PMID- 38452403
OWN - NLM
STAT- Publisher
LR  - 20240307
IS  - 1618-095X (Electronic)
IS  - 0944-7113 (Linking)
VI  - 128
DP  - 2024 Mar 2
TI  - Mechanic evaluation of Wu-Mei-Pill on colitis-associated colorectal cancer: An 
      integrated transcriptomics, metabolomics, and experimental validation study.
PG  - 155509
LID - S0944-7113(24)00173-9 [pii]
LID - 10.1016/j.phymed.2024.155509 [doi]
AB  - BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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 [PPARgamma, PPARalpha, 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 [beta-catenin, T-cell factor (TCF), lymphoid enhancer-binding factor (LEF), 
      and matrix metallopeptidase 7 (MMP7)], inhibited the nuclear translocation of the 
      key transcription factor beta-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-1beta, and 
      IL-17A] and decreased CCL3/CCR1 axis factors, including CCL3 protein levels and 
      diminished F4/80(+)CCR1(+) positive expressed cells. CONCLUSION: WMP 
      significantly inhibits CAC tumorigenesis by up-regulating PPARalpha-mediated fatty 
      acid oxidation, inhibiting the Wnt signaling pathway-mediated EMT, and 
      suppressing CCL3/CCR1-mediated inflammatory responses.
CI  - Copyright (c) 2024 Elsevier GmbH. All rights reserved.
FAU - Cui, Huantian
AU  - Cui H
AD  - First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 
      650500, China.
FAU - Jin, Yutong
AU  - Jin Y
AD  - College of Integrative Chinese and Western Medicine, Tianjin University of 
      Traditional Chinese Medicine, Tianjin 301617, China.
FAU - Wang, Ning
AU  - Wang N
AD  - First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 
      650500, China.
FAU - Liu, Haizhao
AU  - Liu H
AD  - College of Integrative Chinese and Western Medicine, Tianjin University of 
      Traditional Chinese Medicine, Tianjin 301617, China.
FAU - Shu, Rongli
AU  - Shu R
AD  - College of Integrative Chinese and Western Medicine, Tianjin University of 
      Traditional Chinese Medicine, Tianjin 301617, China.
FAU - Wang, Jida
AU  - Wang J
AD  - College of Integrative Chinese and Western Medicine, Tianjin University of 
      Traditional Chinese Medicine, Tianjin 301617, China.
FAU - Wang, Xiangling
AU  - Wang X
AD  - College of Integrative Chinese and Western Medicine, Tianjin University of 
      Traditional Chinese Medicine, Tianjin 301617, China.
FAU - Jia, Beitian
AU  - Jia B
AD  - College of Integrative Chinese and Western Medicine, Tianjin University of 
      Traditional Chinese Medicine, Tianjin 301617, China.
FAU - Wang, Yiyang
AU  - Wang Y
AD  - College of Integrative Chinese and Western Medicine, Tianjin University of 
      Traditional Chinese Medicine, Tianjin 301617, China.
FAU - Bian, Yuhong
AU  - Bian Y
AD  - College of Integrative Chinese and Western Medicine, Tianjin University of 
      Traditional Chinese Medicine, Tianjin 301617, China. Electronic address: 
      bianyuhong_2012@163.com.
FAU - Wen, Weibo
AU  - Wen W
AD  - First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 
      650500, China. Electronic address: wenweibo2020@163.com.
LA  - eng
PT  - Journal Article
DEP - 20240302
PL  - Germany
TA  - Phytomedicine
JT  - Phytomedicine : international journal of phytotherapy and phytopharmacology
JID - 9438794
SB  - IM
OTO - NOTNLM
OT  - CCL3/CCR1-mediated inflammatory responses
OT  - Colitis-associated colorectal cancer
OT  - Non-targeted metabolomics
OT  - PPARalpha-mediated fatty acid oxidation
OT  - Transcriptomics
OT  - Wnt signaling pathway-mediated epithelial-to-mesenchymal transition
OT  - Wu-Mei-Pill
COIS- Declaration of competing interest All authors declare no conflict of interests.
EDAT- 2024/03/07 18:42
MHDA- 2024/03/07 18:42
CRDT- 2024/03/07 18:00
PHST- 2023/12/03 00:00 [received]
PHST- 2024/01/26 00:00 [revised]
PHST- 2024/02/29 00:00 [accepted]
PHST- 2024/03/07 18:42 [medline]
PHST- 2024/03/07 18:42 [pubmed]
PHST- 2024/03/07 18:00 [entrez]
AID - S0944-7113(24)00173-9 [pii]
AID - 10.1016/j.phymed.2024.155509 [doi]
PST - aheadofprint
SO  - Phytomedicine. 2024 Mar 2;128:155509. doi: 10.1016/j.phymed.2024.155509.