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1.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077084

RESUMO

Recent studies have shown dysbiosis is associated with inflammatory bowel disease (IBD). However, trying to restore microbial diversity via fecal microbiota transplantation (FMT) or probiotic intervention fails to achieve clinical benefit in IBD patients. We performed a probiotic intervention on a simulated IBD murine model to clarify their relationship. IBD was simulated by the protocol of azoxymethane and dextran sodium sulfate (AOM/DSS) to set up a colitis and colitis-associated neoplasm model on BALB/c mice. A single probiotic intervention using Clostridium butyricum Miyairi (CBM) on AOM/DSS mice to clarify the role of probiotic in colitis, colitis-associated neoplasm, gut microbiota, and immune cytokines was performed. We found dysbiosis occurred in AOM/DSS mice. The CBM intervention on AOM/DSS mice failed to improve colitis and colitis-associated neoplasms but changed microbial composition and unexpectedly increased expression of proinflammatory IL-17A in rectal tissue. We hypothesized that the probiotic intervention caused dysbiosis. To clarify the result, we performed inverse FMT using feces from AOM/DSS mice to normal recipients to validate the pathogenic effect of dysbiosis from AOM/DSS mice and found mice on inverse FMT did develop colitis and colon neoplasms. We presumed the probiotic intervention to some extent caused dysbiosis as inverse FMT. The role of probiotics in IBD requires further elucidation.


Assuntos
Neoplasias Associadas a Colite , Colite , Doenças Inflamatórias Intestinais , Probióticos , Animais , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/terapia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Disbiose/terapia , Doenças Inflamatórias Intestinais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Probióticos/farmacologia , Sulfatos
2.
Int Immunopharmacol ; 111: 109097, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35952517

RESUMO

BACKGROUND: Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are the most common diseases of human digestive system. Nowadays, the influence of the inflammatory microenvironment on tumorigenesis has become a new direction, and the exploration of relative molecular mechanism will facilitate the discovery and identification of novel potential anti-cancer molecules. METHODS: Natural shikonin (SK) and acetyl-shikonin (acetyl-SK) was administered to azoxymethane (AOM)/dextran sodium sulphate (DSS)-induced colitis-associated colorectal cancer (CAC) mice model by gavage to investigate their therapeutic effects. Moreover, fresh feces and colon tissues were collected for determining the function of SK and acetyl-SK on the gut microbes and protein expression, respectively. RESULTS: Both SK and acetyl-SK decreased AOM/DSS-induced CAC, and regulated the intestinal flora structure in CAC mouse model. They, especially SK, improved species richness, evenness and diversity of intestinal flora, recovered the upregulated ratio of Firmicutes to Bacteroidota (F/B ratio) which symbolizes gut microbiota dysbiosis. SK and its derivative increased the beneficial bacteria g__norank_f__Muribaculaceae, Lactobacillus, Lachnospiraceae_NK4A136_Group, and reduced those harmful ones including Ileibacterium and Coriobacteriaceae UCG-002. Notably, AOM/DSS caused significant increase in the abundance of Ileibaterium valens and g__norank_f__norank_o__Clostridia_UCG-014, which were not previously reported in studies of colonic inflammation or cancer, and the disorder was reversed by 20 mg/kg of SK. In our current study, the action of SK and acetyl-SK is dose-dependent, and 20 mg/kg SK exhibited the most effective functions, even better than the positive drug mesalazine. Moreover, differential proteomics and ELISA results showed that SK could recover the increase of pro-inflammatory cytokines (including IL-1ß, IL-6 and TNF-α), the upregulation of pyruvate kinase isozyme type M2 (PKM2) and some other proteins (mainly concentrated in transcriptional mis-regulation in cancer and IL-17 signaling pathways), and the downregulation of Aldh1b1-Acc3-Maoa and Μgt2b34-Aldh1a1-Aldh1a7 involved in Wnt/ß-catenin signaling pathway. CONCLUSION: Our study identified SK and acetyl-SK, especially SK, as potential preventive agents for CAC through regulating both gut microbes and pathways involved in inflammation and cancer such as Wnt/ß-catenin signaling pathway.


Assuntos
Neoplasias Associadas a Colite , Colite , Neoplasias Colorretais , Animais , Azoximetano , Bacteroidetes , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/microbiologia , Neoplasias Associadas a Colite/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Firmicutes , Humanos , Inflamação/complicações , Camundongos , Camundongos Endogâmicos C57BL , Naftoquinonas , Microambiente Tumoral
3.
Turk J Gastroenterol ; 33(9): 731-742, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35946886

