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1.
Nutrients ; 11(9)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509964

RESUMO

Djulis is a cereal crop rich in polyphenols and dietary fiber that may have nutraceutical activity to prevent colon cancer. This study was designed to examine the preventive effect of djulis on colon carcinogenesis in rats treated with 1,2-dimethylhydrazine (DMH). Rats were fed different AIN-93G-based diets: groups N and DMH were fed AIN-93G diet and groups LD, MD, and HD were fed AIN-93G diet containing 5, 10, and 20% djulis, respectively. All rats except for group N were injected with DMH to induce colon carcinogenesis. After 10 weeks, rats were sacrificed and colon and liver tissues were collected for analysis. The results showed that djulis-treated rats had significantly lower numbers of colonic preneoplastic lesions, aberrant crypt foci (ACF), sialomucin-producing (SIM)-ACF, and mucin-depleted foci. Djulis treatment increased superoxide dismutase and catalase activities in colon and liver. Djulis also reduced p53, Bcl-2, and proliferating cell nuclear antigen expressions and increased Bax and caspase-9 expressions. Besides, phenolic compounds and flavonoids were found rich in djulis. These results demonstrate the chemopreventive effect of djulis on carcinogen-induced colon carcinogenesis via regulating antioxidative and apoptotic pathways in rats. Djulis may have the potential to be developed as a valuable cereal product for chemoprevention of colon cancer.


Assuntos
Anticarcinógenos/administração & dosagem , Antioxidantes/administração & dosagem , Apoptose/efeitos dos fármacos , Chenopodium , Colo/efeitos dos fármacos , Neoplasias do Colo/prevenção & controle , Mucosa Intestinal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Lesões Pré-Cancerosas/prevenção & controle , 1,2-Dimetilidrazina , Ração Animal , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proliferação de Células/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Mucinas/metabolismo , Valor Nutritivo , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Ratos Endogâmicos F344 , Transdução de Sinais
2.
Oncol Rep ; 42(2): 479-494, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233199

RESUMO

Skeletal muscle wasting is a feature of cancer cachexia that increases patient morbidity and mortality. Matrine, the main bioactive component of Sophora flavescens, has been approved for the prevention and therapy of cancer cachexia in China. However, to the best of our knowledge, its mechanism in improving muscle wasting remains unknown. The present study demonstrated that matrine increases muscle fiber size and muscle mass in an in vivo CT26 colon adenocarcinoma cachexia mouse model. Concurrently, other cachexia symptoms, including body and organ weight loss, were alleviated. In in vitro experiments, matrine substantially improved C2C12 myoblast differentiation with or without dexamethasone treatment. In addition, matrine reduced C2C12 myotube atrophy and apoptosis induced by dexamethasone, tumor necrosis factor α and conditioned medium. Two E3 ubiquitin ligases, muscle RING­finger containing protein­1 and muscle atrophy F-box protein, which are specifically expressed in wasting skeletal muscle, were also significantly downregulated (P<0.05) by matrine both in C2C12 myotubes and skeletal muscle. Furthermore, matrine increased the phosphorylation of Akt, mTOR and FoxO3α in the atrophying C2C12 myotube induced by dexamethasone. In conclusion, matrine can alleviate muscle atrophy and improve myoblast differentiation possibly by inhibiting E3 ubiquitin ligases and activating the Akt/mTOR/FoxO3α signaling pathway.


Assuntos
Alcaloides/farmacologia , Caquexia/tratamento farmacológico , Neoplasias do Colo/complicações , Regulação da Expressão Gênica/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Quinolizinas/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Animais , Apoptose , Caquexia/etiologia , Caquexia/metabolismo , Proliferação de Células , Neoplasias do Colo/induzido quimicamente , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Humanos , Masculino , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/toxicidade
3.
PLoS Genet ; 15(5): e1007687, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31059499

RESUMO

The transcription factor Oct1/Pou2f1 promotes poised gene expression states, mitotic stability, glycolytic metabolism and other characteristics of stem cell potency. To determine the effect of Oct1 loss on stem cell maintenance and malignancy, we deleted Oct1 in two different mouse gut stem cell compartments. Oct1 deletion preserved homeostasis in vivo and the ability to establish organoids in vitro, but blocked the ability to recover from treatment with dextran sodium sulfate, and the ability to maintain organoids after passage. In a chemical model of colon cancer, loss of Oct1 in the colon severely restricted tumorigenicity. In contrast, loss of one or both Oct1 alleles progressively increased tumor burden in a colon cancer model driven by loss-of-heterozygosity of the tumor suppressor gene Apc. The different outcomes are consistent with prior findings that Oct1 promotes mitotic stability, and consistent with differentially expressed genes between the two models. Oct1 ChIPseq using HCT116 colon carcinoma cells identifies target genes associated with mitotic stability, metabolism, stress response and malignancy. This set of gene targets overlaps significantly with genes differentially expressed in the two tumor models. These results reveal that Oct1 is selectively required for recovery after colon damage, and that Oct1 has potent effects in colon malignancy, with outcome (pro-oncogenic or tumor suppressive) dictated by tumor etiology.


