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A type of colorectal cancer (CRC)ï¼Colitis-associated colorectal cancer (CAC)ï¼ is closely associated with chronic inflammation and gut microbiota dysbiosis. Berberine (BBR) has a long history in the treatment of intestinal diseases, which has been reported to inhibit colitis and CRC. However, the mechanism of its action is still unclear. Here, this study aimed to explore the potential protective effects of BBR on azoxymethane (AOM)/dextransulfate sodium (DSS)-induced colitis and tumor mice, and to elucidate its potential molecular mechanisms by microbiota, genes and metabolic alterations. The results showed that BBR inhibited the gut inflammation and improved the function of mucosal barrier to ameliorate AOM/DSS-induced colitis. And BBR treatment significantly reduced intestinal tumor development and ki-67 expression of intestinal tissue along with promoted apoptosis. Through microbiota analysis based on the 16â¯S rRNA gene, we found that BBR treatment improved intestinal microbiota imbalance in AOM/DSS-induced colitis and tumor mice, which were characterized by an increase of beneficial bacteria, for instance Akkermanisa, Lactobacillus, Bacteroides uniformis and Bacteroides acidifaciens. In addition, transcriptome analysis showed that BBR regulated colonic epithelial signaling pathway in CAC mice particularly by tryptophan metabolism and Wnt signaling pathway. Notably, BBR treatment resulted in the enrichment of amino acids metabolism and microbiota-derived SCFA metabolites. In summary, our research findings suggest that the gut microbiota-amino acid metabolism-Wnt signaling pathway axis plays critical role in maintaining intestinal homeostasis, which may provide new insights into the inhibitory effects of BBR on colitis and colon cancer.
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BACKGROUND: Pien Tze Huang (PZH), a traditional Chinese medicine formulation, is recognized for its therapeutic effect on colitis and colorectal cancer. However, its protective role and underlying mechanism in colitis-associated colorectal cancer (CAC) remain to be elucidated. METHODS: A CAC mouse model was established using AOM/DSS. Twenty mice were randomly divided into four groups (n = 5/group): Control, PZH, AOM/DSS, and AOM/DSS + PZH groups. Mice in the PZH and AOM/DSS + PZH group were orally administered PZH (250 mg/kg/d) from the first day of experiment, while the control and AOM/DSS group received an equivalent volume of distilled water. Parameters such as body weight, disease activity index (DAI), colon weight, colon length, colon histomorphology, intestinal tumor formation, serum concentrations of pro-inflammatory cytokines, proliferation and apoptosis in colon tissue were assessed. RNA sequencing was employed to identify the differentially expressed transcripts (DETs) in colonic tissues and related signaling pathways. Wnt/ß-Catenin Pathway-Related genes in colon tissue were detected by QPCR and immunohistochemistry (IHC). RESULTS: PZH significantly attenuated AOM/DSS-induced weight loss, DAI elevation, colonic weight gain, colon shortening, histological damage, and intestinal tumor formation in mice. PZH also notably decreased serum concentration of IL-6, IL-1ß, and TNF-α. Furthermore, PZH inhibited cell proliferation and promote apoptosis in tumor tissues. RNA-seq and KEGG analysis revealed key pathways influenced by PZH, including Wnt/ß-catenin signaling pathway. IHC staining confirmed that PZH suppressed the expression of ß-catenin, cyclin D1 and c-Myc in colonic tissues. CONCLUSIONS: PZH ameliorates AOM/DSS-induced CAC in mice by suppressing the activation of Wnt/ß-catenin signaling pathway.
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One of the factors contributing to colorectal cancer (CRC) development is inflammation, which is mostly hypoxia-associated. This study aimed to characterize the morphological and molecular biological features of colon tumors in mice that were tolerant and susceptible to hypoxia based on colitis-associated CRC (CAC). Hypoxia tolerance was assessed through a gasping time evaluation in a decompression chamber. One month later, the animals were experimentally modeled for colitis-associated CRC by intraperitoneal azoxymethane administration and three dextran sulfate sodium consumption cycles. The incidence of tumor development in the distal colon in the susceptible to hypoxia mice was two times higher and all tumors (100%) were represented by adenocarcinomas, while in the tolerant mice, only 14% were adenocarcinomas and 86% were glandular intraepithelial neoplasia. The tumor area assessed on serially stepped sections was statistically significantly higher in the susceptible animals. The number of macrophages, CD3-CD19+, CD3+CD4+, and NK cells in tumors did not differ between animals; however, the number of CD3+CD8+ and vimentin+ cells was higher in the susceptible mice. Changes in the expression of genes regulating the response to hypoxia, inflammation, cell cycle, apoptosis, and epithelial barrier functioning in tumors and the peritumoral area depended on the initial mouse's hypoxia tolerance, which should be taken into account for new CAC diagnostics and treatment approaches development.