RESUMO

BACKGROUND: Colorectal cancer is related to ulcerative colitis. This study aimed to investigate the effects of aspirin on non-specific inflammation developing into cancer. METHODS: Ulcerative colitis model was generated by administrating azoxymethane/dextran sulfate sodium to mice. Weight, tumor size/ amount, and intestinal mucositis scores were analyzed. Inflammatory cell infiltration and atypical hyperplasia were determined with hematoxylin-eosin staining. Immunohistochemical assay was used to detect the proliferating cell nuclear antigen. Interleukin-6 and interleukin-10 were detected using enzyme-linked immunosorbent assay. Signal transducer and activator of transcription 3, phosphorylated-STAT3, cyclin D1, and suppressor of cytokine signaling 3 were examined with western blotting. RESULTS: Aspirin remarkably decreased tumor size/amount compared to those of the ulcerative colitis model group (P < .05). Interleukin-6 was increased and interleukin-10 was decreased in mice of ulcerative colitis model group compared with the control group (P < .05). Aspirin markedly reduced interleukin-6 and enhanced interleukin-10 compared to the ulcerative colitis model group (P < .05) induced Azoxymethane/dextran sulfate sodium inflammation (3 weeks) and atypical hyperplasia (8 weeks). Aspirin predominantly inhibited the "inflammation-atypical hyperplasia-cancer" process and alleviated inflammatory cell infiltration of mice in the ulcerative colitis model group. Aspirin promoted apoptosis and alleviated proliferating cell nuclear antigen of atypical hyperplastic intestinal mucosal cells at 8 weeks post-modeling. The expression of phosphorylated-STAT3, signal transducer and activator of transcription 3, cyclin D1, and suppressor of cytokine signaling 3 was significantly increased in mice of ulcerative colitis model group compared to the control group (P < .05). Aspirin remarkably decreased phosphorylated-STAT3, signal transducer and activator of transcription, and cyclin D1 expression compared with ulcerative colitis model group (P < .05). CONCLUSION: Aspirin inhibited carcinogenesis of intestinal mucosal cells in the ulcerative colitis model by inhibiting the interleukin-6/ Janus kinase/signal transducer and activator of transcription 3 signaling pathway and promoted apoptosis, thereby suppressing proliferation.


Assuntos
Colite Ulcerativa , Fator de Transcrição STAT3 , Animais , Apoptose , Aspirina/efeitos adversos , Azoximetano/efeitos adversos , Carcinogênese , Proliferação de Células , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Ciclina D1/metabolismo , Ciclina D1/farmacologia , Sulfato de Dextrana/toxicidade , Amarelo de Eosina-(YS)/efeitos adversos , Hematoxilina/farmacologia , Hiperplasia/prevenção & controle , Inflamação/patologia , Interleucina-10 , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Camundongos , Antígeno Nuclear de Célula em Proliferação , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
4.
Phytomedicine ; 105: 154279, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35963192

RESUMO

BACKGROUND: Portulaca oleracea is a known medicinal plant with antioxidant, anti-inflammatory, and anticancer activities, and it may also function an important role in colorectal cancer (CRC). PURPOSE: We probed into study the critical function of Portulaca oleracea extract (POE) in CRC and the related downstream factors. METHODS: Azoxymethane (AOM) and dextransodiumsulfate (DSS) were used to induce mouse models of CRC, which were then administered different doses of POE to evaluate the therapeutic effects of POE on CRC. Diversity, abundance, and function of gut microbiota were analyzed. Moreover, the potential molecular targets of POE inhibiting CRC development were determined. Expression of c-Myc and cyclin D1 as well as CRC cell proliferation and apoptosis was detected. RESULTS: POE treatment inhibited AOM/DSS-induced CRC development in mice and ameliorated gut microbial imbalance. Bioinformatic analysis revealed marked differences in the gut microbiota between CRC samples and normal samples and that 20 differential microbiota may be involved in CRC development through the Wnt signaling pathway. Additionally, c-Myc and cyclin D1 were identified to be the key downstream target genes of the Wnt/ß-catenin signaling pathway. In vitro data revealed that POE played a suppressive role in the proliferation of CRC cells by reducing the expression of c-Myc and cyclin D1 and inactivating the Wnt/ß-catenin signaling pathway. CONCLUSION: This study underlines that POE reduces gut microbiota imbalance and inhibits CRC development and progression via inactivation of the Wnt/ß-catenin signaling pathway and downregulation of c-Myc and cyclin D1 expression, which is expected to be a potential biomarker for CRC.


Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Portulaca , Animais , Azoximetano , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1 , Regulação Neoplásica da Expressão Gênica , Camundongos , Via de Sinalização Wnt , beta Catenina
5.
Theranostics ; 12(12): 5574-5595, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910798

RESUMO

The survival rate of colorectal cancer patients is adversely affected by the selection of tumors resistant to conventional anti-cancer drugs such as 5-fluorouracil (5FU). Although there is mounting evidence that commensal gut microbiota is essential for effective colon cancer treatment, the detailed molecular mechanisms and the role of gut microbial metabolites remain elusive. The goal of this study is to decipher the impact and mechanisms of gut microbial metabolite, urolithin A (UroA) and its structural analogue, UAS03 on reversal of 5FU-resistant (5FUR) colon cancers. Methods: We have utilized the SW480 and HCT-116 parental (5FU-sensitive) and 5FUR colon cancer cells to examine the chemosensitization effects of UroA or UAS03 by using both in vitro and in vivo models. The effects of mono (UroA/UAS03/5FU) and combinatorial therapy (UroA/UAS03 + 5FU) on cell proliferation, apoptosis, cell migration and invasion, regulation of epithelial mesenchymal transition (EMT) mediators, expression and activities of drug transporters, and their regulatory transcription factors were examined using molecular, cellular, immunological and flowcytometric methods. Further, the anti-tumor effects of mono/combination therapy (UroA or UAS03 or 5FU or UroA/UAS03 + 5FU) were examined using pre-clinical models of 5FUR-tumor xenografts in NRGS mice and azoxymethane (AOM)-dextran sodium sulfate (DSS)-induced colon tumors. Results: Our data showed that UroA or UAS03 in combination with 5FU significantly inhibited cell viability, proliferation, invasiveness as well as induced apoptosis of the 5FUR colon cancer cells compared to mono treatments. Mechanistically, UroA or UAS03 chemosensitized the 5FUR cancer cells by downregulating the expression and activities of drug transporters (MDR1, BCRP, MRP2 and MRP7) leading to a decrease in the efflux of 5FU. Further, our data suggested the UroA or UAS03 chemosensitized 5FUR cancer cells to 5FU treatment through regulating FOXO3-FOXM1 axis. Oral treatment with UroA or UAS03 in combination with low dose i.p. 5FU significantly reduced the growth of 5FUR-tumor xenografts in NRGS mice. Further, combination therapy significantly abrogated colonic tumors in AOM-DSS-induced colon tumors in mice. Conclusions: In summary, gut microbial metabolite UroA and its structural analogue UAS03 chemosensitized the 5FUR colon cancers for effective 5FU chemotherapy. This study provided the novel characteristics of gut microbial metabolites to have significant translational implications in drug-resistant cancer therapeutics.