Assuntos
Carcinogênese/genética , Colo/metabolismo , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Fator 1 de Transcrição de Octâmero/genética , Animais , Azoximetano/administração & dosagem , Carcinogênese/metabolismo , Carcinogênese/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Células HCT116 , Humanos , Integrases/genética , Integrases/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fator 1 de Transcrição de Octâmero/deficiência , Organoides/efeitos dos fármacos , Organoides/metabolismo , Organoides/patologia , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Regeneração , Transdução de Sinais , Análise de Sobrevida , Tamoxifeno/administração & dosagem
4.
Cancer Res Treat ; 51(4): 1620-1631, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31096733

RESUMO

PURPOSE: Nonylphenol (NP) is an endocrine disruptor found in products such as cleaners, plastics, and detergents. It exerts actions similar to endogenous 17ß-estradiol (E2) and is reported to influence various cancers. However, its role in colon cancer remains elusive. Materials and Methods: Colon cancer cell lines COLO 205 and SW480 were employed in our study. The cells were treated with NP or E2 followed by measurement of apoptosis and proliferation using flow cytometry and MTT assays, respectively. G protein-coupled estrogen receptor 30 (GPR30) expression was visualized using immunofluorescence and Western blot. To investigate the underlying mechanism, the expression levels of GPR30, p-protein kinase A (PKA), c-myc, cyclin D1, and ERK1/2 were analyzed using Western blot. Meanwhile, the GPR30 antagonist G15 was utilized to validate the role of GPR30 in colon cancer progression. Finally, the effect of a GPR30 inhibitor on tumor growth was determined in vivo using tumor xenograft mouse models. RESULTS: NP facilitated the proliferation of colon cancer cells and induced apoptosis failure in vitro. Western blot revealed increased GPR30 expression levels in response to NP treatment. Cyclin D1, p-PKA, c-myc, and proliferating cell nuclear antigen, proteins that regulate the cell cycle, were all upregulated by NP, and NP-mediated ERK1/2 activation and subsequent cell proliferation were abrogated by the GPR30 inhibitor G15. Moreover, colon cancer mice that received G15 administration demonstrated impaired tumor growth in vivo. CONCLUSION: Low dose NP promotes the growth of colon tumors through GPR30-mediated activation of ERK1/2 signaling.


Assuntos
Neoplasias do Colo/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fenóis/efeitos adversos , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Fenóis/farmacologia , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Regulação para Cima/efeitos dos fármacos
5.
Cell Physiol Biochem ; 52(6): 1517-1534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120230

RESUMO

BACKGROUND/AIMS: Cadmium (Cd) is a heavy metal contaminant whose toxicity is associated with colorectal cancer (CRC). However, the underlying molecular mechanisms of Cd-induced CRC malignancy remain obscure. METHODS: A monolayer scratch assay was employed to assess the migration of HT-29 human adenocarcinoma cells. Luciferase reporter assay was used to determine cyclooxygenase-2 (COX-2) transcriptional activity, and Western blotting was used to detect p38 Mitogen Activated Protein Kinase (MAPK) and Akt phosphorylation as well as COX-2 expression. Prostaglandin E2 (PGE2) levels were measured using Enzyme Linked Immunosorbent Assay (ELISA) and reactive oxygen species (ROS) formation was assessed using dihydroethidium (DHE) stain. RESULTS: Here, we show that Cd potentiates the migratory capacity of HT-29 CRC cells. Cd caused a time-dependent increase in COX-2 expression. Celecoxib, a COX-2 selective inhibitor, significantly reduced Cd-induced migration. Cd also increased levels of ROS and phosphorylated p38. Importantly, Cd-induced COX-2 expression and migration were significantly abolished by N-Acetyl-Cysteine (NAC), a ROS scavenger, or SB202190, a specific p38 inhibitor. Furthermore, Cd-induced p38 phosphorylation was inhibited by NAC. Cd (100 nM) also increased PGE2 levels, which was abrogated by NAC, SB202190, or celecoxib. Exogenous PGE2 significantly potentiated cell migration. Cd caused a significant increase in Akt phosphorylation in a ROS-mediated pathway. Moreover, Cd-induced migration was significantly attenuated by LY294 002, a phosphatidylinositol-3-kinase inhibitor. CONCLUSION: Taken together, our results suggest that exposure to low levels of Cd promotes a more migratory cancer phenotype in a ROS-p38-COX-2-PGE2 pathway as well as ROS-Akt pathway. Therefore, COX-2, PGE2 receptors or Akt represent potential targets in the treatment of CRC, particularly in patients exposed to Cd.


