RESUMO
BACKGROUND: Gastrointestinal adverse effects occurring during cancer chemotherapy are well known and feared; those persisting once treatment has finished are relatively unknown. We characterized the alterations occurring in the rat small intestine, after repeated treatment with cisplatin. METHODS: Male Wistar rats received saline or cisplatin (2 mg kg-1 week-1 , for 5 weeks, ip). Gastric motor function was studied non-invasively throughout treatment (W1-W5) and 1 week after treatment finalization (W6). During W6, upper gastrointestinal motility was also invasively studied and small intestinal samples were collected for histopathological and molecular studies. Structural alterations in the small intestinal wall, mucosa, submucosa, muscle layers, and lymphocytic nodules were histologically studied. Periodic acid-Schiff staining and immunohistochemistry for Ki-67, chromogranin A, and neuronal-specific enolase were used to detect secretory, proliferating, endocrine and neural cells, respectively. The expression of different markers in the tunica muscularis was analyzed by RT/qPCR. KEY RESULTS: Repeated cisplatin induced motility alterations during and after treatment. After treatment (W6), the small intestinal wall showed histopathological alterations in most parameters measured, including a reduction in the thickness of circular and longitudinal muscle layers. Expression of c-KIT (for interstitial cells of Cajal), nNOS (for inhibitory motor neurons), pChAT, and cChAT (for excitatory motor neurons) increased significantly (although both ChATs to a lesser extent). CONCLUSIONS & INFERENCES: Repeated cisplatin induces relatively long-lasting gut dysmotility in rat associated with important histopathological and molecular alterations in the small intestinal wall. In cancer survivors, the possible chemotherapy-induced histopathological, molecular, and functional intestinal sequelae should be evaluated.
Assuntos
Cisplatino/toxicidade , Motilidade Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Cisplatino/administração & dosagem , Motilidade Gastrointestinal/fisiologia , Mucosa Intestinal/fisiopatologia , Intestino Delgado/fisiopatologia , Masculino , Ratos , Ratos WistarRESUMO
AIMS/HYPOTHESIS: Glucose-dependent insulinotropic peptide (GIP) plays a pivotal role in the regulation of glucose homeostasis. Rates of diet-induced obesity, insulin resistance and type 2 diabetes are decreased when GIP signalling is disturbed in mice, suggesting that GIP plays a role in the onset of type 2 diabetes. WNT signalling is linked to type 2 diabetes and induces synthesis of the other incretin, glucagon-like peptide 1 (GLP-1). GLP-1 analogues improve treatment of type 2 diabetes patients in whom GLP-1 signalling is intact and have captured clinical attention. GIP levels are altered at the onset of type 2 diabetes and later on, while GIP signalling is impaired. Thus, GIP is not a candidate for treatment but might be an important target from a prevention perspective. Hypothesising that hypersecretion of GIP links altered WNT signalling to the onset of type 2 diabetes, we sought to determine whether WNT signalling induces GIP production by entero-endocrine cells. METHODS: RT-PCR and chromatin immunoprecipitation (ChIP) were used to study Gip gene induction. Gip promoter elements mediating WNT/lithium induction were identified (electrophoretic mobility shift assay, co-transfection of deletion mutants, ChIP). RESULTS: Lithium or WNT/beta-catenin signalling enhanced GIP production by entero-endocrine cells through a conserved site in the proximal Gip promoter. Lithium favours lymphoid enhancer factor-1/beta-catenin binding to Gip promoter and diminishes ChIP through T cell factor-4 and histone deacetylase 1. CONCLUSIONS/INTERPRETATION: Lithium and WNT are incretin inducers in general. This work provides a novel link between WNT signalling, obesity and diabetes.
