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1.
Braz J Med Biol Res ; 57: e13306, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38958363

RESUMEN

Arbutin is utilized in traditional remedies to cure numerous syndromes because of its anti-microbial, antioxidant, and anti-inflammatory properties. This study aimed to evaluate chemopreventive effects of arbutin on azoxymethane (AOM)-induced colon aberrant crypt foci (ACF) in rats. Five groups of rats were used: normal control group (rats injected hypodermically with sterile phosphate-buffered saline once per week for two weeks) and groups 2-5, which were subcutaneously inoculated with 15 mg/kg AOM once a week for two weeks. AOM control and 5-fluorouracil (5-FU) control groups were fed 10% Tween orally daily for 8 weeks using a feeding tube. The treated groups were fed 30 and 60 mg/kg arbutin every day for 2 months. ACF from the AOM control group had aberrant nuclei in addition to multilayered cells and an absence of goblet cells. The negative control group displayed spherical cells and nuclei in basal positions. Histological examination revealed a reduced number of AFC cells from colon tissues of the 5-FU reference group. Arbutin-fed animals showed down-regulation of proliferating cell nuclear antigen (PCNA) and up-regulation of Bax protein compared to AOM control. Rats fed with arbutin displayed a significant increase of superoxide dismutase (SOD) and catalase (CAT) activities in colon tissue homogenates compared to the AOM control group. In conclusion, arbutin showed therapeutic effects against colorectal cancer, explained by its ability to significantly decrease ACF, down-regulate PCNA protein, and up-regulate Bax protein. In addition, arbutin significantly increased SOD and CAT, and decreased malondialdehyde (MDA) levels, which might be due to its anti-proliferative and antioxidant properties.


Asunto(s)
Focos de Criptas Aberrantes , Arbutina , Azoximetano , Antígeno Nuclear de Célula en Proliferación , Proteína X Asociada a bcl-2 , Animales , Focos de Criptas Aberrantes/inducido químicamente , Focos de Criptas Aberrantes/patología , Focos de Criptas Aberrantes/prevención & control , Focos de Criptas Aberrantes/tratamiento farmacológico , Antígeno Nuclear de Célula en Proliferación/metabolismo , Masculino , Arbutina/farmacología , Ratas , Proteína X Asociada a bcl-2/metabolismo , Colon/efectos de los fármacos , Colon/patología , Ratas Wistar , Fluorouracilo , Carcinógenos
2.
Bull Exp Biol Med ; 177(1): 162-168, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38960963

RESUMEN

In adult male C57BL/6 mice with high (HR) and low (LR) resistance to hypoxia, morphological features of colon tumors and blood parameters were evaluated 70 days after intraperitoneal injection of azoxymethane and subsequent consumption of 3 cycles of dextran sulfate sodium. On macroscopic analysis, tumors were found in the distal colon in 35% (7 of 20 animals) of HR and 31% (4 of 13 animals) of LR animals. Microscopic analysis of the distal colon revealed tumors in 75% (15 of 20 animals) of HR and 69% (9 of 13 animals) of LR mice. The tumors were presented by areas of glandular intraepithelial neoplasia and adenocarcinomas; the incidence and the area of the tumors did not differ in groups of HR and LR mice. The number of neuroendocrine and goblet cells in the distal colon mucosa in the areas of tumors was similar in the compared groups. However, in both HR and LR mice of the experimental groups, the content of goblet cells in tumors was lower and the content of endocrine cells was higher than in the corresponding control groups. In the peripheral blood, the erythrocyte count and hemoglobin content decreased in HR and LR mice of the experimental groups; the relative number of monocytes increased only in HR mice and the absolute number of lymphocytes and monocytes decreased in LR mice. Thus, 70 days after azoxymethane administration and dextran sulfate sodium consumption, the tumors in mice were presented by glandular intraepithelial neoplasia and adenocarcinomas, and their incidence and area did not differ between animals with different tolerance to hypoxia.


Asunto(s)
Adenocarcinoma , Azoximetano , Neoplasias del Colon , Sulfato de Dextran , Ratones Endogámicos C57BL , Animales , Ratones , Neoplasias del Colon/patología , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/metabolismo , Masculino , Sulfato de Dextran/toxicidad , Azoximetano/toxicidad , Adenocarcinoma/patología , Adenocarcinoma/inducido químicamente , Adenocarcinoma/metabolismo , Hipoxia/patología , Colon/patología , Células Caliciformes/patología , Células Caliciformes/metabolismo , Mucosa Intestinal/patología , Hemoglobinas/metabolismo , Monocitos/patología , Monocitos/metabolismo , Recuento de Eritrocitos
3.
J Ethnopharmacol ; 333: 118411, 2024 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-38824980