Assuntos
Adenocarcinoma/induzido quimicamente , Cádmio/toxicidade , Neoplasias do Colo/induzido quimicamente , Ciclo-Oxigenase 2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Ativação Enzimática/efeitos dos fármacos , Células HT29 , Humanos , Ativação Transcricional/efeitos dos fármacos
6.
J Ethnopharmacol ; 238: 111858, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30953819

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Brachystegia eurycoma seed is used as dietary condiment and as part of recipes for treating colorectal disorders, while laboratory studies have established that it contains crude fiber and polyphenols which are important in cancer prevention. AIM OF THE STUDY: To establish the efficacy of a Nigerian diet in colon cancer prevention, a study was conducted to evaluate dietary inclusion of Brachystegia eurycoma seed in experimental colon carcinogenesis. METHODS: Rats undergoing intra-rectal instillations of N-Methyl-N-nitrosourea (MNU) were fed B. eurycoma included diets at 0%, 2.5%, 5% and 10% for a period of ten (10) weeks following which they were sacrificed; blood and tissues were monitored for biochemical, histological and immunohistochemical parameters. RESULTS: Brachystegia eurycoma significantly (P < 0.05) prevented MNU-induced elevation of malondialdehyde and carcinoembryonic antigen (CEA) as well as reduced activities of catalase and superoxide dismutase. The colon showed deep mucosal ulceration with moderate inter-glandular inflammation in the MNU control group, but only mild or no inflammation was observed in the colon of the MNU groups fed experimental diets. Similarly, colon immunohistochemistry assay showed that the dietary inclusion significantly prevented MNU-induced damage to mismatch repair gene (MutL homolog1). Positive relationship existed between fiber content of B. eurycoma seeds and MutL homolog1 protein expression while that between polyphenol/flavonoids contents of diets and CEA was negative. CONCLUSION: These data suggest that both dietary fiber and polyphenol/flavonoids contribute synergistically or additively to the potential preventive effect of B. eurycoma seeds in colon carcinogenesis, presumably through mechanisms that involve limiting the extent of oxidative stress and preventing or delaying the onset of pro-carcinogenic inflammatory processes.


Assuntos
Neoplasias do Colo/dietoterapia , Fabaceae , Sementes , Animais , Antígeno Carcinoembrionário/sangue , Carcinogênese , Catalase/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fibras na Dieta/análise , Flavonoides/análise , Masculino , Malondialdeído/metabolismo , Metilnitrosoureia , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Polifenóis/análise , Ratos Wistar , Superóxido Dismutase/metabolismo
7.
J Immunol ; 202(11): 3326-3333, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31019062

RESUMO

Inflammatory bowel diseases are known to be the origin of colitis-associated colon cancer (CAC). We previously reported that dextran sulfate sodium (DSS)-induced colitis is exacerbated in mouse-IL-21-isoform transgenic (Tg) mice. In this study, we assessed the CAC development induced by azoxymethane (AOM) and DSS in our Tg mice. AOM-DSS-induced tumor development was dramatically increased in the Tg mice compared with wild-type mice. IL-21 is known to enhance activation-induced cytidine deaminase (AID) expression in B cells and induce Ab class switching. In contrast, the AID expression in cells other than B cells initiates tumor development in many tissues. Therefore, we investigated whether IL-21 induces the AID expression in the large intestinal epithelial cells (IECs) during CAC development. AID gene and protein expression was increased in the IECs of AOM-DSS- or DSS-treated Tg mice compared with those of wild-type mice. Furthermore, we confirmed IL-21 induced AID gene expression in the purified IECs ex vivo. The present study also showed IL-21R gene expression in unstimulated wild-type mouse IECs, and this gene expression was augmented by TNF-α stimulation. The IL-21R expression and IL-21-induced AID gene activation were further confirmed in the Colon-38 cell line. Taken together, IL-21 may be involved in increasing the risk of CAC by enhancing the AID expression in IECs.


