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1.
J Ethnopharmacol ; 271: 113843, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33493588

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The flower buds of Sophora japonica L. are a major traditional medicine in China, Japan, and Korea and are used to stop bleeding and 'cool the blood'. Accordingly, they are used to treat bleeding haemorrhoids, hypertension, and pyoderma. In addition, it was recently found that the flower buds of S. japonica (SJ) have cosmetic whitening properties. MATERIALS AND METHODS: Compounds in SJ and their targets and related diseases were investigated using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform. Target gene information was obtained from the UniProt database. Network construction was carried out using Cytoscape 3.72. Contact dermatitis (CD)-related gene searching was performed using the Cytoscape string App. Docking analysis was conducted using AutoDock Vina. Six-week-old Balb/c male mice with DNFB (1-fluoro-2,4-dinitrofluorobenzene)-induced CD were treated with a methanol extract of the flower buds of S. japonica (MESJ), and its effects on skin colour, lesions, and immune cell infiltration, and on histopathological abnormalities such as epidermal hyperplasia were investigated. RESULTS: Eleven compounds targeted 13 CD-related genes, that is, serum albumin (ALB), prostaglandin G/H synthase (COX) 2, C-X-C motif chemokine (CXCL) 2, CXCL10, ICAM1, IFN-γ, IL-10, IL-1α, IL-1ß, IL-2, IL-6, E-selectin, and TNF. In the murine DNFB model, MESJ significantly suppressed scaling, erythema, and skin thickening as compared with DNFB controls and epithelial hyperplasia and immune cell infiltrations induced by repeated DNFB application. CONCLUSIONS: Our animal study showed that the mode of action of MESJ was closely related to the prevention of epithelial hyperplasia and immune cell infiltration. The results obtained demonstrated that the flower buds of S. japonica offer a potential means of treating CD, and suggest that the therapeutic mechanism of CD is explained by relations between 11 major components of SJ, including kaempferol and quercetin, and 13 CD-related genes.


Assuntos
Dermatite de Contato/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Sophora/química , Animais , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Bases de Dados Factuais , Dermatite de Contato/etiologia , Dermatite de Contato/metabolismo , Dermatite de Contato/patologia , Dinitrofluorbenzeno/toxicidade , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Flores/química , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Hiperplasia/tratamento farmacológico , Hiperplasia/metabolismo , Hiperplasia/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Ceratose/induzido quimicamente , Ceratose/tratamento farmacológico , Ceratose/metabolismo , Ceratose/patologia , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular
2.
J Obstet Gynaecol Can ; 43(1): 85-87, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739356

RESUMO

BACKGROUND: Tamoxifen may cause proliferative effects in the endometrium. Patients on tamoxifen have an increased risk for endometriosis, but are not routinely screened for this. CASE: A 49-year-old postmenopausal patient presented for a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy several years after initiating tamoxifen for breast cancer. She had no clinical history to suggest endometriosis, but was found to have extensive pelvic endometriosis intraoperatively with polypoid hyperplasia found on the pathology of the uterine and the ovarian tissue. CONCLUSION: This is the first case reported of an asymptomatic patient on tamoxifen with a new diagnosis of endometriosis along with atypical hyperplasia in the ectopic tissue. The potential for pre-malignant/malignant transformation may alter the treatment course if identified following tamoxifen exposure.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Endometriose/induzido quimicamente , Hiperplasia/induzido quimicamente , Tamoxifeno/efeitos adversos , Neoplasias da Mama/induzido quimicamente , Endometriose/diagnóstico por imagem , Endometriose/cirurgia , Feminino , Humanos , Histerectomia , Laparoscopia , Pessoa de Meia-Idade , Tamoxifeno/uso terapêutico , Ultrassonografia
3.
Toxicology ; 448: 152633, 2021 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-33220336