Assuntos
Neoplasias do Colo , Resistencia a Medicamentos Antineoplásicos , Fluoruracila , Proteína Forkhead Box M1 , Proteína Forkhead Box O3 , Microbioma Gastrointestinal , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Antimetabólitos Antineoplásicos/metabolismo , Azoximetano , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Cumarínicos/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Fluoruracila/metabolismo , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Humanos , Camundongos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
6.
Oxid Med Cell Longev ; 2022: 4061713, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35927991

RESUMO

Wumei Pill (WMP) is a traditional Chinese herbal formulation and widely used to treat digestive system diseases in clinical. S-Adenosylhomocysteine hydrolase (AHCY) can catalyze the hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine in living organisms, and its abnormal expression is linked to the pathogenesis of many diseases including colorectal cancer (CRC). A previous study reported that WMP could prevent CRC in mice; however, the underlying mechanisms especially the roles of AHCY in WMP-induced anti-CRC remain largely unknown. Here, we investigated the regulatory roles and potential mechanisms of AHCY in WMP-induced anti-CRC. WMP notably alleviated the azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colitis-associated colon cancer (CAC) in mice. Besides, WMP inhibited the inflammation and oxidative stress in AOM/DSS-induced CAC mice. AHCY was high expression in clinical samples of colon cancer compared to the adjacent tissues. WMP inhibited the AHCY expression in AOM/DSS-induced CAC mice. An in vitro study found that AHCY overexpression induced cell proliferation, colony formation, invasion, and tumor angiogenesis, whereas its knockdown impaired its oncogenic function. AHCY overexpression enhanced, while its knockdown weakened the inflammation and oxidative stress in colon cancer cells. Interestingly, WMP potently suppressed the hedgehog (Hh) signaling in AOM/DSS-induced CAC mice. A further study showed that AHCY overexpression activated the Hh signaling while AHCY knockdown inactivated the Hh signaling. Moreover, activation of the Hh signaling reversed the effect of AHCY silencing on inflammation and oxidative stress in vitro. In conclusion, WMP alleviated the AOM/DSS-induced CAC through inhibition of inflammation and oxidative stress by regulating AHCY-mediated hedgehog signaling in mice. These findings uncovered a potential molecular mechanism underlying the anti-CAC effect of WMP and suggested WMP as a promising therapeutic candidate for CRC.


Assuntos
Neoplasias Associadas a Colite , Colite , Neoplasias do Colo , Neoplasias Colorretais , Adenosil-Homocisteinase/metabolismo , Animais , Azoximetano/uso terapêutico , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/complicações , Colite/tratamento farmacológico , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Proteínas Hedgehog/metabolismo , Inflamação/complicações , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo
7.
Probiotics Antimicrob Proteins ; 14(5): 947-959, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35788907

RESUMO

Gut microbiota dysbiosis may promote the process of colorectal cancer (CRC). Lacticaseibacillus rhamnosus LS8 (LRL) is a potential gut microbiota regulating strain because it can produce a novel antimicrobial substance (like cycloalanopine). In addition, this probiotic had an inflammation-ameliorating effect on the dextran sulfate sodium (DSS)-induced colitis mice. However, it is not known whether treatment with this probiotic could ameliorate colitis-associated CRC via regulating gut microbiota. In this study, a CRC mouse model was induced by a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg) and followed by three 7-day cycles of 2% DSS administration. Results showed that LRL could inhibit tumor formation. Moreover, LRL enhanced the gut barrier by preventing goblet cell loss and promoting the expression of ZO-1, occludin, and claudin-1. Furthermore, LRL ameliorated gut microbiota dysbiosis, which was conducive to the growth of beneficial bacteria (e.g., Faecalibaculum and Akkermansia), and further led to an increase in SCFAs and a decrease in LPS. In addition, LRL alleviated colonic inflammation by inhibiting the overexpression of TLR4/NF-κB, pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-γ, and IL-17a), and chemokines (Cxcl1, Cxcl2, Cxcl3, Cxcl5, and Cxcl7). In conclusion, LRL could alleviate CRC by regulating gut microbiota and preventing gut barrier damage and inflammation.


