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BACKGROUND: Interleukin-22 (IL-22) has been recently highlighted owing to its biological significance in the modulation of tissue responses during inflammation. However, the role of IL-22 in carcinogenesis has remained unclear. Here, we investigated the pathophysiological significance of IL-22 expression in gastric cancer tissues and examined the mechanism by which IL-22 promotes gastric cancer cell invasion. METHODS: Human gastric cancer specimens were analysed by immunohistochemistry for expression of IL-22 and IL-22 receptor 1 (IL-22R1). The effects of IL-22-induced STAT3 and ERK signalling on invasive ability of gastric cancer cells were examined using a small-interfering RNA system and specific inhibitors. AGS cells were co-cultured with cancer-associated fibroblasts (CAFs) from human gastric cancer tissues and assessed by invasion assay. RESULTS: Interleukin-22 and its receptor were expressed in α-smooth muscle actin-positive stromal cells and tumour cells at the invasive front of gastric cancer tissues, respectively. The expression of IL-22 and IL-22R1 was significantly related to lymphatic invasion. Interleukin-22 treatment promoted the invasive ability of gastric cancer cells through STAT3 and ERK activation. The invasive ability of gastric cancer cells was significantly enhanced by co-culture with IL-22-expressing CAFs. CONCLUSIONS: Interleukin-22 produced by CAFs promotes gastric cancer cell invasion via STAT3 and ERK signalling.
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Fibroblastos/metabolismo , Interleucinas/metabolismo , Sistema de Señalización de MAP Quinasas , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Técnicas de Cocultivo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Fosforilación , Procesamiento Proteico-Postraduccional , Receptores de Interleucina/metabolismo , Neoplasias Gástricas/patología , Interleucina-22RESUMEN
BACKGROUND: The regenerating gene Iα (REG Iα) is involved in gastric carcinogenesis as an antiapoptotic factor. Therefore, we investigated whether REG Iα confers resistance to chemotherapeutic drugs in gastric cancer (GC) cells and whether REG Iα expression is useful for predicting the response to chemotherapy and outcome in patients with GC. METHODS: A total of 70 patients with unresectable stage IV GC received first-line chemotherapy with S-1 and cisplatin (S-1/CDDP). The expression of REG Iα was evaluated immunohistochemically using biopsy samples obtained before chemotherapy, and its relationship to clinicopathological parameters was analysed statistically. The effects of REG Iα gene induction on resistance to 5-FU or CDDP treatment were examined by cell survival assay and flow cytometry. RESULTS: Of the 70 patients with unresectable stage IV GC, 19 (27%) were positive for REG Iα expression. The expression of REG Iα was independently predictive of poorer progression-free and overall survival in such patients (hazard ratio (HR) 2.46; P=0.002 and HR 1.89; P=0.037, respectively). The gene induction of REG Iα conferred resistance to cell death induced by 5-FU or CDDP in GC cells. CONCLUSION: In patients with stage IV GC, REG Iα, which confers resistance to chemotherapeutic drugs in GC cells, is a potential biomarker for predicting resistance to S-1/CDDP treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/uso terapéutico , Fluorouracilo/uso terapéutico , Litostatina/metabolismo , Ácido Oxónico/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Tegafur/uso terapéutico , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Combinación de Medicamentos , Resistencia a Antineoplásicos , Femenino , Humanos , Litostatina/genética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Resultado del TratamientoRESUMEN
An X-ray Raman spectrometer for studies of local structures in minerals is discussed. Contrary to widely adopted back-scattering spectrometers using ≤10 keV X-rays, a spectrometer utilizing ~20 keV X-rays and a bent Laue analyzer is proposed. The 20 keV photons penetrate mineral samples much more deeply than 10 keV photons, so that high intensity is obtained owing to an enhancement of the scattering volume. Furthermore, a bent Laue analyzer provides a wide band-pass and a high reflectivity, leading to a much enhanced integrated intensity. A prototype spectrometer has been constructed and performance tests carried out. The oxygen K-edge in SiO(2) glass and crystal (α-quartz) has been measured with energy resolutions of 4 eV (EXAFS mode) and 1.3 eV (XANES mode). Unlike methods previously adopted, it is proposed to determine the pre-edge curve based on a theoretical Compton profile and a Monte Carlo multiple-scattering simulation before extracting EXAFS features. It is shown that the obtained EXAFS features are reproduced fairly well by a cluster model with a minimal set of fitting parameters. The spectrometer and the data processing proposed here are readily applicable to high-pressure studies.