RESUMO

Perfluoroheptanoic acid (PFHpA) is a short-chain alternative to long-chain perfluoroalkyl substances, which have been reported to possess reproductive toxicity. However, it is unclear whether PFHpA affects Leydig cell development during puberty. The 35-day-old Sprague Dawley male rats were exposed to PFHpA by gavage with 0 (corn oil), 10, 50, and 100 mg/kg/day for 21 days. PFHpA did not affect the body weight of rats, but it reduced testis weight, relative testis weight, and epididymis weight at 100 mg/kg. It significantly increased serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels at a dose of 100 mg/kg without affecting serum estradiol levels. PFHpA suppressed sperm production at a dose of 100 mg/kg. PFHpA induced Leydig cell hyperplasia (increased number of CYP11A1-positive Leydig cells) at a dose of 100 mg/kg, but down-regulated the expression of Cyp11a1, Hsd3b1, and Cyp17a1 in individual Leydig cell pe se and up-regulated the expression of Fshr in the Sertoli cell pe se. PFHpA did not affect the number of HSD11B1 (a biomarker for more mature Leydig cells) positive Leydig cells and SOX9 positive Sertoli cells. PFHpA increased BCL2, and the phosphorylation of AKT1, AKT2, ERK1/2, and JNK, but decreased BAX levels. However, it had no effect on SIRT1 and PGC-1α levels. In conclusion, PFHpA induces Leydig cell hyperplasia due to the increase in the secretion of luteinizing hormone through negative feedback after down-regulating the expression of steroidogenic enzymes and inhibiting testosterone production in individual Leydig cells. This proliferation may be mediated by increasing BCL2 and phosphorylation of AKT, ERK1/2, and JNK, and decreasing BAX level.


Assuntos
Fluorcarbonetos/toxicidade , Ácidos Heptanoicos/toxicidade , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/patologia , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Fatores Etários , Animais , Relação Dose-Resposta a Droga , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologia , Espermatogênese/fisiologia
4.
J Invest Dermatol ; 141(6): 1542-1552, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33333123

RESUMO

Psoriasis is a common inflammatory skin disease characterized by aberrant inflammation and epidermal hyperplasia. Molecular mechanisms that regulate psoriasis-like skin inflammation remain to be fully understood. Here, we show that the expression of Ovol1 (encoding ovo-like 1 transcription factor) is upregulated in psoriatic skin, and its deletion results in aggravated psoriasis-like skin symptoms following stimulation with imiquimod. Using bulk and single-cell RNA sequencing, we identify molecular changes in the epidermal, fibroblast, and immune cells of Ovol1-deficient skin that reflect an altered course of epidermal differentiation and enhanced inflammatory responses. Furthermore, we provide evidence for excessive full-length IL-1α signaling in the microenvironment of imiquimod-treated Ovol1-deficient skin that functionally contributes to immune cell infiltration and epidermal hyperplasia. Collectively, our study uncovers a protective role for OVOL1 in curtailing psoriasis-like inflammation and the associated skin pathology.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Epiderme/patologia , Psoríase/imunologia , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Epiderme/imunologia , Feminino , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/imunologia , Hiperplasia/patologia , Imiquimode/administração & dosagem , Imiquimode/imunologia , Interleucina-1alfa/metabolismo , Masculino , Camundongos Knockout , Psoríase/patologia , RNA-Seq , Transdução de Sinais/imunologia , Análise de Célula Única , Fatores de Transcrição/genética , Regulação para Cima/imunologia
5.
Food Chem Toxicol ; 146: 111786, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33038453

RESUMO

Food-grade titanium dioxide (E171) is a white additive widely used in solid and liquid food products. There is still debate about E171 toxic effects after oral consumption since this additive is deposited in colon, liver, spleen, testis and brain. The consumption of E171 commonly occurs with Western diets that are characterized by a high fat content. Thus, E171 could worsen adverse effects associated with a high fat diet (HFD) such as anxiety, colon diseases and testicular damage. We aimed to evaluate the effects of E171 on anxiety-like behavior, colon, liver and testis and to analyze if the administration of a HFD could exacerbate adverse effects. E171 was administered at ~5 mg/kgbw by drinking water for 16 weeks and mice were fed with a Regular Diet or a HFD. E171 promoted anxiety, induced adenomas in colon, goblet cells hypertrophy and hyperplasia and mucins overexpression, but had no toxic effects on testicular tissue or spermatozoa in regular diet fed-mice. Additionally, E171 promoted microvesicular steatosis in liver in HFD fed-mice and the only HFD administration decreased the spermatozoa concentration and motility. In conclusion, E171 administration increases the number of adenomas in colon, induces hypertrophy and hyperplasia in goblet cells and microvesicular steatosis.


