Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 62
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Acta Pharmacol Sin ; 41(5): 661-669, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31932644

RESUMO

Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction, and eventual organ failure. Therefore, the development of effective antifibrotic drugs is urgently required. IMB-S7 is novel biphenyl compound derived from bifendate (biphenyldicarboxylate) that is used for the treatment of chronic hepatitis in China. In the current study we investigated the potential of IMB-S7 as an antihepatic fibrosis agent. In bile duct ligation (BDL) rat model, oral administration of IMB-S7 (400 mg· kg-1· d-1, for 14 days) significantly ameliorated BDL-induced liver necrosis, bile duct proliferation, and collagen accumulation. We then showed that IMB-S7 treatment markedly suppressed the TGF-ß/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs, as well as in liver samples of BDL rats, thus inhibiting the transcription of most fibrogenesis-associated genes, including TGF-ß1, COL1A1, and ACTA2. Furthermore, IMB-S7 treatment significantly suppressed the expression of integrin αv at the mRNA and protein levels in TGF-ß-treated LX2 cells and liver samples of BDL rats. Using integrin αv overexpression and silencing, we demonstrated that integrin αv activity correlated positively with the activation of TGF-ß/Smad pathway. Based on dual luciferase assay and DNA affinity precipitation assay, we revealed that IMB-S7 inactivated integrin αv through competitively inhibiting the binding of Sp1, a transcription factor, to the integrin αv (ITGAV) promoter (-173/-163 bp). These results suggest that IMB-S7 inhibits HSCs activation and liver fibrosis through Sp1-integrin αv signaling, and IMB-S7 may be a promising candidate to combat hepatic fibrosis in the future.

2.
Br J Pharmacol ; 177(2): 372-387, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31621893

RESUMO

BACKGROUND AND PURPOSE: This study investigates the antifibrotic activities and potential mechanisms of costunolide (COS), a natural sesquiterpene compound. EXPERIMENTAL APPROACH: Rats subjected to bile duct ligation and mice challenged with CCl4 were used to study the antifibrotic effects of COS in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 also served as an in vitro liver fibrosis models. The expression of fibrogenic genes and signaling proteins in the neurogenic locus notch homologue protein 3 (Notch3)-hairy/enhancer of split-1 (HES1) pathway was examined using western blot and/or real-time PCR. Notch3 degradation was analysed using immunofluorescence and coimmunoprecipitation. KEY RESULTS: In animals, COS administration attenuated hepatic histopathological injury and collagen accumulation and reduced the expression of fibrogenic genes. COS time- and dose-dependently suppressed the levels of fibrotic markers in LX-2 cells and mouse pHSCs. Mechanistic studies showed COS destabilized Notch3 and subsequently inhibited the Notch3-HES1 pathway, thus inhibiting HSC activation. Furthermore, COS blocked the WW domain-containing protein 2 (WWP2)/protein phosphatase 1G (PPM1G) interaction and enhanced the effect of WWP2 on Notch3 degradation. CONCLUSIONS AND IMPLICATIONS: COS exerted potent antifibrotic effects in vitro and in vivo by disrupting the WWP2/PPM1G complex, promoting Notch3 degradation and inhibiting the Notch3/HES1 pathway. This indicates that COS may be a potential therapeutic candidate for the treatment of liver fibrosis.

3.
J Drug Target ; 28(1): 23-32, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31094236

RESUMO

Src family kinases (SFKs) are non-receptor tyrosine kinases and are involved in various cellular functions (proliferation, differentiation, migration, survival and invasion) by regulating downstream pathways. Considerable evidence suggests that co- and post-translational modifications are highly related to the activation of SFKs and their downstream signals. How SFKs are activated and how their subsequent cascades were regulated has been reviewed in previous reports. However, the contribution of co- and post-translational modification to SFKs activation has not been fully elucidated. This review focuses on the effect of these modifications on SFKs activity according to structural and biochemical studies and uncovers the significance of co-and post-translational modifications in the regulation of SFKs activity.

