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1.
Biochem Biophys Res Commun ; 522(4): 1052-1058, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31818462

RESUMO

The Zika virus (ZIKV) is a mosquito-borne flavivirus that has reemerged as a serious public health problem around the world. Syndromes of infected people range from asymptomatic infections to severe neurological disorders, such as Guillain-Barré syndrome and microcephaly. Screening anti-ZIKV drugs derived from Chinese medicinal herbs is one method of identifying antiviral agents. In this paper, we report that (1) Cephalotaxine (CET), an alkaloid isolated from Cephalotaxus drupacea, was effective in inhibiting ZIKV activity in vitro (i.e., in Vero and A549 cell lines) and (2) the mechanisms which underlie these effects involve virucidal activity and a decrease in viral replication. Specifically, CET was found to decrease ZIKV RNA and viral protein expression, inhibit ZIKV replication, and inhibit ZIKV mRNA/protein production. We also determined that CET is effective in inhibiting dengue virus 1-4 (DENV1-4). Taken together, our findings indicate that CET could be an effective lead compound in the treatment of ZIKV and also suggest that further investigation and development of CET-derived drugs may lead to a new class of anti-Flavivirus medications.

2.
Mol Cancer Res ; 18(3): 477-487, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31748280

RESUMO

Metastasis of cancer cells is multi-step process and dissemination is an initial step. Here we report a tamoxifen-controllable Twist1a-ERT2 transgenic zebrafish line as a new animal model for metastasis research, and demonstrate that this model can serve as a novel platform for discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells. By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of EGFR) transgenic zebrafish, which develops hepatocellular carcinoma, approximately 80% of the double transgenic zebrafish showed spontaneous cell dissemination of mCherry-labeled hepatocytes from the liver to the entire abdomen region and the tail region. The dissemination is accomplished in 5 days through induction of an epithelial-to-mesenchymal transition. Using this model, we conducted in vivo drug screening and identified three hit drugs. One of them, adrenosterone, an inhibitor for hydroxysteroid (11-beta) dehydrogenase 1 (HSD11ß1), has a suppressor effect on cell dissemination in this model. Pharmacologic and genetic inhibition of HSD11ß1 suppressed metastatic dissemination of highly metastatic human cell lines in a zebrafish xenotransplantation model. Through downregulation of Snail and Slug, adrenosterone-treated cells recovered expression of E-cadherin and other epithelial markers and lost partial expression of mesenchymal markers compared with vehicle-treated cells. Taken together, our model offers a useful platform for the discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells. IMPLICATIONS: This study describes a transgenic zebrafish model for liver tumor metastasis and it has been successfully used for identification of some drugs to inhibit metastatic dissemination of human cancer cells.

3.
Biochem Biophys Res Commun ; 518(4): 732-738, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31472967

RESUMO

Zika virus (ZIKV) is an emerging vector-borne virus that is associated with severe congenital cerebral anomalies in fetuses and paralytic Guillain-Barré syndrome in adults. In the current global health crisis, there are no vaccines or therapeutics available for the treatment of ZIKV infection. In the present study, we evaluated the efficacy of the protoberberine alkaloid, palmatine, in inhibiting ZIKV and Japanese encephalitis virus (JEV). Palmatine was shown to bind to restricted viruses, inhibit ZIKV infection, and resist ZIKV-induced cytopathic effects. Palmatine was also shown to inhibit JEV infection in multiple cell lines. Overall, the effects of palmatine in disrupting ZIKV binding, entry, and stability indicate that this small molecule would be a good starting point for the development of treatments aimed at inhibiting ZIKV infection.

4.
Sci Rep ; 9(1): 10645, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337771

RESUMO

Hepatocellular carcinoma (HCC) is one of the most severe cancer types and many genetic and environmental factors contribute to the development of HCC. Androgen receptor (AR) signaling is increasingly recognized as one of the important factors associated with HCC. Previously, we have developed an inducible HCC model in kras transgenic zebrafish. In the present study, to investigate the role of AR in liver tumor development, we specifically knocked out ar gene in the liver of zebrafish via the CRISPR/Cas9 system and the knockout zebrafish was named L-ARKO for liver-specific ar knockout. We observed that liver-specific knockout of ar attenuated liver tumor development in kras transgenic zebrafish at the early stage (one week of tumor induction). However, at the late stage (two weeks of tumor induction), essentially all kras transgenic fish continue to develop HCC irrespective of the absence or presence of ar gene, indicating an overwhelming role of the driver oncogene kras over ar knockout. Consistently, cell proliferation was reduced at the early stage, but not the late stage, of liver tumor induction in the kras/L-ARKO fish, indicating that the attenuant effect of ar knockout was at least in part via cell proliferation. Furthermore, androgen treatment showed acceleration of HCC progression in kras fish but not in kras/L-ARKO fish, further indicating the abolishment of ar signalling. Therefore, we have established a tissue-specific ar knockout zebrafish and it should be a valuable tool to investigate AR signalling in the liver in future.

5.
Biochem Biophys Res Commun ; 517(1): 155-163, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31353084

RESUMO

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive deterioration of articular cartilage. There have been reports that small molecule inhibitors have anti-osteoarthritis effects; however, the effects of 3-(4-chloro-2-fluorophenyl)-6-(2,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Cm-02) and 6-(2,4-difluorophenyl)-3-(3,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Ck-02), small molecule inhibitors which share many structural similarities with quercetin (a potent anti-inflammatory flavonoid), remain unclear. In this study, TNF-α-stimulated porcine and human chondrocyte models were used to investigate the inhibitory effects of Cm-02 and Ck-02 on the molecular mechanisms underlying the anti-OA effects. TNF-α was used to stimulate porcine and human chondrocytes to mimic immunomodulatory potency in-vitro. Anti-osteoarthritic effects were characterized in terms of protein and mRNA levels associated with the pathogenesis of OA. We also examined (1) the inducible nitric oxide synthase (iNOS)-nitric oxide (NO) system in cultured chondrocytes, (2) matrix metalloproteinases (MMPs) in cultured chondrocytes, and (3) aggrecan degradation in cartilage explants. Finally, we tested the activation of nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), and activate the protein-1 (AP-1), and we tested the signal transduction and activation of transcription-3 (STAT-3). Our results indicate that, in chondrocytes, Cm-02 and Ck-02 inhibit TNF-α induced NO production, iNOS, MMP, the expression of disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and the enzyme activity of MMP-13. Furthermore, both Cm-02 and Ck-02 were found to stimulate TNF-α, which has been shown to suppress the activation of several transcription factors, including NF-κB, STAT-3, and IRF-1 in porcine and human chondrocytes. Cm-02 and Ck-02 were also found to help prevent the release of proteoglycans from cartilage explants. Our findings demonstrate that both Cm-02 and Ck-02 have potent anti-inflammatory activities and the ability to protect cartilage in an OA cell model. These findings indicate that Cm-02 and Ck-02 have the potential to be further developed for the therapeutic treatment of OA.

6.
Acta Histochem ; 121(5): 628-637, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31133374

RESUMO

The identification of prognostic markers for colorectal cancer (CRC) has important clinical implications. However, the association between meningioma 1 (MN1) expression and clinical outcomes of CRC has not been fully investigated. The aim of this study was to investigate the expression of MN1 in the clinical context of CRC. We first used immunohistochemistry (IHC) staining to examine and compare MN1 expression between multiple human cancer tissues and normal tissues. Initial screening revealed that the expression of MN1 proteins was significantly higher in tumor tissues of the breast, colon, and liver than in normal tissues. In further testing conducted on 59 paired CRC samples, we observed that the expression of MN1 in CRC tissue samples was significantly higher than in adjacent normal tissues. Moreover, high MN1 expression was not significantly associated with clinicopathological characteristics. Kaplan-Meier survival analysis revealed that high expression of MN1 mRNA or MN1 protein was significantly associated with poor CRC prognosis. Furthermore, univariate Cox analysis revealed that a high MN1 score was significantly associated with prognostic factors. Multivariate Cox analysis further indicated that gender, histologic grade, tumor-node-metastasis (TNM) stage, and a high MN1 score were independent factors of overall CRC survival rates. Finally, MN1 and PCNA protein levels were positively correlated, which suggests that MN1 may be involved in the cell proliferation process during CRC formation. Our results, which confirm those of other studies, indicate that (1) high levels of MN1 expression contribute to poor CRC prognosis and (2) MN1 can serve as a novel potential biomarker in predicting the prognosis of CRC patients.


Assuntos
Neoplasias Colorretais/mortalidade , Proteínas Supressoras de Tumor/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Proteínas Supressoras de Tumor/genética
7.
Nutrients ; 11(5)2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31137797

RESUMO

Genistein is an isoflavone extracted from soybean (Glycine max). This compound has anti-inflammatory, anti-oxidative, and anti-cancer effects; however, the mechanism underlying the effects of genistein on IL-1ß-stimulated human osteoarthritis (OA) chondrocytes remains unknown. Our objectives in this study were to explore the anti-inflammatory effects of genistein on IL-1ß-stimulated human OA chondrocytes and to investigate the potential mechanisms which underlie them. Our results from an in-vitro model of osteoarthritis indicate that genistein inhibits the IL-1ß-induced expression of the catabolic factors nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX-2), and matrix metalloproteinases (MMPs). Genistein was shown to stimulate Ho-1 expression, which has been associated with Nrf-2 pathway activation in human chondrocytes. In a rat model, genistein was also shown to attenuate the progression of traumatic osteoarthritis. Taken together, these results demonstrate the effectiveness of genistein in mediating the inflammation associated with joint disorders. Our results also indicate that genistein could potentially serve as an alternative therapeutic treatment for OA.


Assuntos
Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Genisteína/farmacologia , Articulações/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Animais , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Heme Oxigenase-1/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/farmacologia , Articulações/metabolismo , Articulações/patologia , Metaloproteinases da Matriz/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais
8.
Gen Comp Endocrinol ; 277: 112-121, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30926469

RESUMO

Hepatocellular carcinoma (HCC) shows clear sex disparity with men being more prone to developing HCC and having higher mortality than women. Previous studies have indicated that sex hormones play important roles in HCC initiation and development, but the effects of sex hormones on HCC in clinical trials remain inconsistent. Using zebrafish liver tumor model co-induced by oncogenes Myc and xmrk, we observed similar sex disparity between male and female zebrafish in liver tumor progression and regression; i.e. male Myc/xmrk transgenic zebrafish developed HCC significantly faster and regressed HCC significantly slower than female Myc/xmrk transgenic zebrtafish. To investigate the effects of sex hormones on liver tumor progression and regression, Myc/xmrk fish were treated with either androgen or estrogen, we observed that androgen promoted HCC progression and retarded HCC regression in females, while estrogen attenuated HCC progression and accelerated HCC regression in males. Furthermore, androgen promoted cell proliferation while estrogen inhibited it. Overall, the present study suggested that sex hormones affected liver tumor progression and regression in the Myc/xmrk transgenic zebrafish.


Assuntos
Progressão da Doença , Hormônios Esteroides Gonadais/farmacologia , Neoplasias Hepáticas/patologia , Oncogenes , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Masculino , Caracteres Sexuais , Proteínas de Peixe-Zebra/genética
9.
Carcinogenesis ; 40(3): 461-473, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30418535

RESUMO

Dysregulation of the enzymes involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. Our recent study demonstrated that ribose-5-phosphate isomerase (RPIA), a key regulator of the PPP, regulates hepatoma cell proliferation and colony formation. Our studies in zebrafish reveal that RPIA-mediated hepatocarcinogenesis requires extracellular signal-regulated kinase (ERK) and ß-catenin signaling. To further investigate RPIA-mediated hepatocarcinogenesis, two independent lines of transgenic zebrafish expressing human RPIA in the liver were generated. These studies reveal that RPIA overexpression triggers lipogenic factor/enzyme expression, steatosis, fibrosis and proliferation of the liver. In addition, the severity of fibrosis and the extent of proliferation are positively correlated with RPIA expression levels. Furthermore, RPIA-mediated induction of hepatocellular carcinoma (HCC) requires the ERK and ß-catenin signaling pathway but is not dependent upon transaldolase levels. Our study presents a mechanism for RPIA-mediated hepatocarcinogenesis and suggests that RPIA represents a valuable therapeutic target for the treatment of HCC.


Assuntos
Aldose-Cetose Isomerases/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas Experimentais/patologia , beta Catenina/metabolismo , Animais , Animais Geneticamente Modificados , Linhagem Celular Tumoral , Progressão da Doença , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/metabolismo , Peixe-Zebra/genética
10.
Neoplasia ; 20(12): 1187-1197, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30390498

RESUMO

KRAS mutations are a major risk factor in colorectal cancers. In particular, a point mutation of KRAS of amino acid 12, such as KRASV12, renders it stable activity in oncogenesis. We found that krasV12 promotes intestinal carcinogenesis by generating a transgenic zebrafish line with inducible krasV12 expression in the intestine, Tg(ifabp:EGFP-krasV12). The transgenic fish generated exhibited significant increases in the rates of intestinal epithelial outgrowth, proliferation, and cross talk in the active Ras signaling pathway involving in epithelial-mesenchymal transition (EMT). These results provide in vivo evidence of Ras pathway activation via krasV12 overexpression. Long-term transgenic expression of krasV12 resulted in enteritis, epithelial hyperplasia, and tubular adenoma in adult fish. This was accompanied by increased levels of the signaling proteins p-Erk and p-Akt and by downregulation of the EMT marker E-cadherin. Furthermore, we also observed a synergistic effect of krasV12 expression and dextran sodium sulfate treatment to enhance intestinal tumor in zebrafish. Our results demonstrate that krasV12 overexpression induces intestinal tumorigenesis in zebrafish, which mimics intestinal tumor formation in humans. Thus, our transgenic zebrafish may provide a valuable in vivo platform that can be used to investigate tumor initiation and anticancer drugs for gastrointestinal cancers.


Assuntos
Transformação Celular Neoplásica/genética , Expressão Gênica , Mucosa Intestinal/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Animais Geneticamente Modificados , Biomarcadores , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Elementos de DNA Transponíveis , Modelos Animais de Doenças , Ordem dos Genes , Genes Reporter , Vetores Genéticos/genética , Mucosa Intestinal/patologia , Mutação , Fosforilação , Transdução de Sinais , Peixe-Zebra
11.
Antiviral Res ; 159: 134-142, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30300716

RESUMO

The chikungunya virus (CHIKV) is a mosquito-borne virus that belongs to the genus Alphavirus, family Togaviridae. It is the cause of chikungunya fever in humans, which presents a serious global threat due to its high rate of contagion. The clinical symptoms of CHIKV include fever and persistent, severe arthritis. Micafungin has broad-spectrum fungicidal activity against Candida spp. is a promising echinocandin that was recently approved by the U.S. Food and Drug Administration (FDA) and has demonstrated activity against Candida and Aspergillus. Recent studies have demonstrated the antiviral activity of micafungin; however, the inhibitory effects against CHIKV have yet to be investigated. Our objectives in this study were to explore the antiviral effects of micafungin on CHIKV infection and to elucidate the potential molecular mechanisms of inhibition. We determined that micafungin has the ability to counter CHIKV-induced cytopathic effects. We further discovered that micafungin limits virus replication, release, cell-to-cell transmission, and also slightly affected virus stability during high doses treatment. The efficacy of micafungin was further confirmed against two clinical isolates of CHIKV and two alphaviruses: Sindbis virus (SINV) and Semliki Forest virus (SFV). Our findings suggest that micafungin has considerable potential as a novel inhibitor against the viral replication, and intracellular and extracellular transmission of CHIKV, and has a little effect on virus stability. Our findings also suggest that micafungin could have curative effects on other alphavirus infections.


Assuntos
Alphavirus/efeitos dos fármacos , Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Micafungina/farmacologia , Infecções por Alphavirus/tratamento farmacológico , Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/virologia , Vírus da Floresta de Semliki/efeitos dos fármacos , Vírus Sindbis/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
12.
Biochem Biophys Res Commun ; 503(3): 1442-1449, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30029884

RESUMO

In this study, we investigated the expression of jumonji domain-containing 4 (JMJD4) in colon adenocarcinoma (CA) look for evidences for future studies on clinical diagnostic and prognostic value. The immunohistochemical (IHC) reactivity of JMJD4 was assessed in human tissue microarrays using monoclonal antibodies. An initial investigation revealed that the expression of JMJD4 protein was significantly higher in tumor tissue of the colon and liver than in normal tissue. Upon further investigation, we observed significant positivity of JMJD4 between 59 paired samples from CA tissue and adjacent normal tissue. JMJD4 protein expression in CA differed significantly according to the histological grade and M-class (distant metastasis). We also determined that the mRNA or protein expression of JMJD4 was significantly associated with poor survival in patients with CA. Finally, univariate and multivariate analysis revealed that JMJD4 expression could be a prognostic indicator for patients with CA and may provide a new target for the development of novel therapies for the treatment of CA.


Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , Oxigenases de Função Mista/genética , Adenocarcinoma/diagnóstico , Neoplasias do Colo/diagnóstico , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/análise , RNA Mensageiro/genética , Taxa de Sobrevida
13.
Int J Mol Sci ; 19(5)2018 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-29757957

RESUMO

In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share structural similarity with quercetin, a potent anti-inflammatory flavonoid present in many different fruits and vegetables. We investigated the immunomodulatory effects of this compound, namely 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02), in a side-by-side comparison with quercetin. Chondrocytes were isolated from pig joints or the joints of patients with osteoarthritis that had undergone total knee replacement surgery. Several measures were used to assess the immunomodulatory potency of these compounds in tumor necrosis factor (TNF-α)-stimulated chondrocytes. Characterization included the protein and mRNA levels of molecules associated with arthritis pathogenesis as well as the inducible nitric oxide synthase (iNOS)⁻nitric oxide (NO) system and matrix metalloproteinases (MMPs) in cultured chondrocytes and proteoglycan, and aggrecan degradation in cartilage explants. We also examined the activation of several important transcription factors, including nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-3 (STAT-3), and activator protein-1 (AP-1). Our overall results indicate that the immunomodulatory potency of Cf-02 is fifty-fold more efficient than that of quercetin without any indication of cytotoxicity. When tested in vivo using the induced edema method, Cf-02 was shown to suppress inflammation and cartilage damage. The proposed method shows considerable promise for the identification of candidate disease-modifying immunomodulatory drugs and leads compounds for arthritis therapeutics.


Assuntos
Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Quercetina/química , Quercetina/farmacologia , Animais , Artrite/tratamento farmacológico , Artrite/etiologia , Artrite/metabolismo , Artrite/patologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno/metabolismo , Imunomodulação/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteoglicanas/metabolismo , Relação Estrutura-Atividade , Suínos , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
PLoS Biol ; 16(1): e2003714, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29337987

RESUMO

Altered metabolism is one of the hallmarks of cancers. Deregulation of ribose-5-phosphate isomerase A (RPIA) in the pentose phosphate pathway (PPP) is known to promote tumorigenesis in liver, lung, and breast tissues. Yet, the molecular mechanism of RPIA-mediated colorectal cancer (CRC) is unknown. Our study demonstrates a noncanonical function of RPIA in CRC. Data from the mRNAs of 80 patients' CRC tissues and paired nontumor tissues and protein levels, as well as a CRC tissue array, indicate RPIA is significantly elevated in CRC. RPIA modulates cell proliferation and oncogenicity via activation of ß-catenin in colon cancer cell lines. Unlike its role in PPP in which RPIA functions within the cytosol, RPIA enters the nucleus to form a complex with the adenomatous polyposis coli (APC) and ß-catenin. This association protects ß-catenin by preventing its phosphorylation, ubiquitination, and subsequent degradation. The C-terminus of RPIA (amino acids 290 to 311), a region distinct from its enzymatic domain, is necessary for RPIA-mediated tumorigenesis. Consistent with results in vitro, RPIA increases the expression of ß-catenin and its target genes, and induces tumorigenesis in gut-specific promotor-carrying RPIA transgenic zebrafish. Together, we demonstrate a novel function of RPIA in CRC formation in which RPIA enters the nucleus and stabilizes ß-catenin activity and suggests that RPIA might be a biomarker for targeted therapy and prognosis.


Assuntos
Aldose-Cetose Isomerases/metabolismo , Aldose-Cetose Isomerases/fisiologia , beta Catenina/fisiologia , Polipose Adenomatosa do Colo/metabolismo , Adulto , Idoso , Animais , Animais Geneticamente Modificados , Carcinogênese , Linhagem Celular Tumoral , Núcleo Celular , Proliferação de Células/fisiologia , Transformação Celular Neoplásica , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Regiões Promotoras Genéticas/genética , Domínios Proteicos , RNA Mensageiro/genética , Ubiquitinação , Peixe-Zebra , beta Catenina/genética
15.
Biochem Biophys Res Commun ; 494(1-2): 173-180, 2017 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-29037809

RESUMO

To investigate the relationship between YY1AP1 and various clinicopathological features of colon adenocarcinoma (COAD), we conducted immunohistochemical (IHC) analyses of human tissue microarrays. We found that YY1AP1 protein expression was significantly higher in tumor tissue of the colon and liver, and was significantly lower in tumor tissue of the kidney. An analysis that employed the SurvExpress database indicated that increased expression of YY1AP1 mRNA was significantly associated with the overall survival of COAD patients. To clarify the validity of YY1AP1 or PCNA as determined by the IHC analysis was performed on 59 paired samples from COAD and adjacent normal tissue. Statistically significant differences of immunoreactivity for YY1AP1 or PCNA protein expression was observed between COAD tissue and adjacent normal tissue. High protein expression levels of YY1AP1 and PCNA were also found to be significantly correlated with M-class and distant metastasis. We also determined that YY1AP1 was correlated with PCNA expression in COAD samples, and Kaplan-Meier survival curves indicated that YY1AP1 protein expression was significantly associated with poor survival. Finally, a univariate analysis demonstrated that YY1AP1 protein expression was related to YY1AP1 score, and multivariate analysis revealed that the YY1AP1 protein expression level was an independent risk factor of overall COAD survival. Taken together, our findings indicate that YY1AP1 expression plays an important role in the tumorigenesis and progression of COAD and could serve as a clinical prognostic indicator for COAD.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Proteínas Nucleares/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fatores de Transcrição/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Prognóstico , Antígeno Nuclear de Célula em Proliferação/genética , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Fatores de Transcrição/genética
16.
Biomedicines ; 5(4)2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28961226

RESUMO

Colorectal cancer (CRC) is one of the world's most common cancers and is the second leading cause of cancer deaths, causing more than 50,000 estimated deaths each year. Several risk factors are highly associated with CRC, including being overweight, eating a diet high in red meat and over-processed meat, having a history of inflammatory bowel disease, and smoking. Previous zebrafish studies have demonstrated that multiple oncogenes and tumor suppressor genes can be regulated through genetic or epigenetic alterations. Zebrafish research has also revealed that the activation of carcinogenesis-associated signal pathways plays an important role in CRC. The biology of cancer, intestinal disorders caused by carcinogens, and the morphological patterns of tumors have been found to be highly similar between zebrafish and humans. Therefore, the zebrafish has become an important animal model for translational medical research. Several zebrafish models have been developed to elucidate the characteristics of gastrointestinal diseases. This review article focuses on zebrafish models that have been used to study human intestinal disorders and tumors, including models involving mutant and transgenic fish. We also report on xenograft models and chemically-induced enterocolitis. This review demonstrates that excellent zebrafish models can provide novel insights into the pathogenesis of gastrointestinal diseases and help facilitate the evaluation of novel anti-tumor drugs.