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Objectives: To evaluate whether tumor extracellular volume fraction (fECV) on contrast-enhanced computed tomography (CT) aids in the differentiation between intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). Methods: In this retrospective study, 113 patients with pathologically confirmed ICC (n = 39) or HCC (n = 74) who had undergone preoperative contrast-enhanced CT were enrolled. Enhancement values of the tumor (Etumor) and aorta (Eaorta) were obtained in the precontrast and equilibrium phase CT images. fECV was calculated using the following equation: fECV [%] = Etumor/Eaorta × (100 - hematocrit [%]). fECV values were compared between the ICC and HCC groups using Welch's t-test. The diagnostic performance of fECV for differentiating ICC and HCC was assessed using receiver-operating characteristic (ROC) analysis. fECV and the CT imaging features of tumors were evaluated by two radiologists. Multivariate logistic regression analysis was performed to identify factors predicting a diagnosis of ICC. Results: Mean fECV was significantly higher in ICCs (43.8% ± 13.2%) than that in HCCs (31.6% ± 9.0%, p < 0.001). The area under the curve for differentiating ICC from HCC was 0.763 when the cutoff value of fECV was 41.5%. The multivariate analysis identified fECV (unit OR: 1.10; 95% CI: 1.01-1.21; p < 0.05), peripheral rim enhancement during the arterial phase (OR: 17.0; 95% CI: 1.29-225; p < 0.05), and absence of washout pattern (OR: 235; 95% CI: 14.03-3933; p < 0.001) as independent CT features for differentiating between the two tumor types. Conclusions: A high value of fECV, peripheral rim enhancement during the arterial phase, and absence of washout pattern were independent factors in the differentiation of ICC from HCC.
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Reducing the dose of drug affects treatment efficacy in pegylated interferon (Peg-IFN) and ribavirin combination therapy for patients with hepatitis C virus (HCV) genotype 1. The aim of this study was to investigate the impact of drug exposure, as well as the baseline factors and the virological response on the treatment efficacy for genotype 2 patients. Two-hundred and fifty patients with genotype 2 HCV who were to undergo combination therapy for 24 weeks were included in the study, and 213 completed the treatment. Significantly more patients who achieved a rapid virological response (RVR), defined as HCV RNA negativity at week 4, achieved a sustained virological response (SVR) (92%, 122/133) compared with patients who failed to achieve RVR (48%, 38/80) (P < 0.0001). Multivariate logistic-regression analysis showed that only platelet counts [odds ratio (OR), 1.68; confidence interval (CI), 1.002-1.139] and RVR (OR, 11.251; CI, 5.184-24.419) were independently associated with SVR, with no correlation being found for the mean dose of Peg-IFN and ribavirin for RVR and SVR. Furthermore, in the stratification analysis of the timing of viral clearance, neither mean dose of Peg-IFN (P = 0.795) nor ribavirin (P = 0.649) affected SVR in each group. Among the patients with RVR, the lowest dose group of Peg-IFN (0.77 +/- 0.10 microg/kg/week) and ribavirin (6.9 +/- 0.90 mg/kg/day) showed 100% and 94% of SVR. Hence, RVR served as an important treatment predictor, and drug exposure had no impact on both SVR and RVR in combination therapy for genotype 2 patients.