4.
Biomed Pharmacother ; 120: 109478, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31568987

RESUMO

Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with oral cancer. Proton pump inhibitors (PPIs), essentially H+-K+-ATPase inhibitors which are currently used in the treatment of acid related diseases, have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to investigate whether pantoprazole (PPZ, one of PPIs) could increase the sensitivity of chemoresistant oral epidermoid carcinoma cells (KB/V) to vincristine (VCR) and elucidate the underlying action mechanism. Results showed that combination treatment of PPZ and VCR synergistically inhibited the proliferation of KB/V cells in vitro and in vivo. Furthermore, administration of PPZ and VCR not only induce apoptosis and G2/M phase arrest in KB/V cells but also suppress the migration and invasion of KB/V cells. The mechanism underlying synergistic anti-tumor effect of PPZ and VCR was related to the inhibition of the function and expression of P-glycoprotein (P-gp) and the down-regulation of EGFR/MAPK and PI3K/Akt/mTOR signaling pathways in KB/V cells. Additionally, we observed that PPZ treatment induced an increase in lysosomal pH and inhibited the activity of lysosomal enzyme acid phosphatase in KB/V cells, which could functionally reduce the sequestration of VCR in lysosomes and sensitized KB/V cells to VCR. In conclusion, our study demonstrated that PPZ could be included in new combined therapy of human oral cancer (especially on VCR-resistant therapy) together with VCR.

5.
Polymers (Basel) ; 11(5)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052529

RESUMO

Paper-based relics, which are an important part of cultural heritage worldwide, are at risk of imminent damage from various environmental sources. To protect them, the atmospheric pressure plasma polymerization of hexamethyldisiloxane (HMDSO) precursor has been explored on paper-based relics in situ. The macro and micro images taken during this process suggest that the in situ plasma treatment does not change the macro morphology and the micro structure of the treated paper-based relic samples. On the other hand, plasma treatment causes the polymerization of the HMDSO which then produces nanoparticles deposited onto the paper-based relics. These nanoparticles provide good waterproof properties with large static water contact angles and smaller rolling angles, which protect the paper-based relics from water penetration. Moreover, since the nanoparticles are deposited onto the fibers, waterproof fastness is ensured. Also, the examined mechanical properties of the treated and untreated paper-based relics indicate that the atmospheric pressure plasma treatment does not affect the strength of the paper very much. The results in this study show that atmospheric pressure plasma treatment with the use of HMDSO precursor is a good method to preserve paper-based relics.

6.
Polymers (Basel) ; 11(3)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30960514

RESUMO

Electrospinning (e-spinning) is an emerging technique to prepare ultrafine fibers. Polyphenylene sulfide (PPS) is a high-performance resin which does not dissolve in any solvent at room temperature. Commercial PPS fibers are produced mainly by meltblown or spunbonded process to give fibers ~20 µm in diameter. In this research, an in-house designed melt electrospinning device was used to fabricate ultrafine PPS fibers, and the e-spinning operation conducted under inert gas to keep PPS fibers from oxidizing. Under the optimum e-spinning conditions (3 mm of nozzle diameter, 30 kV of electrostatic voltage, and 9.5 cm of tip-to-collector distance), the as-spun fibers were less than 8.0 µm in diameter. After characterization, the resultant PPS fibers showed uniform diameter and structural stability. Compared with commercial PPS staple fibers, the obtained fibers had a cold crystallization peak and 10 times higher storage modulus, thereby offering better tensile tenacity and more than 400% elongation at break.

7.
Biochem Pharmacol ; 164: 152-164, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30978324

RESUMO

The conversion of cholesterol to bile acids (BAs) contributes to the elimination of total cholesterol from the body. In addition, manipulating BA homeostasis by modulating cholesterol 7α-hydroxylase (CYP7A1) may affect the metabolic processing of cholesterol, exerting therapeutic effects on hypercholesterolemia and cardiovascular diseases. Multiple mechanisms (such as various nuclear receptors and regulatory factors) are involved in CYP7A1 modulation. Recently, microRNAs, protein degradation pathways, and the gut microbiota have been identified to participate in these sophisticated networks. In this review, research progress on the regulatory mechanism of CYP7A1 is summarized.


