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1.
Vet Comp Oncol ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31652393

RESUMO

KIT is a tyrosine kinase receptor involved in carcinogenesis. Two alternatively spliced transcripts, differed from presence of four amino acids (GNSK) at exon 9 of c-kit, were identified in various human tumours and canine hemangiosarcoma (HSA). The biological function and clinical implications of these isoforms have not yet been elucidated in canine tumours. The current study aimed to validate the expression profile and ultimately to evaluate the correlation of c-kit isoform levels with clinicopathological factors of canine mammary tumours (CMTs). In total, the expression profiles of c-kit isoforms in 196 samples obtained from normal mammary glands (NMGs) of healthy controls and dogs with CMTs, benign and malignant CMTs, and HSAs were determined by polymerase chain reaction (PCR) and quantified via real-time PCR. Overall, the expression levels of the two isoforms were equivalent in NMGs, whereas the GNSK- /GNSK+ ratio sharply increased to 7.44- and 8.33-fold, indicating abundant GNSK- isoforms in benign and malignant CMTs, respectively. However, a significant decrease in GNSK- expression was detected in dogs with high-grade malignant CMTs (mCMTs) and with metastatic CMTs compared with expression in those with a lower grade and non-metastatic CMTs. In addition, the median survival time was shorter in mCMT canines with a lower GNSK- /GNSK+ ratio than that in mCMT canines with a higher ratio (899 days vs 1534 days). In conclusion, two c-kit isoforms are ubiquitously expressed with great variability in HSAs and CMTs with both benign and malignant status. The GNSK- /GNSK+ ratio could serve as a prognostic indicator for dogs with mCMTs.

2.
Anticancer Res ; 39(10): 5495-5504, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570443

RESUMO

BACKGROUND/AIM: Most patients with hepatocellular carcinoma (HCC) cannot be treated using traditional therapies. Boron neutron capture therapy (BNCT) may provide a new treatment for HCC. In this study, the therapeutic efficacy and radiobiological effects of boric acid (BA)-mediated BNCT in a VX2 multifocal liver tumor-bearing rabbit model are investigated. MATERIALS AND METHODS: Rabbits were irradiated with neutrons at the Tsing Hua Open Pool Reactor 35 min following an intravenous injection of BA (50 mg 10B/kg BW). The tumor size following BNCT treatment was determined by ultrasonography. The radiobiological effects were identified by histopathological examination. RESULTS: A total of 92.85% of the tumors became undetectable in the rabbits after two fractions of BNCT treatment. The tumor cells were selectively eliminated and the tumor vasculature was collapsed and destroyed after two fractions of BA-mediated BNCT, and no injury to the hepatocytes or blood vessels was observed in the adjacent normal liver regions. CONCLUSION: Liver tumors can be cured by BA-mediated BNCT in the rabbit model of a VX2 multifocal liver tumor. BA-mediated BNCT may be a breakthrough therapy for hepatocellular carcinoma.


Assuntos
Ácidos Bóricos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/efeitos da radiação , Terapia por Captura de Nêutron de Boro/métodos , Hepatócitos/efeitos dos fármacos , Hepatócitos/efeitos da radiação , Fígado/efeitos dos fármacos , Fígado/efeitos da radiação , Masculino , Coelhos
3.
Comp Immunol Microbiol Infect Dis ; 65: 96-102, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31300134

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) has been endemic in Taiwan since 1991. This study aimed to present a highly virulent PRRSV in Taiwan based on farm data collection and both in vitro and in vivo evaluations in virus challenge studies. This virulent PRRSV strain was first noticed on Farm TSYM due to continuously high nursery mortality rate and severe PRRSV-associated pneumonia. In phylogenetic surveillance, the PRRSV TSYM-strain remained in the predominant position for years, even with several other PRRSV strain invasions. In laboratory challenge trials, the TSYM-strain led to prolonged pyrexia, growth retardation, high mortality rates and high viremia titer that similar to the highly pathogenic PRRSV. The TSYM-strain isolate also triggered early interleukin-10 up-regulation and significantly higher infection rates under in vitro experiments. This study provides information of a comparably virulent strain in Taiwan and its appearance in both farm and laboratory levels.