Assuntos
Colite , Microbioma Gastrointestinal , Lactobacillus rhamnosus , Animais , Azoximetano/toxicidade , Carcinogênese , Colite/induzido quimicamente , Colite/complicações , Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Disbiose/tratamento farmacológico , Inflamação/tratamento farmacológico , Camundongos
8.
Mol Carcinog ; 61(10): 941-957, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35856887

RESUMO

Dietary rice bran (RB) has shown capacity to influence metabolism by modulation of gut microbiota in individuals at risk for colorectal cancer (CRC), which warranted attention for delineating mechanisms for bidirectional influences and cross-feeding between the host and RB-modified gut microbiota to reduce CRC. Accordingly, in the present study, fermented rice bran (FRB, fermented with a RB responsive microbe Bifidobacterium longum), and non-fermented RB were fed as 10% w/w (diet) to gut microbiota-intactspf or germ-free micegf to investigate comparative efficacy against inflammation-associated azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC. Results indicated both microbiota-dependent and independent mechanisms for RB meditated protective efficacy against CRC that was associated with reduced neoplastic lesion size and local-mucosal/systemic inflammation, and restoration of colonic epithelial integrity. Enrichment of beneficial commensals (such as, Clostridiales, Blautia, Roseburia), phenolic metabolites (benzoate and catechol metabolism), and dietary components (ferulic acid-4 sulfate, trigonelline, and salicylate) were correlated with anti-CRC efficacy. Germ-free studies revealed gender-specific physiological variables could differentially impact CRC growth and progression. In the germ-free females, the RB dietary treatment showed a ∼72% reduction in the incidence of colonic epithelial erosion when compared to the ∼40% reduction in FRB-fed micegf . Ex vivo fermentation of RB did not parallel the localized-protective benefits of gut microbial metabolism by RB in damaged colonic tissues. Findings from this study suggest potential needs for safety considerations of fermented fiber rich foods as dietary strategies against severe inflammation-associated colon tumorigenesis (particularly with severe damage to the colonic epithelium).


Assuntos
Bifidobacterium longum , Microbioma Gastrointestinal , Oryza , Animais , Azoximetano/toxicidade , Carcinogênese/patologia , Transformação Celular Neoplásica/patologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Dieta , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Oryza/metabolismo
9.
Phytomedicine ; 102: 154217, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35660350

RESUMO

BACKGROUND: Colitis-associated cancer (CAC) is known to be a complex combination of tumor cells, non-tumor cells and a large intestinal flora. The increasing role of intestinal flora in CAC may represent a new approach to improving CAC treatment. Berberine can reduce colorectal adenoma recurrence and inhibit colorectal carcinogenesis. PURPOSE: Berberine has demonstrated efficacy for the control and suppression of CAC. Given the low oral absorption into the blood and large intestinal excretion of berberine, intestinal flora may be one of the important targets of berberine inhibiting the occurrence of colorectal cancer (CRC). The purpose of this study was to investigate the effects of berberine on intestinal flora in CAC mice and its ability to remodel intestinal flora to improve short-chain fatty acid metabolism. STUDY DESIGN AND METHODS: The CAC model in mice was induced by Azoxymethane/Dextran sodium sulfate (AOM/DSS). Berberine was administered daily at doses of 50 and 100 mg/kg, and aspirin was used as the positive control. The effect of berberine on colitis-associated colorectal tumorigenesis was assessed by general imaging, tumor counting, and Ki67 staining. Intestinal flora changes were detected by 16S rDNA sequencing technology. Targeted short-chain fatty acid detection was performed by GC-MS/MS, and Lipopolysaccharide (LPS) levels in feces were quantified with an ELISA kit. The signaling pathway of TLR4/NF-κB P65/IL-6/p-STAT3 was evaluated by Western blotting and immunofluorescence. The expression levels of intestinal barrier functional biomarkers Occludin and ZO-1 were detected by immunohistochemistry. Fecal flora transplantation (FMT) was used to evaluate the effect of intestinal flora in inhibiting inflammatory cancer transformation by berberine. RESULTS: Berberine reduced the number and load of tumors in CAC mice. Berberine remodeled the composition of pathogenic and beneficial bacteria in mice with colitis-associated colorectal tumorigenesis. Berberine treatment resulted in increases in fecal butyric acid, acetic acid and propionic acid levels, but did not alter isobutyric acid, isovaleric acid, valeric acid and caproic acid. In addition, berberine reduced LPS content in feces in mice with colitis-associated colorectal tumorigenesis. Occludin and ZO-1 were upregulated, and the TLR4/p-NF-κB p65/IL-6/p-STAT3 inflammatory-cancer transformation pathway was inhibited with berberine. The FMT results further verified that the berberine-treated intestinal flora was sufficient to alleviate the occurrence of colonic tumors associated with colitis in mice. CONCLUSION: Our study showed that berberine alleviated the colitis-associated colorectal tumorigenesis from three equilibrium levels: (1) Pathogenic and beneficial bacteria; (2) Short-chain fatty acids and LPS produced by intestinal flora; and (3) Inflammatory cancer transformation signaling and intestinal barrier function. This study provided a new approach and experimental basis for the application of berberine in the treatment of CAC in clinical practice.


Assuntos
Berberina , Colite , Neoplasias Colorretais , Microbioma Gastrointestinal , Animais , Azoximetano , Berberina/farmacologia , Carcinogênese , Transformação Celular Neoplásica , Colite/induzido quimicamente , Colite/complicações , Colite/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Ácidos Graxos Voláteis , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Ocludina , Espectrometria de Massas em Tandem , Receptor 4 Toll-Like
10.
Biomed Pharmacother ; 149: 112883, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35692123

RESUMO

Euphorbia lathyris seeds have been used to treat various medical conditions. We previously reported that ethanolic extract from the defatted seed of Euphorbia lathyris (EE) (variety S3201) possesses a potent in vitro antitumor activity against colon cancer (CRC) cell lines. However, the effects of EE on CRC in vivo models and its possible preventive activity have not been elucidated. The aim of this study is to develop an in vivo study to corroborate its efficacy. For this purpose, two tumor induction models have been developed. In orthotopic xenograft model, it has been shown that EE reduces tumor size without hematological toxicity. The ethanolic extract induced an intense apoptosis in tumors mediated by caspase 3. Using the Azoxymethane/Dextran Sulfate Sodium model, a reduction of dysplastic polyps has been demonstrated, showing its preventive power. Furthermore, EE promoted the presence of an eubiotic microbiotal environment in the mucosa of the colon and induced an increase in antioxidant enzyme activity. This fact was accompanied by a modulation of cytokine expression that could be related to its protective mechanism. Therefore, although further experiments will be necessary to determine its applicability in the treatment of CRC, ES could be a new prevention strategy as well as treatment for this type of tumor, being a powerful candidate for future clinical trials.