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Apoptosis , Ciclo Celular , Neoplasias Asociadas a Colitis , Inflamación , Animales , Ratones , Apoptosis/genética , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/metabolismo , Neoplasias Asociadas a Colitis/etiología , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Ciclo Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/etiología , Regulación Neoplásica de la Expresión Génica , Hipoxia/metabolismo , Hipoxia/genética , Hipoxia/complicaciones , Colitis/genética , Colitis/metabolismo , Colitis/complicaciones , Colitis/inducido químicamente , Colitis/patología , MasculinoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Tang (HQT), a traditional Chinese medicine formula, is commonly used in clinical practice for the treatment of inflammatory bowel diseases. It has been reported that HQT exerts antitumor effects on colitis-associated colorectal cancer (CAC). However, the mechanism by which HQT interferes with the inflammation-to-cancer transformation remains unclear. AIMS OF THE STUDY: The purpose of this study was to dynamically evaluate the efficacy of HQT in alleviating or delaying CAC and to reveal the underlying mechanism. METHODS: We established a mouse model of CAC using azoxymethane combined with 1.5% dextran sodium sulphate. The efficacy of HQT was evaluated based on pathological sections and serum biochemical indices. Subsequently, amino acids (AAs) metabolism analyses were performed using ultra-performance liquid chromatography-tandem mass spectrometry, and the phosphatidylinositol 3 kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway was detected by western blotting. RESULTS: The data demonstrated that HQT could alleviate the development of CAC in the animal model. HQT effectively reduced the inflammatory response, particularly interleukin-6 (IL-6), in the inflammation induction stage, as well as in the stages of proliferation initiation and tumorigenesis. During the proliferation initiation and tumorigenesis stages, immunohistochemistry staining showed that the expression of the proliferation marker Ki67 was reduced, while apoptosis was increased in the HQT group. Accordingly, HQT substantially decreased the levels of specific AAs in the colon with CAC, including glutamic acid, glutamine, arginine, and isoleucine. Furthermore, HQT significantly inhibited the activated PI3K/AKT/mTOR pathway, which may contribute to suppression of cell proliferation and enhancement of apoptosis. CONCLUSION: HQT is effective in alleviating and delaying the colon "inflammation-to-cancer". The mechanism of action may involve HQT maintained AAs metabolism homeostasis and regulated PI3K/AKT/mTOR pathway, so as to maintain the balance between proliferation and apoptosis, and then interfere in the occurrence and development of CAC.
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Aminoácidos , Neoplasias Asociadas a Colitis , Sulfato de Dextran , Medicamentos Herbarios Chinos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Masculino , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Azoximetano/toxicidad , Modelos Animales de Enfermedad , Homeostasis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Ratones Endogámicos C57BL , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/complicaciones , Colitis/metabolismo , Apoptosis/efectos de los fármacos , Fosfatidilinositol 3-Quinasa/metabolismo , Proliferación Celular/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Based on the core pathogenesis of hepatosplenic disorder and qi transformation disorder in ulcerative colitis, Tong-Xie-Yao-Fang (TXYF) is a classical traditional Chinese medicine commonly used to treat ulcerative colitis. Our study revealed that it has the potential to prevent colitis-associated colorectal cancer, which embodies the academic concept in traditional Chinese medicine of treating the disease before it develops. AIM OF THE STUDY: This study was aimed at evaluating the therapeutic role of TXYF in treating colitis-associated colorectal cancer and exploring its possible underlying mechanisms. MATERIALS AND METHODS: A colitis-associated colorectal cancer model was established in mice using azoxymethane and dextran sulfate sodium salt to examine the therapeutic effect of TXYF. The mouse body weights were observed. Hematoxylin-eosin staining was used to evaluate mouse colon histopathology. Colon cancer cells and colon epithelial cells were used to explore the potential molecular mechanisms. The proliferation and apoptosis of cells were detected by CCK8 and cell colony assays, flow cytometry and western blotting. The epithelial-mesenchymal transition (EMT) and mitophagy markers were examined by immunohistochemistry, western blotting, quantitative real-time PCR and immunofluorescence staining. RESULTS: TXYF inhibited the tumorigenesis of mice with colitis-associated colorectal cancer and the growth of inflammatory colon cells. TXYF induced mitophagy in colon cancer cells through the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway to reverse EMT, which was consistent with the results in mice with colitis-associated colorectal cancer. CONCLUSIONS: The results of the present study demonstrated that TXYF effectively inhibited the progression of colitis-associated colorectal cancer through the PINK1/Parkin pathway, which provides new evidence for prevention strategies for this disease.
