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1.
J Diabetes Res ; 2020: 6894684, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32258168

RESUMO

Objective: Type 2 diabetes mellitus (T2DM) is featured by insulin resistance and lipid metabolism dysregulation. A large number of miRNAs were identified in exosomes derived from adipose tissue macrophages associated with T2DM pathogenesis, but its pathogenic roles remain unknown. This study is aimed at investigating the function of miR-210 in diabetic obesity. Methods: Exosomes from mouse macrophage RAW264.7 cells were characterized by electron microscopy, combined with biomarker expression by western blot. Expression of miR-210 was determined by quantitative RT-PCR. Glucose uptake was measured by a fluorometric method, and the mitochondrial respiratory chain activity was evaluated by ELISA. The target gene of miR-210 was validated by dual-luciferase reporter and pull-down assays. A mouse obese diabetic model was established by a high-fat diet and streptozocin treatment. Results: miR-210 was highly expressed in exosomes derived from high glucose-induced macrophage RAW264.7 cells. Macrophage-derived exosomes impaired glucose uptake and mitochondrial CIV complex activity and suppressed NADH dehydrogenase ubiquinone 1 alpha subcomplex 4 (NDUFA4) expression in 3T3-L1 adipocytes. miR-210 directly bind with mRNA sequences of NDUFA4 gene. Inhibition of miR-210 mitigated the effects of macrophage-derived exosomes on the glucose uptake and complex IV (CIV) activity in 3T3-L1 adipocytes, and NDUFA4 overexpression offset the inhibition of glucose uptake and CIV activity by macrophage-derived exosomes. Furthermore, mice with miR-210 knockout showed greatly repressed diabetic obesity development. Conclusion: miR-210 derived from adipose tissue macrophages promotes mouse obese diabetes pathogenesis by regulating glucose uptake and mitochondrial CIV activity through targeting NDUFA4 gene expression.

2.
J Clin Invest ; 130(4): 2069-2080, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32175919

RESUMO

BACKGROUNDHBV-related acute-on-chronic liver failure (HBV-ACLF) is hallmarked by high short-term mortality rates, calling for accurate prognostic biomarkers for initial risk stratification.METHODSThree tandem mass tag-labeled (TMT-labeled) quantitative proteomic studies were performed on 10 patients with HBV-related acute hepatic decompensation and on 20 patients with HBV-ACLF. Candidate biomarkers were preliminarily verified in a cross-sectional cohort (n = 144) and further confirmed in 2 prospective cohorts (n = 207 and n = 148).RESULTSPlasminogen, a potential prognostic biomarker for HBV-ACLF, was identified by TMT quantitative proteomics and preliminarily verified in the cross-sectional cohort. Further validation with a prospective cohort (n = 207) showed that plasminogen levels at admission were significantly lower (P < 0.001) in HBV-ACLF nonsurvivors than in survivors. The cumulative survival duration of patients with high plasminogen levels was significantly longer (P < 0.001) than that of patients with low plasminogen levels. During hospitalization, plasminogen levels significantly decreased (P = 0.008) in the deterioration group but significantly increased (P < 0.001) in the improvement group. Additionally, plasminogen levels gradually increased in survivors but gradually decreased in nonsurvivors. The P5 score, a prognostic panel incorporating plasminogen levels, hepatic encephalopathy occurrence, age, international normalized ratio (INR), and total bilirubin, was significantly superior to the Child-Pugh, Model for End-stage Liver Disease (MELD), Chronic Liver Failure Consortium ACLF (CLIF-C ACLF), Chinese Group on the Study of Severe Hepatitis B (COSSH), and HINT (a prognostic score based on hepatic encephalopathy occurrence, INR, neutrophil count, and thyroid-stimulating hormone) scores (all P < 0.05). The performances of the plasminogen level and P5 score were validated in a second multicenter, prospective cohort (n = 148).CONCLUSIONSPlasminogen is a promising prognostic biomarker for HBV-ACLF, and sequential plasminogen measurements could profile the clinical course of HBV-ACLF. P5 is a high-performance prognostic score for HBV-ACLF.FUNDINGThe National Key Research and Development Program (2017YFC1200204); the National Natural Science Foundation of China (81400589, 81600497); the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81121002); the Chinese High-Tech Research and Development Programs (2012AA020204); the National S&T Major Project (2012ZX10002004); and the Zhejiang Provincial Medicine and Health Science and Technology Project (2016147735).