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Previous studies have revealed that a high-fat diet (HFD) promotes the progression of colorectal cancer (CRC) in close association with disturbances in the intestinal flora and metabolic disorders. Xianglian pill (XLP) is a well-established traditional prescription with unique advantages in controlling intestinal flora imbalance and inflammation. However, its therapeutic effects on HFD-related CRC remain largely unknown. AIM OF THE STUDY: The primary objective of this research was to investigate the anticancer mechanism of XLP in countering HFD-related CRC. MATERIALS AND METHODS: The protective effect of XLP was evaluated using azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC model of mice exposed to a HFD. The degree of colorectal carcinogenesis, including body weight, colon length, and histopathology, was measured in mice treated with XLP and untreated mice. The effect of XLP on gut microbiota and its metabolites was detected using 16S rDNA and liquid chromatography/mass spectrometry analysis. Furthermore, a "pseudo-sterile" mouse model was constructed using antibiotics (Abx) to verify whether the gut microbiota and metabolites play a role in the pathogenesis of CRC. RESULTS: XLP inhibited colorectal tumorigenesis in a dose-dependent fashion. Our findings also highlighted that XLP protected the integrity of the intestinal barrier by reducing the expression of pro-inflammatory cytokines, such as IL-6 and TNF-α, as well as the infiltration of pro-inflammatory macrophages. Mechanistically, XLP inhibited the TLR4/MyD88 pathway. Notably, the XLP treatment increased the proportion of probiotics (particularly Akkermansia) and significantly reduced fecal deoxycholic acid (DCA), a microbiota-derived metabolite of bile acids (BA) closely related to Muribaculaceae. Furthermore, after Abx treatment, XLP showed no clear antitumor effects on CRC. Simultaneously, DCA-supplemented feedings promoted colorectal tumorigenesis and provoked obvious colonic inflammation, M1 macrophage infiltration, and colonic injury. In vitro, the results of RAW-264.7 macrophages and normal intestinal epithelial cells treated with DCA corroborated our in vivo findings, demonstrating consistent patterns in inflammatory responses and intestinal barrier protein expression. CONCLUSION: Our findings suggest that XLP inhibits colorectal cancer associated with HFD via inactivating TLR4/MyD88 by remodeling gut microbiota composition and BA metabolism.


Asunto(s)
Ácidos y Sales Biliares , Neoplasias Colorrectales , Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide , Receptor Toll-Like 4 , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Dieta Alta en Grasa/efectos adversos , Factor 88 de Diferenciación Mieloide/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Ratones , Masculino , Medicamentos Herbarios Chinos/farmacología , Ácidos y Sales Biliares/metabolismo , Azoximetano/toxicidad , Sulfato de Dextran
4.
Mol Biol Rep ; 51(1): 704, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38824233

RESUMEN

BACKGROUND: Tumor modeling using organoids holds potential in studies of cancer development, enlightening both the intracellular and extracellular molecular mechanisms behind different cancer types, biobanking, and drug screening. Intestinal organoids can be generated in vitro using a unique type of adult stem cells which are found at the base of crypts and are characterized by their high Lgr5 expression levels. METHODS AND RESULTS: In this study, we successfully established intestinal cancer organoid models by using both the BALB/c derived and mouse embryonic stem cells (mESCs)-derived intestinal organoids. In both cases, carcinogenesis-like model was developed by using azoxymethane (AOM) treatment. Carcinogenesis-like model was verified by H&E staining, immunostaining, relative mRNA expression analysis, and LC/MS analysis. The morphologic analysis demonstrated that the number of generated organoids, the number of crypts, and the intensity of the organoids were significantly augmented in AOM-treated intestinal organoids compared to non-AOM-treated ones. Relative mRNA expression data revealed that there was a significant increase in both Wnt signaling pathway-related genes and pluripotency transcription factors in the AOM-induced intestinal organoids. CONCLUSION: We successfully developed simple carcinogenesis-like models using mESC-based and Lgr5 + stem cell-based intestinal organoids. Intestinal organoid based carcinogenesi models might be used for personalized cancer therapy in the future.