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Antivirales/administración & dosificación , Hepacivirus/clasificación , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Interferón-alfa/administración & dosificación , Polietilenglicoles/administración & dosificación , Ribavirina/administración & dosificación , Adulto , Anciano , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/genética , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , ARN Viral/sangre , Proteínas Recombinantes , Resultado del Tratamiento , Carga ViralRESUMEN
Necl-5 is an immunoglobulin-like molecule that was originally identified as a poliovirus receptor. Although Necl-5 expression is often up-regulated in cancer cells, its pathophysiological significance in the development of cancer remains unclear. We investigated the roles of Necl-5 in the development of colitis-associated neoplasia. Necl-5-deficient mice were generated and treated with dimethylhydrazine (DMH) and/or dextran sodium sulphate (DSS) to induce colitis and its associated neoplasias. Colon tissues were examined for histology, Ki-67 expression by immunohistochemistry and K-ras gene mutation. Colon tumours occurred significantly less frequently in heterozygous (Necl-5(+/-)) or homozygous Necl-5-deficient (Necl-5(-/-)) mice than in wild-type (WT) mice with DMH/DSS treatment. Total ulcer index and inflammatory cell infiltration were significantly lower in Necl-5(-/-) mice than in WT mice with DSS alone or DMH/DSS treatment. Colon tumours in both WT and Necl-5(-/-) mice showed high cell proliferation ability but lacked K-ras mutation. The total Ki-67 labelling index in non-neoplastic colon epithelium was significantly higher in WT (45.9 +/- 0.94) than in Necl-5(+/-) (34.3 +/- 1.40) or Necl-5(-/-) (27.7 +/- 1.15) mice with DMH/DSS treatment (p < 0.001). Necl-5 plays a role in the development of colitis-associated cancer by up-regulating colonic mucosal cell proliferation.
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Antígenos de Neoplasias/fisiología , Moléculas de Adhesión Celular/fisiología , Neoplasias Colorrectales/fisiopatología , Proteínas de Neoplasias/fisiología , Animales , Peso al Nacer , Moléculas de Adhesión Celular/deficiencia , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/patología , Colon/patología , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/patología , Sulfato de Dextran , Dimetilhidrazinas , Modelos Animales de Enfermedad , Genes ras/genética , Crecimiento , Mucosa Intestinal/patología , Antígeno Ki-67/metabolismo , Ratones , Ratones Noqueados , Mutación , Proteínas de Neoplasias/deficiencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
It has been well established that histaminergic neurons innervate densely the anterior hypothalamus and regulate several functions through the histamine H1 receptor (H1R). However, the physiological function of the histaminergic neurons in other regions including the posterior hypothalamus has not been fully investigated. Recently, we have found a selective c-Fos expression in the caudal part of the arcuate nucleus of the hypothalamus (cARC) by food deprivation under scheduled feeding in rats. In this study, we histochemically examined the correlation of this c-Fos expression with the activation of histaminergic neurons in this region using an anti-H1R antibody. Strong H1R immunoreactivity was observed in the perikarya of the c-Fos positive cells. Abundant histamine-containing fibers were also found in the cARC and in the area between the cARC and the tuberomammillary nucleus (TM), where the histaminergic neuronal cell bodies are exclusively distributed. Our morphological observations suggest that c-Fos expression in the cARC by food deprivation under scheduled feeding is caused by the activation of histaminergic neurons projected from the TM.