3.
J Proteome Res ; 19(1): 174-185, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31802674

RESUMO

To elucidate the dynamic alterations of metabolites in rat plasma during liver regeneration and search for potential biomarkers of liver regeneration, 65 male Sprague-Dawley rats were divided into three groups: 70% partial hepatectomy group (PHx, n = 30), sham-operated group (Sham, n = 30), and pre-PHx group (pre-PHx, n = 5). Rats in the Sham and PHx groups were sacrificed after 30 min (min), 6 h (h), 24, 48, 72, and 168 h of surgery (n = 5 per time point). The gas chromatography-mass spectrometry-based metabolomic approach was used to identify the dynamic metabolites. Liver regeneration in the rats was evidenced by an increase in the liver weight/body weight ratio, expression of proliferating cell nuclear antigen, and yes-associated protein-1. Thirty-four differentially abundant metabolites between the Sham and PHx groups were identified, which were involved in arginine and proline metabolism, aminoacyl-tRNA biosynthesis, and cysteine and methionine metabolism pathways. Of these metabolites, low 1,5-anhydroglucitol may indicate proliferation of liver parenchymal cells during liver regeneration. Thus, a series of metabolic changes occurred with the progression of liver regeneration, and 1,5-anhydroglucitol could function as a novel hallmark of proliferation of liver parenchymal cells.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31696114

RESUMO

Conventional chemotherapy for cancer treatment is usually compromised by shortcomings such as insufficient therapeutic outcome and undesired side effects. The past decade has witnessed the rapid development of combination therapy by integrating chemotherapy with hyperthermia for enhanced therapeutic efficacy. Near-infrared (NIR) light-mediated photothermal therapy, which has advantages such as great capacity of heat ablation and minimally invasive manner, has emerged as a powerful approach for cancer treatment. A variety of nanomaterials absorbing NIR light to generate heat have been developed to simultaneously act as carriers for chemotherapeutic drugs, contributing as heat trigger for drug release and/or inducing hyperthermia for synergistic effects. This review aims to summarize the recent development of advanced nanomaterials in chemo-photothermal combination therapy, including metal-, carbon-based nanomaterials and particularly organic nanomaterials. The potential challenges and perspectives for the future development of nanomaterials-based chemo-photothermal therapy were also discussed.

5.
Sci Rep ; 9(1): 16462, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712684

RESUMO

Artificial liver support systems (ALSS) are widely used to treat patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). The aims of the present study were to investigate the subgroups of patients with HBV-ACLF who may benefit from ALSS therapy, and the relevant patient-specific factors. 489 ALSS-treated HBV-ACLF patients were enrolled, and served as derivation and validation cohorts for classification and regression tree (CART) analysis. CART analysis identified three factors prognostic of survival: hepatic encephalopathy (HE), prothrombin time (PT), and total bilirubin (TBil) level; and two distinct risk groups: low (28-day mortality 10.2-39.5%) and high risk (63.8-91.1%). The CART model showed that patients lacking HE and with a PT ≤ 27.8 s and a TBil level ≤455 µmol/L experienced less 28-day mortality after ALSS therapy. For HBV-ACLF patients with HE and a PT > 27.8 s, mortality remained high after such therapy. Patients lacking HE with a PT ≤ 27.8 s and TBil level ≤ 455 µmol/L may benefit markedly from ALSS therapy. For HBV-ACLF patients at high risk, unnecessary ALSS therapy should be avoided. The CART model is a novel user-friendly tool for screening HBV-ACLF patient eligibility for ALSS therapy, and will aid clinicians via ACLF risk stratification and therapeutic guidance.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31704080