Asunto(s)
Azoximetano , Carcinogénesis , Células Madre Embrionarias de Ratones , Organoides , Vía de Señalización Wnt , Animales , Organoides/metabolismo , Organoides/patología , Ratones , Azoximetano/toxicidad , Carcinogénesis/patología , Carcinogénesis/inducido químicamente , Carcinogénesis/genética , Células Madre Embrionarias de Ratones/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ratones Endogámicos BALB C , Intestinos/patología , Neoplasias Intestinales/patología , Neoplasias Intestinales/inducido químicamente , Neoplasias Intestinales/genética , Neoplasias Intestinales/metabolismo , Modelos Animales de Enfermedad , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología
5.
Yakugaku Zasshi ; 144(5): 475-481, 2024.
Artículo en Japonés | MEDLINE | ID: mdl-38692920

RESUMEN

Zinc is one of the essential trace elements, and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism is not fully understood. Therefore, we focused our research on tumor immunity to elucidate the effect of zinc on colorectal cancer and its mechanisms. Mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to develop colorectal cancer, then the relationship between zinc content in the diet and the number and area of tumors in the colon was observed. The number of tumors in the colon was significantly higher in the no-zinc-added diet group compared to the normal zinc intake group, and about half the number in the high-zinc-intake group compared to the normal-zinc-intake group. In T-cell-deficient mice, the number of tumors in the high-zinc-intake group was similar to that in the normal-zinc-intake group, suggesting that the inhibitory effect of zinc was dependent on T cells. Furthermore, we found that the amount of granzyme B transcript released by cytotoxic T cells upon antigen stimulation was significantly increased by the addition of zinc. We also showed that granzyme B transcriptional activation by zinc addition was dependent on calcineurin activity. Collectively, we have shown that zinc exerts its tumor-suppressive effect by acting on cytotoxic T cells, the center of cellular immunity, and that it increases the transcription of granzyme B, one of the key molecules involved in tumor immunity. In this symposium, we would like to introduce our latest data on the relationship between zinc and tumor immunity.


Asunto(s)
Neoplasias Colorrectales , Inmunidad Celular , Zinc , Animales , Humanos , Ratones , Azoximetano , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/prevención & control , Modelos Animales de Enfermedad , Granzimas/metabolismo , Linfocitos T Citotóxicos/inmunología
6.
Cancer Lett ; 593: 216940, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38729554

RESUMEN

Decreased levels of ß-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.


Asunto(s)
Ácido 3-Hidroxibutírico , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neovascularización Patológica , Ácido 3-Hidroxibutírico/farmacología , Ácido 3-Hidroxibutírico/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Animales , Ratones , Humanos , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Línea Celular Tumoral , Carcinogénesis/efectos de los fármacos , Masculino , Azoximetano/toxicidad , Colitis/complicaciones , Colitis/metabolismo , Colitis/patología , Colitis/inducido químicamente , Sulfato de Dextran , Modelos Animales de Enfermedad , Angiogénesis
7.
Int J Mol Sci ; 25(9)2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38731854

RESUMEN

Factors that reduce the risk of developing colorectal cancer include biologically active substances. In our previous research, we demonstrated the anti-inflammatory, immunomodulatory, and antioxidant effects of oat beta-glucans in gastrointestinal disease models. The aim of this study was to investigate the effect of an 8-week consumption of a diet supplemented with low-molar-mass oat beta-glucan in two doses on the antioxidant potential, inflammatory parameters, and colonic metabolomic profile in azoxymethane(AOM)-induced early-stage colorectal cancer in the large intestine wall of rats. The results showed a statistically significant effect of AOM leading to the development of neoplastic changes in the colon. Consumption of beta-glucans induced changes in colonic antioxidant potential parameters, including an increase in total antioxidant status, a decrease in the superoxide dismutase (SOD) activity, and a reduction in thiobarbituric acid reactive substance (TBARS) concentration. In addition, beta-glucans decreased the levels of pro-inflammatory interleukins (IL-1α, IL-1ß, IL-12) and C-reactive protein (CRP) while increasing the concentration of IL-10. Metabolomic studies confirmed the efficacy of oat beta-glucans in the AOM-induced early-stage colon cancer model by increasing the levels of metabolites involved in metabolic pathways, such as amino acids, purine, biotin, and folate. In conclusion, these results suggest a wide range of mechanisms involved in altering colonic metabolism during the early stage of carcinogenesis and a strong influence of low-molar-mass oat beta-glucan, administered as dietary supplement, in modulating these mechanisms.


Asunto(s)
Antioxidantes , Azoximetano , Neoplasias Colorrectales , beta-Glucanos , Animales , beta-Glucanos/farmacología , Azoximetano/toxicidad , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/patología , Ratas , Masculino , Antioxidantes/farmacología , Antioxidantes/metabolismo , Modelos Animales de Enfermedad , Avena/química , Superóxido Dismutasa/metabolismo , Colon/metabolismo , Colon/patología , Colon/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Proteína C-Reactiva/metabolismo
8.
J Agric Food Chem ; 72(21): 12130-12145, 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38748495

RESUMEN

Colorectal cancer (CRC) is a common malignant tumor that occurs in the colon. Gut microbiota is a complex ecosystem that plays an important role in the pathogenesis of CRC. Our previous studies showed that the soluble dietary fiber of foxtail millet (FMB-SDF) exhibited significant antitumor activity in vitro. The present study evaluated the anticancer potential of FMB-SDF in the azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced mouse CRC models. The results showed that FMB-SDF could significantly alleviate colon cancer symptoms in mice. Further, we found that FMB-SDF consumption significantly altered gut microbiota diversity and the overall structure and regulated the abundance of some microorganisms in CRC mice. Meanwhile, KEGG pathway enrichment showed that FMB-SDF can also alleviate the occurrence of colon cancer in mice by regulating certain cancer-related signaling pathways. In conclusion, our findings may provide a novel approach for the prevention and biotherapy of CRC.