Assuntos
Colesterol 7-alfa-Hidroxilase/metabolismo , Colesterol/metabolismo , Microbioma Gastrointestinal/fisiologia , Homeostase/fisiologia , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo
8.
Acta Pharmacol Sin ; 40(7): 895-907, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30573812

RESUMO

The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.


Assuntos
Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade
9.
Nanomaterials (Basel) ; 8(10)2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332837

RESUMO

To meet the urgent need of society for advanced photocatalytic materials, novel visible light driven heterostructured composite was constructed based on graphitic carbon nitride (g-C3N4) and fibrous TiO2. The g-C3N4/TiO2 (CNT) composite was prepared through electrospinning technology and followed calcination process. The state of the g-C3N4 and fibrous TiO2 was tightly coupled. The photocatalytic performance was measured by degrading the Rhodamine B. Compared to commercial TiO2 (P25®) and electrospun TiO2 nanofibers, the photocatalytic performance of CNT composite was higher than them. The formation of CNT heterostructures and the enlarged specific surface area enhanced the photocatalytic performance, suppressing the recombination rate of photogenerated carriers while broadening the absorption range of light spectrum. Our studies have demonstrated that heterostructured CNT composite with an appropriate proportion can rational use of visible light and can significantly promote the photogenerated charges transferred at the contact interface between g-C3N4 and TiO2.

10.
Adv Mater ; 30(49): e1804644, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30284321

RESUMO

Optical characteristics of luminescent materials, including emission color (wavelength), lifetime, and excitation mode, play crucial roles in data communication and information security. Conventional luminescent materials generally display unicolor, unitemporal, and unimodal (occasionally bimodal) emission, resulting in low-level readout and decoding. The development of multicolor, multitemporal, and multimodal luminescence in a single material has long been considered to be a significant challenge. In this study, for the first time, the superior integration of colorful (red-orange-yellow-green), bitemporal (fluorescent and delayed), and four-modal (thermo-/mechano-motivated and upconverted/downshifted) emissions in a particular piezoelectric particle via optical multiplexing of dual-lanthanide dopants is demonstrated. The as-prepared versatile NaNbO3 :Pr3+ ,Er3+ luminescent microparticles shown are particularly suitable for embedding into polymer films to achieve waterproof, flexible/wearable and highly stretchable features, and synchronously to provide multidimensional codes that can be visually read-out using simple and commonly available tools (including the LED of a smartphone, pen writing, cooling-heating stimuli, and ultraviolet/near-infrared lamps). These findings offer unique insight for designing highly integrated stimuli-responsive luminophors and smart devices toward a wide variety of applications, particularly advanced anticounterfeiting technology.

11.
Molecules ; 23(1)2018 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-29324690

RESUMO

The effects of temperature, agitation and aeration on glycoprotein GP-1 production by Streptomyces kanasenisi ZX01 in bench-scale fermentors were systematically investigated. The maximum final GP-1 production was achieved at an agitation speed of 200 rpm, aeration rate of 2.0 vvm and temperature of 30 °C. By using a dynamic gassing out method, the effects of agitation and aeration on volumetric oxygen transfer coefficient (kLa) were also studied. The values of volumetric oxygen transfer coefficient in the logarithmic phase increased with increase of agitation speed (from 14.53 to 32.82 h-1) and aeration rate (from 13.21 to 22.43 h-1). In addition, a successful scale-up from bench-scale to pilot-scale was performed based on volumetric oxygen transfer coefficient, resulting in final GP-1 production of 3.92, 4.03, 3.82 and 4.20 mg/L in 5 L, 15 L, 70 L and 500 L fermentors, respectively. These results indicated that constant volumetric oxygen transfer coefficient was appropriate for the scale-up of batch fermentation of glycoprotein GP-1 by Streptomyces kanasenisi ZX01, and this scale-up strategy successfully achieved 100-fold scale-up from bench-scale to pilot-scale fermentor.