RESUMO

BACKGROUND: For its better differentiated hepatocyte phenotype, C3A cell line has been utilized in bioartificial liver system. However, up to now, there are only a few of studies working at the metabolic alternations of C3A cells under the culture conditions with liver failure plasma, which mainly focus on carbohydrate metabolism, total protein synthesis and ureagenesis. In this study, we investigated the effects of acute liver failure plasma on the growth and biological functions of C3A cells, especially on CYP450 enzymes. METHODS: C3A cells were treated with fresh DMEM medium containing 10% FBS, fresh DMEM medium containing 10% normal plasma and acute liver failure plasma, respectively. After incubation, the C3A cells were assessed for cell viabilities, lactate dehydrogenase leakage, gene transcription, protein levels, albumin secretion, ammonia metabolism and CYP450 enzyme activities. RESULTS: Cell viabilities decreased 15%, and lactate dehydrogenase leakage had 1.3-fold elevation in acute liver failure plasma group. Gene transcription exhibited up-regulation, down-regulation or stability for different hepatic genes. In contrast, protein expression levels for several CYP450 enzymes kept constant, while the CYP450 enzyme activities decreased or remained stable. Albumin secretion reduced about 48%, and ammonia accumulation increased approximately 41%. CONCLUSIONS: C3A cells cultured with acute liver failure plasma showed mild inhibition of cell viabilities, reduction of albumin secretion, and increase of ammonia accumulation. Furthermore, CYP450 enzymes demonstrated various alterations on gene transcription, protein expression and enzyme activities.

7.
Eur J Clin Invest ; : e13098, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30838641

RESUMO

There is a complex oxidant and antioxidant system that maintains the redox homoeostasis in the liver. While suffering from exogenous or endogenous risk factors, the balance between oxidants and antioxidants is disturbed and excessive reactive oxygen species are generated, resulting in oxidative stress. Oxidative stress is prevalent in various liver diseases and is thought to be involved in their pathophysiology. Advanced oxidation protein products are generated under conditions of oxidative damage and are newly described protein markers of oxidative stress. Previous studies have underscored the universal pathogenic roles of oxidation protein products in various diseases. However, investigations into how these products participate in the development of liver diseases have been superficial and insufficient. In this review, we highlight the current understanding of the roles of advanced oxidation protein products in liver disease pathogenesis and the underlying mechanisms. Moreover, we summarize the current studies on advanced oxidation protein products in infectious and noninfectious, acute and chronic liver diseases. Different strategies for targeting these advanced oxidation protein products and future perspectives, which may pave the way for developing new therapeutic strategies, will also be discussed here.

8.
Int J Mol Sci ; 19(4)2018 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-29677135

RESUMO

Homocysteine methyltransferase (HMT) converts homocysteine to methionine using S-methylmethionine (SMM) or S-adenosylmethionine (SAM) as methyl donors in organisms, playing an important role in supplying methionine for the growth and the development of plants. To better understand the functions of the HMT genes in plants, we conducted a wide evolution and expression analysis of these genes. Reconstruction of the phylogenetic relationship showed that the HMT gene family was divided into Class 1 and Class 2. In Class 1, HMTs were only found in seed plants, while Class 2 presented in all land plants, which hinted that the HMT genes might have diverged in seed plants. The analysis of gene structures and selection pressures showed that they were relatively conserved during evolution. However, type I functional divergence had been detected in the HMTs. Furthermore, the expression profiles of HMTs showed their distinct expression patterns in different tissues, in which some HMTs were widely expressed in various organs, whereas the others were highly expressed in some specific organs, such as seeds or leaves. Therefore, according to our results in the evolution, functional divergence, and expression, the HMT genes might have diverged during evolution. Further analysis in the expression patterns of AthHMTs with their methyl donors suggested that the diverged HMTs might be related to supply methionine for the development of plant seeds.