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Privación de Alimentos , Histamina/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Receptores Histamínicos H1/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Regulación de la Expresión Génica , Masculino , Neuronas/metabolismo , Ratas , Ratas Wistar , Receptores Histamínicos H1/inmunologíaRESUMEN
Administration of antihistamines 2-4 weeks before the pollen season showed a greater inhibitory effect on nasal allergy symptoms in patients with seasonal allergic rhinitis. However, the mechanism of slow-onset effects of preseasonal treatment with antihistamines remains unclear. Here, we investigated the effect of preseasonal prophylactic treatment with antihistamines on nasal symptoms and the expression of histamine H1 receptor (H1R) mRNA of the nasal mucosa in patients with cedar pollen pollinosis. During the peak pollen period, the expression of H1R mRNA in the nasal mucosa and the scores of sneezing and watery rhinorrhea in patients receiving preseasonal prophylactic treatment with antihistamines were significantly suppressed in comparison with those in the patients without treatment. Moreover, there was a significant correlation between the nasal symptoms and the expression of H1R mRNA in both patients with or without preseasonal prophylactic treatment. These findings suggest that preseasonal prophylactic treatment with antihistamines is more effective than on-seasonal administration to patients with pollinosis in reducing nasal symptoms during the peak pollen period by suppressing H1R gene expression in the nasal mucosa.
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Antagonistas de los Receptores Histamínicos/farmacología , Mucosa Nasal/efectos de los fármacos , Receptores Histamínicos H1/efectos de los fármacos , Rinitis Alérgica Estacional/prevención & control , Cryptomeria/inmunología , Femenino , Estudios de Seguimiento , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Mucosa Nasal/inmunología , Polen/inmunología , ARN Mensajero/metabolismo , Receptores Histamínicos H1/genética , Rinitis Alérgica Estacional/inmunologíaRESUMEN
The regenerating gene (Reg) was originally isolated from regenerating rat pancreatic islets and revealed recently to constitute a multi-gene family in humans. REG Ialpha protein is known to be overexpressed not only in various human inflammatory diseases but also in various experimental models of inflammation in animal tissues. However, its involvement in pathophysiology of the minor salivary gland (MSG) is not clear. We investigated REG Ialpha expression in the MSG of patients with primary Sjögren's syndrome (SS) and assessed its role in ductal epithelial cell proliferation in such tissues. Lip biopsy specimens were obtained from 40 patients with primary SS and examined using immunohistochemistry for REG Ialpha protein, Ki67 and single-strand DNA (ssDNA). The relationships among clinicopathological factors and expression of REG Ialpha protein, Ki67 and ssDNA in the MSG were then analysed. REG Ialpha protein was expressed rarely in ductal epithelial cells of the normal MSG but was apparently overexpressed in those of patients with SS. The labelling indices for both Ki67 and ssDNA in the ductal cells of the MSGs were significantly higher in SS patients than in controls. Moreover, these labelling indices were significantly higher in REG Ialpha-positive than in negative SS patients. REG Ialpha protein may play a role in the regeneration of ductal epithelial cells in the MSGs of patients with SS.
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Células Epiteliales/fisiología , Litostatina/análisis , Regeneración/fisiología , Conductos Salivales/fisiología , Glándulas Salivales Menores , Síndrome de Sjögren/patología , Adolescente , Adulto , Anciano , Biomarcadores/análisis , División Celular/fisiología , ADN de Cadena Simple/análisis , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Litostatina/metabolismo , Masculino , Persona de Mediana Edad , Conductos Salivales/metabolismo , Conductos Salivales/patología , Síndrome de Sjögren/metabolismo , Adulto JovenRESUMEN
Experimental systems that are amenable to genetic manipulation can be used to address fundamental questions about genetic and nongenetic determinants of longevity. Analysis of large cohorts of ten genotypes of Drosophila melanogaster raised under conditions that favored extended survival has revealed variation between genotypes in both the slope and location of age-specific mortality curves. More detailed examination of a single genotype showed that the mortality trajectory was best fit by a two-stage Gompertz model, with no age-specific increase in mortality rates beyond 30 days after emergence. These results are contrary to the limited life-span paradigm, which postulates well-defined, genotype-specific limits on life-span and brief periods of intense and rapidly accelerating mortality rates at the oldest age.
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Drosophila melanogaster/fisiología , Mortalidad , Envejecimiento , Animales , Genotipo , Esperanza de VidaRESUMEN
When pregnant rats were fed a 50 percent galactose diet there was a striking reduction in oocyte number in the offspring. The most prominent effects were noted after exposure to galactose during the premeiotic stages of oogenesis. Prenatal exposure to galactose or its metabolites may contribute to the premature ovarian failure characteristic of human galactosemia.
