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1.
Biochem Biophys Res Commun ; 628: 91-97, 2022 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-36084556

RESUMEN

The adaptor protein GAREM has two subtypes. Each is involved in Erk activation signaling downstream of the cell growth factor receptor in cultured cells. Regarding their role in individual animals, we have previously reported that mice deficient in GAREM2, which is highly expressed in the brain, exhibit emotional changes. In this paper, we report an amino acid substitution mutation (K291R) in GAREM1, in a patient with idiopathic short stature, which indicates that the mutant exhibits dominant-negative properties. The GAREM K291R mutant did not promote Erk activation in EGF-stimulated cultured cells. Similar features were also observed in cells in which GAREM1 expression was suppressed by genome editing; along with Erk, phosphorylation of S6 kinase and 4EBP1, whose activation is necessary for cell proliferation and biological growth, were inhibited Furthermore, we generated mice deficient in GAREM1 and showed that the mutant mice are lighter in weight. Overall, the results of this paper suggest that GAREM1 is required for normal growth and for maintaing average body size in humans and mice.


Asunto(s)
Peso Corporal , Enanismo , Proteína Adaptadora GRB2 , Proteínas Adaptadoras Transductoras de Señales , Animales , Peso Corporal/genética , Proteínas de Ciclo Celular , Línea Celular , Enanismo/genética , Factor de Crecimiento Epidérmico/metabolismo , Proteína Adaptadora GRB2/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Fosforilación , Proteínas Quinasas S6 Ribosómicas/metabolismo
2.
Bioelectromagnetics ; 43(4): 218-224, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35476263

RESUMEN

Radiofrequency radiation (RFR) was classified as a "possible" human carcinogen in 2011, which caused great public concern. A carcinogenicity study by the National Toxicology Program (NTP) found Code Division Multiple Access-and Global System for Mobile Communications-modulated mobile phone RFR to be carcinogenic to the brain and heart of male rats. As part of an investigation of mobile phone carcinogenesis, and to verify the NTP study results, a 5-year collaborative animal project was started in Korea and Japan in 2019. An international animal study of this type has two prerequisites: use of the same study protocol and the same RF-exposure system. This article discusses our experience in the design of this global study on radiofrequency electromagnetic fields (RF-EMFs).© 2022 The Authors. Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society.


Asunto(s)
Teléfono Celular , Ondas de Radio , Animales , Encéfalo , Carcinogénesis , Campos Electromagnéticos , Masculino , Ratas
3.
Pathol Int ; 70(6): 340-347, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32083387

RESUMEN

This present study was conducted in an attempt to examine proliferative lesion-promoting effect in the lung by compensatory lung growth after left pulmonary ligation. To examine a strong proliferative lesion-promoting effect in the lung, the effects of left pulmonary ligation on lung proliferative lesions induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were examined for 12 weeks. The number of proliferative lesions induced by NNK in the right lung after left pulmonary ligation increased significantly after 12 weeks, indicated by an increase in the weight of the right lung. In addition, several messenger RNA (mRNA) markers, including insulin growth factor 1, were highly expressed in the right lung on the seventh day after left ligation. These experiments demonstrated the clear proliferative lesion-promoting effects of pulmonary ligation on the induction of the expression of mRNAs related to the cell cycle, cell division and mitosis. However, the proliferative lesion-promoting effects were not strong enough to allow a shortened experimental period for the establishment of the lung bioassay model. The results also indicated the necessity to pay attention to the possibility of a recurrence of lung cancer in the residual lung after resection in humans.


Asunto(s)
Carcinógenos/toxicidad , Modelos Animales de Enfermedad , Neoplasias Pulmonares/inducido químicamente , Nitrosaminas/toxicidad , Animales , Femenino , Ligadura , Pulmón/cirugía , Ratones
4.
J Toxicol Pathol ; 31(4): 231-240, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30393427