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Neoplasias Asociadas a Colitis , Medicamentos Herbarios Chinos , Células Epiteliales , Mitofagia , Animales , Mitofagia/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ratones , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/prevención & control , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Azoximetano/toxicidad , Masculino , Transición Epitelial-Mesenquimal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sulfato de Dextran , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Ratones Endogámicos C57BL , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Colitis/tratamiento farmacológico , Colitis/complicaciones , Colitis/inducido químicamente , Proteínas QuinasasRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory disease of the intestines that can significantly impact quality of life and lead to various complications. Currently, 5-aminosalicylic acid derivatives, corticosteroids, immunosuppressants, and biologics are the major treatment strategies for UC, but their limitations have raised concerns. Atractylenolides (ATs), sesquiterpene metabolites found in Atractylodes macrocephala Koidz., have shown promising effects in treating UC by exerting immune barrier modulation, alleviating oxidative stress, gut microbiota regulation, improving mitochondrial dysfunction and repairing the intestinal barrier. Furthermore, ATs have been shown to possess remarkable anti-fibrosis, anti-thrombus, anti-angiogenesis and anti-cancer. These findings suggest that ATs hold important potential in treating UC and its complications. Therefore, this review systematically summarizes the efficacy and potential mechanisms of ATs in treating UC and its complications, providing the latest insights for further research and clinical applications.
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Colitis-associated colorectal cancer has been a hot topic in public health issues worldwide. Numerous studies have demonstrated the significance of myeloid-derived suppressor cells (MDSCs) in the progression of this ailment, but the specific mechanism of their role in the transformation of inflammation to cancer is unclear, and potential therapies targeting MDSC are also unclear. This paper outlines the possible involvement of MDSC to the development of colitis-associated colorectal cancer. It also explores the immune and other relevant roles played by MDSC, and collates relevant targeted therapies against MDSC. In addition, current targeted therapies for colorectal cancer are analyzed and summarized.
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Neoplasias Asociadas a Colitis , Neoplasias Colorrectales , Células Supresoras de Origen Mieloide , Humanos , Células Supresoras de Origen Mieloide/inmunología , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/etiología , Neoplasias Asociadas a Colitis/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Animales , Colitis/complicaciones , Colitis/inmunologíaRESUMEN
BACKGROUND AND AIM: Huangqin decoction (HQD) is a Chinese medicine used to treat colitis and colorectal cancer (CRC). However, the specific compounds and mechanisms of HQD remain unclear despite its good curative clinical results. Through bioinformatics, network pharmacology, and experiments, this study aims to explore the progressive mechanisms of colitis-associated colorectal cancer (CAC) from ulcerative colitis (UC) while examining the protective effects of HQD and its compounds against this. METHODS: Bioinformatics was utilized to identify the hub genes between UC and CRC, and their clinical predictive significance, function, and expression were validated. Employing network pharmacology in combination with hub genes, key targets of HQD for preventing the development of UC into CAC were identified. Molecular docking and molecular dynamics (MD) were utilized to procure compounds that effectively bind to these targets and their transcription factors (TFs). Finally, the expression and mechanism of key targets were demonstrated in mice with UC or CAC. RESULTS: (1) Joint analysis of UC and CRC gene sets resulted in 14 hub genes, mainly related to extracellular matrix receptor binding, biological processes in the extracellular matrix, focal adhesion and neutrophil migration; (2) Network pharmacology results show HQD has 133 core targets for treating UC and CRC, acting on extracellular matrix, inflammatory bowel disease, chemical carcinogen receptor activation and other pathways; (3) The intersection of hub genes and core targets yielded two key targets, MMP1 and MMP3; (4) STAT3 is a shared TF of MMP1 and MMP3. (5) Molecular docking and MD verified that the dockings between Glabridin and STAT3/MMP1/MMP3 are stable and reliable; (6) In murine vivo experiments verified that Glabridin reduces inflammation, extracellular matrix degradation, and the occurrence of epithelial-mesenchymal transition to prevent UC transforming into CAC by inhibiting the phosphorylation of STAT3 and regulating the activity of MMP1/3.
