD (
<emphasis id="B951EACAFFECEF73FCFDFB77BF8EFB6F" bold="true" box="[880,915,1202,1221]" pageId="3" pageNumber="4">14</emphasis>
), were isolated from the EtOAc fraction. The subsequent chiral resolution gave rise to three pairs of enantiomers,
<emphasis id="B951EACAFFECEF73FAC8FB08B99FFB4A" bold="true" box="[1349,1410,1229,1248]" pageId="3" pageNumber="4">1a/1b</emphasis>
,
<emphasis id="B951EACAFFECEF73FA00FB08B9D7FB4A" bold="true" box="[1421,1482,1229,1248]" pageId="3" pageNumber="4">2a/2b</emphasis>
, and
<emphasis id="B951EACAFFECEF73FCD3FB2CBF86FB56" bold="true" box="[862,923,1257,1276]" pageId="3" pageNumber="4">3a/3b</emphasis>
, whose absolute configurations were determined by ECD calculation. Amovillosumins A (
<emphasis id="B951EACAFFECEF73FBE1FAC0B865FAB2" bold="true" box="[1132,1144,1285,1304]" pageId="3" pageNumber="4">1</emphasis>
) and B (
<emphasis id="B951EACAFFECEF73FB5AFAC0B8FEFAB2" bold="true" box="[1239,1251,1285,1304]" pageId="3" pageNumber="4">2</emphasis>
) could stimulate GLP-1 secretion by 375.1% and 222.7% at 25.0
<emphasis id="B951EACAFFECEF73FB4EFAE4B8D3FA9C" bold="true" box="[1219,1230,1313,1334]" italics="true" pageId="3" pageNumber="4">μ</emphasis>
M, and 166.9% and 62.7% at 12.5
<emphasis id="B951EACAFFECEF73FC09FAF8BF92FAF8" bold="true" box="[900,911,1341,1362]" italics="true" pageId="3" pageNumber="4">μ</emphasis>
M, representing a new
<typeStatus id="549E887AFFECEF73FBF0FAFBB8BBFAFB" box="[1149,1190,1342,1361]" pageId="3" pageNumber="4">type</typeStatus>
of GLP-1 secretagogues. This investigation provides new clues for understanding the antidiabetic effects of
<taxonomicName id="4C254D5BFFECEF73FC05FAB0BFEFFA22" box="[904,1010,1397,1416]" class="Liliopsida" family="Zingiberaceae" genus="Amomum" kingdom="Plantae" order="Zingiberales" pageId="3" pageNumber="4" phylum="Tracheophyta" rank="species" species="villosum">
<emphasis id="B951EACAFFECEF73FC05FAB0BFEFFA22" bold="true" box="[904,1010,1397,1416]" italics="true" pageId="3" pageNumber="4">A. villosum</emphasis>
</taxonomicName>
and the active norlignans as promising GLP-1 secretagogues.
</paragraph>
</subSubSection>
</treatment>
</document>