Assuntos
Evolução Molecular , Homocisteína S-Metiltransferase/metabolismo , Plantas/metabolismo , Animais , Homocisteína S-Metiltransferase/genética , Humanos , Filogenia , Plantas/genética , S-Adenosilmetionina/metabolismo , Vitamina U/metabolismo
9.
Drug Deliv ; 24(sup1): 45-55, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29069996

RESUMO

To develop novel therapies for clinical treatments, it increasingly depends on sophisticated delivery systems that facilitate the drugs entry into targeting cells. Profound understanding of cellular uptake routes for transporting carriers promotes the optimization of performance in drug delivery systems. Although endocytic pathway is the most important part of cellular uptake routes for many delivery systems, it suffers the trouble of enzymatic degradation of transporting carriers trapped in endosomes/lysosomes. Therefore, it is desirable to develop alternative transporting methods for delivery systems via non-endocytic pathways to achieve more effective intracellular delivery. In this review, we summarize the literature exploring transporting carriers that mediate intracellular delivery via non-endocytic pathways to present the current research status in this field. Cell-penetrating peptides, pH (low) insertion peptides, and nanoparticles are categorized to exhibit their ability to directly transport various cargos into cytoplasm via non-endocytic uptake in different cell lines. It is hoped that this review can spur the interesting on development of drug delivery systems via non-endocytic uptake pathway.


Assuntos
Transporte Biológico/fisiologia , Portadores de Fármacos/metabolismo , Endocitose/fisiologia , Nanopartículas/metabolismo , Peptídeos Penetradores de Células/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Endossomos/metabolismo , Endossomos/fisiologia , Humanos
10.
Biomed Pharmacother ; 93: 480-489, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28668767

RESUMO

Metabolomics facilitates investigation of the mechanisms of disease and screening for biomarkers. Here, a gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomics approach was employed to identify plasma biomarkers of acute liver failure (ALF) in pigs. Blood was collected from pigs at 12h intervals during ALF. Hepatic injury was quantified by determining liver function and histopathology. Based on a multivariate data matrix and pattern recognition, two upregulated metabolites, namely, amino acids and conjugated bile acids, and two downregulated metabolites, lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs), were identified. All of these metabolites showed a strong relationship with the extent of liver injury. Amino acids were biomarkers of the severity of liver impairment, conjugated bile acids were predictive of early stage liver damage, and LPCs and PCs were related to the prognosis of liver injury. In conclusion, our results demonstrated the occurrence of marked metabolic disturbances during ALF and that integrated metabolomics analysis facilitates identification of biomarkers of disease.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Falência Hepática Aguda/sangue , Falência Hepática Aguda/metabolismo , Metaboloma , Animais , Biomarcadores/sangue , Galactosamina , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Redes e Vias Metabólicas , Metabolômica , Análise Multivariada , Sus scrofa
11.
Mol Cell Proteomics ; 16(7): 1188-1199, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28336726

RESUMO

Acute liver failure (ALF) is a fatal condition hallmarked by rapid development. The present study aimed to describe the dynamic alterations of serum proteins associated with ALF development, and to seek for novel biomarkers of ALF. Miniature pigs (n = 38) were employed to establish ALF models by infusing d-galactosamine (GALN, 1.3 g/kg). A total of 1310 serum proteins were compared in pooled serum samples (n = 10) before and 36 h after GALN administration through label-free quantitation (LFQ) based shotgun proteomics. Functional analysis suggested a significant enrichment of ALF-related proteins involved in energy metabolism. Temporal changes of 20 energy metabolism related proteins were investigated in individual pigs (n = 8) via parallel reaction monitoring (PRM) based targeted proteomics. In addition, mitochondrion degeneration and gene expression alteration of aerobic metabolism genes were confirmed in GALN-insulted pig liver. In clinical validation study enrolled 34 ALF patients and 40 healthy controls, fructose-1,6-bisphosphatase 1 (FBP1) showed a prognostic value for short-term survival (30 days) equal to that of the Model of End-stage Liver Disease score (ROC-AUC = 0.778). Survival analysis suggested significantly higher death-related hazard in ALF patients with higher FBP1 levels (>16.89 µg/dL) than in those with lower FBP1 levels (p = 0.002). Additionally, serum retinol binding protein 4 (RBP4) level was found decreased prior to ALT elevation in GALN-insulted pig model. We also confirmed that serum level of RBP4 is significantly lower in ALF patients (p < 0.001) as compared with healthy controls. In summary, this translational study, displayed by multistaged proteomics techniques, unveiled underlying functional changes related to the development of ALF and facilitated the discovery of novel ALF markers.