Asunto(s)
Bacterias , Neoplasias Colorrectales , Fibras de la Dieta , Microbioma Gastrointestinal , Setaria (Planta) , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/metabolismo , Ratones , Setaria (Planta)/química , Fibras de la Dieta/metabolismo , Fibras de la Dieta/farmacología , Humanos , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Masculino , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/química , Azoximetano , Ratones Endogámicos C57BL
9.
Theranostics ; 14(7): 2719-2735, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38773969

RESUMEN

Aim: To elucidate dynamics and functions in colonic macrophage subsets, and their regulation by Bifidobacterium breve (B. breve) and its associated metabolites in the initiation of colitis-associated colorectal cancer (CAC). Methods: Azoxymethane (AOM) and dextran sodium sulfate (DSS) were used to create a CAC model. The tumor-suppressive effect of B. breve and variations of macrophage subsets were evaluated. Intestinal macrophages were ablated to determine their role in the protective effects of B. breve. Efficacious molecules produced by B. breve were identified by non-targeted and targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The molecular mechanism was further verified in murine bone marrow-derived macrophages (BMDMs), macrophages derived from human peripheral blood mononuclear cells (hPBMCs), and demonstrated in CAC mice. Results: B. breve alleviated colitis symptoms, delayed colonic tumorigenesis, and promoted phenotypic differentiation of immature inflammatory macrophages into mature homeostatic macrophages. On the contrary, the ablation of intestinal macrophages largely annulled the protective effects of B. breve. Microbial analysis of colonic contents revealed the enrichment of probiotics and the depletion of potential pathogens following B. breve supplementation. Moreover, indole-3-lactic acid (ILA) was positively correlated with B. breve in CAC mice and highly enriched in the culture supernatant of B. breve. Also, the addition of ILA directly promoted AKT phosphorylation and restricted the pro-inflammatory response of murine BMDMs and macrophages derived from hPBMCs in vitro. The effects of ILA in murine BMDMs and macrophages derived from hPBMCs were abolished by the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or the AKT inhibitor MK-2206. Furthermore, ILA could protect against tumorigenesis by regulating macrophage differentiation in CAC mice; the AhR antagonist largely abrogated the effects of B. breve and ILA in relieving colitis and tumorigenesis. Conclusion: B. breve-mediated tryptophan metabolism ameliorates the precancerous inflammatory intestinal milieu to inhibit tumorigenesis by directing the differentiation of immature colonic macrophages.


Asunto(s)
Bifidobacterium breve , Diferenciación Celular , Colitis , Indoles , Macrófagos , Probióticos , Animales , Ratones , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Bifidobacterium breve/metabolismo , Indoles/farmacología , Indoles/metabolismo , Humanos , Colitis/inducido químicamente , Colitis/microbiología , Colitis/complicaciones , Diferenciación Celular/efectos de los fármacos , Probióticos/farmacología , Probióticos/administración & dosificación , Modelos Animales de Enfermedad , Carcinogénesis/efectos de los fármacos , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/microbiología , Neoplasias Asociadas a Colitis/metabolismo , Ratones Endogámicos C57BL , Colon/microbiología , Colon/patología , Colon/metabolismo , Sulfato de Dextran , Masculino , Microbioma Gastrointestinal , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/microbiología , Azoximetano
10.
Biomed Pharmacother ; 175: 116580, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38723513

RESUMEN

Colitis-associated cancer (CAC) in inflammatory bowel diseases exhibits more aggressive behavior than sporadic colorectal cancer; however, the molecular mechanisms remain unclear. No definitive preventative agent against CAC is currently established in the clinical setting. We investigated the molecular mechanisms of CAC in the azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model and assessed the antitumor efficacy of erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR). Erlotinib premixed with AIN-93 G diet at 70 or 140 parts per million (ppm) inhibited tumor multiplicity significantly by 96%, with ∼60% of the treated mice exhibiting zero polyps at 12 weeks. Bulk RNA-sequencing revealed more than a thousand significant gene alterations in the colons of AOM/DSS-treated mice, with KEGG enrichment analysis highlighting 46 signaling pathways in CAC development. Erlotinib altered several signaling pathways and rescued 40 key genes dysregulated in CAC, including those involved in the Hippo and Wnt signaling. These findings suggest that the clinically-used antitumor agent erlotinib might be repurposed for suppression of CAC, and that further studies are warranted on the crosstalk between dysregulated Wnt and EGFR signaling in the corresponding patient population.