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Colitis Ulcerosa , Medicamentos Herbarios Chinos , Isoflavonas , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 3 de la Matriz , Simulación del Acoplamiento Molecular , Fenoles , Factor de Transcripción STAT3 , Animales , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Fenoles/uso terapéutico , Fenoles/farmacología , Ratones , Masculino , Factor de Transcripción STAT3/metabolismo , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Neoplasias Asociadas a Colitis/prevención & control , Ratones Endogámicos C57BL , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/prevención & control , Modelos Animales de Enfermedad , Sulfato de DextranRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2023.1095098.].
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This paper investigates the intervention effect and mechanism of Banxia Xiexin Decoction(BXD) on colitis-associated colorectal cancer(CAC) infected with Fusobacterium nucleatum(Fn). C57BL/6 mice were randomly divided into a control group, Fn group, CAC group [azoxymethane(AOM)/dextran sulfate sodium salt(DSS)](AOM/DSS), model group, and BXD group. Except for the control and AOM/DSS groups, the mice in the other groups were orally administered with Fn suspension twice a week. The AOM/DSS group, model group, and BXD group were also injected with a single dose of 10 mg·kg~(-1) AOM combined with three cycles of 2.5% DSS taken intragastrically. The BXD group received oral administration of BXD starting from the second cycle until the end of the experiment. The general condition and weight changes of the mice were monitored during the experiment, and the disease activity index(DAI) was calculated. At the end of the experiment, the colon length and weight of the mice in each group were compared. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissue. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of interleukin(IL)-2, IL-4, and IL-6 inflammatory factors in the serum. Immunohistochemistry(IHC) was used to detect the expression of Ki67, E-cadherin, and ß-catenin in the colon tissue. Western blot was used to detect the protein content of Wnt3a, ß-catenin, E-cadherin, annexin A1, cyclin D1, and glycogen synthase kinase-3ß(GSK-3ß) in the colon tissue. The results showed that compared with the control group, the Fn group had no significant lesions. The mice in the AOM/DSS group and model group had decreased body weight, increased DAI scores, significantly increased colon weight, and significantly shortened colon length, with more significant lesions in the model group. At the same time, the colon histology of the model group showed more severe adenomas, inflammatory infiltration, and cellular dysplasia. The levels of IL-4 and IL-6 in the serum were significantly increased, while the IL-2 content was significantly decreased. The IHC results showed low expression of E-cadherin and high expression of Ki67 and ß-catenin in the model group, with a decreased protein content of E-cadherin and GSK-3ß and an increased protein content of Wnt3a, ß-catenin, annexin A1, and cyclin D1. After intervention with BXD, the body weight of the mice increased; the DAI score decreased; the colon length increased, and the tumor decreased. The histopathology showed reduced tumor proliferation and reduced inflammatory infiltration. The levels of IL-6 and IL-4 in the serum were significantly decreased, while the IL-2 content was increased. Meanwhile, the expression of E-cadherin was upregulated, and that of Ki67 and ß-catenin was downregulated. The protein content of E-cadherin and GSK-3ß increased, while that of Wnt3a, ß-catenin, annexin A1, and cyclin D1 decreased. In conclusion, BXD can inhibit CAC infected with Fn, and its potential mechanism may be related to the inhibition of Fn binding to E-cadherin, the decrease in annexin A1 protein level, and the regulation of the Wnt/ß-catenin pathway.
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Anexina A1 , Neoplasias Asociadas a Colitis , Colitis , Medicamentos Herbarios Chinos , Ratones , Animales , Colitis/complicaciones , Colitis/tratamiento farmacológico , Colitis/genética , beta Catenina/genética , beta Catenina/metabolismo , Ciclina D1/metabolismo , Fusobacterium nucleatum/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Antígeno Ki-67/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Ratones Endogámicos C57BL , Cadherinas/metabolismo , Peso Corporal , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , AzoximetanoRESUMEN
OBJECTIVE: The aim of this study is to examine the M1 and M2 macrophages distribution in the rat's colon of DMH-induced inflammation associated colorectal cancer. METHODS: Colon tissue of three groups of 4 rats that induced using 1,2 dimethylhydrazine (DMH) at 30 mg/kg bw every week for 9, 11, and 13 weeks were used. The M1 and M2 distribution was examined by using antibody anti iNOS for M1 and anti-CD163 for M2 with immunohistochemistry method. The data was presents in figure and table in the form of percentage. RESULT: M1 macrophage was found in all groups in the low distribution level (25% - 50%), while M2 macrophage was observed in all groups with 100% distribution. In the longer period of DMH induction, M2 macrophages was distributed more abundant. CONCLUSION: All of the rat's colon showing chronic inflammation that led to the tumorigenesis.