Assuntos
DNA Helicases/sangue , Proteínas de Ligação a DNA/sangue , Falência Hepática Aguda/metabolismo , Proteômica/métodos , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Adulto , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Metabolismo Energético , Feminino , Galactosamina/efeitos adversos , Regulação da Expressão Gênica , Humanos , Falência Hepática Aguda/sangue , Falência Hepática Aguda/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Prognóstico , Proteínas de Ligação a RNA , Análise de Sobrevida , Suínos , Porco Miniatura
12.
BMC Plant Biol ; 17(1): 16, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28100173

RESUMO

BACKGROUND: Seed germination is important to soybean (Glycine max) growth and development, ultimately affecting soybean yield. A lower seed field emergence has been the main hindrance for breeding soybeans low in phytate. Although this reduction could be overcome by additional breeding and selection, the mechanisms of seed germination in different low phytate mutants remain unknown. In this study, we performed a comparative transcript analysis of two low phytate soybean mutants (TW-1 and TW-1-M), which have the same mutation, a 2 bp deletion in GmMIPS1, but show a significant difference in seed field emergence, TW-1-M was higher than that of TW-1 . RESULTS: Numerous genes analyzed by RNA-Seq showed markedly different expression levels between TW-1-M and TW-1 mutants. Approximately 30,000-35,000 read-mapped genes and ~21000-25000 expressed genes were identified for each library. There were ~3900-9200 differentially expressed genes (DEGs) in each contrast library, the number of up-regulated genes was similar with down-regulated genes in the mutant TW-1and TW-1-M. Gene ontology functional categories of DEGs indicated that the ethylene-mediated signaling pathway, the abscisic acid-mediated signaling pathway, response to hormone, ethylene biosynthetic process, ethylene metabolic process, regulation of hormone levels, and oxidation-reduction process, regulation of flavonoid biosynthetic process and regulation of abscisic acid-activated signaling pathway had high correlations with seed germination. In total, 2457 DEGs involved in the above functional categories were identified. Twenty-two genes with 20 biological functions were the most highly up/down- regulated (absolute value Log2FC >5) in the high field emergence mutant TW-1-M and were related to metabolic or signaling pathways. Fifty-seven genes with 36 biological functions had the greatest expression abundance (FRPM >100) in germination-related pathways. CONCLUSIONS: Seed germination in the soybean low phytate mutants is a very complex process, which involves a series of physiological, morphological and transcriptional changes. Compared with TW-1, TW-1-M had a very different gene expression profile, which included genes related to plant hormones, antioxidation, anti-stress and energy metabolism processes. Our research provides a molecular basis for understanding germination mechanisms, and is also an important resource for the genetic analysis of germination in low phytate crops. Plant hormone- and antioxidation-related genes might strongly contribute to the high germination rate in the TW-1-M mutant.


