RESUMEN
Colorectal cancer, which is one of the most common causes of cancer-related deaths worldwide, has a slow natural history that provides a great opportunity for prevention strategies. Plant-derived natural products have received considerable attention because of their inherent colorectal cancer chemopreventive effects. The plant lectin jacalin specifically recognizes the tumor-associated Thomsen-Friedenreich antigen and has antiproliferative effects on human colon cancer cells, highlighting its potential antitumor activity. To evaluate jacalin's potential application in colorectal cancer chemoprevention, we studied its effects on the early stages of carcinogenesis. Balb/c mice were given 4 intrarectal deposits of 0.1 ml solution of Methyl-N'-Nitro-N-Nitroso-Guanidine (5 mg/ml) twice a week (with a 3-day interval) for 2 weeks. Starting 2 weeks before carcinogen administration, animals were treated orally with jacalin (0.5 and 25 µg) three times a week (on alternate weekdays) for 10 weeks. We show that jacalin treatment reduced the number of preneoplastic lesions in carcinogen-exposed mice. This anticarcinogenic activity was associated with decreased colonic epithelial cell proliferation and stromal COX-2 expression and with increased intestinal production of TNF-α. Our results demonstrate that jacalin is able to modulate the early stages of colon carcinogenesis and emphasize its promising chemopreventive activity in colorectal cancer.
Asunto(s)
Neoplasias del Colon/prevención & control , Lectinas de Plantas/farmacología , Administración Oral , Animales , Carcinógenos/toxicidad , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Ciclooxigenasa 2/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas de Neoplasias/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: Physical exercise has been shown to be protective against colon carcinogenesis. Physical exercise, however, covers a wide range of modalities, from which different effects on the human body have been reported. We sought to clarify whether aerobic and resistance trainings would differently affect the development of early carcinogenic events in the colon. METHODS: Male BALB/c, C57/BL6, and interleukin 10 knockout (IL-10; on C57/BL6 background) mice were exposed to the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine. BALB/c mice were subjected to either aerobic (swimming) or resistance trainings (climbing a ladder with load attached to the tail). C57/BL6 and IL-10 mice only swam. RESULTS: In BALB/c carcinogen-exposed mice, aerobic and resistance trainings decreased serum creatine kinase levels (P < 0.001). Although aerobic and resistance trainings reduced the generation of lipid thiobarbituric reactive species (P < 0.01 and P < 0.001), only aerobic exercises enhanced serum glutathione levels aside from carcinogenic exposure (P < 0.05). Carcinogen-exposed and aerobic-trained mice developed 36% less colon preneoplastic lesions than its control group (P < 0.05). Aerobic training reduced colonic subepithelial cyclooxygenase-2 expression in carcinogen-exposed mice (P < 0.001). Interestingly, in this same group, colonic IL-10 expression was upregulated sevenfold (P < 0.001). Current findings were confirmed in C57/BL6 carcinogen-exposed mice, in which aerobic training promoted antipreneoplastic effects (P < 0.05). Knocking IL-10 out of C57/BL6 mice abrogated antipreneoplastic effects of aerobic training on the colon tissue (P > 0.05). CONCLUSIONS: IL-10 is a pivotal element for antipreneoplastic effects of aerobic training on the colon.
Asunto(s)
Neoplasias del Colon/inmunología , Neoplasias del Colon/prevención & control , Interleucina-10/fisiología , Condicionamiento Físico Animal/métodos , Entrenamiento de Fuerza , Natación/fisiología , Animales , Carcinógenos , Modelos Animales de Enfermedad , Humanos , Masculino , Metilnitronitrosoguanidina , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/prevención & controlRESUMEN
In a previous study, our group verified that mice pretreated with concanavalin-A (Con-A) produced more tumour necrosis factor (TNF)-alpha and presented greater Candida clearance from the peritoneal cavity, liver and spleen, which yielded a higher survival rate than control animals. In this work, the hypothesis that macrophages were of crucial importance in overcoming the infection was tested. Thus, peritoneal macrophages from mice pretreated for 3 days with Con-A or phosphate-buffered saline (PBS) were coincubated with CR1, CR15 and 577 isolates of Candida albicans for 0.5, 1 and 2 h. The ability of Con-activated macrophages to produce TNF-alpha, ingest via mannose receptors and kill all the isolates was significantly greater compared with PBS-treated macrophages, and activated macrophages exhibited a lower incidence of apoptosis, verified by binding to annexin V-fluorescein isothiocyanate. The transition of yeast cells to filamentous forms during coincubation for 2 h with control macrophages was about 73-80%, whereas in the presence of Con-A-activated macrophages, it was 35-40%. Our results suggest that a greater clearance of C. albicans infection through treatment with Con-A is probably due to the activation of macrophages, which produce more TNF-alpha, express more mannose receptors and are better endowed to kill ingested C. albicans.