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Carbohidratos de la Dieta/fisiología , Galactosa/farmacología , Oocitos/fisiología , Óvulo/fisiología , Animales , Femenino , Feto/efectos de los fármacos , Feto/fisiología , Intercambio Materno-Fetal , Oocitos/efectos de los fármacos , Embarazo , Ratas , Ratas EndogámicasRESUMEN
Although stromal cell-derived factor (SDF)-1 alpha and its receptor CXCR4 are experimentally suggested to be involved in tumorigenicity, the clinicopathological significance of their expression in human disease is not fully understood. We examined SDF-1 alpha and CXCR4 expression in colorectal cancers (CRCs) and their related lymph nodes (LNs), and investigated its relationship to clinicopathological features. Specimens of 60 primary CRCs and 27 related LNs were examined immunohistochemically for not only positivity but also immunostaining patterns for SDF-1 alpha and CXCR4. The relationships between clinicopathological features and SDF-1 alpha or CXCR4 expression were then analysed. Stromal cell-derived factor-1 alpha and CXCR4 expression were significantly associated with LN metastasis, tumour stage, and survival of CRC patients. Twenty-nine of 47 CXCR4-positive CRCs (61.7%) showed clear CXCR4 immunoreactivity in the nucleus and a weak signal in the cytoplasm (nuclear type), whereas others showed no nuclear immunoreactivity but a diffuse signal in the cytoplasm and at the plasma membrane (cytomembrane type). Colorectal cancer patients with nuclear CXCR4 expression showed significantly more frequent LN metastasis than did those with cytomembrane expression. Colorectal cancer patients with nuclear CXCR4 expression in the primary lesion frequently had cytomembrane CXCR4-positive tumours in their LNs. In conclusion, expression of SDF-1 alpha and nuclear CXCR4 predicts LN metastasis in CRCs.
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Biomarcadores de Tumor/análisis , Quimiocina CXCL12/análisis , Neoplasias Colorrectales/química , Neoplasias Colorrectales/patología , Ganglios Linfáticos/química , Ganglios Linfáticos/patología , Receptores CXCR4/análisis , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
The relativistic calculation of nuclear magnetic shielding tensors in hydrogen halides is performed using the second-order regular approximation to the normalized elimination of the small component (SORA-NESC) method with the inclusion of the perturbation terms from the metric operator. This computational scheme is denoted as SORA-Met. The SORA-Met calculation yields anisotropies, Delta sigma = sigma(parallel) - sigma(perpendicular), for the halogen nuclei in hydrogen halides that are too small. In the NESC theory, the small component of the spinor is combined to the large component via the operator sigma x piU/2c, in which pi = p + A, U is a nonunitary transformation operator, and c approximately = 137.036 a.u. is the velocity of light. The operator U depends on the vector potential A (i.e., the magnetic perturbations in the system) with the leading order c(-2) and the magnetic perturbation terms of U contribute to the Hamiltonian and metric operators of the system in the leading order c(-4). It is shown that the small Delta sigma for halogen nuclei found in our previous studies is related to the neglect of the U(0,1) perturbation operator of U, which is independent of the external magnetic field and of the first order with respect to the nuclear magnetic dipole moment. Introduction of gauge-including atomic orbitals and a finite-size nuclear model is also discussed.