Assuntos
Genoma de Planta , Ácido Fítico/metabolismo , Proteínas de Plantas/genética , Sementes/genética , Soja/genética , Soja/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Mutação , Ácido Fítico/análise , Proteínas de Plantas/metabolismo , Sementes/química , Sementes/crescimento & desenvolvimento , Sementes/metabolismo , Soja/química , Soja/crescimento & desenvolvimento
13.
Cancer Med ; 6(2): 452-462, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28064447

RESUMO

The occurrence of an inherent or acquired resistance to temozolomide (TMZ) is a major burden for patients suffering from glioma. Recently, studies have demonstrated that microRNAs play an important role in the regulation of tumor properties in cancers. However, whether miR-497 contributes to glioma resistance to chemotherapy is not fully understood. In this study, we showed that the expression of miR-497 was markedly up-regulated in TMZ-resistant glioma cells; high miR-497 expression level was associated with TMZ-resistant phenotype of glioma cells. The down-regulation of miR-497 in glioma cells enhanced the apoptosis-induction and growth inhibition effects of TMZ both in vitro and in vivo, whereas promotion of miR-497 increased the chemosensitization of glioma cells to TMZ. The increased level of miR-497 in TMZ-resistant glioma cells was concurrent with the up-regulation of insulin-like growth factor 1 receptor (IGF1R)/insulin receptor substrate 1 (IRS1) pathway-related proteins, that is, IGF1R, IRS1, mammalian target of rapamycin (mTOR), and Bcl-2. In addition, the knockdown of mTOR and Bcl-2 reduced the tolerance of glioma cells to TMZ. Our results demonstrated that overexpression of miR-497 is significantly correlated with TMZ resistance in glioma cells by regulating the IGF1R/IRS1 pathway. Therefore, miR-497 may be used as a new target for treatment of chemotherapy-resistant glioma.


Assuntos
Neoplasias Encefálicas/genética , Resistencia a Medicamentos Antineoplásicos , Glioma/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Serina-Treonina Quinases TOR/genética , Regulação para Cima , Regiões 3' não Traduzidas , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Camundongos , Transdução de Sinais , Temozolomida
14.
Int J Mol Med ; 39(1): 101-112, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27959388

RESUMO

Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two­dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases.


Assuntos
Indóis/farmacologia , Fígado/metabolismo , Tiazóis/farmacologia , Triptofano/metabolismo , Alginatos/química , Western Blotting , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Humanos , Fígado/efeitos dos fármacos , Microesferas , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
Int Immunopharmacol ; 39: 63-70, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27424080

RESUMO

The RNA-binding protein tristetraprolin (TTP) is an adenine/uridine (AU)-rich elements (AREs)-binding protein that can induce the decay of AREs containing mRNAs. In this study, we demonstrated that TTP is significantly down-regulated in human glioma tissue samples and cell lines. It is also associated with diminished survival in glioma patients. Gain- and loss-of-function studies demonstrated that TTP inhibited the growth, migration and invasion of glioma cells through regulation of interleukin (IL)-13. Furthermore, mechanistic investigations showed that TTP attenuated activation of PI3K/Akt/mTOR pathway by IL-13, and the ectopic expression of IL-13 markedly abrogated the anti-invasive effect of TTP. Additionally, TTP were found inversely correlated with IL-13 in glioma specimens. In conclusion, our results suggested that the low expression of TTP is significantly associated with the growth and metastasis of human glioma cells by targeting IL-13, while TTP may be a potential therapeutic target for glioma treatment.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Interleucina-13/metabolismo , Tristetraprolina/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Engenharia Genética , Glioma/mortalidade , Glioma/patologia , Humanos , Interleucina-13/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estadiamento de Neoplasias , Transdução de Sinais/genética , Análise de Sobrevida , Tristetraprolina/genética
16.
Int J Oncol ; 49(2): 589-602, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27221337