Asunto(s)
Azoximetano , Neoplasias Asociadas a Colitis , Sulfato de Dextran , Modelos Animales de Enfermedad , Clorhidrato de Erlotinib , Animales , Clorhidrato de Erlotinib/farmacología , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Ratones , Azoximetano/toxicidad , Receptores ErbB/metabolismo , Receptores ErbB/genética , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Ratones Endogámicos C57BL , Masculino , Transducción de Señal/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/complicaciones , Colitis/patología
11.
Cell Mol Gastroenterol Hepatol ; 18(1): 105-131, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38614455

RESUMEN

BACKGROUND & AIMS: Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR1) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR1 antagonism on colitis-associated carcinogenesis. METHODS: A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR1 antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn's disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR1 agonist proteinases. RESULTS: AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The ß-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota ß-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR1 mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca2+ concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR1 at the thrombin cleavage site. CONCLUSIONS: PAR1 antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis.


Asunto(s)
Azoximetano , Sulfato de Dextran , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Receptor PAR-1 , Animales , Receptor PAR-1/metabolismo , Receptor PAR-1/antagonistas & inhibidores , Humanos , Ratones , Células CACO-2 , Sulfato de Dextran/toxicidad , Azoximetano/toxicidad , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Colitis/complicaciones , Colitis/inducido químicamente , Colitis/patología , Colitis/tratamiento farmacológico , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Factor de Transcripción STAT3/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patología , Miofibroblastos/efectos de los fármacos , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/microbiología , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Neoplasias Asociadas a Colitis/inmunología , Trombina/metabolismo , Ratones Endogámicos C57BL , Enfermedad de Crohn/patología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/inducido químicamente
12.
Int Immunopharmacol ; 133: 112125, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38657499

RESUMEN

Bone fracture as a consequence of colorectal cancer (CRC) and associated osteoporosis (OP) is considered a risk factor for increasing the mortality rate among CRC patients. SNHG16/ miRNA-146a/ TRAF6 signaling pathway is a substantial contributor to neoplastic evolution, progression, and metastasis. Here, we investigated the effect of zoledronate (ZOL) on the growth of CRC and associated OP in a mouse model. Thirty Balb/c mice were divided into Naïve, azoxymethane (AOM)/dextran sodium sulfate (DSS), and ZOL groups. Body weight and small nucleolar RNA host gene 16 (SNHG16) expression, microRNA-146a, and TRAF6 in bone, colon, and stool were investigated. Samples of colon and bone were collected and processed for light microscopic, immunohistochemical staining for cytokeratin 20 (CK20), nuclear protein Ki67 (pKi-67), and caudal type homeobox transcription factor 2 (CDx2) in colon and receptor activator of nuclear factor kB (RANK) and osteoprotegerin (OPG) in bone. A computerized tomography (CT) scan of the femur and tibia was studied. ZOL produced a significant decrease in the expression of SNHG16 and TRAF6 and an increase in miRNA-146a in the colon and bone. ZOL administration improved the histopathological changes in the colon, produced a significant decrease in CK20 and Ki-67, and increased CDx2 expressions. In bone, ZOL prevented osteoporotic changes and tumour cell invasion produced a significant decrease in RANK and an increase in OPG expressions, alongside improved bone mineral density in CT scans. ZOL could be a promising preventive therapy against colitis-induced cancer and associated OP via modulation expression of SNHG16, miRNA-146a, and TRAF6.


Asunto(s)
Neoplasias Colorrectales , MicroARNs , Osteoporosis , ARN Largo no Codificante , Factor 6 Asociado a Receptor de TNF , Ácido Zoledrónico , Animales , Humanos , Masculino , Ratones , Azoximetano , Conservadores de la Densidad Ósea/uso terapéutico , Conservadores de la Densidad Ósea/farmacología , Colon/patología , Colon/efectos de los fármacos , Colon/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Sulfato de Dextran , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , MicroARNs/metabolismo , MicroARNs/genética , Osteoporosis/metabolismo , Osteoporosis/tratamiento farmacológico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/genética , Ácido Zoledrónico/uso terapéutico
13.
Gut Microbes ; 16(1): 2341647, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38659246

RESUMEN

The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.