Asunto(s)
Candida albicans/inmunología , Concanavalina A/farmacología , Factores Inmunológicos/farmacología , Lectinas Tipo C/metabolismo , Macrófagos Peritoneales/inmunología , Lectinas de Unión a Manosa/metabolismo , Fagocitosis , Receptores de Superficie Celular/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Apoptosis , Candida albicans/citología , Candida albicans/fisiología , Técnicas de Cocultivo , Macrófagos Peritoneales/efectos de los fármacos , Masculino , Receptor de Manosa , Ratones , Viabilidad MicrobianaRESUMEN
Candida albicans pode causar graves infecções em pacientes que estão imunocomprometidos por doenças, por cirurgias ou por terapia imunossupressiva. Os altos níveis de morbidade e mortalidade resultantes de infecções em pacientes hospitalizados mostraram que C. albicans tornou-se um patógeno humano de grande relevância clínica. Mesmo o sistema imune sendo o principal fator que define a transição do fungo de comensal para patogênico, fatores de virulência expressos por C. albicans, tais como adesinas, mudança fenotípica, comportamento dimórfico, e secreção de enzimas hidrolíticas, podem contribuir para a persistência da colonização, assim como o desenvolvimento de episódios sintomáticos. A defesa do hospedeiro compreende ingestão e eliminação do fungo por células fagocíticas que possuem vários receptores, como o Toll-4, dectina-1 associado a receptores tipo Toll-2 e receptores de manose. A interleucina-10 (IL-10) produzida por fagócitos determina a susceptibilidade do hospedeiro a infecção fúngica, enquanto a IL-10 produzida por células T reguladoras é responsável pelo comensalismo. Em contraste, a produção de fator de necrose tumoral- α (TNF-α), interleucina 1 β (lL-1 β), (IL-6), (Il-12) e IL-17 conferem imunidade protetora. O interferon-γ (IFN- γ) produzido por células natural killer e células Th1 estimula a migração de fagócitos e maior eficácia na destruição do fungo. Nas células epiteliais de mucosas os receptores NOD-like e defensinas-β citoplasmáticos evitam a translocação de C. albicans da microbiota para os tecidos os quais são modulados por citocinas IL-1 β,IL-17 e IL-22.
Candida albicans can cause grave infections in patients who are immunocompromised by diseases, by surgery, or by immunesupresive therapy. The high levels of morbidity and mortality resulting from those infections in hospitalized patients show that C. albicans became a prominent human pathogen. Although the host immune system is the major factor balancing the transition from commensalisms to pathogenicity, several virulence attributes expressed by C. albicans, such as adhesion factors, phenotypic switching, dimorphic behavior, and secretion of hydrolytic enzymes, might contribute to the persistence of colonization as well as the development of symptomatic episodes. Host defense against candidiasis relies mainly on the ingestion and elimination of C. albicans by phagocytic cells, which present receptors Toll-like 4, dectin1 associated to receptors Toll-like2 and mannose receptors. The cytokine IL-10 (IL-10) produced by phagocytes has a crucial role on susceptibility of host fungal infection, whereas IL-10 produced by regulatory T cells is mainly responsible by commensalisms. In contrast, productions of tumour necrosis factor - α (TNF-α), interleukin1 β (lL-1 β), (IL-6) and (Il-12) provided protective cellmediated immunity. The interferon-γ produced by natural killer and TH1 cells stimulates migration of phagocytes and major efficacy on destruction of fungi. In epithelial cells from mucosas the NOD-like receptors and defensins-β cytoplasmatic prevent the translocation of C. albicans from microbiota to tissues, which are modulated by IL-1 β, Il-17 and Il-22 cytokines.