Assuntos
Adenoma/induzido quimicamente , Ansiedade/induzido quimicamente , Neoplasias do Colo/induzido quimicamente , Dieta Hiperlipídica , Fígado Gorduroso/induzido quimicamente , Alimentos , Células Caliciformes/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Titânio/farmacologia , Animais , Células Caliciformes/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Titânio/administração & dosagem , Titânio/toxicidade
6.
Dermatol Clin ; 38(4): 523-533, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32892860

RESUMO

Adverse reactions to medications are common and may have a variety of clinical presentations in the oral cavity. Targeted therapies and new biologic agents have revolutionized the treatment of cancers, autoimmune diseases, and inflammatory and rheumatologic diseases but have also been associated with adverse events in the oral cavity. This review describes the most common clinical presentations of oral mucosal reactions to medications, namely hyposalivation, lichenoid reactions, ulcers, bullous disorders, pigmentation, fibrovascular hyperplasia, reactive keratosis, dysesthesia, osteonecrosis, infection, angioedema, and malignancy.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/complicações , Erupções Liquenoides/induzido quimicamente , Doenças da Boca/induzido quimicamente , Boca/patologia , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Humanos , Hiperpigmentação/induzido quimicamente , Hiperplasia/induzido quimicamente , Leucoplasia/induzido quimicamente , Neoplasias Bucais/induzido quimicamente , Úlceras Orais/induzido quimicamente , Parestesia/induzido quimicamente , Dermatopatias Vesiculobolhosas/induzido quimicamente , Xerostomia/induzido quimicamente
7.
Environ Health Prev Med ; 25(1): 56, 2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32979924

RESUMO

BACKGROUND: We previously demonstrated that continuous exposure to nitrous acid gas (HONO) for 4 weeks, at a concentration of 3.6 parts per million (ppm), induced pulmonary emphysema-like alterations in guinea pigs. In addition, we found that HONO affected asthma symptoms, based on the measurement of respiratory function in rats exposed to 5.8 ppm HONO. This study aimed to investigate the dose-response effects of HONO exposure on the histopathological alterations in the respiratory tract of guinea pigs to determine the lowest observed adverse effect level (LOAEL) of HONO. METHODS: We continuously exposed male Hartley guinea pigs (n = 5) to four different concentrations of HONO (0.0, 0.1, 0.4, and 1.7 ppm) for 4 weeks (24 h/day). We performed histopathological analysis by observing lung tissue samples. We examined samples from three guinea pigs in each group under a light microscope and measured the alveolar mean linear intercept (Lm) and the thickness of the bronchial smooth muscle layer. We further examined samples from two guinea pigs in each group under a scanning electron microscope (SEM) and a transmission electron microscope (TEM). RESULTS: We observed the following dose-dependent changes: pulmonary emphysema-like alterations in the centriacinar regions of alveolar ducts, significant increase in Lm in the 1.7 ppm HONO-exposure group, tendency for hyperplasia and pseudostratification of bronchial epithelial cells, and extension of the bronchial epithelial cells and smooth muscle cells in the alveolar duct regions. CONCLUSIONS: These histopathological findings suggest that the LOAEL of HONO is < 0.1 ppm.


Assuntos
Enfisema/induzido quimicamente , Hiperplasia/induzido quimicamente , Exposição por Inalação/efeitos adversos , Pulmão/patologia , Ácido Nitroso/toxicidade , Células Epiteliais Alveolares/efeitos dos fármacos , Animais , Brônquios/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Cobaias , Pulmão/efeitos dos fármacos , Pulmão/ultraestrutura , Masculino , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Miócitos de Músculo Liso/efeitos dos fármacos
8.
Toxicol Lett ; 334: 60-65, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961271