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Sedation is the most frequent side effect of H(1)-antihistamines, and, sometimes, it may be life-threatening for patients. Evaluation of the sedative properties of H(1)-antihistamines is important to improve the patients' quality of life (QOL). Therefore, we carried out a large-scale surveillance quantified through a questionnaire using visual analog scale (VAS) from 1,742 patients. The results showed that the degree of sleepiness caused by some nonsedative second-generation antihistamines, including fexofenadine, olopatadine and cetirizine, was disease dependent. In atopic dermatitis, an unexpectedly low VAS score of sleepiness was obtained for the first-generation antihistamine d-chlorpheniramine, which is similar to those obtained for bepotastine and epinastine. d-Chlorpheniramine also showed a high VAS score in efficacy. Meanwhile, fexofenadine showed a higher VAS score of sleepiness in atopic dermatitis than those obtained in the other allergic diseases including allergic rhinitis, urticaria and asthma. In asthma, a higher VAS score of sleepiness was found for olopatadine, ebastine and cetirizine, when compared with d-chlorpheniramine. On the other hand, bepotastine showed the lowest VAS score for sleepiness. Our findings suggest the existence of unknown factors influencing the sedative properties of H(1)-antihistamines. Therefore, appropriate H(1)-antihistamines may need to be selected, depending on allergic diseases, to improve patients' QOL.
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Antagonistas de los Receptores Histamínicos H1/efectos adversos , Antagonistas de los Receptores Histamínicos H1/farmacología , Dimensión del Dolor , Vigilancia de la Población , Fases del Sueño/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Asma/tratamiento farmacológico , Butirofenonas/efectos adversos , Butirofenonas/farmacología , Butirofenonas/uso terapéutico , Cetirizina/farmacología , Cetirizina/uso terapéutico , Niño , Clorfeniramina/efectos adversos , Clorfeniramina/farmacología , Clorfeniramina/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Dibenzazepinas/efectos adversos , Dibenzazepinas/farmacología , Dibenzazepinas/uso terapéutico , Dibenzoxepinas/farmacología , Dibenzoxepinas/uso terapéutico , Femenino , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Antagonistas de los Receptores Histamínicos H1 no Sedantes/farmacología , Antagonistas de los Receptores Histamínicos H1 no Sedantes/uso terapéutico , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacología , Imidazoles/uso terapéutico , Japón/epidemiología , Masculino , Persona de Mediana Edad , Clorhidrato de Olopatadina , Piperidinas/efectos adversos , Piperidinas/farmacología , Piperidinas/uso terapéutico , Desempeño Psicomotor/efectos de los fármacos , Piridinas/efectos adversos , Piridinas/farmacología , Piridinas/uso terapéutico , Calidad de Vida , Rinitis Alérgica Perenne/tratamiento farmacológico , Rinitis Alérgica Estacional/tratamiento farmacológico , Encuestas y Cuestionarios , Terfenadina/análogos & derivados , Terfenadina/farmacología , Terfenadina/uso terapéutico , Urticaria/tratamiento farmacológicoRESUMEN
Cyclooxygenase-2 (COX-2) plays important roles in tumor development. Especially in the early-stage colorectal tumors, COX-2 expression is often observed in the tumor stroma. However, the mechanism regulating such stromal expression of COX-2 remains unknown. In the present study, we simulated the indirect interaction between epithelial cells and stromal cells in the process of colorectal tumor development using an in vitro co-culture model in which NIH3T3 fibroblasts were co-cultured with 'sparsely' or 'densely' populated intestinal epithelial cells, Intestine-407 as a model of premalignant or benign intestinal epithelial cells, and DLD-1 and Caco-2 as models of malignant epithelial cells. COX-2 expression in NIH3T3 fibroblasts was upregulated when co-cultured with the 'dense' epithelial cells regardless of their character. Interestingly, there was pericellular hypoxia in the vicinity of NIH3T3 fibroblasts when co-cultured with 'dense' epithelial cells, and the recovery of the partial pressure of oxygen level resulted in the reduction of enhanced COX-2 expression only in NIH3T3 fibroblasts co-cultured with 'dense' Intestine-407 cells. Furthermore, COX-2 expression was also reduced by the inhibition of transcription factor AP-1. Thus, pericellular hypoxia of the stromal cells caused by densely populated epithelial cells may be one of the potent COX-2 enhancers before completion of malignant transformation during intestinal tumor development.