Asunto(s)
Azoximetano , Ratones de Colaboración Cruzada , Neoplasias Colorrectales , Microbioma Gastrointestinal , Polimorfismo de Nucleótido Simple , Animales , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inducido químicamente , Humanos , Ratones , Ratones de Colaboración Cruzada/genética , Oxidasas Duales/genética , Oxidasas Duales/metabolismo , Predisposición Genética a la Enfermedad , Masculino , Bacterias/genética , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/aislamiento & purificación , Modelos Animales de Enfermedad , Femenino
14.
Nutrients ; 16(8)2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38674816

RESUMEN

Colorectal cancer (CRC) accounts for 30% of all cancer cases worldwide and is the second leading cause of cancer-related deaths. CRC develops over a long period of time, and in the early stages, pathological changes can be mitigated through nutritional interventions using bioactive plant compounds. Our study aims to determine the effect of highly purified oat beta-glucan on an animal CRC model. The study was performed on forty-five male Sprague-Dawley rats with azoxymethane-induced early-stage CRC, which consumed feed containing 1% or 3% low molar mass oat beta-glucan (OBG) for 8 weeks. In the large intestine, morphological changes, CRC signaling pathway genes (RT-PCR), and proteins (Western blot, immunohistochemistry) expression were analyzed. Whole blood hematology and blood redox status were also performed. Results indicated that the histologically confirmed CRC condition led to a downregulation of the WNT/ß-catenin pathway, along with alterations in oncogenic and tumor suppressor gene expression. However, OBG significantly modulated these effects, with the 3% OBG showing a more pronounced impact. Furthermore, CRC rats exhibited elevated levels of oxidative stress and antioxidant enzyme activity in the blood, along with decreased white blood cell and lymphocyte counts. Consumption of OBG at any dose normalized these parameters. The minimal effect of OBG in the physiological intestine and the high activity in the pathological condition suggest that OBG is both safe and effective in early-stage CRC.


Asunto(s)
Avena , Suplementos Dietéticos , Estrés Oxidativo , Ratas Sprague-Dawley , beta-Glucanos , Animales , Masculino , beta-Glucanos/farmacología , beta-Glucanos/administración & dosificación , Avena/química , Ratas , Estrés Oxidativo/efectos de los fármacos , Neoplasias del Colon/prevención & control , Anticarcinógenos/farmacología , Azoximetano , Vía de Señalización Wnt/efectos de los fármacos , Modelos Animales de Enfermedad , Alimentación Animal , Colon/patología , Colon/efectos de los fármacos , Colon/metabolismo , Neoplasias Colorrectales/prevención & control , Antioxidantes/farmacología
15.
Nutrients ; 16(8)2024 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-38674851

RESUMEN

Colorectal cancer stands as the third most prevalent form of cancer worldwide, with a notable increase in incidence in Western countries, mainly attributable to unhealthy dietary habits and other factors, such as smoking or reduced physical activity. Greater consumption of vegetables and fruits has been associated with a lower incidence of colorectal cancer, which is attributed to their high content of fiber and bioactive compounds, such as flavonoids. In this study, we have tested the flavonoids quercetin, luteolin, and xanthohumol as potential antitumor agents in an animal model of colorectal cancer induced by azoxymethane and dodecyl sodium sulphate. Forty rats were divided into four cohorts: Cohort 1 (control cohort), Cohort 2 (quercetin cohort), Cohort 3 (luteolin cohort), and Cohort 4 (xanthohumol cohort). These flavonoids were administered intraperitoneally to evaluate their antitumor potential as pharmaceutical agents. At the end of the experiment, after euthanasia, different physical parameters and the intestinal microbiota populations were analyzed. Luteolin was effective in significantly reducing the number of tumors compared to the control cohort. Furthermore, the main significant differences at the microbiota level were observed between the control cohort and the cohort treated with luteolin, which experienced a significant reduction in the abundance of genera associated with disease or inflammatory conditions, such as Clostridia UCG-014 or Turicibacter. On the other hand, genera associated with a healthy state, such as Muribaculum, showed a significant increase in the luteolin cohort. These results underline the anti-colorectal cancer potential of luteolin, manifested through a modulation of the intestinal microbiota and a reduction in the number of tumors.


Asunto(s)
Neoplasias Colorrectales , Flavonoides , Microbioma Gastrointestinal , Luteolina , Propiofenonas , Quercetina , Animales , Luteolina/farmacología , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Propiofenonas/farmacología , Flavonoides/farmacología , Quercetina/farmacología , Ratas , Masculino , Modelos Animales de Enfermedad , Azoximetano , Antineoplásicos/farmacología , Ratas Wistar
16.
Zhongguo Zhong Yao Za Zhi ; 49(5): 1266-1274, 2024 Mar.
Artículo en Chino | MEDLINE | ID: mdl-38621974

RESUMEN

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.