RESUMO

Iron oxides are Group 3 (not classifiable as to its carcinogenicity to humans) according to the International Agency for Research on Cancer (IARC). Occupational exposures during iron and steel founding and hematite underground mining as well as other iron predominant exposures such as welding are Group 1 (carcinogenic to humans). The objective of this study was to investigate the potential of iron as iron (III) oxide (Fe2O3) to initiate lung tumors in A/J mice, a lung tumor susceptible strain. Male A/J mice were exposed by oropharyngeal aspiration to suspensions of Fe2O3 (1 mg) or calcium chromate (CaCrO4; 100 µg; positive control) for 26 weeks (once per week). Shams were exposed to 50 µL phosphate buffered saline (PBS; vehicle). Mice were euthanized 70 weeks after the first exposure and lung nodules were enumerated. Both CaCrO4 and Fe2O3 significantly increased gross-observed lung tumor multiplicity in A/J mice (9.63 ± 0.55 and 3.35 ± 0.30, respectively) compared to sham (2.31 ± 0.19). Histopathological analysis showed that bronchiolo-alveolar adenomas (BAA) and carcinomas (BAC) were the primary lung tumor types in all groups and were increased in the exposed groups compared to sham. BAC were significantly increased (146 %) in the CaCrO4 group and neared significance in the Fe2O3 group (100 % increase; p = 0.085). BAA and other histopathological indices of toxicity followed the same pattern with exposed groups increased compared to sham control. In conclusion, evidence from this study, in combination with our previous studies, demonstrate that exposure to iron alone may be a potential risk factor for lung carcinogenesis.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Compostos de Cálcio/toxicidade , Carcinogênese/efeitos dos fármacos , Cromatos/toxicidade , Compostos Férricos/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Animais , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Soldagem
9.
Spec Care Dentist ; 40(5): 506-510, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32691895

RESUMO

OBJECTIVE: The objective of this study is to report the case of a patient who underwent hematopoietic stem cell transplantation for Hodgkin's lymphoma treatment and developed multiple tongue lesions during recovery. METHODS AND RESULTS: This is the case report of a patient who developed ulcerated lesions with areas of depapillation on the border and dorsum of the tongue. The ulcer evolved to a reddish fibrous hyperplastic nodule, similar to adjacent mucosa. The patient was using a series of medications, such as antifungals, antibiotics, antivirals, corticosteroids, and analgesics in addition to immunosuppression with cyclosporine. Considering the medical history of the patient, a biopsy was performed. Histopathological analyses describe hyperplasia, granulation tissue, vascular proliferation, and intense inflammatory infiltrate, and the diagnosis was of medication-related fibrovascular hyperplasia (MRFH). CONCLUSION: Patients in use of cyclosporine are at risk to develop oral lesions, such as MRFH. The correct diagnosis is important, so the adequate treatment and follow-up are instituted even considering the immunosuppression protocol.


Assuntos
Úlceras Orais , Doenças da Língua , Biópsia , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Úlceras Orais/patologia , Língua , Doenças da Língua/induzido quimicamente , Doenças da Língua/diagnóstico , Doenças da Língua/patologia
10.
Am J Pathol ; 190(9): 1843-1858, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32479820

RESUMO

The progression of Crohn disease to intestinal stricture formation is poorly controlled, and the pathogenesis is unclear, although increased smooth muscle mass is present. A previously described rat model of trinitrobenzenesulfonic acid-induced colitis is re-examined here. Although inflammation of the mid-descending colon typically resolved, a subset showed characteristic stricturing by day 16, with an inflammatory infiltrate in the neuromuscular layers including eosinophils, CD3-positive T cells, and CD68-positive macrophages. Closer study identified CD163-positive, CD206-positive, and arginase-positive cells, indicating a M2 macrophage phenotype. Stricturing involved ongoing proliferation of intestinal smooth muscle cells (ISMC) with expression of platelet-derived growth factor receptor beta and progressive loss of phenotypic markers, and stable expression of hypoxia inducible factor 1 subunit alpha. In parallel, collagen I and III showed a selective and progressive increase over time. A culture model of the stricture phenotype of ISMC showed stable hypoxia inducible factor 1 subunit alpha expression that promoted growth and improved both survival and growth in models of experimental ischemia. This phenotype was hyperproliferative to serum and platelet-derived growth factor BB, and unresponsive to transforming growth factor beta, a prominent cytokine of M2 macrophages, compared with control ISMC. We identified a hyperplastic phenotype of ISMC, uniquely adapted to an ischemic environment to drive smooth muscle layer expansion, which may reveal new targets for treating intestinal fibrosis.


Assuntos
Doença de Crohn/patologia , Intestinos/patologia , Macrófagos/metabolismo , Músculo Liso/patologia , Animais , Constrição Patológica/induzido quimicamente , Constrição Patológica/patologia , Hiperplasia/induzido quimicamente , Hiperplasia/metabolismo , Hiperplasia/patologia , Músculo Liso/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fenótipo , Ratos , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico/toxicidade
11.
FASEB J ; 34(8): 10657-10667, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32598088

RESUMO

Autophagy is a multistage catabolic process that mediates stress responses. However, the role of autophagy in epidermal proliferation, particularly under conditions when the epidermis becomes "activated" (hyperproliferative), remains unclear. We have shown that inhibition of Beclin 1, a key activator in the initiation phase of autophagy, attenuates imiquimod (IMQ)-induced epidermal hyperplasia in adult mice as well as naturally occurring hyperproliferation in neonatal mouse epidermis. Inhibition of Beclin 1 did not change the levels of several key inflammatory molecules or the numbers of immune cells in lesional skins. This indicates that autophagy does not affect inflammatory regulators in IMQ-treated mouse skin. Bioinformatic analysis combined with gene expression quantitative assays, revealed that a deficiency in autophagy decreases the expression of PDZ Binding Kinase (PBK), a regulator of the cell cycle, in mouse epidermis and human epidermal keratinocytes (HEKs). Interestingly, the decrease in PBK results in inhibition of proliferation in HEKs and such reduced proliferation can be rescued by activation of p38, the downstream signaling of PBK. Collectively, autophagy plays a positive role in epidermal proliferation, which is in part via regulating PBK expression.


Assuntos
Autofagia/fisiologia , Proliferação de Células/fisiologia , Epiderme/fisiologia , Animais , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Epiderme/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/fisiopatologia , Imiquimode/farmacologia , Inflamação/fisiopatologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/fisiologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Pele/efeitos dos fármacos , Pele/metabolismo
12.
J Oncol Pharm Pract ; 26(7): 1780-1784, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32192389

RESUMO

INTRODUCTION: Trastuzumab emtansine is an antibody-drug conjugate targeting the human epidermal growth factor receptor 2 use in recurrent metastatic breast cancer. Cases of trastuzumab emtansine-induced nodular regenerative hyperplasia are often reported as overt noncirrhotic portal hypertension with ascites and variceal bleeding. CASE REPORT: We report the case of a 61-year-old woman who present multiple stellate angiomas with gradual increased liver transaminases and reduced platelet count during a 27-months course on trastuzumab emtansine therapy for recurrent metastatic breast cancer. After the nodular regenerative hyperplasia was histologically confirmed, the trastuzumab emtansine was stopped. After two months, trastuzumab was restarted together with exemestane. During trastuzumab therapy, the patient had a normalization of liver transaminases, platelet count and a gradual improvement of her stellate angiomas. Trastuzumab was continued for 15 months without any reoccurrence of nodular regenerative hyperplasia. MANAGEMENT AND OUTCOME: Nodular regenerative hyperplasia should be suspected after one year of trastuzumab emtansine treatment in patients with signs of portal hypertension without cirrhosis. Definitive cessation of trastuzumab emtansine is required after a diagnosis of nodular regenerative hyperplasia and complete resolution of symptoms generally takes several months. DISCUSSION: Based on fundamental studies, nodular regenerative hyperplasia is probably caused by the emtansine (DM1) part of the trastuzumab emtansine. It is still unclear if trastuzumab therapy can be reintroduced after nodular regenerative hyperplasia induced by trastuzumab emtansine, depriving the patient of a HER2-targeted therapy. Only one case reported having given trastuzumab in this situation over one month. In our case, trastuzumab was reintroduced without any complications for a long extent following TDM1-associated nodular regenerative hyperplasia.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hiperplasia/induzido quimicamente , Ado-Trastuzumab Emtansina/administração & dosagem , Antineoplásicos/efeitos adversos , Varizes Esofágicas e Gástricas/induzido quimicamente , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Receptor ErbB-2/metabolismo
14.
Biochem Biophys Res Commun ; 521(2): 492-498, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31677783