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Ciclooxigenasa 2/biosíntesis , Hipoxia/enzimología , Mucosa Intestinal/citología , Mucosa Intestinal/enzimología , Proteínas de la Membrana/biosíntesis , Transducción de Señal/fisiología , Factor de Transcripción AP-1/fisiología , Animales , Células CACO-2 , Recuento de Células , Línea Celular Tumoral , Técnicas de Cocultivo , Ciclooxigenasa 2/fisiología , Inducción Enzimática/fisiología , Humanos , Hipoxia/patología , Mucosa Intestinal/patología , Proteínas de la Membrana/fisiología , Ratones , Células 3T3 NIH , Lesiones Precancerosas/enzimología , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Células del Estroma/enzimología , Células del Estroma/patologíaRESUMEN
This study was designed to investigate the mechanism for ethanol-induced hepatic vasoconstriction in isolated perfused rat liver. Upon initiation of ethanol infusion into the portal vein at concentrations ranging from 25 to 100 mM, portal pressure began to increase in a concentration-dependent manner and reached maximal levels in 2-5 min (initial phase), followed by a gradual decrease over the period of ethanol infusion (escape phenomenon). Endothelin-1 antiserum significantly inhibited this ethanol-induced hepatic vasoconstriction by 45-80%. Cessation of infusion of endothelin-1 antiserum was followed by a subsequent increase in portal pressure. On the other hand, when a nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA), was infused into the portal vein simultaneously with ethanol, the initial phase of the response of portal pressure to ethanol was not altered and the peak values of portal pressure remained unchanged. However, after the peak increase in portal pressure, the rate of decrease was less than in the absence of L-NMMA. Thus, L-NMMA diminished the escape phenomenon and sustained the vasoconstriction. This study supports the hypothesis that two endothelium-derived vasoactive factors, endothelin-1 and nitric oxide, regulate hepatic vascular tone in the presence of ethanol.
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Endotelinas/fisiología , Etanol/farmacología , Hígado/irrigación sanguínea , Óxido Nítrico/metabolismo , Vasoconstricción/efectos de los fármacos , Animales , Arginina/análogos & derivados , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Endotelinas/inmunología , Sueros Inmunes/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , omega-N-MetilargininaRESUMEN
BACKGROUND: Gastric accommodation is a reflex reaction related to gastric reservoir function. Psychological stress, such as anxiety, inhibits gastric accommodation in humans. Acotiamide enhances the effect of acetylcholine in the enteric nervous system, enhances gastric contractility, and accelerates delayed gastric emptying. However, the effect of acotiamide on stress-induced impaired gastric accommodation remains unclear. Therefore, we examined the effect of acotiamide on gastric accommodation and stress-induced impaired gastric accommodation using a conscious guinea pig model. METHODS: A polyethylene bag was inserted through the distal region of the gastric body into the proximal stomach of 5-week-old male Hartley guinea pigs. Gastric accommodation was evaluated by measuring the intrabag pressure in the proximal stomach after oral administration of a liquid meal. In the stress model, animals were subjected to water-avoidance stress. Acotiamide (Z-338) or nizatidine was administered subcutaneously. Fecal output was determined as the number of fecal pellets. KEY RESULTS: Administration of the liquid meal significantly decreased intrabag pressure, indicating induction of gastric accommodation. Acotiamide treatment prolonged liquid meal-induced gastric accommodation and significantly increased the number of fecal pellets compared to controls. Water-avoidance stress significantly inhibited liquid meal-induced gastric accommodation. Pretreatment with acotiamide significantly improved stress-induced impaired gastric accommodation. The number of fecal pellets in the acotiamide group increased significantly compared to controls. Acotiamide, but not nizatidine, significantly decreased gastric emptying. CONCLUSIONS & INFERENCES: Acotiamide prolongs gastric accommodation and improves stress-induced impaired gastric accommodation, indicating a potential role for acotiamide in the treatment of functional dyspepsia through its effects on gastric accommodation reactions.