RESUMEN

Surfactant proteins (SPs) are essential for the proper structure and respiratory function of the lungs. There are four subtypes of SPs: SP-A, SP-B, SP-C, and SP-D. The expectorant drug ambroxol hydrochloride is clinically used to stimulate pulmonary surfactant and airway serous secretion. In addition, previous studies showed that ambroxol regulated SP production and attenuated pulmonary inflammation, with ambroxol hydrochloride being found to suppress quartz-induced lung inflammation via stimulation of pulmonary surfactant and airway serous secretion. In this study, we investigated the expression of SP-A, SP-B, SP-C, and SP-D in neoplastic and inflammatory lung lesions in rodents, as well as their possible application as potential markers for diagnostic purposes. SP-B and SP-C showed strong expression in lung hyperplasia and adenoma, whereas SP-A and SP-D were expressed in the mucus or exudates of inflammatory alveoli. Rodent tumorigenic hyperplasic tissues induced by various carcinogens were positive for napsin A, an aspartic proteinase involved in the maturation of SP-B; this indicated a focal increase in type II pneumocytes in the lungs. Therefore, high expression of napsin A in the alveolar walls may serve as a useful marker for prediction of the tumorigenic potential of lung hyperplasia in rodents.

5.
J Toxicol Pathol ; 31(4): 255-265, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30393429

RESUMEN

Ambroxol hydrochloride (AH) is an expectorant drug used to stimulate pulmonary surfactant and serous airway secretion. Surfactant proteins (SPs) are essential for maintaining respiratory structure and function, although SP expression has also been reported in lung inflammatory and proliferative lesions. To determine whether AH exerts modulatory effects on these lung lesions, we examined its effects on pleural thickening induced by intrathoracic administration of dipotassium titanate (TISMO) in A/JJmsSlc (A/J) mice. We also analyzed the modulatory effects of AH on neoplastic lung lesions induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice and by N-nitrosobis (2-hydroxypropyl) amine (DHPN) in F344/DuCrlCrj (F344) rats. A/J mice treated with TISMO showed decreased body weight, increased white blood cell (WBC) counts, and pleural thickening caused by pleuritis and poor general condition. However, A/J mice treated with TISMO + 120 ppm showed significant recovery of body weight and WBC counts to the same levels as those of A/J mice not treated with TISMO, although no significant differences were observed in histopathological changes including the immunohistopathological expression of IL-1ß in the lung and maximum pleural thickness regardless of AH treatment. In the NNK and DHPN experiments, no significant differences in body weight, hematology, plasma biochemistry, and histopathological changes were associated with AH concentration. These results suggest that AH potentially exerts anti-inflammatory effects but does not have a direct suppressive effect on lung tumorigenesis in rodents.

6.
J Toxicol Pathol ; 31(3): 163-168, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30093785

RESUMEN

It is known that γH2AX, which is formed when there is a double-strand break in DNA, can act as a sensitive marker of genomic instability. In this experiment, the time-course manner of the expression of γH2AX in the lung was examined in the early phase after treatment with a lung carcinogen, N-bis (2-hydroxypropyl) nitrosamine (DHPN). The expression of γH2AX is expected to be one of the useful markers for lung carcinogenesis in early stages. Rats were separated into 10 groups of 5 rats. The DHPN groups were administered 0.1% DHPN in drinking tap water for two weeks, while the control group received drinking tap water. At 0, 1, 3, 7, and 14 days after finishing DHPN treatment, one group each from the DHPN and control groups was sacrificed. The removed lung tissues were examined for immunostaining of γH2AX and PCNA, and positive cells were counted. The γH2AX levels of the DHPN-treated groups were found to be increased significantly at 0, 1, 3, and 7 days (4.4 ± 1.4, 5.1 ± 2.7, 3.3 ± 1.0, and 4.1 ± 1.3%, respectively), and they dropped significantly on day 14 (1.1 ± 0.4%). The experiment showed that the γH2AX-positive score could be effectively measured for up to 7 days after exposure, as a significance difference was observed between the treated group and the control group. It can be deduced that γH2AX is an effective marker for DHPN-induced double-strand breaks in pulmonary epithelial cells.