Assuntos
Reatores Biológicos , Fermentação , Glicoproteínas/biossíntese , Oxigênio/metabolismo , Streptomyces/metabolismo , Temperatura , Técnicas de Cultura Celular por Lotes/métodos
12.
Acta Pharmacol Sin ; 39(2): 213-221, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28748913

RESUMO

Cholestatic liver diseases are important causes of liver cirrhosis and liver transplantation, but few drugs are available for treatment. D-chiro-inositol (DCI), an isomer of inositol found in many Leguminosae plants and in animal viscera, is used clinically for the treatment of polycystic ovary syndrome (PCOS) and diabetes mellitus. In this study, we investigated whether DCI exerted an anti-cholestatic effect and its underlying mechanisms. A cholestatic rat model was established via bile duct ligation (BDL). After the surgery, the rats were given DCI (150 mg·kg-1·d-1) in drinking water for 2 weeks. Oral administration of DCI significantly decreased the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and attenuated bile duct proliferation, parenchymal necrosis and fibrosis in BDL rats. Furthermore, DCI treatment significantly increased the serum and bile levels of total bile acid (TBA), and decreased TBA levels in the liver. Moreover, DCI treatment significantly increased expression of the genes encoding bile acid transporters BSEP (Abcb11) and MRP2 (Abcc2) in liver tissues. DCI treatment also markedly decreased hepatic CD68 and NF-kappaB (NF-κB) levels, significantly decreased the serum and hepatic MDA levels, markedly increased superoxide dismutase activity in both serum and liver tissues. Using whole-genome oligonucleotide microarray, we revealed that DCI treatment altered the expression profiles of oxidation reduction-related genes in liver tissues. Collectively, DCI effectively attenuates BDL-induced hepatic bile acid accumulation and decreases the severity of injury and fibrosis by improving bile acid secretion, repressing inflammation and decreasing oxidative stress. The results suggest that DCI might be beneficial for patients with cholestatic disorders.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase/prevenção & controle , Inositol/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Alanina Transaminase/sangue , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Aspartato Aminotransferases/sangue , Ductos Biliares/cirurgia , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Inositol/administração & dosagem , Ligadura , Fígado/patologia , Cirrose Hepática/prevenção & controle , Masculino , NF-kappa B/metabolismo , Substâncias Protetoras/administração & dosagem , Ratos Sprague-Dawley , Estereoisomerismo , Superóxido Dismutase/metabolismo
13.
Autophagy ; 13(5): 900-913, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28521610

RESUMO

SPHK1 (sphingosine kinase 1), a regulator of sphingolipid metabolites, plays a causal role in the development of hepatocellular carcinoma (HCC) through augmenting HCC invasion and metastasis. However, the mechanism by which SPHK1 signaling promotes invasion and metastasis in HCC remains to be clarified. Here, we reported that SPHK1 induced the epithelial-mesenchymal transition (EMT) by accelerating CDH1/E-cadherin lysosomal degradation and facilitating the invasion and metastasis of HepG2 cells. Initially, we found that SPHK1 promoted cell migration and invasion and induced the EMT process through decreasing the expression of CDH1, which is an epithelial marker. Furthermore, SPHK1 accelerated the lysosomal degradation of CDH1 to induce EMT, which depended on TRAF2 (TNF receptor associated factor 2)-mediated macroautophagy/autophagy activation. In addition, the inhibition of autophagy recovered CDH1 expression and reduced cell migration and invasion through delaying the degradation of CDH1 in SPHK1-overexpressing cells. Moreover, the overexpression of SPHK1 produced intracellular sphingosine-1-phosphate (S1P). In response to S1P stimulation, TRAF2 bound to BECN1/Beclin 1 and catalyzed the lysine 63-linked ubiquitination of BECN1 for triggering autophagy. The deletion of the RING domain of TRAF2 inhibited autophagy and the interaction of BECN1 and TRAF2. Our findings define a novel mechanism responsible for the regulation of the EMT via SPHK1-TRAF2-BECN1-CDH1 signal cascades in HCC cells. Our work indicates that the blockage of SPHK1 activity to attenuate autophagy may be a promising strategy for the prevention and treatment of HCC.