Asunto(s)
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 , Azoximetano
17.
Phytomedicine ; 128: 155385, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38569292

RESUMEN

BACKGROUND: Xianlian Jiedu Decoction (XLJDD) has been used for the treatment of colorectal cancer (CRC) for several decades because of the prominent efficacy of the prescription. Despite the clear clinical efficacy of XLJDD, the anti-CRC mechanism of action is still unclear. PURPOSE: The inhibitory effect and mechanism of XLJDD on CRC were investigated in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mice. METHODS: The AOM/DSS-induced mice model was adopted to evaluate the efficacy after administering the different doses of XLJDD. The therapeutic effects of XLJDD in treating AOM/DSS-induced CRC were investigated through histopathology, immunofluorescence and ELISA analysis methods. In addition, metabolomics profile and 16S rRNA analysis were used to explore the effective mechanisms of XLJDD on CRC. RESULTS: The results stated that the XLJDD reduced the number of tumor growth on the inner wall of the colon and the colorectal weight/length ratio, and suppressed the disease activity index (DAI) score, meanwhile XLJDD also increased body weight, colorectal length, and overall survival rate. The treatment of XLJDD also exhibited the ability to lower the level of inflammatory cytokines in serum and reduce the expression levels of ß-catenin, COX-2, and iNOS protein in colorectal tissue. The findings suggested that XLJDD has anti-inflammatory properties and may provide relief for those suffering from inflammation-related conditions. Mechanistically, XLJDD improved gut microbiota dysbiosis and associated metabolic levels of short chain fatty acids (SCFAs), sphingolipid, and glycerophospholipid. This was achieved by reducing the abundance of Turicibacter, Clostridium_sensu_stricto_1, and the levels of sphinganine, LPCs, and PCs. Additionally, XLJDD increased the abundance of Enterorhabdus and Alistipes probiotics, as well as the content of butyric acid and isovaleric acid. CONCLUSION: The data presented in this article demonstrated that XLJDD can effectively inhibit the occurrence of colon inner wall tumors by reducing the level of inflammation and alleviating intestinal microbial flora imbalance and metabolic disorders. It provides a scientific basis for clinical prevention and treatment of CRC.


Asunto(s)
Azoximetano , Neoplasias Colorrectales , Sulfato de Dextran , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Ratones , Masculino , Modelos Animales de Enfermedad , Metaboloma/efectos de los fármacos , Colon/efectos de los fármacos , Colon/patología , Colon/microbiología
18.
Discov Med ; 36(183): 778-787, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38665026

RESUMEN

BACKGROUND: Tropomyosin 2 (TPM2) has been linked to the advancement of various tumor types, exhibiting distinct impacts on tumor progression. In our investigation, the primary objective was to identify the potential involvement of TPM2 in the development of colitis-associated cancer (CAC) using a mice model. METHODS: This study used lentiviral vector complex for TPM2 knockdown (sh-TPM2) and the corresponding negative control lentiviral vector complex (sh-NC) for genetic interference in mice. CAC was induced in mice using azoxymethane (AOM) and dextran sulfate sodium salt (DSS). This study included 6 groups of mice models: Control, Control+sh-NC, Control+sh-TPM2, CAC, CAC+sh-NC, and CAC+sh-TPM2. Subsequently, colon tissues were collected and assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for TPM2 mRNA levels and flow cytometry for infiltrating immune cells. Tumor number, size, and weight within colon tissues from CAC mice were measured and recorded. The hematoxylin-eosin staining was used for observing tissue pathology changes. The intestinal epithelial cells (IECs) were isolated and analyzed for cell proliferation. This analysis included examining the levels of 5-bromo-2-deoxyuridine (BrdU) and Ki-67 using immunohistochemistry. Additionally, the mRNA levels of proliferating cell nuclear antigen (PCNA) and Ki-67 were detected by qRT-PCR. This study also investigated the activation of the c-Jun N-terminal kinase (JNK) pathway using western blot analysis. Immunogenicity analyses were conducted using immunohistochemistry for F4/80 and flow cytometry. RESULTS: In 8-week-old mice, AOM injections and three cycles of DSS treatment induced TPM2 upregulation in tumor tissues compared to normal tissues (p < 0.05). Fluorescence-activated cell sorting (FACS)-isolated lamina CAC adenomas revealed macrophages and dendritic cells as primary TPM2 contributors (p < 0.001). Lentiviral TPM2 gene knockdown significantly reduced tumor numbers and sizes in CAC mice (p < 0.01, and p < 0.001), without invasive cancer cells. TPM2 suppression resulted in decreased IEC proliferation (p < 0.001) and reduced PCNA and Ki-67 expression (p < 0.05). Western blot analysis indicated reduced JNK pathway activation in TPM2-knockdown CAC mice (p < 0.05, p < 0.001). TPM2 knockdown decreased tumor-associated macrophage infiltration (p < 0.01) and increased CD3+ and CD8+ T cells (p < 0.01, and p < 0.001), with increased levels of regulator of inflammatory cytokines (CD44+, CD107a+) (p < 0.01, and p < 0.001), decreased levels of PD-1+ and anti-inflammatory factor (IL10+) (p < 0.01, and p < 0.001). CONCLUSIONS: Our results demonstrated that TPM2 knockdown suppressed the proliferation of CAC IECs, enhanced immune suppression on CAC IECs, and inhibited the JNK signaling pathway within the framework of CAC. These findings suggest TPM2 can serve as a potential therapeutic target for CAC treatment.