7.
Respir Res ; 18(1): 118, 2017 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-28619066

RESUMEN

BACKGROUND: The influence of lung fibroblasts on lung cancer progression is not fully understood. METHODS: Lung fibroblasts (HFL1, MRC5, and IMR90 cells) and non-small cell lung cancer (NSCLC)-derived cell lines (A549, EBC1, and HI1017) were cultured under serum-free conditions, and the resulting culture media were designated "cell-conditioned media". Cell survival (viability) was assessed by WST-1 assay. Concentrations of hepatocyte growth factor (HGF) were measured by ELISA. The BALB/c-nu mouse strain was used for the xenograft model. RESULTS: Lung fibroblast-conditioned media enhanced the survival of the three NSCLC cell lines tested. HGF was produced to a greater extent by lung fibroblasts than NSCLC cells. Exogenous HGF enhanced the survival of NSCLC cells. Either an anti-HGF neutralizing antibody or the Met inhibitor PHA-665752 inhibited the fibroblast-conditioned media-enhanced survival of NSCLC cells. The co-inoculation of mice with NSCLC cells and fibroblasts enhanced tumorigenicity and tumor progression in a mouse xenograft model. PHA-665752 significantly inhibited tumor progression that occurred after the co-inoculation of NSCLC cells and fibroblasts. In addition, HGF production by fibroblasts was stimulated by NSCLC cells. CONCLUSIONS: The current study provides evidence for an interaction between fibroblasts and NSCLC cells via the HGF/Met signaling pathway, which affects NSCLC cell survival and tumor progression. These findings may contribute to the development of anti-cancer-associated fibroblast therapeutic strategies. TRIAL REGISTRATION: No trial registration is required because this study is not a clinical trial. This study does not include any participants or patients.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Fibroblastos/metabolismo , Factor de Crecimiento de Hepatocito/biosíntesis , Neoplasias Pulmonares/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Supervivencia Celular/fisiología , Fibroblastos/patología , Humanos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
8.
J Toxicol Pathol ; 30(2): 153-159, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28458453

RESUMEN

Surfactant proteins (SPs) are essential to respiratory structure and function. The expectorant drug ambroxol hydrochloride is clinically prescribed to stimulate pulmonary surfactant and airway serous secretion. Therefore, ambroxol hydrochloride may affect SP production and pulmonary inflammation. Lung toxicity of fine particles of various materials has been examined previously in our in vivo bioassay using the intratracheal (i.t.) instillation approach. In the present study, we evaluated modulatory effects of ambroxol hydrochloride on quartz-induced lung inflammation in F344 rats. Male 6-week-old F344 rats were exposed by i.t. instillation to 2 mg of quartz particles suspended in 0.2 mL of saline. Ambroxol hydrochloride was administered at 0, 12, and 120 ppm in rat basal diet for 28 days, and then formalin-fixed paraffin-embedded lung, liver, and kidney samples were prepared. No changes in general condition, body and organ weights, or food consumption upon exposure to quartz were noted. The mean ambroxol intake in rats of the 12 ppm group was comparable to the human conventional dose. Histopathology of lung lesions was evaluated, and the degree of inflammation was scored. At 120 ppm, ambroxol hydrochloride significantly decreased individual lung inflammation scores for pulmonary edema and lymph follicle proliferation around the bronchiole, as well as the total inflammation score, in quartz-treated rats. Expression of SP-C in the type II alveolar cells and macrophages was greater in inflammatory lesions than in non-inflamed areas. Ambroxol treatment did not affect expression of SP-B and SP-C. In conclusion, we demonstrated that ambroxol hydrochloride relieves quartz-induced lung inflammation.

9.
Cancer Sci ; 107(7): 1047-54, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27088262

RESUMEN

Fiber-shaped particles of potassium octatitanate (tradename TISMO; chemical formula K2 O·6TiO2 ), which are morphologically similar to asbestos particles, were shown to induce severe proliferative reactions in the pleural mesothelium in a previous experiment carried out over 21 weeks. The present study aims to determine whether these fibers induce malignant mesotheliomas in rodents, and to examine chronic toxicity induced. Additionally, we investigated the specific differences observable between the biological responses to the direct infusion of the fibers alone into the pleural cavity and those induced by the co-administration of the fibers with a known carcinogen. To detect the induction of malignant pleural mesotheliomas, two experiments were undertaken. In Experiment 1, four strains of mice, A/J, C3H, ICR, and C57BL, were examined for 52 weeks after experimental treatment with TISMO. In Experiment 2, the F344 rats were treated with TISMO alone, the lung carcinogen N-bis (2-hydroxypropyl) nitrosamine (DHPN) alone, both TISMO and DHPN, or left untreated and were then examined for 52 weeks. In this experiment, malignant lesion induction was expected in the co-administration group. TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura in mice and rats. The histopathological detection of TISMO fibers in the liver and kidneys of mice and rats indicated migration of the fibers out of the pleural cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. Among the rats, there were no observed malignant alterations in the mesothelium induced by DHPN-TISMO co-administration.