Assuntos
Incretinas/biossíntese , Proteínas Wnt/fisiologia , beta Catenina/fisiologia , Animais , Linhagem Celular Tumoral , Cromatina/fisiologia , DNA de Neoplasias/genética , Polipeptídeo Inibidor Gástrico/genética , Polipeptídeo Inibidor Gástrico/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Neoplasias Intestinais/fisiopatologia , Lítio/farmacologia , Luciferases/genética , Camundongos , RNA Mensageiro/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , TransfecçãoRESUMO
Ante un brote de una enfermedad infecto-contagiosa, el estudio de contactos limita la transmisión de esta. El objetivo de este trabajo fue identificar a los contactos de los posibles casos de influenza en trabajadores de la UNAM para establecer una comunicación y proporcionar educación para la salud sobre medidas higiénicas. Material y métodos: Se elaboró un cuestionario, se estableció contacto con los casos por vía telefónica y se llevó a cabo una visita domiciliaria. Se llevó a cabo un análisis descriptivo de los datos y una descripción de las experiencias y percepciones durante las visitas. Resultados: Se identificó que la mayoría de los contactos eran familiares directos de los casos, que no contaban con un esquema de vacunación completo, ni contra la influenza y la frecuencia de síntomas varió de 1 hasta 4. Comentarios finales: Ante una situación de este tipo (la Pandemia del Virus de la Influenza Humana A (H1N1)) el papel de la enfermera en salud pública es de suma importancia no solo en la búsqueda de los casos y sus contactos, sino también en la orientación y educación de la población en relación a las medidas preventivas.
In the view of an infectious and contagious disease epidemic, the identification of the contacts limits its transmission. The objective of this work was to identify the contacts of the possible cases of UNAM workers in order to establish communication and provide health education about hygiene measures. Material and methods: A questionnaire was prepared, telephone contact was established with the cases, and a home visit was arranged. A descriptive analysis of the data was carried out, as well as, a description of the experiences and perception during the home visit. Results: Most identified contacts were relatives of the cases, which did not have a complete vaccine scheme, no even against influenza, and the frequency of symptoms varied between 1 a 4. Final comments: In a situation like this (A(H1N1) human influenza virus pandemic) the public health nurse roll is of great importance, not just in the identification of the cases and its contacts, but also in the orientation and education of the population in relation to preventive measures.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Influenza Humana , Prevenção Primária , Saúde PúblicaAssuntos
Hematopoese , Leucemia/fisiopatologia , Proteínas Oncogênicas/metabolismo , Proteínas de Saccharomyces cerevisiae , Animais , Núcleo Celular/fisiologia , Histona Desacetilase 1 , Histona Desacetilases/metabolismo , Humanos , Leucemia Promielocítica Aguda/fisiopatologia , Proteínas de Neoplasias/metabolismo , Proteínas Oncogênicas v-erbA/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Receptores do Ácido Retinoico/metabolismo , Proteínas Repressoras/metabolismo , Receptor alfa de Ácido Retinoico , Fatores de Transcrição/metabolismoRESUMO
Brown adipose tissue (BAT) is composed of highly specialized cells, whose main function is to produce heat under adrenergic stimulation, uncoupling oxidative phosphorylation. For this function, lipogenesis must be accurately regulated. Malic enzyme has a central role in lipogenesis and is strongly expressed in brown adipocytes. In this work, we study the modulation by adrenergic stimuli, cAMP effectors and retinoic acid on the induction produced by insulin and 3,5,3'-triiodothyronine on malic-enzyme-gene expression. Primary cultures of differentiating brown adipocytes have been used. The results obtained demonstrate that physiological doses of norepinephrine do not modify malic-enzyme mRNA levels when acting alone, but considerably reduce the induction produced by insulin, 3,5,3'-triiodothyronine or both together. Other cAMP inducers such as glucagon, forskolin or 8-bromo-cAMP, greatly inhibit both, basal and 3,5,3'-triiodothyronine-induced malic-enzyme-gene gene expression. Retinoic acid abolishes basal and also inhibits 3,5,3'-triiodothyronine-induced malic-enzyme-gene expression.