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1,2-Dimetilhidrazina , Colon , Neoplasias Colorrectales , Inflamación , Macrófagos , Animales , Ratas , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/inducido químicamente , Macrófagos/patología , Macrófagos/metabolismo , Inflamación/inducido químicamente , Inflamación/patología , Colon/patología , Colon/metabolismo , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígenos CD/metabolismo , Carcinógenos/toxicidad , Receptores de Superficie Celular/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Wumei Wan (WMW), a traditional Chinese medicine prescription, has been proved to be effective in treating Colitis-associated colorectal cancer (CAC), but it has not been proven to be effective in different stages of CAC. AIM OF THE STUDY: The purpose of our study is to investigate the therapeutic effect and mechanism of WMW on the progression of CAC. MATERIALS AND METHODS: Azioximethane (AOM) and dextran sulfate sodium (DSS) were used to treat mice for the purpose of establishing CAC models. WMW was administered in different stages of CAC. The presentative chemical components in WMW were confirmed by LC-MS/MS under the optimized conditions. The detection of inflammatory cytokines in the serum and colon of mice were estimated by qRT-PCR and ELISA. The changes of T cells and myeloid-derived suppressor cells (MDSCs) in each group were detected by flow cytometry. The metabolic components in serum of mice were detected by UPLC-MS/MS. Expression of genes and proteins were detected by eukaryotic transcriptomics and Western blot to explore the key pathway of WMW in preventing CAC. RESULTS: WMW had significant effect on inhibiting inflammatory responses and tumors during the early development stage of CAC when compared to other times. WMW increased the length of mice's colons, reduced the level of IL-1ß, IL-6, TNF-α in colon tissues, and effectively alleviated colonic inflammation, and improved the pathological damage of colon tissues. WMW could significantly reduce the infiltration of MDSCs in the spleen, increase CD4+ T cells and CD8+ T cells in the spleen of CAC mice, and effectively reform the immune microenvironment in CAC mice. Transcriptomics analysis revealed that 2204 genes had different patterns of overlap in the colon tissues of mice between control group, AOM + DSS group, and early administration of WMW group. And KEGG enrichment analysis showed that PI3K/Akt signaling pathway, ECM-receptor interaction, IL-17 signaling pathway, MAPK signaling pathway, pancreatic secretion, thermogenesis, and Rap1 signaling pathway were all involved. The serum metabolomics results of WMW showed that the metabolic compositions of the control group, AOM + DSS group and the early stage of WMW were different, and 42 differential metabolites with the opposite trends of changes were screened. The metabolic pathways mainly included pyrimidine metabolism, glycine, serine and threonine metabolism, tryptophan metabolism, and purine metabolism. And amino acids and related metabolites may play an important role in WMW prevention of CAC. CONCLUSION: WMW can effectively prevent the occurrence and development of CAC, especially in the initial stage. WMW can reduce the immune infiltration of MDSCs in the early stage. Early intervention of WMW can improve the metabolic disorder caused by AOM + DSS, especially correct the amino acid metabolism. PI3K/Akt signaling pathway was inhabited in early administration of WMW, which can regulate the amplification and function of MDSCs.
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Neoplasias Asociadas a Colitis , Sulfato de Dextran , Medicamentos Herbarios Chinos , Células Supresoras de Origen Mieloide , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ratones , Transducción de Señal/efectos de los fármacos , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Neoplasias Asociadas a Colitis/prevención & control , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/metabolismo , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Citocinas/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Colitis/tratamiento farmacológico , Colitis/complicaciones , Colitis/metabolismo , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Ratones Endogámicos C57BLRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be the driving factor of colitis carcinogenesis. Effective control of inflammation is helpful to prevent and treat colitis-related colorectal cancer (CAC). Anchang Yuyang Decoction (AYD), a traditional Chinese medicine (TCM) formula, is originated from the ancient prescription of TCM for treating colitis and colorectal cancer. AYD has demonstrated efficacy in treating IBD and potential anti-carcinogenic properties. AIM OF THE STUDY: This research aims to assess the therapeutic efficacy of AYD in ameliorating experimental colitis-related carcinogenesis induced by AOM/DSS. It further seeks to elucidate its potential mechanisms by integrating multiple omics sequencing approaches. MATERIALS AND METHODS: A rat model for colitis-related carcinogenesis was developed using azoxymethane (AOM)/dextran sulfate sodium (DSS). UPLC-MS identified AYD's chemical constituents. Rats were administered varying doses of AYD (18.37, 9.19 and 4.59 g/kg) orally for 53 days, with mesalazine as a positive control. The study evaluated anti-carcinogenic effects by examining adenoma number, adenoma load, abnormal crypt foci (ACF), histopathological damage, and tumor-related protein expression. Anti-inflammatory and reparative effects were assessed through body weight, disease activity index (DAI), colon length, spleen index, inflammatory cytokine levels, and