Asunto(s)
Mesotelioma/inducido químicamente , Cavidad Pleural/efectos de los fármacos , Titanio/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Femenino , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Mesotelioma/patología , Ratones , Ratones Endogámicos , Nitrosaminas/toxicidad , Tamaño de los Órganos/efectos de los fármacos , Tamaño de la Partícula , Cavidad Pleural/patología , Ratas , Ratas Endogámicas F344 , Especificidad de la Especie , Titanio/química
11.
Int J Toxicol ; 34(4): 325-35, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26023052

RESUMEN

The present study was conducted to examine the chronic effects of potassium octatitanate fibers (trade name TISMO; chemical formula K2O·6TiO2) on the mouse lung and thoracic cavity. This method of infusion was employed to examine the direct effects of the fibers to the pleura. In the present study, 52- and 65-week experiments were employed to examine the long-term chronic effects after infusion of fiber-shaped TISMO into the thoracic cavities of A/J mice. Following this infusion, TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura. The additional histopathological detection of TISMO fibers in the liver, spleen, kidneys, ovary, heart, bone marrow, and brain of TISMO-infused mice indicated migration of the fibers out from the thoracic cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. This study demonstrated that intrathoracic infusion of TISMO fiber did not cause malignant mesothelioma but did cause severe chronic inflammation and proliferation of pleural mesothelial cells.


Asunto(s)
Células Epiteliales/efectos de los fármacos , Pleura/efectos de los fármacos , Cavidad Torácica/efectos de los fármacos , Titanio/toxicidad , Animales , Células Epiteliales/metabolismo , Femenino , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/diagnóstico , Mesotelioma/inducido químicamente , Mesotelioma/diagnóstico , Mesotelioma Maligno , Ratones , Ratones Endogámicos A , Tamaño de los Órganos/efectos de los fármacos , Bazo/efectos de los fármacos , Bazo/metabolismo , Cavidad Torácica/metabolismo , Pruebas de Toxicidad Crónica
12.
Int J Mol Sci ; 15(5): 9160-72, 2014 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-24857924

RESUMEN

Activation of peroxisome proliferator-activated receptor (PPAR) α disrupts growth-related activities in a variety of human cancers. This study was designed to determine whether fenofibrate, a PPARα agonist, can suppress 4-nitroquinoline 1-oxide (4-NQO)-induced proliferative lesions in the lung of obese hyperlipidemic mice. Male Tsumura Suzuki Obese Diabetic mice were subcutaneously injected with 4-NQO to induce lung proliferative lesions, including adenocarcinomas. They were then fed a diet containing 0.01% or 0.05% fenofibrate for 29 weeks, starting 1 week after 4-NQO administration. At week 30, the incidence and multiplicity (number of lesions/mouse) of pulmonary proliferative lesions were lower in mice treated with 4-NQO and both doses of fenofibrate compared with those in mice treated with 4-NQO alone. The incidence and multiplicity of lesions were significantly lower in mice treated with 4-NQO and 0.05% fenofibrate compared with those in mice treated with 4-NQO alone (p<0.05). Both doses of fenofibrate significantly reduced the proliferative activity of the lesions in 4-NQO-treated mice (p<0.05). Fenofibrate also significantly reduced the serum insulin and insulin-like growth factor (IGF)-1 levels, and decreased the immunohistochemical expression of IGF-1 receptor (IGF-1R), phosphorylated Akt, and phosphorylated Erk1/2 in lung adenocarcinomas. Our results indicate that fenofibrate can prevent the development of 4-NQO-induced proliferative lesions in the lung by modulating the insulin-IGF axis.


Asunto(s)
Fenofibrato/farmacología , Hipolipemiantes/farmacología , PPAR alfa/agonistas , Alveolos Pulmonares/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Fenofibrato/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Hipolipemiantes/uso terapéutico , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Obesos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , PPAR alfa/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/patología , Receptor IGF Tipo 1/metabolismo
13.
J Toxicol Pathol ; 27(3-4): 175-82, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25378802