4.
BMC Vet Res ; 15(1): 155, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101115

RESUMO

BACKGROUND: Sphingosine kinase 1 (SPHK1) is an enzyme that converts pro-apoptotic ceramide and sphingosine into anti-apoptotic sphingosine-1-phosphate. There is growing evidence that SPHK1 activation promotes oncogenic transformation, tumor growth, chemotherapy resistance, and metastatic spread. High SPHK1 expression has been associated with a poor prognosis in several human cancers. RESULTS: In the present study, the expression level of SPHK1 was examined in feline mammary tumor (FMT) specimens, and the IHC expression level of SPHK1 was associated with the histological grade of FMTs. IHC analysis of 88 FMT cases revealed that the expression level of SPHK1 was upregulated in 53 tumor tissues (60.2%) compared to adjacent mammary tissues. SPHK1 expression in FMTs was significantly associated with histological grade, presence of lymphovascular invasion, and estrogen receptor negativity. Treatment of primary FMT cells with SPHK1 inhibitors reduced cell viability, indicating that SPHK1 acts to promote FMT cell survival. These results indicate that SPHK1 may play an important role in FMTs and may be a therapeutic target in cats with FMT. CONCLUSIONS: SPHK1 over-expression in breast cancer tissues is associated with a poor prognosis in humans. SPHK1 over-expression in more aggressive FMTs provides support for a potential role of SPHK1 inhibitors for the treatment of FMTs. Targeting SPHK1 has potent cytotoxic effects in primary FMT cells. These findings suggest that further examination of the role SPHK1 plays in FMTs will pave the way for the investigation of SPHK1 inhibitors in future clinical applications.


Assuntos
Doenças do Gato/patologia , Neoplasias Mamárias Animais/enzimologia , Neoplasias Mamárias Animais/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Vasos Sanguíneos/patologia , Doenças do Gato/enzimologia , Gatos , Feminino , Regulação Neoplásica da Expressão Gênica , Sistema Linfático/patologia , Glândulas Mamárias Animais/enzimologia , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Invasividade Neoplásica , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo
5.
J Exp Clin Cancer Res ; 38(1): 186, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068208

RESUMO

BACKGROUND: Breast cancer is the most prevalent cancer among women. In triple-negative breast cancer (TNBC) cells, a novel quinone derivative, coenzyme Q0 (CoQ0), promotes apoptosis and cell-cycle arrest. This study explored the anti-epithelial-mesenchymal transition (EMT) and antimetastatic attributes of CoQ0 in TNBC (MDA-MB-231). METHODS: Invasion, as well as MTT assays were conducted. Lipofectamine RNAiMAX was used to transfect cells with ß-catenin siRNA. Through Western blotting and RT-PCR, the major signaling pathways' protein expressions were examined, and the biopsied tumor tissues underwent immunohistochemical and hematoxylin and eosin staining as well as Western blotting. RESULTS: CoQ0 (0.5-2 µM) hindered tumor migration, invasion, and progression. Additionally, it caused MMP-2/- 9, uPA, uPAR, and VEGF downregulation. Furthermore, in highly metastatic MDA-MB-231 cells, TIMP-1/2 expression was subsequently upregulated and MMP-9 expression was downregulated. In addition, CoQ0 inhibited metastasis and EMT in TGF-ß/TNF-α-stimulated non-tumorigenic MCF-10A cells. Bioluminescence imaging of MDA-MB-231 luciferase-injected live mice demonstrated that CoQ0 significantly inhibited metastasis of the breast cancer to the lungs and inhibited the development of tumors in MDA-MB-231 xenografted nude mice. Silencing of ß-catenin with siRNA stimulated CoQ0-inhibited EMT. Western blotting as well as histological analysis established that CoQ0 reduced xenografted tumor development because apoptosis induction, cell-cycle inhibition, E-cadherin upregulation, ß-catenin downregulation, and metastasis and EMT regulatory protein modulation were observed. CONCLUSIONS: CoQ0 inhibited the progression of metastasis as well as EMT (in vitro and in vivo). The described approach has potential in treating human breast cancer metastasis.