Assuntos
Neoplasias do Colo , Euphorbia , Azoximetano/toxicidade , Neoplasias do Colo/tratamento farmacológico , Sulfato de Dextrana , Etanol , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
11.
Phytomedicine ; 103: 154227, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35679795

RESUMO

BACKGROUND: A growing body of evidence reveals that dysregulation of Hedgehog signaling pathway and dysbiosis of gut microbiota are associated with the pathogenesis of colorectal cancer (CRC). Berberine, a botanical benzylisoquinoline alkaloid, possesses powerful activities against various malignancies including CRC, with the underlying mechanisms to be illuminated. PURPOSE: The present study investigated the potencies of berberine on CRC and deciphered the action mechanisms in the context of Hedgehog signaling cascade and gut microbiota. METHODS: The effects of berberine on the malignant phenotype, apoptosis, cell cycle and Hedgehog signaling of CRC cells were examined in vitro. In azoxymethane/dextran sulfate sodium-caused mouse CRC, the efficacies of berberine on the carcinogenesis, pathological profile, apoptosis, cell cycle and Hedgehog signaling were determined in vivo. Also, the influences of berberine on gut microbiota in CRC mice were assessed by high-throughput DNA sequencing analysis of 16S ribosomal RNA of fecal microbiome in CRC mice. RESULTS: In the present study, berberine was found to dampen the proliferation, migration, invasion and colony formation of CRC cells, without toxicity to normal colonic cells. Additionally, berberine induced apoptosis and arrested cell cycle at G0/G1 phase in CRC cells, accompanied by reduced Hedgehog signaling pathway activity in vitro. In mouse CRC, berberine suppressed tumor growth, ameliorated pathological manifestations, and potentially induced the apoptosis and cell cycle arrest of CRC, with lowered Hedgehog signaling cascade in vivo. Additionally, berberine decreased ß-diversity of gut microbiota in CRC mice, without influence on α-diversity. Berberine also enriched probiotic microbes and depleted pathogenic microbes, and modulated the functionality of gut microbiota in CRC mice. CONCLUSIONS: Overall, berberine may suppress colorectal cancer, orchestrated by down-regulation of Hedgehog signaling pathway activity and modulation of gut microbiota.


Assuntos
Berberina , Neoplasias Colorretais , Microbioma Gastrointestinal , Animais , Azoximetano , Berberina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos
12.
Nutr Cancer ; 74(10): 3651-3661, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35695489

RESUMO

Fucoxanthin (Fx) is a critical pigment required for photosynthesis in brown algae and microalgae. Fx is also a dietary marine carotenoid that with potent anticancer activity in vitro and in vivo. Some popular light meals for increased satiety, such as biscuits, cereals, and crackers, are frequently fortified with micronutrients for human health benefits. However, data on the anticancer potential of Fx-supplemented light meals in humans and animal models remain limited. In the present study, we investigated the anticancer effects of a Fx-supplemented biscuit using a carcinogenic murine azoxymethane/dextran sodium sulfate (AOM/DSS) model. We observed that periodic administration of biscuits containing 0.3% Fx (Fx-biscuit) at an interval of 3 days (each 15 h) per week for 15 weeks significantly inhibited colorectal carcinogenesis in AOM/DSS mice. Comprehensive gene analysis demonstrated that the Fx-biscuit significantly altered the expression of 138 genes in the colorectal mucosal tissue of the mice. In particular, the expression of heat shock protein 70 (HSP70) genes, Hspa1b (-35.7-fold) and Hspa1a (-34.9-fold), was markedly downregulated. HSP70 is a polyfunctional chaperone protein that is involved in cancer development. Compared to the control-biscuit group, the number of cells with markedly high fluorescence for HSP70 protein (HSP70high) in colorectal mucosal crypts and adenocarcinomas significantly reduced by 0.3- and 0.2-fold, respectively, in the Fx-biscuit group. Our results suggested that Fx-biscuit possesses chemopreventive potential in the colorectal cancer of AOM/DSS mice via the downregulation of HSP70.


Assuntos
Colite , Neoplasias Colorretais , Animais , Azoximetano/toxicidade , Carcinogênese , Colite/patologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/prevenção & controle , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Camundongos , Xantofilas
13.
World J Gastroenterol ; 28(18): 1981-1995, 2022 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-35664967