RESUMEN

Surfactant proteins (SPs), originally known as human lung surfactants, are essential to respiratory structure and function. There are 4 subtypes, SP-A, SP-B, SP-C and SP-D, with SP-A and SP-D having immunological functions, and SP-B and SP-C having physicochemical properties that reduce the surface tension at biological interfaces. In this experiment, the expressions of SP-A, SP-B, SP-C and SP-D in lung neoplastic lesions induced by N-bis (2-hydroxypropyl) nitrosamine (DHPN) and inflammatory lesions due to quartz instillation were examined and compared immunohistochemically. Formalin fixed paraffin embedded (FFPE) lung samples featuring inflammation were obtained with a rat quartz instillation model, and neoplastic lesions, hyperplasias and adenomas, were obtained with the rat DHPN-induced lung carcinogenesis model. In the rat quartz instillation model, male 10-week old F344 rats were exposed by intratracheal instillation (IT) to quartz at a dose of 2 mg/rat suspended in saline (0.2 ml) on day 0, and sacrificed on day 28. Lung tumorigenesis in F344 male rats was initiated by DHPN in drinking water for 2 weeks, and the animals were then sacrificed in week 30. Lung proliferative lesions, hyperplasias and adenomas, were observed with DHPN, and inflammation was observed with quartz. The expressions of SP-A, SP-B, SP-C and SP-D were examined immunohistochemically. SP-B and SP-C showed strong expression in lung hyperplasias and adenomas, while SP-A and SP-D were observed in mucus or exudates in inflammatory alveoli. These results suggest the possibility that SP-B and SP-C are related to lung tumorigenesis.

14.
Gan To Kagaku Ryoho ; 41(8): 1009-12, 2014 Aug.
Artículo en Japonés | MEDLINE | ID: mdl-25132035

RESUMEN

CASE: An 82-year-old man died because of squamous cell carcinoma of the right lung with metastasis to the left femoral bone. At the age of 75 years, he was admitted to our hospital because of hematemesis. Widespread type 3 gastric cancer was detected in the lesser curvature. Computed tomography(CT)showed multiple liver metastases. Preoperative chemotherapy with TS-1/cisplatin(CDDP)was administered. TS-1 was orally administered at 80mg/body/day and CDDP was administered by intravenous infusion at 20mg/body/day every week for 3 weeks and this was followed by a drug-free 2-week period as the first course. After the fourth course, gastrectomy was performed for the primary lesion and radiofrequency ablation(RFA)was performed for the liver metastases. The patient survived for more than 7 years with a complete response (CR)and died thereafter because of squamous cell carcinoma of the lung.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias de Células Escamosas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Anciano de 80 o más Años , Autopsia , Cisplatino/administración & dosificación , Combinación de Medicamentos , Humanos , Neoplasias Hepáticas/secundario , Masculino , Neoplasias de Células Escamosas/cirugía , Ácido Oxónico/administración & dosificación , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Tegafur/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento
15.
J Natl Cancer Inst ; 115(2): 208-218, 2023 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-36567450

RESUMEN

BACKGROUND: Telomere dysfunction has been reported to be directly involved in carcinogenesis owing to chromosomal instability and immortalization; however, the clinicopathological significance of telomeres remains controversial. We have shown that telomere shortening occurs in normal-appearing duct cells at initiation and then continues during the progression of pancreatic cancer. In this study, we determined the clinicopathological and prognostic value of telomere length (TL) in cancer progression. METHODS: TL in both cancer cells and cancer-associated fibroblasts (CAFs) was analyzed by high-throughput quantitative fluorescence in situ hybridization using a previously reported cohort comprising 1434 cases of adenocarcinoma (ADC), squamous cell carcinoma (SCC), adenosquamous carcinoma, hepatocellular carcinoma, and renal cell carcinoma (RCC), which are known cancers with a statistically significantly low incidence of alternative lengthening of telomeres. Cases were divided into 2 groups as follows: longer and shorter telomeres, according to the median TL of cancer cells and CAFs. The statistical significance of TL in cancer cells and CAFs on clinicopathological characteristics and prognosis was analyzed. RESULTS: There was a close association between TL in cancer cells and CAFs. Longer telomeres in cancer cells and CAFs were associated with aggressive features such as advanced stage, high mitosis score and nuclear score, poorly differentiated cancer, and desmoplastic stroma in ADC. Furthermore, a longer TL was an independent prognostic factor for ADC, SCC, and RCC. CONCLUSIONS: Longer telomeres are associated with worse prognosis in ADC, SCC, and RCC. Thus, TL is a novel biomarker for the diagnosis of aggressive cancers with poor prognoses.


Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma de Células Renales , Carcinoma de Células Escamosas , Neoplasias Renales , Neoplasias Hepáticas , Humanos , Fibroblastos Asociados al Cáncer/patología , Hibridación Fluorescente in Situ , Pronóstico , Acortamiento del Telómero , Telómero , Carcinoma de Células Escamosas/patología , Neoplasias Hepáticas/patología , Homeostasis del Telómero
16.
J Toxicol Pathol ; 25(4): 257-63, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23345928

RESUMEN

In vivo, nicotine in cigarette smoke induces various effects not only on the respiratory system but also the central and peripheral nerve systems, circulatory organs and digestive organs, and there is a possibility of promotion of lung tumorigenesis. The present experiment was conducted to examine histopathological changes caused by nicotine in the lung with repeated intratracheal instillation (i.t.). Six-week-old male F344 rats were administered nicotine by i.t. at doses of 0.05, 0.1 and 0.2 mg nicotine/rat every 3 weeks beginning at week 4, for up to a total of 9 times and were then sacrificed at week 30. The total number of administrations, total dose of nicotine and effective number of rats were 9 times, 0.45 mg and 5 rats and 4 times, 0.20 mg and 5 rats for the 0.05 mg nicotine/rat group; 3 times, 0.30 mg and 5 rats and 4 times, 0.40 mg and 3 rats for the 0.1 mg group; and 3 times, 0.60 mg and 3 rats for the 0.2 mg group, respectively. As a control group, 5 rats were administered 0.2 ml saline/rat 9 times. Some rats administered 0.1 and 0.2 mg nicotine suffered convulsions just after administration. Histopathologically, though proliferative changes were not observed, neutrophil infiltration, edema and fibrosis in the lung were induced by nicotine. In conclusion, repeated treatment of nicotine promoted neurologic symptoms in the acute phase, and strong inflammation in the lungs in the chronic phase, even at a low dose. Toxicity of nicotine is suggested to depend not on total dose of nicotine in the experiment but rather on repeated injury with consecutive administration.

17.
Cancers (Basel) ; 13(12)2021 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-34200786

RESUMEN

Lung cancer remains the leading cause of cancer-related deaths, with an estimated 1.76 million deaths reported in 2018. Numerous studies have focused on the prevention and treatment of lung cancer using rodent models. Various chemicals, including tobacco-derived agents induce lung cancer and pre-cancerous lesions in rodents. In recent years, transgenic engineered rodents, in particular, those generated with a focus on the well-known gene mutations in human lung cancer (KRAS, EGFR, and p53 mutations) have been widely studied. Animal studies have revealed that chronic inflammation significantly enhances lung carcinogenesis, and inhibition of inflammation suppresses cancer progression. Moreover, the reduction in tumor size by suppression of inflammation in animal experiments suggests that chronic inflammation influences the promotion of tumorigenesis. Here, we review rodent lung tumor models induced by various chemical carcinogens, including tobacco-related carcinogens, and transgenics, and discuss the roles of chronic inflammation in lung carcinogenesis.

18.
Ann Surg Oncol ; 17(12): 3386-93, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20589433

RESUMEN

BACKGROUND: As is known for many types of human cancers, the hepatocellular carcinoma (HCC) associated with chronic liver disease shows an obvious multistage process of tumor progression. Despite the demonstrated importance of cell-cycle regulators in tumor biology, there have only been a few studies of their role in multistep hepatocarcinogenesis. Recently, we reported that a high level of p27(Kip1) expression is evident from the very early stages of hepatocarcinogenesis. METHODS: In the present study, expression of p27(Kip1) and Jun activation domain binding protein-1 (Jab1), which is a key molecule involved in posttranslational regulation of p27(Kip1), was evaluated in surgically resected specimens of 8 dysplastic nodules (DNs), 16 early HCCs, and 126 classical HCCs. RESULTS: Immunohistochemistry revealed no Jab1 expression in the majority of hepatocytes in noncancerous normal liver tissue and cases of chronic hepatitis or cirrhosis. In contrast, Jab1 was overexpressed in 50% (4/8) and 50% (8/16) of DNs and early HCCs, respectively, and the labeling index was increased in line with the degree of loss of differentiation in classical HCCs. Real-time quantitative reverse transcription polymerase chain reactions revealed the Jab1 mRNA levels in all tested early and well-differentiated HCCs to be increased compared with matched nontumorous liver specimens. The Spearman coefficient pointed to a high correlation between p27(Kip1) and Jab1 mRNA expression levels (P = 0.0014). CONCLUSIONS: Jab1 expression, as well as p27(Kip1) upregulation, is evident from the very early stages of hepatocarcinogenesis, suggesting that Jab1 could be a diagnostic marker and a treatment target for precancerous lesions and early HCCs.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Hígado/metabolismo , Péptido Hidrolasas/metabolismo , Adulto , Anciano , Complejo del Señalosoma COP9 , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Estudios de Casos y Controles , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Péptidos y Proteínas de Señalización Intracelular/genética , Hígado/patología , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Péptido Hidrolasas/genética , Lesiones Precancerosas/genética , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Pronóstico , ARN Mensajero/genética , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas Asociadas a Fase-S/genética , Proteínas Quinasas Asociadas a Fase-S/metabolismo
19.
Toxicol Pathol ; 38(1): 182-7, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20080933

