Mechanic evaluation of Wu-Mei-Pill on colitis-associated colorectal cancer: An integrated transcriptomics, metabolomics, and experimental validation study
•Wu-Mei pill (WMP) inhibited tumor progression in CAC mice.•WMP activated the PPAR signaling pathway.•WMP inhibited Wnt signaling pathway-mediated EMT.•WMP limited the inflammatory response and inhibited the CCL3/CCR1 axis. Chronic intestinal inflammatory diseases play a crucial role in the onset of...
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| creator | Cui, Huantian Jin, Yutong Wang, Ning Liu, Haizhao Shu, Rongli Wang, Jida Wang, Xiangling Jia, Beitian Wang, Yiyang Bian, Yuhong Wen, Weibo |
| description | •Wu-Mei pill (WMP) inhibited tumor progression in CAC mice.•WMP activated the PPAR signaling pathway.•WMP inhibited Wnt signaling pathway-mediated EMT.•WMP limited the inflammatory response and inhibited the CCL3/CCR1 axis.
Chronic intestinal inflammatory diseases play a crucial role in the onset of colorectal cancer (CRC). Effectively impeding the progression of colitis-associated colorectal cancer (CAC) can be instrumental in hindering CRC development. Wu-Mei-Pill (WMP), a formulation comprising various herbal extracts, is clinically employed for CAC treatment, yet the underlying mechanism of WMP's efficacy in CAC remains unclear. Our study firstly demonstrated the effects and mechanisms of WMP on transcriptional and metabolic levels based on integrated transcriptomics and untargeted metabolomics and relative experimental validations.
A CAC mouse model was established through a single injection of azoxymethane (AOM) followed by intermittent dextran sodium sulfate (DSS) intervention, with subsequent WMP administration. Initially, the therapeutic impact of WMP on the CAC model was assessed by observing survival rate, body weight change, colon length, tumor number, tumor load, and pathological changes in the colon tissue of CAC mice post-WMP intervention. Subsequently, differential genes and metabolites in the colorectal tissue of CAC mice following WMP intervention were identified through transcriptomics and non-targeted metabolomics. Finally, the influence of WMP on the peroxisome proliferator activated receptor (PPAR) pathway, Wnt pathway, and CC motif chemokine ligand 3 (CCL3)/ CC motif chemokine receptor 1 (CCR1) axis in CAC mice was verified through western blot, immunofluorescence, and ELISA based on the results of transcriptomics and non-targeted metabolomics.
WMP intervention enhanced survival, alleviated body weight loss, shortened colon length, tumor occurrence, and pathological changes in the colorectal tissue of CAC mice, such as glandular damage, tumourigenesis, and inflammatory cell infiltration. Transcriptomic and non-targeted metabolomic results revealed that WMP intervention up-regulated the expression of key regulatory mechanisms of fatty acid oxidation PPAR pathway-related genes (Pparg, Ppara, Cpt1a, and Acadm) and metabolites (L-carnitine and L-palmitoylcarnitine). Additionally, it down-regulated Wnt pathway-related genes (Wnt3, Axin2, Tcf7, Mmp7, Lgr5, Wnt5a, Fzd6, Wnt7b, Lef1, and Fzd10 etc.) and pro-inflammatory related genes (Il1b, |
| doi_str_mv | 10.1016/j.phymed.2024.155509 |
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Chronic intestinal inflammatory diseases play a crucial role in the onset of colorectal cancer (CRC). Effectively impeding the progression of colitis-associated colorectal cancer (CAC) can be instrumental in hindering CRC development. Wu-Mei-Pill (WMP), a formulation comprising various herbal extracts, is clinically employed for CAC treatment, yet the underlying mechanism of WMP's efficacy in CAC remains unclear. Our study firstly demonstrated the effects and mechanisms of WMP on transcriptional and metabolic levels based on integrated transcriptomics and untargeted metabolomics and relative experimental validations.
A CAC mouse model was established through a single injection of azoxymethane (AOM) followed by intermittent dextran sodium sulfate (DSS) intervention, with subsequent WMP administration. Initially, the therapeutic impact of WMP on the CAC model was assessed by observing survival rate, body weight change, colon length, tumor number, tumor load, and pathological changes in the colon tissue of CAC mice post-WMP intervention. Subsequently, differential genes and metabolites in the colorectal tissue of CAC mice following WMP intervention were identified through transcriptomics and non-targeted metabolomics. Finally, the influence of WMP on the peroxisome proliferator activated receptor (PPAR) pathway, Wnt pathway, and CC motif chemokine ligand 3 (CCL3)/ CC motif chemokine receptor 1 (CCR1) axis in CAC mice was verified through western blot, immunofluorescence, and ELISA based on the results of transcriptomics and non-targeted metabolomics.
WMP intervention enhanced survival, alleviated body weight loss, shortened colon length, tumor occurrence, and pathological changes in the colorectal tissue of CAC mice, such as glandular damage, tumourigenesis, and inflammatory cell infiltration. Transcriptomic and non-targeted metabolomic results revealed that WMP intervention up-regulated the expression of key regulatory mechanisms of fatty acid oxidation PPAR pathway-related genes (Pparg, Ppara, Cpt1a, and Acadm) and metabolites (L-carnitine and L-palmitoylcarnitine). Additionally, it down-regulated Wnt pathway-related genes (Wnt3, Axin2, Tcf7, Mmp7, Lgr5, Wnt5a, Fzd6, Wnt7b, Lef1, and Fzd10 etc.) and pro-inflammatory related genes (Il1b, Il6, Il17a, Ccl3, and Ccr1 etc.). Experimental validation demonstrated that WMP up-regulated PPAR pathway-related proteins [PPARγ, PPARα, carnitine palmitoyltransferase 1A (CPT1A), and acyl-CoA dehydrogenase medium chain (ACADM)] in the colorectal tissue of CAC mice. It also down-regulated Wnt pathway-related proteins [β-catenin, T-cell factor (TCF), lymphoid enhancer-binding factor (LEF), and matrix metallopeptidase 7 (MMP7)], inhibited the nuclear translocation of the key transcription factor β-catenin in the Wnt pathway, and suppressed epithelial-to-mesenchymal transition (EMT) activation induced by the Wnt pathway (up-regulated E-cadherin and down-regulated Vimentin). Furthermore, WMP intervention reduced pro-inflammatory factors [interleukin (IL)-6, IL-1β, and IL-17A] and decreased CCL3/CCR1 axis factors, including CCL3 protein levels and diminished F4/80+CCR1+ positive expressed cells.
WMP significantly inhibits CAC tumorigenesis by up-regulating PPARα-mediated fatty acid oxidation, inhibiting the Wnt signaling pathway-mediated EMT, and suppressing CCL3/CCR1-mediated inflammatory responses.
[Display omitted]</description><identifier>ISSN: 0944-7113</identifier><identifier>EISSN: 1618-095X</identifier><identifier>DOI: 10.1016/j.phymed.2024.155509</identifier><identifier>PMID: 38452403</identifier><language>eng</language><publisher>Germany: Elsevier GmbH</publisher><subject>acyl-CoA dehydrogenase ; Animals ; Azoxymethane ; beta oxidation ; body weight changes ; cadherins ; carcinogenesis ; carnitine ; carnitine palmitoyltransferase ; CCL3/CCR1-mediated inflammatory responses ; CCR1 receptor ; chemokines ; Colitis - chemically induced ; Colitis-associated colorectal cancer ; Colitis-Associated Neoplasms ; colon ; Colon - drug effects ; Colon - metabolism ; Colon - pathology ; Colorectal Neoplasms ; dextran ; Dextran Sulfate ; Disease Models, Animal ; Drugs, Chinese Herbal - pharmacology ; fluorescent antibody technique ; interleukin-17 ; interleukin-6 ; ligands ; Male ; metabolites ; Metabolomics ; Mice ; Mice, Inbred C57BL ; Non-targeted metabolomics ; peroxisome proliferator-activated receptor alpha ; peroxisome proliferator-activated receptor gamma ; PPARα-mediated fatty acid oxidation ; sodium sulfate ; survival rate ; T-lymphocytes ; therapeutics ; transcription (genetics) ; Transcriptome ; Transcriptomics ; vimentin ; Western blotting ; wnt proteins ; Wnt signaling pathway-mediated epithelial-to-mesenchymal transition ; Wu-Mei-Pill</subject><ispartof>Phytomedicine (Stuttgart), 2024-06, Vol.128, p.155509-155509, Article 155509</ispartof><rights>2024 Elsevier GmbH</rights><rights>Copyright © 2024 Elsevier GmbH. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c344t-8ba8f486ec6358cdb8a2ab48cc0e6e17c135dab46e754433fb494f580498c7d23</cites><orcidid>0000-0002-9303-7341</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0944711324001739$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38452403$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cui, Huantian</creatorcontrib><creatorcontrib>Jin, Yutong</creatorcontrib><creatorcontrib>Wang, Ning</creatorcontrib><creatorcontrib>Liu, Haizhao</creatorcontrib><creatorcontrib>Shu, Rongli</creatorcontrib><creatorcontrib>Wang, Jida</creatorcontrib><creatorcontrib>Wang, Xiangling</creatorcontrib><creatorcontrib>Jia, Beitian</creatorcontrib><creatorcontrib>Wang, Yiyang</creatorcontrib><creatorcontrib>Bian, Yuhong</creatorcontrib><creatorcontrib>Wen, Weibo</creatorcontrib><title>Mechanic evaluation of Wu-Mei-Pill on colitis-associated colorectal cancer: An integrated transcriptomics, metabolomics, and experimental validation study</title><title>Phytomedicine (Stuttgart)</title><addtitle>Phytomedicine</addtitle><description>•Wu-Mei pill (WMP) inhibited tumor progression in CAC mice.•WMP activated the PPAR signaling pathway.•WMP inhibited Wnt signaling pathway-mediated EMT.•WMP limited the inflammatory response and inhibited the CCL3/CCR1 axis.
Chronic intestinal inflammatory diseases play a crucial role in the onset of colorectal cancer (CRC). Effectively impeding the progression of colitis-associated colorectal cancer (CAC) can be instrumental in hindering CRC development. Wu-Mei-Pill (WMP), a formulation comprising various herbal extracts, is clinically employed for CAC treatment, yet the underlying mechanism of WMP's efficacy in CAC remains unclear. Our study firstly demonstrated the effects and mechanisms of WMP on transcriptional and metabolic levels based on integrated transcriptomics and untargeted metabolomics and relative experimental validations.
A CAC mouse model was established through a single injection of azoxymethane (AOM) followed by intermittent dextran sodium sulfate (DSS) intervention, with subsequent WMP administration. Initially, the therapeutic impact of WMP on the CAC model was assessed by observing survival rate, body weight change, colon length, tumor number, tumor load, and pathological changes in the colon tissue of CAC mice post-WMP intervention. Subsequently, differential genes and metabolites in the colorectal tissue of CAC mice following WMP intervention were identified through transcriptomics and non-targeted metabolomics. Finally, the influence of WMP on the peroxisome proliferator activated receptor (PPAR) pathway, Wnt pathway, and CC motif chemokine ligand 3 (CCL3)/ CC motif chemokine receptor 1 (CCR1) axis in CAC mice was verified through western blot, immunofluorescence, and ELISA based on the results of transcriptomics and non-targeted metabolomics.
WMP intervention enhanced survival, alleviated body weight loss, shortened colon length, tumor occurrence, and pathological changes in the colorectal tissue of CAC mice, such as glandular damage, tumourigenesis, and inflammatory cell infiltration. Transcriptomic and non-targeted metabolomic results revealed that WMP intervention up-regulated the expression of key regulatory mechanisms of fatty acid oxidation PPAR pathway-related genes (Pparg, Ppara, Cpt1a, and Acadm) and metabolites (L-carnitine and L-palmitoylcarnitine). Additionally, it down-regulated Wnt pathway-related genes (Wnt3, Axin2, Tcf7, Mmp7, Lgr5, Wnt5a, Fzd6, Wnt7b, Lef1, and Fzd10 etc.) and pro-inflammatory related genes (Il1b, Il6, Il17a, Ccl3, and Ccr1 etc.). Experimental validation demonstrated that WMP up-regulated PPAR pathway-related proteins [PPARγ, PPARα, carnitine palmitoyltransferase 1A (CPT1A), and acyl-CoA dehydrogenase medium chain (ACADM)] in the colorectal tissue of CAC mice. It also down-regulated Wnt pathway-related proteins [β-catenin, T-cell factor (TCF), lymphoid enhancer-binding factor (LEF), and matrix metallopeptidase 7 (MMP7)], inhibited the nuclear translocation of the key transcription factor β-catenin in the Wnt pathway, and suppressed epithelial-to-mesenchymal transition (EMT) activation induced by the Wnt pathway (up-regulated E-cadherin and down-regulated Vimentin). Furthermore, WMP intervention reduced pro-inflammatory factors [interleukin (IL)-6, IL-1β, and IL-17A] and decreased CCL3/CCR1 axis factors, including CCL3 protein levels and diminished F4/80+CCR1+ positive expressed cells.
WMP significantly inhibits CAC tumorigenesis by up-regulating PPARα-mediated fatty acid oxidation, inhibiting the Wnt signaling pathway-mediated EMT, and suppressing CCL3/CCR1-mediated inflammatory responses.
[Display omitted]</description><subject>acyl-CoA dehydrogenase</subject><subject>Animals</subject><subject>Azoxymethane</subject><subject>beta oxidation</subject><subject>body weight changes</subject><subject>cadherins</subject><subject>carcinogenesis</subject><subject>carnitine</subject><subject>carnitine palmitoyltransferase</subject><subject>CCL3/CCR1-mediated inflammatory responses</subject><subject>CCR1 receptor</subject><subject>chemokines</subject><subject>Colitis - chemically induced</subject><subject>Colitis-associated colorectal cancer</subject><subject>Colitis-Associated Neoplasms</subject><subject>colon</subject><subject>Colon - drug effects</subject><subject>Colon - metabolism</subject><subject>Colon - pathology</subject><subject>Colorectal Neoplasms</subject><subject>dextran</subject><subject>Dextran Sulfate</subject><subject>Disease Models, Animal</subject><subject>Drugs, Chinese Herbal - pharmacology</subject><subject>fluorescent antibody technique</subject><subject>interleukin-17</subject><subject>interleukin-6</subject><subject>ligands</subject><subject>Male</subject><subject>metabolites</subject><subject>Metabolomics</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Non-targeted metabolomics</subject><subject>peroxisome proliferator-activated receptor alpha</subject><subject>peroxisome proliferator-activated receptor gamma</subject><subject>PPARα-mediated fatty acid oxidation</subject><subject>sodium sulfate</subject><subject>survival rate</subject><subject>T-lymphocytes</subject><subject>therapeutics</subject><subject>transcription (genetics)</subject><subject>Transcriptome</subject><subject>Transcriptomics</subject><subject>vimentin</subject><subject>Western blotting</subject><subject>wnt proteins</subject><subject>Wnt signaling pathway-mediated epithelial-to-mesenchymal transition</subject><subject>Wu-Mei-Pill</subject><issn>0944-7113</issn><issn>1618-095X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFuFSEUhonR2NvqGxjD0kXnCgPMgAuTprFq0kYXGt0RBs5YbmaGEZjG-yo-rYzTbnVFOPz_-Q_nQ-gFJXtKaPP6sJ9vjyO4fU1qvqdCCKIeoR1tqKyIEt8fox1RnFctpewEnaZ0IIRy1ZKn6IRJLmpO2A79vgF7ayZvMdyZYTHZhwmHHn9bqhvw1Wc_DLhUbBh89qkyKQXrTQa3lkIEm82ArZksxDf4YsJ-yvAj_hXkaKZko59zGL1N53iEbLri2m5mchh-zRD9CNPapeR7tw2Q8uKOz9CT3gwJnt-fZ-jr1bsvlx-q60_vP15eXFeWcZ4r2RnZc9mAbZiQ1nXS1Kbj0loCDdDWUiZcKTTQCs4Z6zuueC8k4Ura1tXsDL3a-s4x_FwgZT36ZGEYzARhSZpRwYSqaS3_K62V4G2jpBJFyjepjSGlCL2ey09NPGpK9ApQH_QGUK8A9Qaw2F7eJyzd-vZgeiBWBG83AZSV3HmIOlkPZf_OrzS0C_7fCX8ANwSxkA</recordid><startdate>20240601</startdate><enddate>20240601</enddate><creator>Cui, Huantian</creator><creator>Jin, Yutong</creator><creator>Wang, Ning</creator><creator>Liu, Haizhao</creator><creator>Shu, Rongli</creator><creator>Wang, Jida</creator><creator>Wang, Xiangling</creator><creator>Jia, Beitian</creator><creator>Wang, Yiyang</creator><creator>Bian, Yuhong</creator><creator>Wen, Weibo</creator><general>Elsevier GmbH</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><orcidid>https://orcid.org/0000-0002-9303-7341</orcidid></search><sort><creationdate>20240601</creationdate><title>Mechanic evaluation of Wu-Mei-Pill on colitis-associated colorectal cancer: An integrated transcriptomics, metabolomics, and experimental validation study</title><author>Cui, Huantian ; Jin, Yutong ; Wang, Ning ; Liu, Haizhao ; Shu, Rongli ; Wang, Jida ; Wang, Xiangling ; Jia, Beitian ; Wang, Yiyang ; Bian, Yuhong ; Wen, Weibo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c344t-8ba8f486ec6358cdb8a2ab48cc0e6e17c135dab46e754433fb494f580498c7d23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>acyl-CoA