RESUMO

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) has long been known to cause opportunistic infections and has recently been implicated in colorectal cancer (CRC), which has attracted broad attention. However, the mechanism by which it is involved in CRC development is not fully understood. AIM: To explore its potential causative role in CRC development, we evaluated the colon pathology, mucosa barrier, colon microbiota and host transcriptome profile after F. nucleatum infection in an azoxymethane/dextran sulfate sodium salt (AOM/DSS) mouse model. METHODS: Three groups of mice were compared to reveal the differences, i.e., the control, AOM/DSS-induced CRC and AOM/DSS-FUSO infection groups. RESULTS: Both the AOM/DSS and AOM/DSS-FUSO groups exhibited a significantly reduced body weight and increased tumor numbers than the control group, and AOM/DSS mice with F. nucleatum infection showed the highest tumor formation ratio among the three groups. Moreover, the colon pathology was the most serious in the AOM/DSS-FUSO group. We found that the structure of the colon microbiota changed considerably after F. nucleatum infection; striking differences in mucosal microbial population patterns were observed between the AOM/DSS-FUSO and AOM/DSS groups, and inflammation-inducing bacteria were enriched in the mucosal microbiota in the AOM/DSS-FUSO group. By comparing intestinal transcriptomics data from AOM vs AOM/DSS-FUSO mice, we showed that transcriptional activity was strongly affected by dysbiosis of the gut microbiota. The most microbiota-sensitive genes were oncogenes in the intestine, and the cyclic adenosine monophosphate signaling pathway, neuroactive ligand-receptor interaction, PPAR signaling pathway, retinol metabolism, mineral absorption and drug metabolism were highly enriched in the AOM/DSS-FUSO group. Additionally, we showed that microbial dysbiosis driven by F. nucleatum infection enriched eight taxa belonging to Proteobacteria, which correlates with increased expression of oncogenic genes. CONCLUSION: Our study demonstrated that F. nucleatum infection altered the colon mucosal microbiota by enriching pathogens related to the development of CRC, providing new insights into the role of F. nucleatum in the oncogenic microbial environment of the colon.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Infecções por Fusobacterium , Microbioma Gastrointestinal , Animais , Azoximetano/toxicidade , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/complicações , Neoplasias do Colo/genética , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Sulfato de Dextrana , Modelos Animais de Doenças , Disbiose/complicações , Infecções por Fusobacterium/complicações , Fusobacterium nucleatum , Humanos , Mucosa Intestinal/patologia , Camundongos , Transcriptoma
14.
Biochem Pharmacol ; 202: 115138, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35700756

RESUMO

INTRODUCTION: Madecassic acid (MA), a triterpene compound isolated from Centella Asiatica herbs, has previously been shown to attenuate colitis induced by DSS in mice. In the present study, we address whether and how MA ameliorates colitis-associated colorectal cancer (CAC), which accounts for a considerable proportion of colorectal cancer. METHODS: CAC was induced by AOM/DSS in mice, and MA was administered orally once a day. To identify the source cells of IL-17 and the target cells for MA reducing the expression of IL-17 in the colons of CAC mice, single-cell suspensions were prepared from the colons of CAC mice and analyzed by flow cytometry. An adoptive transfer experiment was performed to verify the importance of the decreasing γδT17 cell population in the anti-CAC effect of MA. RESULTS: Oral administration of MA reduced the burden and incidence of tumors in the CAC mice. MA decreased the number of MDSCs in the colon tissues of CAC mice and ameliorated anti-tumor immune responses. MA could prevent the migration of MDSCs by inhibiting the activation of γδT17 cells and the expression of chemokines. The population of activated-γδT17 cells in the tumor microenvironment of CAC mice positively correlated with the number of MDSCs and tumors as well as tumor load. Moreover, the anti-CAC effect of MA was significantly counteracted by the adoptive transfer of γδT17 cells. CONCLUSIONS: MA alleviates CAC by blocking the recruitment of MDSCs to increase the population of anti-tumor immune cells in tumor microenvironment via inhibition of the activation of γδT17 cells.


Assuntos
Neoplasias Associadas a Colite , Colite , Neoplasias Colorretais , Células Supressoras Mieloides , Triterpenos , Animais , Azoximetano , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Interleucina-17/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Transdução de Sinais , Células Th17 , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Microambiente Tumoral
15.
PLoS One ; 17(6): e0270338, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35737651

RESUMO

Cancer patients can develop visceral, somatic, and neuropathic pain, largely due to the malignancy itself and its treatments. Often cancer patients and survivors turn to the use of complementary and alternative medicine (CAM) to alleviate pain and fatigue. Thus, it is necessary to investigate how CAM therapies work as novel analgesics to treat cancer pain. Ojeok-san (OJS) is an herbal formula consisting of seventeen herbs. This herbal formula has been shown to possess anti-inflammatory, immunoregulatory, and analgesic properties. In this study, we examined the potential beneficial effects and mechanism of action of OJS in a preclinical model of colitis-associated colorectal cancer. Male and female C57BL/6J mice were exposed to the carcinogen, azoxymethane (AOM, 10 mg/kg) and a chemical inflammatory driver, dextran sulfate sodium (DSS1-2%), to promote tumorigenesis in the colorectum. OJS was given orally (500, 1000, and 2000 mg/kg) to determine its influence on disease activity, tumor burden, nociception, sedation, Erk signaling, and behavioral and metabolic outcomes. In addition, in vitro studies were performed to assess CT-26 cell viability, dorsal root ganglia (DRG) activation, and bone-marrow-derived macrophage (BMDM) inflammatory response to lipopolysaccharide stimulation after OJS treatment. We found that administration of 2000 mg/kg of OJS was able to mitigate mechanical somatic and visceral nociception via Erk signaling without affecting symptom score and polyp number. Moreover, we discovered that OJS has sedative properties and elicits prolonged total sleeping time in AOM/DSS mice. Our in vitro experiments showed that OJS has the capacity to reduce TNFα gene expression in LPS-stimulated BMDM, but no changes were observed in DRG spike number and CT-26 cell proliferation. Taken together, these data suggest that OJS ameliorates nociception in mice and warrants further examination as a potential CAM therapy to promote analgesia.