RESUMEN

The Ito Liver Model and the Ito Multi-organ Model are used in conjunction and constitute an efficient and rapid bioassay for the identification of both genotoxic and nongenotoxic carcinogenic chemicals. The Ito Liver Model is an 8-week bioassay system that uses the number and size of foci of hepatocytes positive for glutathione S-transferase placental form (GST-P) as the end-point marker. One hundred fifty-nine compounds were tested using the Ito Liver Model: 61 of 66 hepatocarcinogens tested positive, and 10 of 43 nonliver carcinogens were also positive. The false-positive detection of noncarcinogens was low; a single false-positive result was obtained from the 50 noncarcinogens tested. Since more than half of all known carcinogens are hepatocarcinogens in rodents, the initial 8-week bioassay is able to detect most carcinogens. The Ito Multi-organ Model is a 28-week bioassay system for the detection of carcinogens that were not identified by the Ito Liver Model. Results are evaluated by preneoplastic and neoplastic lesions in major organs. Forty-four compounds were tested using the Ito Multi-organ Model: 17 out of 17 liver carcinogens were positive, and 19 out of 22 (86%) nonliver carcinogens were positive. None of the five noncarcinogens tested positive.


Asunto(s)
Pruebas de Carcinogenicidad/métodos , Modelos Animales de Enfermedad , Neoplasias Hepáticas Experimentales/inducido químicamente , Animales , Gutatión-S-Transferasa pi/análisis , Masculino , Ratas , Ratas Endogámicas F344
20.
Biol Pharm Bull ; 33(7): 1206-11, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20606314

RESUMEN

Corticosteroids are routinely used in patients with pulmonary fibrosis, yet they have several adverse effects. To improve this situation, we used an animal model of pulmonary injury and early fibrosis and investigated whether the combination of an intrapulmonary inhalation device with antedrug budesonide (BUD) administered to the lung had greater efficacy and fewer systemic adverse effects compared to long-acting dexamethasone (DEX). BUD or DEX was administrated either intrapulmonary or intravenously to bleomycin-treated rats. Anti-inflammatory and antifibrotic effects were evaluated according to inflammatory cell count, total protein concentration and soluble collagen concentration in bronchoalveolar lavage fluid. The systemic immunosuppressive effects were also assessed by measuring body, spleen and thymus weight. BUD and DEX were compared with respect to their pharmacokinetic profiles in plasma and lung. Intrapulmonary treatment of BUD attenuates various inflammatory and early fibrotic indices with minimal systemic adverse effects compared with DEX. The area under the curve (AUC) of BUD by intrapulmonary spray was 6.6-fold higher than the AUC of DEX in the lung. This study suggests that antedrug BUD by intrapulmonary treatment has local anti-inflammatory and antifibrotic effects with minimal systemic adverse effects.


Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Bleomicina/toxicidad , Budesonida/uso terapéutico , Pulmón , Animales , Área Bajo la Curva , Líquido del Lavado Bronquioalveolar , Budesonida/administración & dosificación , Budesonida/efectos adversos , Budesonida/farmacocinética , Cromatografía Líquida de Alta Presión , Dexametasona/farmacocinética , Dexametasona/uso terapéutico , Semivida , Pulmón/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Ratas
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