Assuntos
Linfócitos B/imunologia , Colite/imunologia , Neoplasias do Colo/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucinas/metabolismo , Mucosa Intestinal/fisiologia , Animais , Azoximetano , Linhagem Celular Tumoral , Colite/induzido quimicamente , Neoplasias do Colo/induzido quimicamente , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Humanos , Switching de Imunoglobulina , Doenças Inflamatórias Intestinais/induzido quimicamente , Interleucinas/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos
8.
Molecules ; 24(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939812

RESUMO

Maslinic acid triggers compelling antiproliferative and pro-apoptotic effects in different human cancer cell lines. Hence, the chemopreventive activity was investigated on early stages of carcinogenesis induced by 1,2-dimethylhydrazine (DMH) which is a model that mimics human sporadic colorectal cancer. Male Sprague-Dawley rats were orally administered either maslinic acid at 5, 10 or 25 mg/kg dissolved in (2-hydroxypropyl)-ß-cyclodextrin 20% (w/v) or the solvent for 49 days. After one week of treatment, animals received three weekly intraperitoneal injections of DMH at the dose of 20 mg/kg. Maslinic acid reduced the preneoplastic biomarkers, aberrant crypt foci (ACF) and mucin-depleted foci (MDF), already at 5 mg/kg in a 15% and 27%, respectively. The decline was significant at 25 mg/kg with decreases of 33% and 51%, respectively. Correlation analysis showed a significant association between the concentrations of maslinic acid found in the colon and the reduction of ACF (r = 0.999, P = 0.019) and MDF (r = 0.997, P = 0.049). The present findings demonstrate that maslinic acid induced an inhibition of the initiation stages of carcinogenesis. The assessment of this pentacyclic triterpene at the colon sheds light for designing diets with foods rich in maslinic acid to exert a chemopreventive activity in colorectal cancer.


Assuntos
1,2-Dimetilidrazina/toxicidade , Focos de Criptas Aberrantes/prevenção & controle , Neoplasias do Colo/prevenção & controle , Olea/química , Extratos Vegetais/farmacologia , Lesões Pré-Cancerosas/prevenção & controle , Triterpenos/farmacologia , Focos de Criptas Aberrantes/induzido quimicamente , Focos de Criptas Aberrantes/patologia , Animais , Carcinógenos/toxicidade , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Masculino , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Ratos , Ratos Sprague-Dawley
9.
J Cancer Res Clin Oncol ; 145(6): 1417-1426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30923945

RESUMO

PURPOSE: Callistemon citrinus (Curtis) Skeels is a shrub native of Australia. In spite of containing an important number of bioactive compounds (1,8-cineole, limonene and α-terpineol) recognized as a potential chemotherapeutic agents, it is only used as an ornamental plant in Mexico. This study investigated the chemopreventive effect of C. citrinus leaves extract on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats. METHODS: Twenty-four rats were divided into 3 groups of eight rats. Group 1 served as negative control, groups 2 and 3 were given subcutaneous injections of DMH (65 mg/kg b.w.) twice a week the first 2 weeks, and then one the third week. In addition, group 3 was administrated with leaves extracts (250 mg/kg b.w., orally daily) during the 22 weeks of the experiment. Animals were killed and the presence of colon tumors and aberrant crypt foci (ACF) were scored for number and distribution pattern along the colon. The activity of two-phase II enzymes quinone reductase (QR) and glutathione S-transferase (GST) was determined in the liver and three segments of the colon: proximal, middle and distal. RESULTS: The results show that rats feed with C. citrinus leaves extract significantly reduced the size of tumors, the number of ACF and the crypt multiplicity. Additionally, C. citrinus leaves extract increased or maintained the activity of QR and GST in the different tissues as compared with DHM-treated group (p > 0.05). CONCLUSION: This study demonstrates that Callistemon citrinus extract could have a chemopreventive effect against colon carcinogenesis.