tight junction protein expression. The effects on intestinal microbiota and host metabolism were explored through 16S rRNA sequencing, targeted short-chain fatty acid (SCFA) metabonomics, and non-targeted colon metabolomics. Potential AYD targets were identified through transcriptomic sequencing and validated by qRT-PCR and western blotting. RESULTS: AYD significantly reduced adenoma number, adenoma load, neoplasm-associated lesions, ACF, and tumor-related protein expression (e.g., p53, PCNA) in AOM/DSS-induced rats, thus impeding colitis-related carcinogenesis progression. AYD also alleviated histopathological damage and inflammation, promoting intestinal mucosal barrier repair. Furthermore, AYD modulated intestinal flora structure, enhanced SCFA production, and regulated colon metabolites. Transcriptomic sequencing revealed a significant impact on the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Subsequent qRT-PCR and western blotting experiments indicated AYD's influence in up-regulating PPAR-γ and down-regulating PPAR-α, PPAR-ß/δ, and related proteins (thrombomodulin [Thbd], fatty acid binding protein 5 [Fabp5], stearoyl-CoA desaturase 2 [Scd2], phospholipid transfer protein [Pltp]). CONCLUSIONS: This study demonstrates AYD's ability to inhibit experimental colitis-related carcinogenesis induced by AOM/DSS. Its mechanism likely involves modulation of the PPAR signaling pathway, impacting intestinal microbiota and host metabolic equilibrium.
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Adenoma , Colitis , Neoplasias Colorrectales , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Ratas , Animales , Ratones , Receptores Activados del Proliferador del Peroxisoma , ARN Ribosómico 16S , Cromatografía Liquida , Espectrometría de Masas en Tándem , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Inflamación/patología , Transducción de Señal , Carcinogénesis , Azoximetano/toxicidad , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Homeostasis , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , ColonRESUMEN
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 [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 [ß-catenin, T-cell factor (TCF), lymphoid enhancer-binding factor (LEF), and matrix metallopeptidase 7 (MMP7)], inhibited the nuclear translocation of the key transcription factor ß-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-1ß, 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 PPARα-mediated fatty acid oxidation, inhibiting the Wnt signaling pathway-mediated EMT, and suppressing CCL3/CCR1-mediated inflammatory responses.
Asunto(s)
Azoximetano , Neoplasias Asociadas a Colitis , Sulfato de Dextran , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Metabolómica , Transcriptoma , Animales , Medicamentos Herbarios Chinos/farmacología , Ratones , Masculino , Neoplasias Colorrectales , Ratones Endogámicos C57BL , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Colitis/inducido químicamenteRESUMEN
Constitutive activation of STAT3 plays important role in the pathogenesis of colorectal cancer (CRC). Inhibition of STAT3 has been proposed as a reasonable strategy to suppress CRC. Gamabufotalin (Gam), an effective bioactive compound of ChanChu, has been used for cancer therapy due to its desirable metabolic stability and less adverse effect. However, its effect on CRC is still unclear. In this study, we found that Gam significantly inhibited the CRC in vitro and vivo. Furthermore, Gam induced apoptosis to inhibit the viability of HCT-116 and HT-29 cell lines in dose-dependent manner by suppressing the transcription factor STAT3. In addition, Gam was also found to inhibit carcinogenesis of colitis-associated cancer (CAC) in AOM/DSS mice model by inhibiting STAT3. Our findings suggest that Gam may be an effective way to prevent occurrence and development of CRC and CAC.
Asunto(s)
Bufanólidos , Neoplasias Asociadas a Colitis , Colitis , Neoplasias Colorrectales , Animales , Ratones , Colitis/complicaciones , Colitis/tratamiento farmacológico , Colitis/metabolismo , Factores de Transcripción/metabolismo , Transducción de Señal , Proliferación Celular , Neoplasias Colorrectales/metabolismo , Factor de Transcripción STAT3/metabolismo , Sulfato de Dextran/farmacología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Colorectal cancer (CRC) is one of the most common neoplasms worldwide. Among the risk factors of CRC, inflammatory bowel disease (IBD) is one of the most important ones leading to the development of colitis-associated CRC (CAC). G-protein coupled receptors (GPCR) are transmembrane receptors that orchestrate a multitude of signaling cascades in response to external stimuli. Because of their functionality, they are promising targets in research on new strategies for CRC diagnostics and treatment. Recently, regulators of G-proteins (RGS) have been attracting attention in the field of oncology. Typically, they serve as negative regulators of GPCR responses to both physiological stimuli and medications. RGS activity can lead to both beneficial and harmful effects depending on the nature of the stimulus. However, the atypical RGS-AXIN uses its RGS domain to antagonize key signaling pathways in CRC development through the stabilization of the ß-catenin destruction complex. Since AXIN does not limit the efficiency of medications, it seems to be an even more promising pharmacological target in CRC treatment. In this review, we discuss the current state of knowledge on RGS significance in sporadic CRC and CAC with particular emphasis on the regulation of GPCR involved in IBD-related inflammation comprising opioid, cannabinoid and serotonin receptors.