Asunto(s)
Proliferación Celular , Neoplasias Asociadas a Colitis , Sistema de Señalización de MAP Quinasas , Tropomiosina , Animales , Humanos , Masculino , Ratones , Azoximetano/toxicidad , Colitis/inducido químicamente , Colitis/patología , Colitis/complicaciones , Colitis/inmunología , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/inmunología , Neoplasias Asociadas a Colitis/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Sistema de Señalización de MAP Quinasas/inmunología , Ratones Endogámicos C57BL , Tropomiosina/metabolismo , Tropomiosina/inmunología , Tropomiosina/genética
19.
Arq Gastroenterol ; 61: e23062, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38451659

RESUMEN

BACKGROUND: Colorectal cancer is one of the most prevalent pathologies worldwide whose prognosis is linked to early detection. Colonoscopy is the gold standard for screening, and diagnosis is usually made histologically from biopsies. Aiming to reduce the inspection and diagnostic time as well as the biopsies and resources involved, other techniques are being promoted to conduct accurate in vivo colonoscopy assessments. Optical biopsy aims to detect normal and neoplastic tissues analysing the autofluorescence spectrum based on the changes in the distribution and concentration of autofluorescent molecules caused by colorectal cancer. Therefore, the autofluorescence contribution analysed by image processing techniques could be an approach to a faster characterization of the target tissue. OBJECTIVE: Quantify intensity parameters through digital processing of two data sets of three-dimensional widefield autofluorescence microscopy images, acquired by fresh colon tissue samples from a colorectal cancer murine model. Additionally, analyse the autofluorescence data to provide a characterization over a volume of approximately 50 µm of the colon mucosa for each image, at second (2nd), fourth (4th) and eighth (8th) weeks after colorectal cancer induction. METHODS: Development of a colorectal cancer murine model using azoxymethane/dextran sodium sulphate induction, and data sets acquisition of Z-stack images by widefield autofluorescence microscopy, from control and colorectal cancer induced animals. Pre-processing steps of intensity value adjustments followed by quantification and characterization procedures using image processing workflow automation by Fiji's macros, and statistical data analysis. RESULTS: The effectiveness of the colorectal cancer induction model was corroborated by a histological assessment to correlate and validate the link between histological and autofluorescence changes. The image digital processing methodology proposed was then performed on the three-dimensional images from control mice and from the 2nd, 4th, and 8th weeks after colorectal cancer chemical induction, for each data set. Statistical analyses found significant differences in the mean, standard deviation, and minimum parameters between control samples and those of the 2nd week after induction with respect to the 4th week of the first experimental study. This suggests that the characteristics of colorectal cancer can be detected after the 2nd week post-induction. CONCLUSION: The use of autofluorescence still exhibits levels of variability that prevent greater systematization of the data obtained during the progression of colorectal cancer. However, these preliminary outcomes could be considered an approach to the three-dimensional characterization of the autofluorescence of colorectal tissue, describing the autofluorescence features of samples coming from dysplasia to colorectal cancer. BACKGROUND: • A new digital image processing method was developed to measure intensity in 3D autofluorescence images of colorectal samples using a CRC mouse model. BACKGROUND: • This method showed that autofluorescence intensity in colon mucosa is similar in healthy tissue but changes significantly in tumor development. BACKGROUND: • Statistical analysis revealed CRC traits detectable from the second week post-induction, aiding in early CRC detection. BACKGROUND: • The study provides a basis for 3D autofluorescence characterization in colorectal tissue from dysplasia to cancer, although variability in autofluorescence limits data systematization during cancer progression.


Asunto(s)
Neoplasias Colorrectales , Microscopía , Animales , Ratones , Modelos Animales de Enfermedad , Azoximetano , Biopsia , Neoplasias Colorrectales/diagnóstico por imagen
20.
Phytomedicine ; 128: 155509, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38452403

RESUMEN

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 químicamente
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