RESUMO

Hepatocellular carcinoma (HCC) is a common solid tumor worldwide with a poor prognosis. Accumulating evidence has implicated important regulatory roles of epigenetic modifications in the occurrence and progression of HCC. In the present study, we analyzed 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) levels in the tumor tissues and paired adjacent peritumor tissues (APTs) from four individual HCC patients using a (hydroxy)methylated DNA immunoprecipitation approach combined with deep sequencing [(h)MeDIP-Seq]. Bioinformatics analysis revealed that the 5-mC levels in the promoter regions of 2796 genes and the 5-hmC levels in 507 genes differed significantly between HCC tissues and APTs. These differential genes were grouped into various clusters and pathways and found to be particularly enriched in the 'metabolic pathways' that include 'Glycolysis/gluconeogenesis', 'Oxidative phosphorylation' and 'Citrate cycle (TCA cycle)', implicating a potential role of metabolic alterations in HCC. Furthermore, 144 genes had both 5-mC and 5-hmC changes in HCC patients, and 10 of them (PCNA, MDM2, STAG1, E2F4, FGF4, FGF19, RHOBTB2, UBE2QL1, DCN and HSP90AA1) were enriched and interconnected in five pathways including the 'Cell cycle', 'Pathway in cancer', 'Ubiquitin mediated proteolysis', 'Melanoma' and 'Prostate cancer' pathways. The genome-wide mapping of 5-mC and 5-hmC in HCC tissues and APTs indicated that both 5-mC and 5-hmC epigenetic modifications play important roles in the regulation of HCC, and there may be some interconnections between them. Taken together, in the present study we conducted the first genome-wide mapping of DNA methylation combined with hydroxymethylation in HBV-related HCC and provided a series of potential novel epigenetic biomarkers for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Metilação de DNA , Hepatite B Crônica/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Carcinoma Hepatocelular/metabolismo , Estudo de Associação Genômica Ampla , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/metabolismo , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/metabolismo , Regiões Promotoras Genéticas
17.
Chemphyschem ; 17(14): 2256-62, 2016 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-27062329

RESUMO

The degree of oxidation of conducting polymers has great influence on their thermoelectric properties. Free-standing poly(3-methylthiophene) (P3MeT) films were prepared by electrochemical polymerization in boron trifluoride diethyl etherate, and the fresh films were treated electrochemically with a solution of propylene carbonate/lithium perchlorate as mediator. The conductivity of the resultant P3MeT films depends on the doping level, which is controlled by a constant potential from -0.5 to 1.4 V. The optimum electrical conductivity (78.9 S cm(-1) at 0.5 V) and a significant increase in the Seebeck coefficient (64.3 µV K(-1) at -0.5 V) are important for achieving an optimum power factor at an optimal potential. The power factor of electrochemically treated P3MeT films reached its maximum value of 4.03 µW m(-1) K(-2) at 0.5 V. Moreover, after two months, it still exhibited a value of 3.75 µW m(-1) K(-2) , and thus was more stable than pristine P3MeT due to exchange of doping ions in films under ambient conditions. This electrochemical treatment is a significant alternative method for optimizing the thermoelectric power factor of conducting polymer films.

18.
Biotechnol Lett ; 38(6): 909-17, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26943346

RESUMO

OBJECTIVES: To determine the optimal storage solution containing suitable protective agents for the preservation of microencapsulated hepatocytes at 4 °C as well as the optimum incubation time after hypothermic preservation. RESULTS: L15 was the optimum solution for both maintaining microcapsule integrity and cell viability. Furthermore, 5 %(v/v) PEG (20 or 35 kDa) added to Leibovitz-15 medium was optimal for microencapsulated C3A cells, enhancing cell viability and liver-specific functions, including albumin and urea synthesis as well as CYP1A2 and CYP3A4 activities. The transcription levels of several CYP450-related genes were also dramatically increased in cells incubated in the optimal solution. Pre-incubation for 2 h was the optimal time for restoring favorable levels of CYP1A2 and CYP3A4 activities in microencapsulated C3A cells for short term, 2 day storage. CONCLUSIONS: Leibovitz-15 medium supplemented with 5 % (v/v) PEG is a promising cold solution for microencapsulated hepatocytes at 4 °C, with an incubation of 2 h at 37 °C after hypothermic preservation being the best incubation duration for further cell application.