RESUMO

Microcystin-leucine arginine (MC-LR) is a potent specific hepatotoxin produced by cyanobacteria in diverse water systems, and it has been documented to induce liver injury and hepatocarcinogenesis. However, its toxic effects on intrahepatic biliary epithelial cells have not been invested in detail. In this study, we aimed to investigate the effects of MC-LR exposure on the intrahepatic biliary epithelial cells in the liver. MC-LR was orally administered to mice at 1 µg/L, 7.5 µg/L, 15 µg/L, or 30 µg/L for 180 consecutive days for histopathological and immunoblot analysis. We observed that MC-LR can enter intrahepatic bile duct tissue and induce hyperplasia of mice. Human primary intrahepatic biliary epithelial cells (HiBECs) were cultured with various concentrations of MC-LR for 24 h, meanwhile the cell viability and proteins level were detected. Western blotting analysis revealed that MC-LR increased RSK phosphorylation via ERK signaling. RSK participated in cell proliferation and cell cycle progression. Taken together, after chronic exposure, MC-LR-treated mice exhibited abnormal bile duct hyperplasia and thickened bile duct morphology through activating the ERK-RSK signaling. These data support the potential toxic effects of MC-LR on bile duct tissue of the liver.


Assuntos
Ductos Biliares/patologia , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/patologia , Hiperplasia/induzido quimicamente , Microcistinas/toxicidade , Animais , Arginina , Células Cultivadas , Humanos , Leucina , Sistema de Sinalização das MAP Quinases , Camundongos , Fosforilação , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
J Zoo Wildl Med ; 51(3): 725-728, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33480551

RESUMO

Follicular thyroid hyperplasia was diagnosed in nine out of 32 (28%) marine tropical teleosts housed in a public aquarium over a 9.5-mo period. These proliferative lesions were considered to be the cause of death in five of these fish. Iodine concentration was undetectable in nonozonized water (<0.005 mg/L), suggesting that an environmental iodine deficiency was the cause of these hyperplastic thyroid lesions. The only significant modification in the husbandry was a change, 18 mo before the first case, of the commercial salt mix brand used to make artificial seawater. The iodine content in this replacement salt mix was five times lower than that of the salt mix used before. This case series suggests that the iodine concentration in this new salt mix was insufficient to maintain thyroid homeostasis in reef teleosts under the husbandry provided in this institution.


Assuntos
Peixes , Hiperplasia/veterinária , Iodo/deficiência , Glândula Tireoide/patologia , Animais , Animais de Zoológico , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Smegmamorpha
16.
Sci Adv ; 5(12): eaaw3413, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31844660

RESUMO

The human bronchial epithelium is composed of multiple distinct cell types that cooperate to defend against environmental insults. While studies have shown that smoking alters bronchial epithelial function and morphology, its precise effects on specific cell types and overall tissue composition are unclear. We used single-cell RNA sequencing to profile bronchial epithelial cells from six never and six current smokers. Unsupervised analyses led to the characterization of a set of toxin metabolism genes that localized to smoker ciliated cells, tissue remodeling associated with a loss of club cells and extensive goblet cell hyperplasia, and a previously unidentified peri-goblet epithelial subpopulation in smokers who expressed a marker of bronchial premalignant lesions. Our data demonstrate that smoke exposure drives a complex landscape of cellular alterations that may prime the human bronchial epithelium for disease.


Assuntos
Brônquios/efeitos dos fármacos , Lesões Pré-Cancerosas/genética , Fumar/efeitos adversos , Transcrição Genética/efeitos dos fármacos , Brônquios/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/patologia , Heterogeneidade Genética/efeitos dos fármacos , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/genética , Hiperplasia/patologia , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Análise de Sequência de RNA , Análise de Célula Única , Transcrição Genética/genética
18.
Toxicol Appl Pharmacol ; 384: 114770, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628919

RESUMO

The aim of the study was to evaluate the time course of the effects of urban air pollutants on the ocular surface, focusing on the morphological changes, the redox balance, and the inflammatory response of the cornea. 8-week-old mice were exposed to urban or filtered air (UA-group and FA-group, respectively) in exposure chambers for 1, 2, 4, and 12 weeks. After each time, the eyes were enucleated and the corneas were isolated for biochemical analysis. UA-group corneas exhibited a continuous increase in NADPH oxidase-4 levels throughout the exposure time, suggesting an increased production of reactive oxygen species (ROS). After 1 week, an early adaptive response to ROS was observed as an increase in antioxidant enzymes. After 4 weeks, the enzymatic antioxidants were decreased, meanwhile an increase of the glutathione was shown, as a later compensatory antioxidant response. However, redox imbalance took place, evidenced by the increased oxidized proteins, which persisted up to 12 weeks. At this time point, corneal epithelium hyperplasia was also observed. The inflammatory response was modulated by the increase in IL-10 levels after 1 week, which early regulates the release of TNF-α and IL-6. These results suggest that air pollution alters the ocular surface, supported by the observed cellular hyperplasia. The redox imbalance and the inflammatory response modulated by IL-10 play a key role in the response triggered by air pollutants on the cornea. Taking into account this time course study, the ocular surface should also be considered as a relevant target of urban air pollutants.


Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Epitélio Corneano/patologia , Animais , Brasil , Cidades , Epitélio Corneano/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Interleucina-10/metabolismo , Masculino , Camundongos , NADPH Oxidase 4/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo , Testes de Toxicidade Subaguda , Testes de Toxicidade Subcrônica
19.
Proc Natl Acad Sci U S A ; 116(43): 21727-21731, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31591243

RESUMO

Electronic-cigarettes (E-cigs) are marketed as a safe alternative to tobacco to deliver the stimulant nicotine, and their use is gaining in popularity, particularly among the younger population. We recently showed that mice exposed to short-term (12 wk) E-cig smoke (ECS) sustained extensive DNA damage in lungs, heart, and bladder mucosa and diminished DNA repair in lungs. Nicotine and its nitrosation product, nicotine-derived nitrosamine ketone, cause the same deleterious effects in human lung epithelial and bladder urothelial cells. These findings raise the possibility that ECS is a lung and bladder carcinogen in addition to nicotine. Given the fact that E-cig use has become popular in the past decade, epidemiological data on the relationship between ECS and human cancer may not be known for a decade to come. In this study, the carcinogenicity of ECS was tested in mice. We found that mice exposed to ECS for 54 wk developed lung adenocarcinomas (9 of 40 mice, 22.5%) and bladder urothelial hyperplasia (23 of 40 mice, 57.5%). These lesions were extremely rare in mice exposed to vehicle control or filtered air. Current observations that ECS induces lung adenocarcinomas and bladder urothelial hyperplasia, combined with our previous findings that ECS induces DNA damage in the lungs and bladder and inhibits DNA repair in lung tissues, implicate ECS as a lung and potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, whether ECS poses any threat to humans is not yet known and warrants careful investigation.


Assuntos
Adenocarcinoma de Pulmão/induzido quimicamente , Sistemas Eletrônicos de Liberação de Nicotina , Hiperplasia/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Fumaça/efeitos adversos , Fumar/efeitos adversos , Adenocarcinoma de Pulmão/patologia , Animais , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Hiperplasia/patologia , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Nicotina/administração & dosagem , Bexiga Urinária/patologia , Urotélio/patologia
20.
J Pharmacol Sci ; 141(1): 32-40, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31564550

RESUMO

The role of nitric oxide (NO) in the changes in enterochromaffin cells and ileal 5-hydroxytryptamine (5-HT) content induced by a single i.p. administration of methotrexate was investigated in rats. Methotrexate significantly increased inducible NO synthase (iNOS) mRNA and protein expressions in the intestinal tissue at 96 h. Methotrexate also significantly caused hyperplasia of the enterochromaffin cells at 96 h; this was associated with a significant increase in 5-HT content. The methotrexate-induced hyperplasia of enterochromaffin cells and increase in 5-HT content were, however, completely suppressed by daily treatment with dexamethasone, and with NG-nitro-l-arginine methyl ester (l-NAME); this was not observed when meloxicam was administered. Histological examination showed slight but not pronounced mucosal injury, at 96 h after methotrexate administration. The methotrexate-induced decrease in body weight did not fully recover to the control level up to 96 h; however, the methotrexate-induced decrease in food/water intake slightly returned to the control level up to 96 h. l-NAME had no significant effect on methotrexate-induced body weight loss and anorexia. To conclude, the present study suggests that NO derived from methotrexate-induced iNOS plays a critical role in the mechanism of hyperplasia of enterochromaffin cells containing 5-HT in the intestinal tissue of rats.


Assuntos
Células Enterocromafins/metabolismo , Células Enterocromafins/patologia , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Metotrexato/efeitos adversos , Óxido Nítrico/fisiologia , Serotonina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Expressão Gênica , Hiperplasia/induzido quimicamente , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
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