dehydrogenase</topic><topic>Animals</topic><topic>Azoxymethane</topic><topic>beta oxidation</topic><topic>body weight changes</topic><topic>cadherins</topic><topic>carcinogenesis</topic><topic>carnitine</topic><topic>carnitine palmitoyltransferase</topic><topic>CCL3/CCR1-mediated inflammatory responses</topic><topic>CCR1 receptor</topic><topic>chemokines</topic><topic>Colitis - chemically induced</topic><topic>Colitis-associated colorectal cancer</topic><topic>Colitis-Associated Neoplasms</topic><topic>colon</topic><topic>Colon - drug effects</topic><topic>Colon - metabolism</topic><topic>Colon - pathology</topic><topic>Colorectal Neoplasms</topic><topic>dextran</topic><topic>Dextran Sulfate</topic><topic>Disease Models, Animal</topic><topic>Drugs, Chinese Herbal - pharmacology</topic><topic>fluorescent antibody technique</topic><topic>interleukin-17</topic><topic>interleukin-6</topic><topic>ligands</topic><topic>Male</topic><topic>metabolites</topic><topic>Metabolomics</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Non-targeted metabolomics</topic><topic>peroxisome proliferator-activated receptor alpha</topic><topic>peroxisome proliferator-activated receptor gamma</topic><topic>PPARα-mediated fatty acid oxidation</topic><topic>sodium sulfate</topic><topic>survival rate</topic><topic>T-lymphocytes</topic><topic>therapeutics</topic><topic>transcription (genetics)</topic><topic>Transcriptome</topic><topic>Transcriptomics</topic><topic>vimentin</topic><topic>Western blotting</topic><topic>wnt proteins</topic><topic>Wnt signaling pathway-mediated epithelial-to-mesenchymal transition</topic><topic>Wu-Mei-Pill</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cui, Huantian</creatorcontrib><creatorcontrib>Jin, Yutong</creatorcontrib><creatorcontrib>Wang, Ning</creatorcontrib><creatorcontrib>Liu, Haizhao</creatorcontrib><creatorcontrib>Shu, Rongli</creatorcontrib><creatorcontrib>Wang, Jida</creatorcontrib><creatorcontrib>Wang, Xiangling</creatorcontrib><creatorcontrib>Jia, Beitian</creatorcontrib><creatorcontrib>Wang, Yiyang</creatorcontrib><creatorcontrib>Bian, Yuhong</creatorcontrib><creatorcontrib>Wen, Weibo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Phytomedicine (Stuttgart)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cui, Huantian</au><au>Jin, Yutong</au><au>Wang, Ning</au><au>Liu, Haizhao</au><au>Shu, Rongli</au><au>Wang, Jida</au><au>Wang, Xiangling</au><au>Jia, Beitian</au><au>Wang, Yiyang</au><au>Bian, Yuhong</au><au>Wen, Weibo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanic evaluation of Wu-Mei-Pill on colitis-associated colorectal cancer: An integrated transcriptomics, metabolomics, and experimental validation study</atitle><jtitle>Phytomedicine (Stuttgart)</jtitle><addtitle>Phytomedicine</addtitle><date>2024-06-01</date><risdate>2024</risdate><volume>128</volume><spage>155509</spage><epage>155509</epage><pages>155509-155509</pages><artnum>155509</artnum><issn>0944-7113</issn><eissn>1618-095X</eissn><abstract>•Wu-Mei pill (WMP) inhibited tumor progression in CAC mice.•WMP activated the PPAR signaling pathway.•WMP inhibited Wnt signaling pathway-mediated EMT.•WMP limited the inflammatory response and inhibited the CCL3/CCR1 axis.
Chronic intestinal inflammatory diseases play a crucial role in the onset of colorectal cancer (CRC). Effectively impeding the progression of colitis-associated colorectal cancer (CAC) can be instrumental in hindering CRC development. Wu-Mei-Pill (WMP), a formulation comprising various herbal extracts, is clinically employed for CAC treatment, yet the underlying mechanism of WMP's efficacy in CAC remains unclear. Our study firstly demonstrated the effects and mechanisms of WMP on transcriptional and metabolic levels based on integrated transcriptomics and untargeted metabolomics and relative experimental validations.