Assuntos
Autofagia/fisiologia , Caderinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Antígenos CD , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Hepáticas/metabolismo
14.
J Asian Nat Prod Res ; 19(2): 109-113, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28133978

RESUMO

Hepatic fibrosis is a wound-healing response to chronic liver injury caused by various pathogenesis, such as hepatitis virus infection, drugs toxicity and autoimmune imbalances. Autophagy, a cellular process degrading damaged organelles or aggregative proteins, participates in multiple human diseases including hepatic fibrosis. However, the precise role of autophagy in the pathogenesis of hepatic fibrosis is yet to be elucidated. Accumulated evidences indicate that several nature compounds exhibit anti-fibrotic potential through modulating autophagy activity. For a better understanding of the relationships among autophagy, hepatic fibrosis, and autophagy-regulating nature compounds, this review highlights the recent advancement of nature compounds treating hepatic fibrosis through regulating autophagy.


Assuntos
Autofagia , Cirrose Hepática/tratamento farmacológico , Animais , Humanos , Fígado/metabolismo , Estrutura Molecular , Transdução de Sinais
15.
AMB Express ; 7(1): 6, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28050846

RESUMO

Streptomyces kanasenisi ZX01 was found to produce a novel glycoprotein GP-1 previously, which was secreted into medium and had significant activity against tobacco mosaic virus. However, the low production of GP-1 by strain ZX01 limited its further studies. In order to improve the yield of GP-1, a series of statistical experimental design methods were applied to optimize medium of strain ZX01 in this work. Millet medium was chosen to be the optimal original medium for optimization. Soluble starch and yeast extract were identified as the optimal carbon and nitrogen source using one-factor-at-a-time method. Response surface methodology was used to optimize medium compositions (soluble starch, yeast extract and inorganic salts). A higher yield of GP-1 was 601.33 µg/L after optimization. The optimal compositions of medium were: soluble starch 13.61 g/L, yeast extract 4.19 g/L, NaCl 3.54 g/L, CaCO3 0.28 g/L, millet, 10 g/L. The yield of GP-1 in a 5 L fermentor using optimized medium was 2.54 mg/L, which is much higher than the result of shake flask. This work will be helpful for the improvement of GP-1 production on a large scale and lay a foundation for developing it to be a novel anti-plant virus agent.

16.
Yao Xue Xue Bao ; 52(2): 189-97, 2017 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-29979499

RESUMO

Bile acids play critical roles in the regulation of metabolism and absorption of lipids. The ileal apical sodium-dependent bile acid transporter (ASBT) located at the enterocyte brush border is responsible for the reuptake of bile acids and the maintenance of bile acid homeostasis. Recently, a number of investigations have been made concerning the regulation and control of ASBT and the relationship between ASBT and intestinal inflammation, tumorigenesis, diabetes mellitus and hyperlipemia, which suggests ASBT as a potential therapeutic target of these diseases. In this review, advances in the study of above-mentioned issues were summarized.