Assuntos
Colite , Neoplasias Colorretais , Animais , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/complicações , Colite/tratamento farmacológico , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade , Extratos Vegetais
16.
Int J Mol Sci ; 23(9)2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35563665

RESUMO

Colitis is a major risk factor for the development of colorectal cancer, leading to colitis-associated colorectal cancer (CAC). The most commonly used animal model to study CAC is the azoxymethane-dextran sulphate-sodium (AOM/DSS) model. The ideal experimental conditions of this model depend on several factors, including the used mouse strain. No data on feasibility and conditions for older mice, e.g., for aging studies, have yet been reported. Thus, we conducted a descriptive, observational pilot study where CAC was induced in 14-month-old female Balb/C and C57/Bl6 mice using 12.5 mg/kg AOM i.p. and three different concentrations of DSS (1, 2, and 3%) in drinking water (ad. lib.). The mice were monitored regularly during the three-month experimental phase. After euthanasia, the colons of the mice were evaluated macroscopically and microscopically. Both the mouse strains showed a DSS-concentration-dependent induction of CAC. Carcinomas were only observed at 3% DSS. The DSS dose was found to be significantly correlated with the histology score and % Ki67 positive cells only in C57/Bl6 mice but not in Balb/C mice, which showed a variable response to the CAC induction. No differences in colon length, weight, or mucin content were observed. Optimal conditions for CAC induction in these aged animals are thus considered to be 3% DSS, as carcinomas did not develop when 2% DSS was used. On the other hand, Balb/C mice reacted severely to 3% DSS, indicating that 2.5% DSS may be the "sweet spot" for future experiments comparing CAC in aged Balb/C and C57/Bl6 mice. This model will allow investigation of the effect of aging on CAC development and therapy.


Assuntos
Carcinoma , Neoplasias Associadas a Colite , Colite , Neoplasias Colorretais , Animais , Azoximetano , Carcinogênese , Colite/induzido quimicamente , Colite/complicações , Colite/patologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Projetos Piloto
17.
Food Funct ; 13(13): 6947-6961, 2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35575226

RESUMO

This study aimed to investigate the alleviative effects of Lactobacillus kefiranofaciens JKSP109 (LK) and Saccharomyces cerevisiae JKSP39 (SC) isolated from Tibetan kefir grain on colon inflammation and colorectal carcinogenesis. Azoxymethane (AOM) and dextran sulfate sodium (DSS) were used to establish a mouse model of colorectal cancer (CRC). The treatment group mice were administered with LK, SC, or the combination of LK and SC for five days per week from the day of receiving AOM. The composition of the gut microbiota was assessed using internal transcribed spacer 2 and 16S rRNA gene high-throughput sequencing. Furthermore, the biomarkers associated with gut barrier integrity, inflammation, regulators of cell proliferation, and apoptosis were evaluated. The results showed that the administration of LK, SC, and their combination increased the body weights and decreased the disease activity index (DAI) score and tumor multiplicity. As compared to the CRC model group, the three treatment groups positively regulated the gut microbiota. Meanwhile, the three treatments also enhanced the gut barrier, decreased the expression of proinflammatory cytokines and oncocyte proliferation indicators, and increased the expression of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive tumor epithelial cells and content of short chain fatty acids in fecal samples. All these results indicated that the LK and SC alleviated the inflammation and colorectal carcinogenesis in AOM/DSS-induced CRC mouse models, and the majority of tested indexes in the combination group were superior to single strain groups.


Assuntos
Colite , Neoplasias Colorretais , Kefir , Animais , Azoximetano/farmacologia , Carcinogênese , Colite/metabolismo , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Inflamação/metabolismo , Lactobacillus , Camundongos , RNA Ribossômico 16S , Saccharomyces cerevisiae , Tibet
18.
BMC Cancer ; 22(1): 566, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35596224

RESUMO

BACKGROUND: The role of Berberine (BBR) in colorectal cancer (CRC) and gut microbiota has begun to appreciate. However, there was no direct evidence confirm that the gut microbiota regulated by BBR could inhibit CRC. This report investigated the effect of stool from BBR treated subjects and its effect on CRC. METHODS: A mouse model for CRC was developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissue from affected mice were used to determine the efficacy of BBR against CRC. Stool samples were collected for the 16s rRNA gene sequencing and fecal microbiota transplantation (FMT). Finally, the mechanism of gut microbiota from BBR treated mice on CRC was explored using immunohistochemistry, RNA-Sequencing, quantitative RT-PCR, and western blot analyses. RESULTS: BBR significantly reduced intestinal tumor development. The richness of gut microbiota were notably decreased by BBR. Specifically, the relative abundance of beneficial bacteria (Roseburia, Eubacterium, Ruminococcaceae, and Firmicutes_unclassified) was increased while the level of bacteria (Odoribacter, Muribaculum, Mucispirillum, and Parasutterella) was decreased by BBR treatment. FMT experiment determined that the mice fed with stool from BBR treated AOM/DSS mice demonstrated a relatively lower abundance of macroscopic polyps and a significantly lower expression of ß-catenin, and PCNA in intestinal tissue than mice fed with stool from AOM/DSS mice. Mechanistically, intestinal tissue obtained from mice fed with stool from BBR treated AOM/DSS mice demonstrated a decreased expression of inflammatory cytokines including interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), C-C motif chemokine 1 (Ccl1), Ccl6, and C-X-C motif ligand (Cxcl9). In addition, the NF-κB expression was greatly suppressed in mice fed with stool from BBR treated AOM/DSS mice. Real-time PCR arrays revealed a down-regulation of genes involved in cell proliferation, angiogenesis, invasiveness, and metastasis in mice fed with stool from BBR treated AOM/DSS mice. CONCLUSIONS: Stool obtained from BBR treated AOM/DSS mice was able to increase colon length while simultaneously decreasing the density of macroscopic polyps, cell proliferation, inflammatory modulators and the expression of NF-κB. Therefore, it was concluded that suppression of pro-inflammatory genes and carcinogens factors by modulating gut microbiota was an important pathway for BBR to inhibit tumor growth in conventional mice.