Asunto(s)
Neoplasias Asociadas a Colitis , Enfermedades Inflamatorias del Intestino , Humanos , Proteína Axina , Proteínas de Unión al GTP , Transducción de Señal , Enfermedades Inflamatorias del Intestino/complicacionesRESUMEN
BACKGROUND: Gliclazide is a potential anti-cancer drug candidate for preventing carcinogenesis. However, the effect of gliclazide on colitis-associated colorectal cancer remains unknown. AIMS: We aimed to evaluate whether gliclazide plays a protective role in colitis-associated colorectal cancer and the underlying molecular mechanism. METHODS: The administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) aimed to induce colitis-associated colorectal cancer in mice. C57BL mice were gavaged with gliclazide (6 mg/kg by gavage 5 days a week) for 12 weeks immediately following AOM administration. After sacrificing the mice, colon tissues were measured for tumor number and tumor burden. The proliferation- and inflammation-related molecular mechanisms were explored. RESULTS: The administration of gliclazide significantly reduced the tumor number and tumor burden in mice. Cell proliferation decreased in the gliclazide group compared with the control group, as indicated by reduced Ki-67 expression. Furthermore, gliclazide alleviated colonic inflammation, significantly decreased pro-inflammatory factor TNF-α levels and increased anti-inflammatory factor IL-10 levels in vivo. In vivo and vitro, it was shown that gliclazide increased the level of phospho-AMPK (p-AMPK) and inhibited NF-κB activity. Further studies demonstrated that the inhibition of NF-κB activity induced by gliclazide was mediated by p-AMPK in vitro. CONCLUSIONS: Gliclazide effectively alleviated colonic inflammation and prevented colonic carcinogenesis in an AOM-DSS mouse model by modulating the AMPK-NF-κB signaling pathway. Thus, gliclazide holds potential as a chemopreventive agent for colitis-associated colorectal cancer.
Asunto(s)
Neoplasias Asociadas a Colitis , Colitis , Neoplasias Colorrectales , Gliclazida , Animales , Ratones , FN-kappa B/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Gliclazida/efectos adversos , Colitis/inducido químicamente , Colitis/complicaciones , Colitis/metabolismo , Ratones Endogámicos C57BL , Inflamación/metabolismo , Transducción de Señal , Carcinogénesis , Azoximetano/toxicidad , Sulfato de Dextran/toxicidad , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The Qi-Qin-Hu-Chang Formula (QQHCF) is a traditional Chinese medicine prescription that is clinically used at the Affiliated Hospital of Nanjing University of Chinese Medicine for the treatment of colitis-associated colorectal cancer (CAC). AIM OF THE STUDY: To evaluate the potential therapeutic effects of QQHCF on a CAC mouse model and investigate its underlying mechanisms using network pharmacology and experimental validation. MATERIALS AND METHODS: The active components and potential targets of QQHCF were obtained from Traditional Chinese Medicine Systems Pharmacology (TCMSP) and herb-ingredient-targets gene network were constructed by Cytoscape 3.9.2. Target genes of CAC were obtained from GeneCards, Online Mendelian Inheritance in Man, and DrugBank database. The drug disease target protein-protein interaction (PPI) network was constructed and the core targets were visualized and identified using Cytoscape. The Metascape database was used for GO and KEGG enrichment analysis. UHPLC-MS/MS was used to further identify the active compounds in QQHCF. Subsequently, the therapeutic effects and potential mechanism of QQHCF against CAC were investigated in AOM/DSS-induced CAC mouse in vivo, and HT-29 and HCT116 cells in vitro. Finally, interactions between JNK, p38, and active ingredients were assessed by molecular docking. RESULTS: A total of 176 active compounds, 273 potential therapeutic targets, and 2460 CAC-related target genes were obtained. The number of common targets between QQHCF and CAC were 165. KEGG pathway analysis indicated that the MAPK signaling pathway was closely associated with CAC, which may be the potential mechanism of QQHCF against CAC. Network pharmacology and UHPLC-MS/MS analyses showed that the active compounds of QQHCF included quercetin, kaempferol, luteolin, wogonin, oxymatrine, lupanine, and baicalin. Animal experiments demonstrated that QQHCF reduced tumor load, number, and size in AOM/DSS-treated mice, and induced apoptosis in colon tissue. In vitro experiments further showed that QQHCF induced apoptosis and inhibited cell viability, migration, and invasion in HCT116 and HT-29 cells. Notably, QQHCF activated the JNK/p38 MAPK signaling pathway both in vivo and in vitro. Molecular docking analysis revealed an ability for the main components of QQHCF and JNK/p38 to bind. CONCLUSION: The present study demonstrated that QQHCF could ameliorate AOM/DSS-induced CAC in mice by activating the JNK/p38 MAPK signaling pathway. These results have important implications for the development of effective treatment strategies for CAC.