Assuntos
Neoplasias do Colo/prevenção & controle , Myrtaceae/química , Extratos Vegetais/farmacologia , 1,2-Dimetilidrazina , Focos de Criptas Aberrantes/induzido quimicamente , Focos de Criptas Aberrantes/tratamento farmacológico , Focos de Criptas Aberrantes/patologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Peso Corporal/efeitos dos fármacos , Carcinógenos , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar
10.
J Med Food ; 22(6): 578-586, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30864851

RESUMO

Our previous studies have demonstrated antioxidant and cytoprotective properties of red ginseng oil (RGO). However, the role of RGO in models of intestinal inflammation has not been elucidated. In this study, we evaluated the chemopreventive effect of RGO in a mouse model of azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis and explored its underlying mechanisms. Male C57BL/6 mice were intraperitoneally injected with a single dose of AOM (10 mg/kg), followed by 1.5% DSS in drinking water for 7 days to produce colon carcinogenesis. RGO at 10 or 100 mg/kg was orally given for 17 weeks. RGO supplementation reduced the plasma nitric oxide (NO) concentration as well as lipid peroxidation and inhibited the production of proinflammatory factors such as inducible NO synthase, cyclooxygenase-2, interleukin 1ß, IL-6, and tumor necrosis factor-α in the mouse colitis tissue. Increased phosphorylation levels of p65 and IκB by AOM/DSS exposure were attenuated by the presence of RGO. In addition, RGO supplementation induced the activity of primary antioxidant enzymes such as superoxide dismutase and catalase as well as the expression of nuclear factor erythroid 2-related factor 2-mediated antioxidant enzyme hemeoxygenase-1 in the colons of AOM/DSS-treated mice. These findings indicate that RGO may be a potent natural chemopreventive agent for ameliorating inflammatory bowel diseases.


Assuntos
Colite/tratamento farmacológico , Neoplasias do Colo/prevenção & controle , Panax/química , Extratos Vegetais/administração & dosagem , Animais , Azoximetano/efeitos adversos , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
EBioMedicine ; 41: 299-309, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30852162

RESUMO

BACKGROUND: Hypoxia suppresses global protein production, yet certain essential proteins are translated through alternative pathways to survive under hypoxic stress. Translation via the internal ribosome entry site (IRES) is a means to produce proteins under stress conditions such as hypoxia; however, the underlying mechanism remains largely uncharacterized. METHODS: Proteomic and bioinformatic analyses were employed to identify hnRNPM as an IRES interacting factor. Clinical specimens and mouse model of tumorigenesis were used for determining the expression and correlation of hnRNPM and its target gene. Transcriptomic and translatomic analyses were performed to profile target genes regulated by hnRNPM. FINDINGS: Hypoxia increases cytosolic hnRNPM binding onto its target mRNAs and promotes translation initiation. Clinical colon cancer specimens and mouse carcinogenesis model showed that hnRNPM is elevated during the development of colorectal cancer, and is associated with poor prognosis. Genome-wide transcriptomics and translatomics analyses revealed a unique set of hnRNPM-targeted genes involved in metabolic processes and cancer neoplasia are selectively translated under hypoxia. INTERPRETATION: These data highlight the critical role of hnRNPM-IRES-mediated translation in transforming hypoxia-induced proteome toward malignancy. FUND: This work was supported by the Ministry of Science and Technology, Taiwan (MOST 104-2320-B-006-042 to HSS and MOST 105-2628-B-001-MY3 to TMC).


Assuntos
Hipóxia Celular , Neoplasias do Colo/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Análise por Conglomerados , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/mortalidade , Modelos Animais de Doenças , Fator 9 de Crescimento de Fibroblastos/genética , Fator 9 de Crescimento de Fibroblastos/metabolismo , Células HEK293 , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/antagonistas & inibidores , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/genética , Humanos , Estimativa de Kaplan-Meier , Camundongos , Biossíntese de Proteínas , Proteínas de Ligação ao Cap de RNA/antagonistas & inibidores , Proteínas de Ligação ao Cap de RNA/genética , Proteínas de Ligação ao Cap de RNA/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo
12.
Inflamm Bowel Dis ; 25(3): 472-478, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30789982

RESUMO

A symposium organized by the Cochrane IBD Group and presented at the 2017 Digestive Disease Week annual meeting reviewed the recent literature on several controversial topics in inflammatory bowel disease (IBD) management including the efficacy of oral aminosalicylates for induction and maintenance of Crohn's disease (CD), the feasibility of drug withdrawal in patients with quiescent CD, and strategies for detecting colon cancer in patients with IBD. This article summarizes the data presented at that session.