Assuntos
Berberina , Colite , Microbioma Gastrointestinal , Animais , Azoximetano , Berberina/farmacologia , Berberina/uso terapêutico , Carcinogênese/metabolismo , Colite/patologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , RNA Ribossômico 16S/genética
19.
Nutrients ; 14(9)2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35565884

RESUMO

In our previous research, Lactiplantibacillus plantarum-12 alleviated inflammation in dextran sodium sulfate (DSS)-induced mice by regulating intestinal microbiota and preventing colon shortening (p < 0.05). The purpose of the present study was to evaluate whether L. plantarum-12 could ameliorate the colon cancer symptoms of azoxymethane (AOM)/DSS-treated C57BL/6 mice. The results showed that L. plantarum-12 alleviated colonic shortening (from 7.43 ± 0.15 to 8.23 ± 0.25) and weight loss (from 25.92 ± 0.21 to 27.75 ± 0.88) in AOM/DSS-treated mice. L. plantarum-12 oral administration down-regulated pro-inflammatory factors TNF-α (from 350.41 ± 15.80 to 247.72 ± 21.91), IL-8 (from 322.19 ± 11.83 to 226.08 ± 22.06), and IL-1ß (111.43 ± 8.14 to 56.90 ± 2.70) levels and up-regulated anti-inflammatory factor IL-10 (from 126.08 ± 24.92 to 275.89 ± 21.87) level of AOM/DSS-treated mice. L. plantarum-12 oral administration restored the intestinal microbiota dysbiosis of the AOM/DSS treated mice by up-regulating beneficial Muribaculaceae, Lactobacillaceae, and Bifidobacteriaceae levels and down-regulating pathogenic Proteobacteria, Desulfovibrionaceae, and Erysipelotrichaceae levels. As a result, the fecal metabolites of the AOM/DSS-treated mice were altered, including xanthosine, uridine, 3,4-methylenesebacic acid, 3-hydroxytetradecanedioic acid, 4-hydroxyhexanoylglycine, beta-leucine, and glycitein, by L. plantarum-12 oral administration. Furthermore, L. plantarum-12 oral administration significantly ameliorated the colon injury of the AOM/DSS-treated mice by enhancing colonic tight junction protein level and promoting tumor cells death via down-regulating PCNA (proliferating cell nuclear antigen) and up-regulating pro-apoptotic Bax. (p < 0.05). Taken together, L. plantarum-12 oral administration could ameliorate the colon cancer burden and inflammation of AOM-DSS-treated C57BL/6 mice through regulating the intestinal microbiota, manipulating fecal metabolites, enhancing colon barrier function, and inhibiting NF-κB signaling. These results suggest that L. plantarum-12 might be an excellent probiotic candidate for the prevention of colon cancer.


Assuntos
Colite , Neoplasias do Colo , Microbioma Gastrointestinal , Animais , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo/metabolismo , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Neoplasias do Colo/prevenção & controle , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Disbiose/metabolismo , Inflamação/metabolismo , Lactobacillaceae , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL
20.
Nutrients ; 14(10)2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35631174

RESUMO

The relationship between colitis-associated colorectal cancer (CAC) and the dysregulation of iron metabolism has been implicated. However, studies on the influence of dietary iron deficiency on the incidence of CAC are limited. This study investigated the effects of dietary iron deficiency and dietary non-heme iron on CAC development in an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. The four-week-old mice were divided into the following groups: iron control (IC; 35 ppm iron/kg) + normal (NOR), IC + AOM/DSS, iron deficient (ID; <5 ppm iron/kg diet) + AOM/DSS, and iron overload (IOL; approximately 2000 ppm iron/kg) + AOM/DSS. The mice were fed the respective diets for 13 weeks, and the AOM/DSS model was established at week five. FTH1 expression increased in the mice's colons in the IC + AOM/DSS group compared with that observed in the ID and IOL + AOM/DSS groups. The reduced number of colonic tumors in the ID + AOM/DSS and IOL + AOM/DSS groups was accompanied by the downregulated expression of cell proliferation regulators (PCNA, cyclin D1, and c-Myc). Iron overload inhibited the increase in the expression of NF-κB and its downstream inflammatory cytokines (IL-6, TNFα, iNOS, COX2, and IL-1ß), likely due to the elevated expression of antioxidant genes (SOD1, TXN, GPX1, GPX4, CAT, HMOX1, and NQO1). ID + AOM/DSS may hinder tumor development in the AOM/DSS model by inhibiting the PI3K/AKT pathway by increasing the expression of Ndrg1. Our study suggests that ID and IOL diets suppress AOM/DSS-induced tumors and that long-term iron deficiency or overload may negate CAC progression.


Assuntos
Colite , Ferro na Dieta , Animais , Azoximetano , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana , Suplementos Nutricionais , Modelos Animais de Doenças , Sobrecarga de Ferro/complicações , Ferro na Dieta/farmacologia , Camundongos , Fosfatidilinositol 3-Quinases
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