Assuntos
Ácidos e Sais Biliares/fisiologia , Íleo/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/fisiologia , Simportadores/fisiologia , Transporte Biológico , Homeostase , Humanos , Intestinos/fisiopatologia
17.
Medicine (Baltimore) ; 95(40): e4989, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27749555

RESUMO

Nucleoside triphosphate diphosphohydrolase-1 (ENTPD1/CD39) is the rate-limiting enzyme in a cascade leading to the generation of immunosuppressive adenosine and plays an important role in tumor progression. This study aimed to evaluate the expression of CD39 and CD39Foxp3 regulatory T cells (Tregs) and to determine their prognostic role in patients with hepatocellular carcinoma (HCC) after radical resection.Immunohistochemistry (IHC) and double IHC were used to analyze CD39 expression or the expression of CD39 and Foxp3 in a cohort of 324 HCC patients who underwent curative resection. The quantification of CD39 expression levels was determined using a computerized image analysis system and was evaluated by mean optical density (MOD), which corresponded to the positive staining intensity of CD39. The number of positive Foxp3 cells and both CD39 and Foxp3 positive cells in each 1-mm-diameter cylinder were counted under high-power magnification (×400). The "minimum P value" approach was used to obtain the optimal cutoff value for the best separation between groups of patients in relation to time to recurrence (TTR) or overall survival (OS). The expression of CD39 in HCC cell lines with stepwise metastatic potential and in human umbilical vein endothelial cells was determined by reverse transcription-polymerase chain reaction, Western blotting, and immunofluorescence. The SPSS 17.0 statistical package was used for statistics.CD39 was principally expressed on vascular endothelial cells, macrophagocytes, Tregs, and tumor cells in HCC. Compared with paired peritumoral tissues, tumoral tissues had a significantly higher expression level of CD39 (P < 0.0001). Overexpression of tumoral CD39 was related to increased tumor recurrence and shortened overall survival. Furthermore, the expression level of peritumoral CD39 showed a prognostic role in TTR and OS. Double IHC showed that tumoral tissues had significantly higher Foxp3Tregs and CD39Foxp3Tregs count per 1 mm core (14.1659 vs 4.9877, P = 0.001; 11.5254 vs 3.3930, P < 0.001) and a higher CD39Foxp3/Foxp3 ratio compared with paired peritumoral tissues. CD39Foxp3Tregs were a better prognosticator than CD39Tregs for TTR.Overexpression of CD39 protein in HCC was an independent predictor of poor outcome after radical resection. The CD39Foxp3Tregs count added prognostic power to Foxp3Tregs, providing a potential target for tumor immunotherapy.


Assuntos
Antígenos CD/biossíntese , Apirase/biossíntese , Carcinoma Hepatocelular/fisiopatologia , Fatores de Transcrição Forkhead/biossíntese , Neoplasias Hepáticas/fisiopatologia , Linfócitos T Reguladores/metabolismo , Biomarcadores Tumorais , Carcinoma Hepatocelular/cirurgia , Feminino , Hepatectomia/métodos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico
18.
Br J Cancer ; 114(7): 767-76, 2016 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-27002937

RESUMO

BACKGROUND: Aberrant expression of interleukin-35 (IL-35) has been implicated in dampening antitumour immunity. The aim of this study was to explore the prognostic significance of IL-35 expression in patients with hepatocellular carcinoma (HCC) following curative resection. Furthermore, we aimed to formulate an effective prognostic nomogram for HCC after hepatectomy. METHODS: Immunohistochemistry was applied to explore IL-35 expression as well as CD39(+)Foxp3(+) and Foxp3(+) regulatory T cell (Treg) infiltration in tissue microarrays in primary cohort comprising 210 randomly selected HCC patients who underwent curative resection. The results were further verified in an independent validation cohort of 138 HCC patients. RESULTS: Patients with higher expression of IL-35 are more likely to suffer postoperative recurrence. Interleukin-35 was also identified as an independent prognostic factor for recurrence free survival in multivariate analysis. No correlation was detected between IL-35 expression and Foxp3(+) Treg infiltration, whereas significant positive correlation was found between IL-35 expression and CD39(+)Foxp3(+) Treg infiltration. In addition, CD39(+)Foxp3(+) Treg infiltration was also an independent predictor for postoperative recurrence. The nomogram comprising tumour size, tumour vascular invasion, IL-35 and CD39(+)Foxp3(+) Tregs had better predictive accuracy when compared with BCLC stage for RFS. These results were further validated in the validation cohort. CONCLUSIONS: Our data suggest for the first time that IL-35 expression correlates with HCC aggressiveness and emerged as a novel independent prognostic factor for recurrence, thus conferring the rationale to develop a novel therapy of targeting IL-35. Furthermore, IL-35 should be incorporated into nomogram to generate a more accurate predictive model.