Assuntos
Ácido Aminossalicílico/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Neoplasias do Colo/diagnóstico , Doença de Crohn/tratamento farmacológico , Administração Oral , Ácido Aminossalicílico/administração & dosagem , Neoplasias do Colo/induzido quimicamente , Humanos , Prognóstico , Suspensão de Tratamento
13.
J Nutr ; 149(2): 249-257, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649390

RESUMO

BACKGROUND: Vegetable consumption reduces colon cancer risk when fed in the initiation stage of carcinogenesis; however, the effect of vegetable consumption during the post-initiation stage has rarely been examined. OBJECTIVE: We investigated the chemopreventive effects of feeding apiaceous and cruciferous vegetables on colon cancer risk in the post-initiation stage. METHODS: Thirty male Wistar rats (∼5 wk, 92 g) were subcutaneously injected with 1,2-dimethylhydrazine 1 time/wk for 2 wk. One week after the last dose, rats were randomly assigned to 3 groups: the basal diet, an apiaceous vegetable-containing diet (API; 21% fresh wt/wt), or a cruciferous vegetable-containing diet (CRU; 21% fresh wt/wt). All diets contained ∼20% protein, 7% fat, and 63% digestible carbohydrate. Experimental diets were fed for 10 wk, after which colons were harvested. RESULTS: CRU reduced aberrant crypt foci (ACF) number compared to the basal group (P = 0.014) and API (P = 0.013), whereas API decreased the proportion of dysplastic ACF relative to the basal group (P < 0.05). Both CRU and API reduced doublecortin-like kinase 1-positive marker expression relative to basal by 57.9% (P = 0.009) and 51.4% (P < 0.02). The numbers of CD44-positive ACF did not differ between the groups. We identified 14 differentially expressed microRNAs (miRNAs). Of these, expression of 6 miRNAs were greater or tended to be greater (P ≤ 0.10) in one or both vegetable-containing groups compared to the basal group. Bioinformatic analysis of these expression changes in miRNA predicted a change in WNT/ß-catenin signaling, indicating downregulation of ß-catenin in the vegetable-fed groups. Consistent with this bioinformatics analysis, ß-catenin-accumulated ACF were decreased in CRU (93.1%, P = 0.012), but not in API (54.4%, P = 0.125), compared to the basal group. CONCLUSION: Both apiaceous and cruciferous vegetables, fed post-initiation, reduce colonic preneoplastic lesions as well as cancer stem cell marker expression in rats, possibly by suppressing oncogenic signaling through changes in miRNA expression.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/dietoterapia , Dieta , Verduras/classificação , 1,2-Dimetilidrazina/toxicidade , Animais , Biomarcadores Tumorais/sangue , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Mucinas/genética , Mucinas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , beta Catenina/genética , beta Catenina/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-30678822

RESUMO

To investigate how intestinal bacteria affect host cytogenetic alterations in the early initiation step of colon carcinogenesis, we conducted a comet assay and micronucleus (MN) test using germ-free (GF) and conventionalized (Cvd) rats after a single subcutaneous injection of the carcinogen, 1,2-dimethylhydrazine dihydrochloride (DMH). DNA damage was also determined in the liver in comet assays, as DMH is metabolized and activated in this organ. The time-response patterns of DNA damage in the liver and colon were similar in both rats, and maximum values were observed at 3 h after the treatment. In contrast, the maximum frequency of micronucleated (MNed) colonic cells was markedly higher in the Cvd rats than in the GF rats and was observed after 72 h and 120 h, respectively. The frequency of MNed cells in non-treated animals was similar in the GF and Cvd rats. In addition, we determined time-responses in the incidence of apoptosis and cell proliferation indices, i.e., the numbers of BrdU-labeled cells, mitotic cells in the crypts, and crypt column heights, using histological sections of the colons in these rats. Maximal incidence of apoptosis was observed at 6 and 24 h in the Cvd and GF rats, respectively. The value in the Cvd rats tended to be higher than that in the GF rats. Cell proliferation was suppressed until 24 and 48 h in the Cvd and GF rats, respectively, and increased subsequently. The rebound response of cell proliferation was more pronounced and occurred earlier in the Cvd rats than that in the GF rats. We demonstrated that cytogenetic alterations other than DNA damage, particularly the MNed colonic cell induction by DMH, were markedly enhanced in rats with bacterial colonization in the intestine compared to those in GF rats.