Assuntos
Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ubiquinona/administração & dosagem , Animais , Antígenos CD/genética , Apoptose/efeitos dos fármacos , Caderinas/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Humanos , Metaloproteinase 9 da Matriz/genética , Camundongos , NF-kappa B/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética
6.
Vet Comp Oncol ; 17(3): 427-438, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31050171

RESUMO

Neutrophil gelatinase-associated lipocalin (NGAL) is a new biomarker for renal injury. It is also involved in tumorigenesis of different human cancer types. The oncogenic role of NGAL is related to its molecular forms, and heterodimer formation with matrix metalloproteinase 9 (MMP9) promotes human breast cancer (HBC) invasion and metastasis. To date, the levels of NGAL and NGAL/MMP9 complex have not yet been explored in canine mammary tumours (CMTs). Hence, this study aimed to investigate whether NGAL and its molecular forms could be the biomarker for CMT diagnosis. To this end, expression profile of NGAL and MMP9 in mammary epithelial cells as well as in urine samples were detected. By immunohistochemistry staining, NGAL was expressed at variable levels. Unlike HBC, a significant reduction in NGAL expression was demonstrated in benign and malignant CMTs as compared with normal controls. Additionally, NGAL expression was significantly reduced in dogs with metastatic CMTs. By contrast, the mean score of MMP9 expression in ascending order was normal groups, benign, and malignant CMTs. Interestingly, analysis of the molecular form revealed the NGAL/MMP9 complex presents in most mammary tissues and urine of dogs with benign or malignant CMTs, whereas the complex was absent in samples from dogs without CMTs. In conclusion, NGAL and MMP9 are ubiquitously expressed in canine mammary epithelial cells in normal and cancerous status. However, the NGAL/MMP9 complex exclusively presents in mammary tissues and urine of dogs with tumours.

7.
Nutrients ; 11(3)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875840

RESUMO

Hedychium coronarium has a long history of use worldwide as a food and in folk medicine. In this study, we aimed to investigate the effect of an aqueous extract of H. coronarium leaves (HC) on type 2 diabetes mellitus (T2DM). Two types of animal models were used in this study: Streptozotocin (STZ)-induced T2DM (Wistar rats; N = 8) and C57BKSdb/db mice (N = 5). After treatment with HC for 28 days, glucose tolerance improved in both of the diabetic animal models. As significant effects were shown after 14 days of treatment in the STZ-induced T2DM model, we carried out the experiments with it. After 28 days of treatment with HC, the levels of cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein were significantly improved in the STZ-induced T2DM model. The lesions degree of islet ß-cells was decreased after the HC treatment. Although the insulin level increased moderately, the aldosterone level was significantly decreased in the HC-treated groups, suggesting that aldosterone might play an important role in this effect. In summary, HC is a natural product and it is worth exploring its effect on T2DM.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Zingiberaceae/química , Aldosterona/sangue , Animais , Diabetes Mellitus Tipo 2/metabolismo , Insulina/sangue , Folhas de Planta/química , Ratos , Estreptozocina
8.
Carcinogenesis ; 40(2): 335-348, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-30726934

RESUMO

Therapeutic administration of glucocorticoids (GCs) is frequently used as add-on chemotherapy for palliative purposes during breast cancer treatment. Recent studies have shown that GC treatment induces microRNA-708 in ovarian cancer cells, resulting in impaired tumor cell proliferation and metastasis. However, the regulatory functions of GCs on miR-708 and its downstream target genes in human breast cancer cells (BCCs) are poorly understood. In this study, we found that treatment with either the synthetic GC dexamethasone (DEX) or the natural GC mimic, antcin A (ATA) significantly increased miR-708 expression by transactivation of glucocorticoid receptor alpha (GRα) in MCF-7 and MDA-MB-231 human BCCs. Induction of miR-708 by GR agonists resulted in inhibition of cell proliferation, cell-cycle progression, cancer stem cell (CSC)-like phenotype and metastasis of BCCs. In addition, GR agonist treatment or miR-708 mimic transfection remarkably inhibited IKKß expression and suppressed nuclear factor-kappaB (NF-κB) activity and its downstream target genes, including COX-2, cMYC, cyclin D1, Matrix metalloproteinase (MMP)-2, MMP-9, CD24, CD44 and increased p21CIP1 and p27KIP1 that are known to be involved in proliferation, cell-cycle progression, metastasis and CSC marker protein. BCCs xenograft models indicate that treatment with GR agonists significantly reduced tumor growth, weight and volume. Overall, our data strongly suggest that GR agonists induced miR-708 and downstream suppression of NF-κB signaling, which may be applicable as a novel therapeutic intervention in breast cancer treatment.

9.
Food Chem Toxicol ; 124: 219-230, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30529123

RESUMO

Antrodia salonea (AS), a fungus that is indigenous to Taiwan has been well known for its anti-cancer properties. We investigated the anti-metastatic and anti-epithelial-mesenchymal transition (EMT) properties of AS in TNBC cells. To determine their EMT and metastasis levels, in vitro wound healing, wound invasion, Western blotting, RT-PCR, luciferase activity and immunofluorescence assays were performed, while the in vivo anti-metastatic efficacy of AS was evaluated in BALB/c-nu mice through bioluminescence imaging, HE staining, and immunohistochemical staining. MDA-MB-231 cells, when treated with AS concentrations (25-100 µg/mL) resulted in significant reduction of invasion and migration as well as the downregulation of VEGF, uPAR, uPA and MMP-9 (inhibition of PI3K/AKT/NFκB pathways). AS treatment prevented morphological changes and reversed EMT through the upregulation of E-cadherin and the downregulation of N-cadherin, Slug, Twist, and Vimentin. Inhibition of Smad3 signaling pathway, downregulation of ß-catenin pathway and upregulation of GSK3ß expression were also observed while, suppression of metastasis and EMT in TGF-ß1-stimulated non-tumorigenic MCF-10A cells was observed when treated with AS. Histological analysis confirmed that AS reduced tumor metastasis and upregulated E-cadherin expression in biopsied lung tissues. Our results indicated that AS exhibits anti-EMT and anti-metastatic activity, that could contribute to develop anticancer drugs against TNBC.


Assuntos
Antrodia/química , Produtos Biológicos/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Invasividade Neoplásica/prevenção & controle , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antígenos CD/genética , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo , Feminino , Carpóforos/química , Humanos , Hifas/química , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C , Fator de Transcrição RelA/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
10.
J Cell Physiol ; 2018 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-30146779

RESUMO

Antrodia camphorata (AC) exhibits potential for engendering cell-cycle arrest as well as prompting apoptosis and metastasis inhibition in triple-negative breast cancer (TNBC) cells. We performed the current study to explore the anti-epithelial-to-mesenchymal transition (EMT) properties of fermented AC broth in TNBC cells. Our results illustrated that noncytotoxic concentrations of AC (20-60 µg/ml) reversed the morphological changes (fibroblastic-to-epithelial phenotype) as well as the EMT by upregulating the observed E-cadherin expression. Furthermore, we discovered treatment with AC substantially inhibit the Twist expression in human TNBC (MDA-MB-231) cells as well as in those that were transfected with Twist. In addition, we determined AC to decrease the observed Wnt/ß-catenin nuclear translocation through a pathway determined to be dependent on GSK3ß. Notably, AC treatment consistently inhibited the EMT by downregulating mesenchymal marker proteins like N-cadherin, vimentin, Snail, ZEB-1, and fibronectin; at that same time upregulating epithelial marker proteins like occludin and ZO-1. Bioluminescence imaging that was executed in vivo demonstrated AC substantially suppressed breast cancer metastasis to the lungs. Notably, we found that western blot analysis confirmed that AC decreased lung metastasis as demonstrated by upregulation of E-cadherin expression in biopsied lung tissue. Together with our results support the anti-EMT activity of AC, indicating AC as having the potential for acting as an anticancer agent for the treatment of human TNBC treatment.

11.
Vet Comp Oncol ; 16(4): 670-676, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30129270

RESUMO

C-met is a receptor normally expressed on epithelial cells and dysregulated in human breast cancers. Mammary tumours are the most common tumour in female dogs. The aims of this study were to detect the expression of c-met in canine mammary tumours (CMTs) and evaluate the correlations between c-met expression and clinicopathological features. A total of 240 specimens of canine mammary tissues composed of 30 normal glands, 30 hyperplastic ones, 90 benign tumours and 90 carcinomas obtained from 127 bitches were examined by immunohistochemical staining. Positive c-met immunoreactivity was demonstrated in the cytoplasm of mammary epithelial cells at variable levels, and in malignant CMTs, higher c-met expression was found in carcinomas whose grade, stage and mitotic index were low, and metastasis was absent. The median survival time was shorter in dogs with malignant CMTs with a maximum diameter ≥5 cm, regional lymph node or distant metastasis, and a high histologic grade. However, the 2-year survival rate was higher in dogs with malignant CMTs of higher c-met expression than those of low c-met expression (80.1% vs 57%). C-met expression could be used as a valuable positive prognostic factor for the clinical outcomes of dogs with malignant CMTs.


Assuntos
Doenças do Cão/diagnóstico , Neoplasias Mamárias Animais/diagnóstico , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Doenças do Cão/metabolismo , Doenças do Cão/mortalidade , Doenças do Cão/patologia , Cães , Feminino , Regulação Neoplásica da Expressão Gênica , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/mortalidade , Neoplasias Mamárias Animais/patologia , Prognóstico
12.
Sci Rep ; 8(1): 7481, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29748549

RESUMO

Swine are a critical amplifying host involved in human Japanese encephalitis (JE) outbreaks. Cross-genotypic immunogenicity and sterile protection are important for the current genotype III (GIII) virus-derived vaccines in swine, especially now that emerging genotype I (GI) JE virus (JEV) has replaced GIII virus as the dominant strain. Herein, we aimed to develop a system to generate GI JEV virus-like particles (VLPs) and evaluate the immunogenicity and protection of the GI vaccine candidate in mice and specific pathogen-free swine. A CHO-heparan sulfate-deficient (CHO-HS(-)) cell clone, named 51-10 clone, stably expressing GI-JEV VLP was selected and continually secreted GI VLPs without signs of cell fusion. 51-10 VLPs formed a homogeneously empty-particle morphology and exhibited similar antigenic activity as GI virus. GI VLP-immunized mice showed balanced cross-neutralizing antibody titers against GI to GIV viruses (50% focus-reduction micro-neutralization assay titers 71 to 240) as well as potent protection against GI or GIII virus infection. GI VLP-immunized swine challenged with GI or GIII viruses showed no fever, viremia, or viral RNA in tonsils, lymph nodes, and brains as compared with phosphate buffered saline-immunized swine. We thus conclude GI VLPs can provide sterile protection against GI and GIII viruses in swine.

13.
Planta Med ; 84(15): 1110-1117, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29763944

RESUMO

Baicalin is the main flavonoid from the roots of an important medicinal plant, Scutellaria baicalensis, which shows a variety biological activities. Psoriasis is a chronic immune-mediated inflammatory disease that affects the skin. The unmet need of psoriasis is that many patients do not respond adequately to available clinical treatment. In this study, we found that baicalin showed inhibited dermal inflammation in a murine model of psoriasis via topical application of imiquimod. After a 5-day topical imiquimod application, baicalin or the control vehicle cream was to applied to the lesions of BALB/c mice for a further 4 days. The erythema, scaling, and thickness of the epidermal layer significantly improved in the baicalin-treated mice. The levels of interleukin-17A, interleukin-22, interleukin-23, and tumor necrosis factor in the skin significantly decreased after baicalin treatment. Baicalin also inhibited imiquimod-induced interleukin-17A production in skin draining lymph node cells. The infiltration of γδ T cells into the skin lesions induced by imiquimod was also suppressed after baicalin treatment. These results suggest that baicalin inhibited skin inflammation through the inhibition of the interleukin-17/interleukin-23 axis in a murine model of psoriasis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Citocinas/metabolismo , Erupção por Droga/tratamento farmacológico , Flavonoides/farmacologia , Psoríase/tratamento farmacológico , Aminoquinolinas/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/química , Modelos Animais de Doenças , Erupção por Droga/patologia , Feminino , Flavonoides/química , Humanos , Imiquimode , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/patologia , Receptores de Interleucina/metabolismo , Pele/patologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-29541145

RESUMO

Dendrobium Taiseed Tosnobile is a new species of herba dendrobii (Shi-Hu) that was developed by crossbreeding D. tosaense and D. nobile. Its pharmacological activity and active component have been reported, but its subchronic toxicity and genetic safety have not yet been investigated. This study assessed the 90-day oral toxicity and genetic safety of the aqueous extracts of D. Taiseed Tosnobile (DTTE) in male and female Sprague-Dawley (SD) rats. Eighty rats were divided into four groups, each consisting of ten male and ten female rats. DTTE was given orally to rats at 800, 1600, or 2400 mg/kg for 90 consecutive days, and distilled water was used for the control group. Genotoxicity studies were performed using a bacterial reverse mutation assay and in vivo mammalian cell micronucleus test in ICR mice and analyzed using flow cytometry. Throughout the study period, no abnormal changes were observed in clinical signs and body weight or on ophthalmological examinations. Additionally, no significant differences were found in urinalysis, hematology, and serum biochemistry parameters between the treatment and control groups. Necropsy and histopathological examination indicated no treatment-related changes. Based on results, the no-observed-adverse-effect level of DTTE is greater than 2400 mg/kg in SD rats.

15.
Food Funct ; 9(2): 871-879, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29292417

RESUMO

Quercetin, a flavonol, displays anti-inflammatory and anti-cancer properties. This study aimed to investigate whether a diet containing 0.1% or 1% quercetin (LQ and HQ, respectively) enhances the anti-tumor effects of trichostatin A (TSA) and prevents muscle wasting induced by TSA. The positive control group received quercetin intraperitoneally (IQ). Three weeks after injecting A549 cells, nude mice were given TSA alone or in combination with quercetin administered orally or intraperitoneally for 16 weeks. Tumor volumes as well as body, muscle and epididymal fat weights were determined during or after the experiment. Quercetin given as a diet supplement dose-dependently enhanced the anti-tumor potency of TSA (p < 0.05). The enhancing effect of HQ was similar to that of IQ. HQ also significantly increased the expression of p53, a tumor suppressor, in tumor tissues compared with the TSA alone group. In addition, TSA-induced loss of gastrocnemius muscle weight was inhibited by oral quercetin in a dose dependent manner; the efficiencies of LQ and HQ were similar to or better than IQ. Moreover, both LQ and HQ decreased TSA-induced activation of Forkhead box O1 (FOXO1), a crucial transcription factor that regulates muscle wasting associated genes. Consistently, LQ and HQ suppressed muscle wasting associated proteins atrophy gene-1 and muscle ring-finger protein-1 expression as well as increased the myosin heavy chain level in the gastrocnemius muscles. Besides, quercetin attenuated TSA-increased oxidative damage and proinflammatory cytokines (p < 0.05). These findings demonstrate that a diet containing 0.1% or 1% quercetin enhances the antitumor effect of TSA and prevents TSA-induced muscle wasting.


Assuntos
Antineoplásicos/efeitos adversos , Ácidos Hidroxâmicos/efeitos adversos , Atrofia Muscular/prevenção & controle , Neoplasias/tratamento farmacológico , Quercetina/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Quimioterapia Combinada , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Masculino , Camundongos , Camundongos Nus , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatologia , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo
16.
Biochem Pharmacol ; 148: 130-146, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29273513

RESUMO

Ultraviolet A (UVA) irradiation is toxic to skin as it penetrates deep into the dermis and damages cellular components through excessive reactive oxygen species (ROS) production, which accelerates photoaging and skin cancer. We evaluated the dermato-protective efficacies of zerumbone (natural sesquiterpene of Zingiber zerumbet) in UVA-irradiated human skin keratinocyte (HaCaT) cells and mouse epidermis. Zerumbone pretreatment (2-10 µM) substantially suppressed UVA (15 J/cm2)-induced HaCaT cell death and lactate dehydrogenase release in a dose-dependent manner. UVA-induced excessive ROS production, DNA single-strand breaks, apoptotic DNA fragmentation and a dysregulated Bax/Bcl-2 ratio were remarkably reversed by zerumbone in keratinocytes. Zerumbone-mediated cytoprotective properties were associated with increased nuclear translocation of nuclear factor-E2-related factor-2 (Nrf2) and elevated antioxidant response element (ARE) luciferase activity. Activation of Nrf2/ARE signaling was accompanied by induction of heme oxygenase-1 (HO-1) and γ-glutamyl cysteine ligase (γ-GCLC) genes in zerumbone-treated keratinocytes. Zerumbone-induced Nrf2 transcriptional activation was mediated by the p38 MAPK, PI3K/AKT and PKC signaling cascades. Notably, silencing of Nrf2 (siRNA transfection) significantly diminished zerumbone-mediated cytoprotective effects, as evidenced by impaired antioxidant genes, uncontrolled ROS/apoptotic DNA fragmentation and keratinocytes death, following UVA irradiation. In vivo evidence demonstrated that zerumbone treatment to nude mice (55 and 110 µg/day) significantly ameliorated UVA (15 J/cm2/every 2-day/14-day) cytotoxicity via increased nuclear localization of Nrf2 and Nrf2-dependent antioxidant genes (HO-1 and γ-GCLC) in UVA-treated skin tissues. Our findings emphasized the significance of Nrf2/ARE-signaling in zerumbone-mediated induction of antioxidant genes against UVA-toxicity. The molecular evidence suggests zerumbone can be a natural medicine to treat/prevent UVA-induced skin damage/photoaging.

17.
Environ Toxicol ; 32(8): 2070-2084, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28370894

RESUMO

Cigarette smoke exposure activates several cellular mechanisms predisposing to atherosclerosis, including oxidative stress, dyslipidemia, and vascular inflammation. Antrodia camphorata, a renowned medicinal mushroom in Taiwan, has been investigated for its antioxidant, anti-inflammatory, and antiatherosclerotic properties in cigarette smoke extracts (CSE)-treated vascular smooth muscle cells (SMCs), and ApoE-deficient mice. Fermented culture broth of Antrodia camphorata (AC, 200-800 µg/mL) possesses effective antioxidant activity against CSE-induced ROS production. Treatment of SMCs (A7r5) with AC (30-120 µg/mL) remarkably ameliorated CSE-induced morphological aberrations and cell death. Suppressed ROS levels by AC corroborate with substantial inhibition of CSE-induced DNA damage in AC-treated A7r5 cells. We found CSE-induced apoptosis through increased Bax/Bcl-2 ratio, was substantially inhibited by AC in A7r5 cells. Notably, upregulated SOD and catalase expressions in AC-treated A7r5 cells perhaps contributed to eradicate the CSE-induced ROS generation, and prevents DNA damage and apoptosis. Besides, AC suppressed AP-1 activity by inhibiting the c-Fos/c-Jun expressions, and NF-κB activation through inhibition of I-κBα degradation against CSE-stimulation. This anti-inflammatory property of AC was accompanied by suppressed CSE-induced VEGF, PDGF, and EGR-1 overexpressions in A7r5 cells. Furthermore, AC protects lung fibroblast (MRC-5) cells from CSE-induced cell death. In vivo data showed that AC oral administration (0.6 mg/d/8-wk) prevents CSE-accelerated atherosclerosis in ApoE-deficient mice. This antiatherosclerotic property was associated with increased serum total antioxidant status, and decreased total cholesterol and triacylglycerol levels. Thus, Antrodia camphorata may be useful for prevention of CSE-induced oxidative stress and diseases. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2070-2084, 2017.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antrodia/química , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fumaça/efeitos adversos , Tabaco/química , Animais , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Linhagem Celular , Meios de Cultura/farmacologia , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Pulmão/citologia , Camundongos , Músculo Liso Vascular/patologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Produtos do Tabaco , Fator de Transcrição AP-1/metabolismo
18.
Integr Cancer Ther ; 16(3): 308-318, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27151590

RESUMO

Toona sinensis (TS) is one of the most popular vegetarian dishes in Taiwan. It has been shown to exhibit antioxidant, antiangiogenic, antiatherosclerotic, and anticancer properties. In this study, we demonstrated the ability of aqueous leaf extracts from TS to promote immune responses in BALB/c mice and to exhibit anti-leukemia activity in murine WEHI-3 cells. BALB/c mice were injected intravenously with WEHI-3 cells and then treated orally with TS (50 mg/kg). In vivo study showed that TS treatment reduced liver and spleen enlargement in WEHI-3 bearing mice compared with the untreated group. Furthermore, TS also decreased white blood cells (WBC), indicating inhibition of differentiation of the precursor of macrophages in WEHI-3 bearing mice. Treatment of WEHI-3 cells with TS (0-75 µg/mL for 24 hours) significantly reduced cell viability. Furthermore, TS treatment-induced late apoptosis was confirmed by Annexin-V/PI staining. Western blot analyses revealed that treatment of WEHI-3 cells with TS statistically increased the protein expression level of cytochrome c in the cytoplasm and activates caspase-3. Notably, TS treatment caused a dramatic reduction in Bcl-2 and increase in Bax protein levels. TS may disturb the Bcl-2 and Bax protein ratio and induce apoptosis. This reports confirms the antitumor activity of this nutritious vegetable potentially against leukemia.


Assuntos
Imunidade/efeitos dos fármacos , Leucemia/tratamento farmacológico , Meliaceae/química , Extratos Vegetais/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Folhas de Planta/química , Baço/efeitos dos fármacos
19.
J Ethnopharmacol ; 196: 9-19, 2017 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-27986611

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Antrodia salmonea (AS), is a well-known folk medicinal mushroom in Taiwan, has been reported to exhibit anti-oxidant, anti-angiogenic, and anti-inflammatory effects. MATERIALS AND METHODS: In the present study, we examined the effects of AS on cell-cycle arrest in vitro in MDA-MB-231 cells and on tumor regression in vivo using an athymic nude mice model. RESULTS: AS (0-200µg/mL) treatment significantly induced G2 cell-cycle arrest in MDA-MB-231 cells by reducing the levels of cyclin B1, cyclin A, cyclin E, and CDC2 proteins. In addition, N-acetylcysteine (NAC) pretreatment prevented AS induced G2 cell-cycle arrest, indicating that ROS accumulation and subsequent cell cycle arrest might be a major mechanism of AS-induced cytotoxicity. Further, AS treatment decreased COX-2 expression and induced PARP cleavage was significantly reversed by NAC pretreatment in MDA-MB-231 cells. The in vivo study results revealed that AS treatment was effective in terms of delaying the tumor incidence and reducing the tumor growth in MDA-MB-231-xenografted nude mice. TUNEL assay, immunohistochemical staining and Western blotting confirmed that AS significantly modulated the xenografted tumor progression as demonstrated by induction of apoptosis, autophagy, and cell-cycle arrest. CONCLUSION: Our data strongly suggest that Antrodia salmonea could be an anti-cancer agent for human breast cancer.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antrodia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral/efeitos dos fármacos
20.
Anim Reprod Sci ; 174: 114-122, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27726904

RESUMO

The aim of this study was to investigate the effect of nonylphenol (NP), a widely used surfactant, on the reproductive performance of male Brown Tsaiya ducks (Anas platyrhynchos) (MBBTDs). Mature MBBTDs (n=100) were treated with NP by daily gavaging of 0, 1 (NP1), 10 (NP10) and 250 (NP250) mg/kg-BW/d for 14 wk. Semen quality, fertilization rate and specific factors in blood plasma were measured. Weights of organs were also measured at 14 wk after NP administration. Ducks from each treatment (n=4) were continually treated with NP thereafter for 12 mo to observe changes of tissue ultrastructure by microscopic examination. The results showed that ducks treated with amounts of NP of greater than 1mg NP/kg BW/d (NP1) for 14 wk had decreased sperm viability (32.3%) compared to those in the control group (74.1%, P<0.05). The fertilization rate of ducks treated with 250mg NP/kg-BW/d (NP250) for 14 wk was reduced (21.0%) compared to the control group (74.5%, P<0.05). Plasma aminotransferase (AST) and alanine aminotransferase (ALT) activities were also greater in NP250 group at the 14th wk post-treatment. Plasma testosterone concentrations were increased by NP1 treatment at the 14th wk post-treatment. Administration at dosage 250mg NP/kg-BW/d for 12 mo resulted in reduced sperm counts (P<0.05) and histopathological changes, such as dilated seminiferous tubules (P<0.05) and degenerated spermatocytes (P<0.05). These findings strongly suggest that NP adversely affects the reproductive performance of MBBTDs.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Patos/fisiologia , Fertilidade/fisiologia , Fenóis/toxicidade , Espermatozoides/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Patos/sangue , Masculino , Fenóis/administração & dosagem , Espermatozoides/fisiologia , Testosterona/sangue , Poluentes Químicos da Água/toxicidade
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