Asunto(s)
Neoplasias Asociadas a Colitis , Medicamentos Herbarios Chinos , Humanos , Animales , Ratones , Qi , Farmacología en Red , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem , Transducción de Señal , Apoptosis , Bases de Datos Genéticas , Proteínas Quinasas p38 Activadas por Mitógenos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
Ephrin B3, a member of Eph/ephrin family, contributes to embryogenesis and carcinogenesis, but few studies have suggested whether this ligand has regulatory effect on colitis. This study was to determine whether ephrin B3 played a role in colitis and colonic carcinogenesis. Dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated carcinogenesis model was established in Efnb3-deficient (Efnb3-/-) mice. Label-free quantitative proteomics were performed to identify the Efnb3-regulated proteins. Our results showed that Efnb3 knock out reduced the symptoms of DSS-induced colitis, such as disease activity index (DAI), inflammatory factors release, and dysfunction of the intestinal barrier. Quantitative proteomics revealed that Efnb3 regulated 95 proteins which clustered in the platelet degranulation, response to elevated platelet cytosolic Ca2+, MAPK signaling for integrins such as ITGB4. Furthermore, ephrin B3 inactived ITGB4/AKT signal pathway and then promoted epithelial barrier dysfunction. Simultaneously, ephrin B3 promoted Gremlin-1/NF-κB signal pathway and thereby increased inflammatory factors release. In addition, the higher level of Efnb3 in colon cancer patients is correlated with worse survival. Efnb3-/- mice exhibited susceptibility to AOM/DSS-induced colorectal cancer. Our finding discovered that Efnb3 played an important role in the development of colitis and colitis-associated colorectal cancer. Efnb3 deficiency improved the intestinal barrier by ITGB4 and suppressed inflammation via Gremlin-1/NF-κB signal pathway, which may provide a novel therapeutic strategy for the treatment of colitis and colitis-associated colorectal cancer.
Asunto(s)
Neoplasias Asociadas a Colitis , Colitis , Neoplasias Colorrectales , Humanos , Animales , Ratones , Efrina-B3 , FN-kappa B/metabolismo , Colitis/inducido químicamente , Colitis/complicaciones , Colitis/metabolismo , Carcinogénesis , Azoximetano/toxicidad , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Neoplasias Colorrectales/metabolismoRESUMEN
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) played an essential role in tumor microenvironment to suppress host antitumor immunity and help cancer cells escape immune surveillance. However, the molecular mechanism behind tumor evasion mediated by MDSCs is not fully understood. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is considered to associate with tumor initiation, metastasis and angiogenesis. Blocking GPNMB function is a potentially valuable therapy for cancer by eliminating GPNMB+MDSCs. Our previous study has proved that blockage the MyD88 signaling with the MyD88 inhibitor, TJ-M2010-5, may completely prevent the development of CAC in mice, accompanying with downregulation of GPNMB mRNA in the inhibitor-treated mice of CAC. METHODS: We here focus on the underlying the relationship between GPNMB function and MyD88 signaling pathway activation in MDSCs' antitumor activity in CAC. RESULTS: CAC development in the mouse model is associated with expanded GPNMB+MDSCs by a MyD88-dependent pathway. The GPNMB expression on MDSCs is associated with MyD88 signaling activation. The inhibitory effect of MDSCs on T cell proliferation, activation and antitumor cytotoxicity in CAC is mediated by GPNMB in a MyD8-dependent manner. CONCLUSION: MyD88 signaling pathway plays an essential role in GPNMB+MDSC-mediated tumor immune escape during CAC development and is a promising focus for revealing the mechanisms of MDSC that facilitate immunosuppression and tumor progression.