Assuntos
1,2-Dimetilidrazina/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/patologia , Carcinógenos/farmacologia , Colo/patologia , Dano ao DNA/genética , Mucosa Intestinal/microbiologia , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Animais , Carcinogênese/induzido quimicamente , Proliferação de Células/efeitos dos fármacos , Colo/citologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Ensaio Cometa , Vida Livre de Germes , Mucosa Intestinal/patologia , Masculino , Testes para Micronúcleos , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Ratos
15.
Mol Carcinog ; 58(6): 922-932, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30676667

RESUMO

Epithelial specific ETS-1 (ESE-1) belongs to the E26 transformation-specific transcription factor superfamily and is of great interest as a potential target for managing several types of cancer. Despite its clinical significance, the documented effects of ESE-1 on cancer development and progression are contradictory and its underlying biological mechanism of action remains elusive. The objectives of this study are to investigate whether ESE-1 is a tumor suppressor and to identify dietary anti-cancer compound to activate ESE-1 expression in human colon cancer model. ESE-1 knockout and xenograft mouse models were used to examine the effect of ESE-1 in colon tumorigenesis. Stable human colon cancer cell lines were used for in vitro mechanistic studies. ESE-1 knockout in mice increased azoxymethane (AOM)-induced and dextran sulfate sodium (DSS)-promoted formation of aberrant crypt foci (ACF). Conversely, overexpression of ESE-1 suppressed tumorigenicity in a xenograft mouse study, and repressed anchorage-independent growth and migration/invasion in human colon cancer cells. Full length ESE-1 localized abundantly in the nucleus, and internal deletion of nuclear localization sequence 2 (NLS2) reduced nuclear ESE-1. Three lysine residues (318 KKK320 ) in the NLS2 determine its nuclear localization. We identified epigallocatechin-3-gallate (EGCG) that acts as a transcriptional activator of ESE-1 in human colon cancer cells. These findings propose a novel and promising molecular target of dietary anti-cancer compounds for prevention of colon cancer.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Catequina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Azoximetano/efeitos adversos , Células CACO-2 , Catequina/administração & dosagem , Catequina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Proteínas de Ligação a DNA/química , Sulfato de Dextrana/efeitos adversos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células HCT116 , Células HT29 , Humanos , Camundongos , Sinais de Localização Nuclear , Proteínas Proto-Oncogênicas c-ets/química , Fatores de Transcrição/química , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Invest New Drugs ; 37(1): 47-56, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29808307

RESUMO

Considerable evidence indicates a negative correlation between the prevalence of some parasitic infections and cancer and their interference with tumor growth. Therefore, parasitic antigens seem to be promising candidates for cancer immunotherapy. In this study, the therapeutic efficacy of autoclaved Schistosoma mansoni and Trichinella spiralis antigens against a colon cancer murine model was investigated. Both antigens showed immunomodulatory potential, as evidenced by a significant decrease in serum IL-17, a significant increase in serum IL-10, and the percentage of splenic CD4+T-cells and intestinal FoxP3+ Treg cells. However, treatment with S. mansoni antigen yielded protection against the deleterious effect of DMH-induced colon carcinogenesis only, with a significant decrease in the average lesion size and number of neoplasias per mouse. For the first time, we report an inhibitory effect of S. mansoni antigen on the progression of chemically induced colon carcinogenesis, but the exact mechanism has yet to be clarified. This anti-tumor strategy could introduce a new era of medicine in which a generation of anticancer vaccines of parasitic origin would boost the therapy for incurable cancers.


Assuntos
Antígenos de Helmintos/uso terapêutico , Neoplasias do Colo/terapia , Modelos Animais de Doenças , Schistosoma mansoni/imunologia , Linfócitos T Reguladores/imunologia , Trichinella spiralis/imunologia , 1,2-Dimetilidrazina/toxicidade , Animais , Antígenos de Helmintos/imunologia , Carcinógenos/toxicidade , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Citocinas/metabolismo , Feminino , Imunização , Camundongos
18.
Oncogene ; 38(7): 1067-1079, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30202097

RESUMO

Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence that SLC7A2 plays a role in modulating colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). SLC7A2 was localized predominantly to colonic epithelial cells in WT mice. Utilizing the AOM-DSS model, Slc7a2-/- mice had significantly increased tumor number, burden, and risk of high-grade dysplasia vs. WT mice. Tumors from Slc7a2-/- mice exhibited significantly increased levels of the proinflammatory cytokines/chemokines IL-1ß, CXCL1, CXCL5, IL-3, CXCL2, CCL3, and CCL4, but decreased levels of IL-4, CXCL9, and CXCL10 compared to tumors from WT mice. This was accompanied by a shift toward pro-tumorigenic M2 macrophage activation in Slc7a2-deficient mice, as marked by increased colonic CD11b+F4/80+ARG1+ cells with no alteration in CD11b+F4/80+NOS2+ cells by flow cytometry and immunofluorescence microscopy. The shift toward M2 macrophage activation was confirmed in bone marrow-derived macrophages from Slc7a2-/- mice. In bone marrow chimeras between Slc7a2-/- and WT mice, the recipient genotype drove the CAC phenotype, suggesting the importance of epithelial SLC7A2 in abrogating neoplastic risk. These data reveal that SLC7A2 has a significant role in the protection from CAC in the setting of chronic colitis, and suggest that the decreased SLC7A2 in inflammatory bowel disease (IBD) may contribute to CAC risk. Strategies to enhance L-Arg availability by supplementing L-Arg and/or increasing L-Arg uptake could represent a therapeutic approach in IBD to reduce the substantial long-term risk of colorectal carcinoma.