Asunto(s)
Benzamidas/farmacología , Vaciamiento Gástrico/fisiología , Fármacos Gastrointestinales/farmacología , Estómago/fisiología , Estrés Psicológico/fisiopatología , Tiazoles/farmacología , Animales , Benzamidas/uso terapéutico , Vaciamiento Gástrico/efectos de los fármacos , Fármacos Gastrointestinales/uso terapéutico , Cobayas , Masculino , Estómago/efectos de los fármacos , Estrés Psicológico/complicaciones , Estrés Psicológico/tratamiento farmacológico , Tiazoles/uso terapéuticoRESUMEN
In the present study, the antigenic phenotype and target cell specificity of the cytotoxic lymphocytes observed in F344 rats following the ip inoculation of a syngeneic MADB106 mammary carcinoma and the single injection of OK-432 were examined. When the cytotoxicity of peritoneal exudate cells (PECs) was measured in a 4-hour 51Cr release assay, appreciable cytotoxicity against MADB106 tumor cells was evident by day 7-14 following OK-432 injection. With the use of an antibody (R1-3B3) and complement depletion of cytotoxic PECs, the MADB106 killer cells appeared to consist of both R1-3B3- (non-T) and R1-3B3+ (T) cells, with most of the anti-MADB106 killing residing in the R1-3B3- cell population. The R1-3B3- killer cells were further defined as: a) phenotypically asialoGM1+, b) present in athymic nude rats, and c) accompanied by some augmentation of YAC-1 killing [the prototype rat natural killer (NK) target], suggesting that some of these R1-3B3- killer cells were typical NK cells. However, it was also observed that most of the R1-3B3- cells that killed MADB106 tumor cells were: 1) phenotypically or functionally different from either cytotoxic T-cells or typical NK cells; 2) observed only in MADB106 tumor-bearing rats challenged with OK-432; 3) not present on day 1-2 following OK-432 injection, the time when YAC-1 killing was maximally augmented; and 4) present in high numbers in a secondary response following reinoculation of the MADB106 tumor cells into cured rats. The in vivo relevance and possible derivation of these various cytotoxic lymphocyte populations in the syngeneic tumor-bearing hosts are discussed.
Asunto(s)
Productos Biológicos/farmacología , Neoplasias Experimentales/inmunología , Picibanil/farmacología , Linfocitos T Citotóxicos/inmunología , Animales , Adhesión Celular , Supervivencia Celular/efectos de los fármacos , Células Asesinas Naturales/inmunología , Neoplasias Experimentales/patología , Fenotipo , Ratas , Ratas Endogámicas F344 , Linfocitos T Citotóxicos/efectos de los fármacosRESUMEN
The effector mechanisms evoked in tumor-bearing rats following a single injection of the avirulent Su strain of type 3, group A Streptococcus pyogenes (OK-432) were sequentially examined. F344 rats challenged ip with a lethal dose of the syngeneic MADB106 mammary carcinoma could survive more than 100 days when given 50 mg OK-432/kg ip 1 day after tumor challenge. When the responsible effector mechanisms were examined in this therapeutic model, two distinct effector phases distinguished by the number of tumor cells were evident. Phase I, 1-6 days following OK-432 injection, resulted in a sharp decrease in tumor cell numbers and was related to the direct antitumor cytotoxicity of OK-432 and was coincident with an increase in the number of polymorphonuclear neutrophils. However, by day 6 a sharp increase in tumor cell numbers was again observed. Subsequently, a second phase of tumor cell destruction was observed 7-20 days following OK-432 injection and was reflected in a strong lymphocyte-mediated cytotoxicity response as well as the production of complement-dependent cytotoxic antibody against the MADB106 tumor cells. Further, the adoptive transfer of either peritoneal exudate cells or sera from the phase II animals revealed that both factors may be responsible for the antitumor activity observed in this therapeutic model. In conclusion, this study has demonstrated that the antitumor effects seen with OK-432 are due to a combination of sequential effector mechanisms leading to the eventual rejection of established tumor.