Assuntos
Criopreservação/métodos , Meios de Cultura , Hepatócitos/fisiologia , Sobrevivência Celular , Crioprotetores/farmacologia , Meios de Cultura/química , Meios de Cultura/farmacologia , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP3A , Composição de Medicamentos , Regulação da Expressão Gênica , Hepatócitos/efeitos dos fármacos , Humanos , Polietilenoglicóis/farmacologia
19.
Hepatobiliary Pancreat Dis Int ; 15(2): 173-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27020634

RESUMO

BACKGROUND: Differentiation of liver progenitor cells (LPCs) to functional hepatocytes holds great potential to develop new strategies for hepatocyte transplantation and the screening of drug-induced cytotoxicity. However, reports on the efficient and convenient hepatic differentiation of LPCs to hepatocytes are few. The present study aims to investigate the possibility of generating functional hepatocytes from LPCs in an indirect co-culture system. METHODS: Mouse LPCs were co-cultured in Transwell plates with an immortalized human hepatic stellate cell line (HSC-Li) we previously established. The morphology, expression of hepatic markers, and functions of mouse LPC-derived cells were monitored and compared with those of conventionally cultured LPCs. RESULTS: Co-culturing with HSC-Li cells induced differentiation of mouse LPCs into functional hepatocyte-like cells. The differentiated cells were morphologically transformed into hepatocyte-like cells 3 days after co-culture initiation. In addition, the differentiated cells expressed liver-specific genes and possessed hepatic functions, including glycogen storage, low-density lipoprotein uptake, albumin secretion, urea synthesis, and cytochrome P450 1A2 enzymatic activity. CONCLUSIONS: Our method, which employs indirect co-culture with HSC-Li cells, can efficiently induce the differentiation of LPCs into functional hepatocytes. This finding suggests that this co-culture system can be a useful method for the efficient generation of functional hepatocytes from LPCs.


Assuntos
Diferenciação Celular , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Comunicação Parácrina , Células-Tronco/metabolismo , Albuminas/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular , Forma Celular , Técnicas de Cocultura , Meios de Cultivo Condicionados/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Regulação da Expressão Gênica , Glicogênio/metabolismo , Humanos , Lipoproteínas LDL/metabolismo , Fígado/citologia , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Fatores de Tempo , Ureia/metabolismo
20.
PLoS One ; 11(3): e0150504, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26930632

RESUMO

BACKGROUND: Suaeda glauca, a succulent halophyte of the Chenopodiaceae family, is widely distributed in coastal areas of China. Suaeda glauca is highly resistant to salt and alkali stresses. In the present study, the salt-responsive transcriptome of Suaeda glauca was analyzed to identify genes involved in salt tolerance and study halophilic mechanisms in this halophyte. RESULTS: Illumina HiSeq 2500 was used to sequence cDNA libraries from salt-treated and control samples with three replicates each treatment. De novo assembly of the six transcriptomes identified 75,445 unigenes. A total of 23,901 (31.68%) unigenes were annotated. Compared with transcriptomes from the three salt-treated and three salt-free samples, 231 differentially expressed genes (DEGs) were detected (including 130 up-regulated genes and 101 down-regulated genes), and 195 unigenes were functionally annotated. Based on the Gene Ontology (GO), Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) classifications of the DEGs, more attention should be paid to transcripts associated with signal transduction, transporters, the cell wall and growth, defense metabolism and transcription factors involved in salt tolerance. CONCLUSIONS: This report provides a genome-wide transcriptional analysis of a halophyte, Suaeda glauca, under salt stress. Further studies of the genetic basis of salt tolerance in halophytes are warranted.


Assuntos
Chenopodiaceae/genética , Perfilação da Expressão Gênica/métodos , Plantas Tolerantes a Sal/genética , Análise de Sequência de RNA/métodos , Chenopodiaceae/fisiologia , DNA de Plantas/genética , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Biblioteca Gênica , Reação em Cadeia da Polimerase em Tempo Real , Plantas Tolerantes a Sal/fisiologia
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