Assuntos
Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias do Colo/metabolismo , Proteínas de Neoplasias/metabolismo , Sistemas de Transporte de Aminoácidos Básicos/genética , Animais , Azoximetano/toxicidade , Linhagem Celular Tumoral , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética
19.
Mol Cell Biochem ; 451(1-2): 117-129, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29980883

RESUMO

p-methoxycinnamic acid (p-MCA) is an active phenolic acid found in rice bran, turmeric, brown rice, Kaempferia galanga, buckwheat inflorescence, etc. Earlier, we have reported that p-methoxycinnamic acid possesses antioxidant and antilipidperoxidative effects on 1,2-dimethylhyrdrazine (DMH)-induced colon carcinogenesis. The purpose of this study is to unravel the anti-inflammatory and anticancer properties of p-MCA against DMH-induced colon carcinogenesis. Male albino Wistar rats were randomly divided into six groups. Group 1 served as control, group 2 rats received 40 mg/kg b.wt. of p-MCA in 0.1% carboxymethylcellulose (CMC) every day, and colon cancer was induced in groups 3-6 using DMH at the dose of (20 mg/kg b.wt. subcutaneously) once a week for 15 weeks. In addition, along with DMH, groups 4 (initiation), 5 (post initiation) and 6 (entire period) rats received p-MCA (40 mg/kg b.wt.) p.o. every day during different time periods for the total experimental period of 30 weeks. Colon of animals treated with DMH showed an increased number of aberrant crypt foci (ACFs), increased nuclear translocation of transcription factor NF-κB p65 subunit, increased expression of inflammatory markers (iNOS, COX-2), cytokines (tumour necrosis factor-α, interleukin-6), cyclin D1, antiapoptotic protein (Bcl-2), metastasis marker (matrix metalloproteinase-2 (MMP-2)) and angiogenic marker (vascular endothelial growth factor VEGF) and decreased expression of pro-apoptotic proteins (Bax, caspases 3 and 9). On supplementing with p-MCA (40 mg/kg b.wt.) throughout the entire experimental period, DMH-induced pathological alterations reversed significantly to normal.


Assuntos
1,2-Dimetilidrazina/toxicidade , Anti-Inflamatórios/farmacologia , Anticarcinógenos/farmacologia , Carcinogênese/efeitos dos fármacos , Cinamatos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Carcinogênese/induzido quimicamente , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinógenos/toxicidade , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Masculino , Ratos , Ratos Wistar
20.
Drug Dev Ind Pharm ; 45(2): 282-291, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30346842

RESUMO

The CaCO3 encapsulated liposome with pH sensitivity is an efficient carrier for the delivery of chemotherapeutic drugs. Herein, we provided an innovative method that take advantage of a W/O emulsion to prepare CaCO3 encapsulated liposomes for the delivery of curcumin. The liposomes with both CaCO3 and curcumin encapsulated (LCC) showed high sensitivity to reduced pH (the environment of lysosomes). Due to the inherent pH sensitivity of CaCO3, LCC swelled and released the encapsulated curcumin rapidly in acidic medium. The lysosome escape capability and promoted accumulation of curcumin in the cytosol from LCC was verified with respect to that of curcumin loaded liposomes (CLIPO). Despite the similar cytotoxicity within curcumin preparations in vitro at high concentration, LCC exhibited optimal antitumor effect in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal cancer model, which was attributed to the long circulation time and efficient intracellular delivery of curcumin from LCC. It is suggested that the solubility and cytosolic delivery of curcumin are greatly improved by LCC, which accounts for the increased pharmacodynamic effect of curcumin. Thus, the CaCO3 encapsulated liposomes developed in this study is an ideal carrier for the hydrophobic drugs in potential clinical application.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Curcumina/administração & dosagem , Curcumina/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacocinética , Carbonato de Cálcio , Linhagem Celular Tumoral , Neoplasias do Colo/induzido quimicamente , Curcumina/farmacocinética , Citosol/metabolismo , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Emulsões , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óleos , Ratos , Ratos Sprague-Dawley , Água
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