17.
APMIS ; 125(11): 985-995, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28913972

RESUMO

This study investigated the clinical implications of SETDB1 (also known as KMT1E) in human colon adenocarcinoma. Expression levels of SETDB1 proteins were analyzed by immunohistochemistry staining, and tissue microarrays were used to examine expression profiles in human patients. Our results revealed that SETDB1 protein expression was significantly higher in tumor tissue than in normal tissue for the breast, colon, liver, and lung (p < 0.05). Moreover, an analysis with SurvExpress software suggested that elevated expression of SETDB1 mRNA was significantly associated with the overall survival of colon adenocarcinoma patients (p < 0.05); and additional analysis involving 90 paired samples of colon adenocarcinoma tissue and normal tissue revealed that SETDB1 protein expression was 82% higher in cancerous cells (p < 0.001). High SETDB1 expression was also found to be significantly correlated with histological grade (p = 0.005), TNM stage (p = 0.003), T-class/primary tumor (p = 0.001), and N-class/regional lymph nodes (p = 0.017); and Kaplan-Meier survival curves indicated that SETDB1 protein expression was significantly associated with poor survival. Finally, univariate analysis demonstrated that SETDB1 protein expression was related to TNM stage (p = 0.004) and SETDB1 score (p = 0.001), whereas multivariate analysis showed that the influence of SETDB1 on overall colon adenocarcinoma survival was independent from other risk factors. Taken together, our results suggest that the SETDB1 protein could serve as a clinical prognostic indicator for colon adenocarcinoma.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias do Colo/diagnóstico , Metiltransferases de Proteína/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico
18.
Biochem Biophys Res Commun ; 491(3): 595-602, 2017 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-28760340

RESUMO

Chikungunya is a severe disease that results from infection with the chikungunya virus (CHIKV), an arbovirus. Thus, we (1) explored a new approach to combining previously researched drugs that have shown the potential to inhibit CHIKV infection; and (2) demonstrated the antiviral effects of (-)-Epigallocatechin-3-gallate (EGCG) and the underlying mechanisms. Specifically, we used U2OS cells infected with CHIVK to assess the synergistic antiviral activities of EGCG and suramin. EGCG presented the ability to inhibit the viral RNA, progeny yield, and cytopathic effect (CPE) of CHIKV and also demonstrated the ability to protect against virus entry, replication, and release. Moreover, the results confirmed that EGCG and suramin can have synergistic effects against CHIKV strain S27 infection and two other clinical isolates of CHIKV. Our findings suggest that treatment with a combination of EGCG and suramin could provide a basis for the development of novel stretages against CHIKV infection.


Assuntos
Catequina/análogos & derivados , Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/virologia , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/fisiologia , Suramina/administração & dosagem , Antivirais/administração & dosagem , Catequina/administração & dosagem , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Sinergismo Farmacológico , Humanos , Resultado do Tratamento
19.
Hepatol Commun ; 1(3): 230-247, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-29404456

RESUMO

α-1,2 mannosidases, key enzymes in N-glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α-1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α-1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α-fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1-overexpressing cells but decreased in MAN1C1-overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1-activated genes. Using the MAN1A1 liver-specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up-regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230-247).

20.
Antiviral Res ; 135: 81-90, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27742486

RESUMO

Chikungunya disease results from an infection with the arbovirus, chikungunya virus (CHIKV). Symptoms of CHIKV include fever and persistent, severe arthritis. In recent years, several antiviral drugs have been evaluated in clinical trials; however, no registered antivirals have been approved for clinical therapy. In this study, we established a high-throughput screening (HTS) system based on CHIKV 26S mediated insect cell fusion inhibition assay. Our screening system was able to search potential anti-CHIKV drugs in vitro. Using this system, four compounds (niclosamide, nitazoxanide, niflumic acid, tolfenamic acid) were identified. These compounds were then further analyzed using a microneutralization assay. We determined that niclosamide and nitazoxanide exhibit ability to against CHIKV-induced CPE. The anti-CHIKV abilities of these compounds were further confirmed by RT-qPCR and IFA. Moreover, niclosamide and nitazoxanide were found to (1) limit virus entry, (2) inhibit both viral release and cell-to-cell transmission, and (3) possess broad anti-alphavius activities, including against two clinical CHIKV isolates and two alphaviruses: Sindbis virus (SINV) and Semliki forest virus (SFV). In conclusion, our findings suggested that niclosamide and nitazoxanide were able to inhibit CHIKV entry and transmission, which might provide a basis for the development of novel human drug therapies against CHIKV and other alphavirus infections.


Assuntos
Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Descoberta de Drogas , Niclosamida/farmacologia , Tiazóis/farmacologia , Internalização do Vírus/efeitos dos fármacos , Animais , Linhagem Celular , Febre de Chikungunya/transmissão , Febre de Chikungunya/virologia , Vírus Chikungunya/fisiologia , Ensaios de Triagem em Larga Escala , Humanos , Vírus da Floresta de Semliki/efeitos dos fármacos , Vírus Sindbis/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
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