A CAC mouse model was established through a single injection of azoxymethane (AOM) followed by intermittent dextran sodium sulfate (DSS) intervention, with subsequent WMP administration. Initially, the therapeutic impact of WMP on the CAC model was assessed by observing survival rate, body weight change, colon length, tumor number, tumor load, and pathological changes in the colon tissue of CAC mice post-WMP intervention. Subsequently, differential genes and metabolites in the colorectal tissue of CAC mice following WMP intervention were identified through transcriptomics and non-targeted metabolomics. Finally, the influence of WMP on the peroxisome proliferator activated receptor (PPAR) pathway, Wnt pathway, and CC motif chemokine ligand 3 (CCL3)/ CC motif chemokine receptor 1 (CCR1) axis in CAC mice was verified through western blot, immunofluorescence, and ELISA based on the results of transcriptomics and non-targeted metabolomics.
WMP intervention enhanced survival, alleviated body weight loss, shortened colon length, tumor occurrence, and pathological changes in the colorectal tissue of CAC mice, such as glandular damage, tumourigenesis, and inflammatory cell infiltration. Transcriptomic and non-targeted metabolomic results revealed that WMP intervention up-regulated the expression of key regulatory mechanisms of fatty acid oxidation PPAR pathway-related genes (Pparg, Ppara, Cpt1a, and Acadm) and metabolites (L-carnitine and L-palmitoylcarnitine). Additionally, it down-regulated Wnt pathway-related genes (Wnt3, Axin2, Tcf7, Mmp7, Lgr5, Wnt5a, Fzd6, Wnt7b, Lef1, and Fzd10 etc.) and pro-inflammatory related genes (Il1b, Il6, Il17a, Ccl3, and Ccr1 etc.). Experimental validation demonstrated that WMP up-regulated PPAR pathway-related proteins [PPARγ, PPARα, carnitine palmitoyltransferase 1A (CPT1A), and acyl-CoA dehydrogenase medium chain (ACADM)] in the colorectal tissue of CAC mice. It also down-regulated Wnt pathway-related proteins [β-catenin, T-cell factor (TCF), lymphoid enhancer-binding factor (LEF), and matrix metallopeptidase 7 (MMP7)], inhibited the nuclear translocation of the key transcription factor β-catenin in the Wnt pathway, and suppressed epithelial-to-mesenchymal transition (EMT) activation induced by the Wnt pathway (up-regulated E-cadherin and down-regulated Vimentin). Furthermore, WMP intervention reduced pro-inflammatory factors [interleukin (IL)-6, IL-1β, and IL-17A] and decreased CCL3/CCR1 axis factors, including CCL3 protein levels and diminished F4/80+CCR1+ positive expressed cells.
WMP significantly inhibits CAC tumorigenesis by up-regulating PPARα-mediated fatty acid oxidation, inhibiting the Wnt signaling pathway-mediated EMT, and suppressing CCL3/CCR1-mediated inflammatory responses.
[Display omitted]</abstract><cop>Germany</cop><pub>Elsevier GmbH</pub><pmid>38452403</pmid><doi>10.1016/j.phymed.2024.155509</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-9303-7341</orcidid></addata></record> |
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| ispartof | Phytomedicine (Stuttgart), 2024-06, Vol.128, p.155509-155509, Article 155509 |
| issn | 0944-7113 1618-095X |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | acyl-CoA dehydrogenase Animals Azoxymethane beta oxidation body weight changes cadherins carcinogenesis carnitine carnitine palmitoyltransferase CCL3/CCR1-mediated inflammatory responses CCR1 receptor chemokines Colitis - chemically induced Colitis-associated colorectal cancer Colitis-Associated Neoplasms colon Colon - drug effects Colon - metabolism Colon - pathology Colorectal Neoplasms dextran Dextran Sulfate Disease Models, Animal Drugs, Chinese Herbal - pharmacology fluorescent antibody technique interleukin-17 interleukin-6 ligands Male metabolites Metabolomics Mice Mice, Inbred C57BL Non-targeted metabolomics peroxisome proliferator-activated receptor alpha peroxisome proliferator-activated receptor gamma PPARα-mediated fatty acid oxidation sodium sulfate survival rate T-lymphocytes therapeutics transcription (genetics) Transcriptome Transcriptomics vimentin Western blotting wnt proteins Wnt signaling pathway-mediated epithelial-to-mesenchymal transition Wu-Mei-Pill |
| title | Mechanic evaluation of Wu-Mei-Pill on colitis-associated colorectal cancer: An integrated transcriptomics, metabolomics, and experimental validation study |
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