Assuntos
Carcinoma Hepatocelular/patologia , Hepatectomia/mortalidade , Interleucinas/metabolismo , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Nomogramas , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Linfócitos T Reguladores , Análise Serial de Tecidos
19.
Life Sci ; 151: 23-29, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26944438

RESUMO

AIM: Sphingosine 1-phosphate (S1P) promotes cell growth, proliferation and survival. Sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, is a key promoter in cancer. We previously found that the SphK1 inhibitor II (SKI II), suppresses the cell growth and induces apoptosis in human hepatoma HepG2 cells. However, the precise regulatory mechanism and signaling pathway on SKI II inhibiting tumor growth remains unknown. MAIN METHODS: The expressions of ß-catenin and related molecules of Wnt/ß-catenin signal were detected by western blot in HepG2 cells. And the mRNA expression of ß-catenin was detected by RT-PCR. The Wnt5A gene was silenced by siRNA. The colony formation was determined by staining with crystal violet. And the cell growth was examined by SRB assay and BrdU assay. KEY FINDINGS: We found that SKI II decreased the expression of ß-catenin and the downstream molecules of ß-catenin signal pathway and promotes the ß-catenin degradation. In addition, SKI II induced the expression of Wnt5A, and then triggered ß-catenin degradation. Furthermore, silencing Wnt5A decreased the anti-tumor effects of SKI II through recovering the expressions of ß-catenin and downstream molecules of ß-catenin signal pathway. SIGNIFICANCE: SKI II-induced downregulation of HepG2 cell proliferation was associated with Wnt signaling pathway through Wnt5A-mediated ß-catenin degradation. Our study revealed that a novel signal pathway was involved in SKI II-inhibited cell proliferation in human hepatoma cells.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Proteína Wnt-5a/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Animais , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentais/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt-5a/metabolismo , beta Catenina/metabolismo
20.
Medicine (Baltimore) ; 95(7): e2784, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26886627

RESUMO

As chronic inflammation is involved in the pathogenesis and progression of hepatocellular carcinoma (HCC), we investigated the prognostic accuracy of a cluster of inflammatory scores, including the Glasgow Prognostic Score, modified Glasgow Prognostic Score, platelet to lymphocyte ratio, Prognostic Nutritional Index, Prognostic Index, and a novel Inflammation-Based Score (IBS) integrated preoperative and postoperative neutrophil to lymphocyte ratio in 2 independent cohorts. Further, we aimed to formulate an effective prognostic nomogram for HCC after hepatectomy.Prognostic value of inflammatory scores and Barcelona Clinic Liver Cancer (BCLC) stage were studied in a training cohort of 772 patients with HCC underwent hepatectomy. Independent predictors of survival identified in multivariate analysis were validated in an independent set of 349 patients with an overall similar clinical feature.In both training and validation cohorts, IBS, microscopic vascular invasion, and BCLC stage emerged as independent factors of overall survival (OS) and recurrence-free survival (RFS). The predictive capacity of the IBS in both OS and RFS appeared superior to that of the other inflammatory scores in terms of C-index. Additionally, the formulated nomogram comprised IBS resulted in more accurate prognostic prediction compared with BCLC stage alone.IBS is a novel and validated prognostic indicator of HCC after curative resection, and a robust HCC nomogram including IBS was developed to predict survival for patients after hepatectomy.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Nomogramas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/mortalidade , Criança , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA