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1.
Med Sci Monit ; 27: e927624, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33436534

RESUMO

BACKGROUND Traditional Chinese medicine has widely used Bolbostemma paniculatum to treat diseases, including cancer, but its underlying mechanisms remain unclear. The present study aimed to elucidate the potential pharmacological mechanisms of "Tu Bei Mu" (TBM), the Chinese name for Bolbostemmatis Rhizoma, the dry tuber of B. paniculatum, for the treatment of hepatocellular carcinoma (HCC). MATERIAL AND METHODS The active components and putative therapeutic targets of TBM were explored using SwissTargetPrediction, Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and Search Tool for Interactions of Chemicals (STITCH). The HCC-related target database was built using DrugBank, DisGeNet, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD). A protein-protein interaction network of the common targets was constructed, based on the matches between TBM potential targets and HCC-related targets, using Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the cluster networks were used to elucidate the biological functions of TBM. RESULTS Pharmacological network diagrams of the TBM compound-target network and HCC-related target network were successfully constructed. A total of 22 active components, 191 predicted biological targets of TBM, and 3775 HCC-related targets were identified. Through construction of an HCC-related target database and a protein-protein interaction network of the common targets, TBM was predicted to be effective in treating HCC mainly through the PI3K-Akt, HIF-1, p53, and PPAR signaling pathways. CONCLUSIONS The PI3K/Akt, HIF1, p53, and PPAR pathways may play vital roles in TBM treatment of HCC. Also, the potential anti-cancer effect of TBM on HCC appears to stem from the synergetic effect of multiple targets and mechanisms.

2.
Rice (N Y) ; 13(1): 77, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33180206

RESUMO

BACKGROUND: Long non-coding RNAs (LncRNAs) have emerged as important regulators in many physiological processes in plant. By high-throughput RNA-sequencing, many pathogen-associated LncRNAs were mapped in various plants, and some of them were proved to be involved in plant defense responses. The rice blast disease caused by Magnaporthe oryzae (M. oryzae) is one of the most destructive diseases in rice. However, M. oryzae-induced LncRNAs in rice is yet to be studied. FINDINGS: We investigated rice LncRNAs that were associated with the rice blast fungus. Totally 83 LncRNAs were up-regulated after blast fungus infection and 78 were down-regulated. Of them, the natural antisense transcripts (NATs) were the most abundant. The expression of some LncRNAs has similar pattern with their host genes or neighboring genes, suggesting a cis function of them in regulating gene transcription level. The deferentially expressed (DE) LncRNAs and genes co-expression analysis revealed some LncRNAs were associated with genes known to be involved in pathogen resistance, and these genes were enriched in terpenoid biosynthesis and defense response by Gene Ontology (GO) enrichment analysis. Interestingly, one of up-regulated DE-intronic RNA was derived from a jasmonate (JA) biosynthetic gene, lipoxygenase RLL (LOX-RLL). Levels of JAs were significantly increased after blast fungus infection. Given that JA is known to regulate blast resistance in rice, we suggested that LncRNA may be involved in JA-mediated rice resistance to blast fungus. CONCLUSIONS: This study identified blast fungus-responsive LncRNAs in rice, which provides another layer of candidates that regulate rice and blast fungus interactions.

3.
J Cell Mol Med ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33145962

RESUMO

Recent studies have demonstrated a marked decrease in peripheral lymphocyte levels in patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Few studies have focused on the changes of NK, T- and B-cell subsets, inflammatory cytokines and virus-specific antibodies in patients with moderate COVID-19. A total of 11 RT-PCR-confirmed convalescent patients with COVID-19 and 11 patients with non-SARS-CoV-2 pneumonia (control patients) were enrolled in this study. NK, CD8+ T, CD4+ T, Tfh-like and B-cell subsets were analysed using flow cytometry. Cytokines and SARS-CoV-2-specific antibodies were analysed using an electrochemiluminescence immunoassay. NK cell counts were significantly higher in patients with COVID-19 than in control patients (P = 0.017). Effector memory CD8+ T-cell counts significantly increased in patients with COVID-19 during a convalescent period of 1 week (P = 0.041). TIM-3+ Tfh-like cell and CD226+ Tfh-like cell counts significantly increased (P = 0.027) and decreased (P = 0.022), respectively, during the same period. Moreover, ICOS+ Tfh-like cell counts tended to decrease (P = 0.074). No abnormal increase in cytokine levels was observed. The high expression of NK cells is important in innate immune response against SARS-CoV-2. The increase in effector memory CD8+ T-cell counts, the up-regulation of inhibitory molecules and the down-regulation of active molecules on CD4+ T cells and Tfh-like cells in patients with COVID-19 would benefit the maintenance of balanced cellular and humoural immune responses, may prevent the development of severe cases and contribute to the recovery of patients with COVID-19.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31809961

RESUMO

Individualized therapy involves genetic test of drug metabolism, which provides information about the initial dose and therapeutic drug monitoring for adjusting the subsequent dose. Consequently, toxic side effects are expected to be minimized and therapeutic effects to be maximized. In this study, an ultra-performance liquid chromatography tandem mass spectrometry method that was specific, accurate and sensitive was developed to simultaneously determine azathioprine two metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methyl-mercaptopurine riboside (6-MMPr) in the whole blood lysate. We precipitated the sample by trifluoroacetic acid under the protection of dithiothreitol, with 6-MMPr and 6-TGN being hydrolyzed to produce 6-methymercaptopurine and 6-thioguanine. In the chromatographic separation, Waters ACQUITY BEH C18 (2.1 × 100 mm, 1.7 µm) chromatographic column was applied and gradient elution was conducted with 0.02 mol/L ammonium acetate buffer (which contains 0.3% formic acid) and acetonitrile at a flow rate of 0.4 ml/min. Tandem mass spectrometry in multiple reaction monitoring mode was applied for detection via electrospray ionization source in positive ionization mode. The analyzing process lasted for no more than 2 min. The calibration curve for each metabolite fitted a least squares model (weighed 1/X) from 1.25 to 5000 ng/ml (r2 > 0.99). The ion pairs were detected as 6-MMP m/z 167.07 â†’ 152.15, 6-TG m/z 168.06 â†’ 134.13, and internal standard m/z 171.07 â†’ 137.14. Under the guidance of FDA guidelines for bioanalytical method validation, we carried out validation and obtained satisfactory results. The method was successfully utilized for monitoring the concentrations of each metabolite from 65 affected patients who had received azathioprine maintenance therapy and achieved optimal results.


Assuntos
Azatioprina/sangue , Azatioprina/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodos , Adulto , Feminino , Nucleotídeos de Guanina/sangue , Nucleotídeos de Guanina/metabolismo , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Metiltioinosina/sangue , Metiltioinosina/metabolismo , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Tionucleotídeos/sangue , Tionucleotídeos/metabolismo
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(6): 1912-1918, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31839059

RESUMO

OBJECTIVE: To explore the effect of the expression regulation of mitotic control protein DIS3 on the proliferation ability of 3 cell Lines of human myeloma. METHODS: Human myeloma cell lines NCI-h929, RPMI 8226 and U266B1 were selected as study objects, and the over-expression vector of DIS3 gene and DIS3-siRNA were designed and constructed, respectively. The cell experiments were divided into 5 groups: control, DIS3 over-expression-empty vector, DIS3-siRNA negative control, DIS3 over-expression and DIS3-siRNA group. After culture for 24 h, 48 h and 72 h, the proliferation capacity of these three cell lines was measured by MTT assay. And cell samples were collected after culture for 72 h, the expression of proliferation cell nuclear antigen (PCNA) was detected by RT-qPCR and Western blot. RESULTS: MTT assay results showed that the proliferation capacity of cells in DIS3 over-expression group was significantly reduced, as compared with the DIS3 over-expression-empty vector group at the same time point (24, 48 or 72 h) (P<0.05, P<0.01). Compared with DIS3-siRNA negative control group at the same time point (24, 48 or 72 h), the proliferation capacity of cells in the DIS3-siRNA group significantly increased (P<0.05, P<0.01). The results of RT-qPCR and Western blot showed that the mRNA and protein expression levels of PCNA in cells of DIS3 over-expression group were significantly reduced, as compared with DIS3 over-expression empty vector group (P<0.01). Compared with the DIS3-siRNA negative control group, the mRNA and protein expression of PCNA in the cells of DIS3-siRNA group very significantly increased (P<0.01). CONCLUSION: Over expression of DIS3 can significantly reduce the proliferation ability of 3 cell lines of human myeloma, which may be closely related with reducing PCNA expression.


Assuntos
Mieloma Múltiplo , Linhagem Celular Tumoral , Proliferação de Células , Complexo Multienzimático de Ribonucleases do Exossomo , Humanos , RNA Interferente Pequeno , Transfecção
6.
Ann Transplant ; 24: 594-604, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712547

RESUMO

BACKGROUND Tacrolimus is a widely used immunosuppressant in renal transplant recipients. It was demonstrated in rats and healthy volunteers that Wuzhi capsules could inhibit metabolism and maintain blood concentration of tacrolimus. However, there are no clinical studies of Wuzhi capsules in renal transplant recipients. This research aimed to assess the effect of Wuzhi capsules on the blood concentration of tacrolimus in renal transplant recipients. MATERIAL AND METHODS A total of 158 Chinese renal transplant recipients receiving tacrolimus with or without Wuzhi capsules were included in this retrospective study. The cohort study included 126 recipients, with 86 recipients receiving Wuzhi capsules (WZCs) and the other 40 recipients not receiving WZCs. Another 32 recipients were involved in a self-control study. RESULTS Dose- and body weight-adjusted trough concentrations (C0/D/W) of tacrolimus in the WZC group were found to be significantly higher than that in the non-WZC group (P<0.05). The improvement of C0/D/W by administration of Wuzhi capsules was more significant in CYP3A5 expressers than in non-expressers following subgroup analysis. Furthermore, the WZC group had a remarkably higher proportion of subjects who reached target tacrolimus concentration than in the non-WZC group, both in CYP3A5 expressers (P=0.01) and non-expressers (P<0.001). Multiple linear regression analysis and self-control analysis confirmed the positive impact of Wuzhi capsules on tacrolimus concentration (P<0.001). CONCLUSIONS Wuzhi capsules can increase tacrolimus trough concentration without adverse effects on allograft function, especially in CYP3A5 expressers. Efficient and convenient immunosuppressive effects on renal transplant recipients can be achieved by treatment including administration of Wuzhi capsules.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Transplante de Rim , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Adulto , Cápsulas , Estudos de Coortes , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Feminino , Humanos , Imunossupressores/farmacocinética , Doadores Vivos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Tacrolimo/farmacocinética , Adulto Jovem
7.
BMC Nephrol ; 20(1): 291, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375084

RESUMO

BACKGROUND: Neutrophil gelatinase-assoicated lipocalin (NGAL) appears to be a promising proximal tubular injury biomarker for early prediction of delayed graft function (DGF) in kidney transplant recipients. However, its predictive values in urine and blood were varied among different studies. Here, we performed the meta-analysis to compare the predictive values of urine NGAL (uNGAL) and blood NGAL (bNGAL) for DGF in adult kidney transplant recipients. METHODS: We systematically searched Medline, Cochrane library and Embase for relevant studies from inception to May 2018. The summary receiver operating characteristic (SROC) curves, the pooled sensitivity, specificity and diagnostic odds ratio (DOR) were used to evaluate the prognostic performance of uNGAL and bNGAL for the identification of DGF. RESULTS: A total of 1036 patients from 14 eligible studies were included in the analysis. 8 studies focused on NGAL in urine and 6 reported NGAL in serum or plasma. The composite area under the ROC (AUC) for 24 h uNGAL was 0.91 (95% CI, 0.89-0.94) and the overall DOR for 24 h uNGAL was 24.17(95% CI, 9.94-58.75) with a sensitivity of 0.88 (95% CI, 0.75-0.94) and a specificity of 0.81 (95% CI, 0.68-0.89). The composite AUC for 24 h bNGAL was 0.95 (95% CI, 0.93-0.97) and the overall DOR for 24 h bNGAL was 43.11 (95% CI, 16.43-113.12) with a sensitivity of 0.91 (95% CI, 0.81-0.96) and a specificity of 0.86 (95% CI, 0.78-0.92). CONCLUSIONS: Urine and serum/plasma NGAL were valuable biomarkers for early identification of DGF in kidney transplantation. In addition, the bNGAL was superior to uNGAL in early prediction of DGF.


Assuntos
Função Retardada do Enxerto/sangue , Função Retardada do Enxerto/urina , Transplante de Rim/efeitos adversos , Lipocalina-2/sangue , Lipocalina-2/urina , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/urina , Adulto , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/urina , Função Retardada do Enxerto/diagnóstico , Humanos , Estudos Observacionais como Assunto , Complicações Pós-Operatórias/diagnóstico , Valor Preditivo dos Testes , Sensibilidade e Especificidade
8.
Int Immunopharmacol ; 75: 105803, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401383

RESUMO

Infection remains a major cause of morbidity and mortality after kidney transplantation (KT). Reliable biomarkers to predict post-transplant infection are lacking. We investigated the predictive performance of pre- and post-transplant levels of T-cell immunoglobulin and mucin domain-3 (Tim-3) and Galectin-9 (Gal-9), two pleiotropic immunomodulatory molecules, in early identification of infection. Serum Tim-3 and Gal-9 were paired measured before and 30 days after transplantation (PTD 30) in 95 KT recipients (KTRs). The decline rates of Tim-3 and Gal-9 were calculated relative to pre-transplant levels. KTRs with infection history had significantly higher levels of PTD 30 Tim-3 and Gal-9, and slower decrease rates of Gal-9 compared to non-infected recipients, while no difference was observed between two groups regarding pre-transplant levels. The AUCs for predicting 1-year post-transplant infection were 0.653 and 0.711 for post-transplant Tim-3 and Gal-9, 0.664 and 0.670 for relative Tim-3 and Gal-9, respectively. After adjusting for potential confounders, PTD 30 Tim-3, Gal-9 and relative Gal-9 remained as independent risk factors for post-transplant infection. Our results suggested that PTD 30 Tim-3 and Gal-9 and relative decrease of Gal-9 were promising predictors for identifying KTRs with high risk of infection, while pre-transplant Tim-3 and Gal-9 showed no predictive power to infection.


Assuntos
Galectinas/sangue , Receptor Celular 2 do Vírus da Hepatite A/sangue , Infecções/sangue , Transplante de Rim , Complicações Pós-Operatórias/sangue , Adulto , Feminino , Humanos , Masculino , Risco
9.
Medicine (Baltimore) ; 98(3): e14137, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30653146

RESUMO

The aim of this study was to investigate the correlation between CYP2C19 genotype and dose-adjusted voriconazole (VCZ) trough concentrations (C0/dose).We analyzed the correlation between CYP2C192(681G>A), CYP2C193(636G>A), and CYP2C1917(-806C>T) genetic polymorphisms and the dose-corrected pre-dose concentration (C0/dose) in 106 South-western Chinese Han patients.The frequencies of variant alleles of CYP2C192, 3, and 17 were 29.7%, 4.25%, and 0.92%. For 49.3% of the VCZ samples, the therapeutic window between 1.5 and 5.5 µg/ml was reached. Following the first dose VCZ measurement, in subsequent samples the proportion of VCZ C0 within the therapeutic window increased, suggesting effective therapeutic drug monitoring (TDM) (P = .001). The VCZ C0 was significantly different (P = .010) between patients with normal metabolism (NMs), intermediate metabolism (IMs), and poor metabolism (PMs). The VZC C0/dose was 12.2 (interquartile range (IQR), 8.33-18.2 µg·ml/kg·day), and 7.68 (IQR, 4.07-16.3 µg·ml/kg·day) in PMs and IMs patients, respectively, which was significantly higher than in NMs phenotype patients (4.68; IQR, 2.51-8.87 µg·ml/kg·day, P = .008 and P = .014).This study demonstrated that the VCZ C0/dose was significantly influenced by the CYP2C19 genotype in South-western Chinese Han patients. In this patient population, more over-exposure was observed in patients with a CYP2C19 genotype associated with poor or intermediate metabolism. CYP2C19 genotype-based dosing combined with TDM will support individualization of VCZ dosing, and potentially will minimize toxicity and maximize therapeutic efficacy.


Assuntos
Antifúngicos/administração & dosagem , Citocromo P-450 CYP2C19/genética , Monitoramento de Medicamentos/métodos , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/administração & dosagem , Adulto , Alelos , Antifúngicos/sangue , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Feminino , Genótipo , Humanos , Infecções Fúngicas Invasivas/genética , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Fenótipo , Polimorfismo Genético , Estudos Retrospectivos , Voriconazol/sangue
10.
Arthritis Res Ther ; 20(1): 200, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157931

RESUMO

BACKGROUND: Follicular helper T (Tfh) cells are specialized in helping B lymphocytes, which play a central role in autoimmune diseases that have a major B cell component, such as in rheumatoid arthritis (RA). Follicular regulatory T (Tfr) cells control the over-activation of Tfh and B cells in germinal centers. Dysregulation of Tfh cells and Tfr cells has been reported to be involved in the pathogenesis of some autoimmune diseases. However, the balance of Tfh and Tfr cells, and their roles in the development and progression of RA are still not clear. METHODS: In this study, we enrolled 44 patients with RA (20 patients with active RA and 24 patients with inactive RA) and 20 healthy controls, and analyzed the frequencies of circulating Tfh and Tfr cells, expression of programmed death-1 (PD-1), inducible co-stimulator (ICOS), intracellular IL-21, and pSTAT3 in Tfh cells, and serum levels of IL-6. The correlation among these parameters and that of Tfh or Tfr cells with disease activity were also analyzed. RESULTS: Patients with RA (especially active RA) had higher frequencies of Tfh cells, but lower percentages of Tfr cells, thereby resulting in elevated ratios of Tfh/Tfr. Expression levels of PD-1 and IL-21 in Tfh cells were higher in patients with RA than in healthy subjects, while no difference in ICOS expression was observed between patients and controls. Both pSTAT3 expression and serum IL-6 levels increased in patients with RA, and positive correlation between them was observed. Additionally, pSTAT3 expression was positively correlated with Tfh cell frequency. The Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP) was negatively correlated with Tfr cell frequency, but was positively correlated with both Tfh/Tfr ratio and PD-1 expression. CONCLUSIONS: Results demonstrated that enhanced IL-6/pSTAT3 signaling may contribute to promotion of Tfh cells, consequently skewing the ratio of Tfh to Tfr cells, which may be crucial for disease progression in RA.


Assuntos
Artrite Reumatoide/metabolismo , Interleucina-6/sangue , Fator de Transcrição STAT3/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto , Artrite Reumatoide/sangue , Feminino , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação , Receptor de Morte Celular Programada 1/metabolismo
11.
Ann Transplant ; 23: 300-309, 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29735966

RESUMO

BACKGROUND We investigated whether a low fixed Tac starting dose regimen could lead to a better achievement of Tac target concentrations, as well as an effective immunosuppressive treatment, in Chinese kidney transplant recipients (KTRs). MATERIAL AND METHODS We collected whole-blood and serum samples from 189 KTRs and the Tac starting dose was 2, 2.5, or 3 mg/day. Information on Tac C0, dose, body weight, body mass index (BMI), Scr, eGFR, and CYP3A5 genotypes were collected from a routine therapeutic drug monitoring database. The correlation between Tac C0 and body weight (or BMI) was investigated by calculating the goodness of fit. Multivariable logistic regression was performed to estimate the independent associated factors. RESULTS The patients with 3 mg per day of Tac had higher C0 at day 7 compared to those with 2 or 2.5 mg. For patients receiving the same Tac starting dose, no significant difference was found in Tac C0 at day 7 among different body weight or BMI groups. There was no significant difference in Scr or eGFR at 1 year after transplant, nor was there a significant difference in the rates of DGF or AR at post-transplant day 30 among different Tac starting dose groups or among the 3 Tac C0 range groups. CYP3A5 genotype and Tac initial dose were independently associated with Tac C0. CONCLUSIONS CYP3A5 genotype and Tac initial dose were independently associated with Tac C0 in renal transplant recipients. Our results suggest that a low Tac target C0 range (5-8 ng/ml) with a low fixed starting dose (3 mg/day) would be safe and effective among Chinese KTRs.


Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Tacrolimo/administração & dosagem , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Peso Corporal , China , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Rejeição de Enxerto , Humanos , Imunossupressores/sangue , Transplante de Rim/efeitos adversos , Modelos Logísticos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Tacrolimo/sangue , Transplantados , Adulto Jovem
12.
Front Aging Neurosci ; 10: 34, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535624

RESUMO

Background: A molecular biomarker of physiologic age, as opposed to chronologic age, is needed in clinical medicine. 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGsn) and 8-oxo-7, 8-dihydroguanosine (8-oxoGsn) are two promising aging biomarkers. Methods: A total of 1,228 healthy Chinese residents (613 males and 615 females) 2-90 years of age were randomly selected. Spot urine samples were collected, and the concentrations of 8-oxodGsn and 8-oxoGsn were measured using ultra-high-performance liquid chromatography with a triple quadrupole mass spectrometer (UPLC-MS/MS). Method validation, including accuracy, precision, linearity and quantification limit, was performed. The relationship between oxidized guanosine and age/gender was evaluated. Results: 8-oxodGsn and 8-oxoGsn were eluted at 1.61 and 1.30 min, respectively. The calibration curve was linear in the range of 0.2-500 ng/ml for both analytes. The lowest limit of quantification (LLOQ) was 0.2 ng/ml for 8-oxodGsn and 0.1 ng/ml for 8-oxoGsn. There was an age-dependent increase in the biomarkers from the 21- to 30-year-old group to the 81- to 90-year-old group in both genders. In the subjects older than 61 years of age, the levels of 8-oxodGsn as well as 8-oxoGsn in urine were much higher in females than in males. The content of 8-oxoGsn correlated more closely with age and was higher (approximately 2-fold) than that of 8-oxodGsn for a given individual. Conclusions: 8-oxodGsn and 8-oxoGsn can be easily measured by UPLC-MS/MS. Urinary 8-oxoGsn may be a potential biomarker to determine a person's physiologic age and identify individuals at high risk of developing age-associated disease.

13.
Int Immunopharmacol ; 55: 330-335, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29310109

RESUMO

BACKGROUND: T cell immunoglobulin mucin-3 (Tim-3) has been reported to participate in the regulation of immune response and the induction of allograft tolerance. However, the association between Tim-3 and renal allograft dysfunction is unclear. We studied the expression of cellular and soluble Tim-3 (sTim-3), soluble galectin-9 (sGal-9) and carcinoembryonic antigen-related cell adhesion molecule-1 (sCEACAM-1) in kidney transplantation recipients (KTRs) to explore their roles in allograft dysfunction. METHODS: 96 KTRs (53 with stable graft and 43 with graft dysfunction) and 30 healthy controls (HC) were enrolled. Among the KTRs, 55 used Tacrolimus (TAC) and 41 used Sirolimus (SRL). In the dysfunction group, 29 recipients have undergone graft biopsy and 14 were classified as biopsy-proven rejection (BPR). Cellular Tim-3 was determined by flow cytometry. sTim-3 was determined by ELISA. sGal-9 and sCEACAM-1 were determined by Bio-Plex® suspension array system. RESULTS: KTRs with renal dysfunction showed significantly higher levels of sTim-3 and sGal-9 but similar levels of cellular Tim-3 and sCEACAM-1 compared with stable recipients. Correlation analysis revealed that estimated glomerular filtration rate (eGFR) was negatively associated with sTim-3 and sGal-9. Both BPR and non-BPR groups showed comparable levels of Tim-3, Gal-9 and CEACAM-1. Moreover, SRL group showed significantly higher levels of sCEACAM-1 than TAC and HC groups. CONCLUSIONS: sTim-3 and sGal-9 were promising biomarkers for allograft dysfunction, but unable to differentiate allograft rejection from other causes of renal dysfunction in KTRs. Moreover, long-term administration of sirolimus would up-regulate sCEACAM-1 level, while exert similar regulatory effects on Tim-3 and Gal-9 compared to tacrolimus.


Assuntos
Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Galectinas/metabolismo , Rejeição de Enxerto/diagnóstico , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Nefropatias/diagnóstico , Transplante de Rim , Adulto , Aloenxertos/imunologia , Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Estudos Transversais , Diagnóstico Diferencial , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico
14.
Acta Pharmacol Sin ; 39(8): 1284-1293, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29345253

RESUMO

3-Acetyl-oleanolic acid (3Ac-OA) is a derivative of oleanolic acid (OA), which has shown therapeutic beneficial effects on diabetes and metabolic syndrome. In this study we investigated whether 3Ac-OA exerted beneficial effect on non-alcoholic fatty liver disease (NAFLD) in rats and its potential underlying mechanisms. Treatment with 3Ac-OA (1-100 µmol/L) dose-dependently decreased the intracellular levels of total cholesterol (TC) and triglyceride (TG) in FFA-treated primary rat hepatocytes and human HepG2 cell lines in vitro. Furthermore, oil red staining studies showed that 3Ac-OA caused dose-dependent decrease in the number of lipid droplets in FFA-treated primary rat hepatocytes. SD rats were fed a high fat diet (HFD) for 6 weeks and subsequently treated with 3Ac-OA (60, 30, 15 mg·kg-1·d-1) for 4 weeks. 3Ac-OA administration significantly decreased the body weight, liver weight and serum TC, TG, LDL-C levels in HFD rats. Furthermore, 3AcOA administration ameliorated lipid accumulation and cell apoptosis in the liver of HFD rats. Using adipokine array analyses, we found that the levels of 11 adipokines (HGF, ICAM, IGF-1, IGFBP-3, IGFBP-5, IGFBP-6, lipocalin-2, MCP-1, M-CSF, Pref-1 and RAGE) were increased by more than twofold in the serum of 3Ac-OA-treated rats, whereas ICAM, IGF-1 and lipocalin-2 had levels increased by more than 20-fold. Moreover, 3Ac-OA administration significantly increased the expression of glucose transporter type 2 (GLUT-2) and low-density lipoprotein receptor (LDLR), as well as the phosphorylation of AMP-activated protein kinase (AMPK), protein kinase B (AKT) and glycogen synthase kinase 3ß (GSK-3ß) in the liver tissues of HFD rats. In conclusion, this study demonstrates that 3Ac-OA exerts a protective effect against hyperlipidemia in NAFLD rats through AMPK-related pathways.


Assuntos
Hiperlipidemias/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Triterpenos/uso terapêutico , Adipocinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos não Esterificados/efeitos adversos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Gotículas Lipídicas/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley
15.
Transpl Immunol ; 46: 1-7, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28974433

RESUMO

BACKGROUND: T follicular helper cells (Tfh) are recently revealed to be vital in antibody-mediated rejection (AMR) in kidney transplant recipients (KTRs). However, the impact of immunosuppressive drugs on Tfh cells is not fully understood. The purpose of this study was to investigate the variation of Tfh cells phenotypically and functionally in KTRs treated with different immunosuppression regimens. METHODS: We recruited 26 KTRs treated with tacrolimus (TAC) -based regimen, 13 with sirolimus (SRL) -based regimen and 10 healthy controls (HC) in this study. The percentage and absolute number of circulating Tfh cells and the co-expression of Tfh related molecules including inducible costimulatory molecule (ICOS), programmed cell death protein 1 (PD-1), interleukin-21 (IL-21) and signal transducer and activator of transcription 3 (STAT3) were analyzed by flow cytometry, while serum IL-6 was detected by electrochemiluminescence immunoassay. RESULTS: The percentage and absolute number of Tfh cells and the co-expression of PD-1, STAT3 in Tfh cells were significantly higher in TAC group than that in SRL group. While no difference was found in regard to IL-21 and ICOS co-expressed with Tfh cells among three groups. Multiple linear regression analysis results showed that pre-transplant PRA level was the significant confounder affecting the absolute numbers of Tfh and CD4+CXCR5+PD-1+ T cells. In addition, correlation analysis showed that CD4+CXCR5+STAT3+ T cells were positively correlated to Tfh cells. CONCLUSIONS: Our study indicates that sirolimus can suppress the quantity of Tfh cells more significantly than tacrolimus. The higher level of circulating Tfh cells in tacrolimus group might be related to STAT3 signaling.


Assuntos
Centro Germinativo/imunologia , Rejeição de Enxerto/imunologia , Imunossupressores/uso terapêutico , Transplante de Rim , Sirolimo/uso terapêutico , Linfócitos T Auxiliares-Indutores/imunologia , Tacrolimo/uso terapêutico , Adulto , Citotoxicidade Celular Dependente de Anticorpos , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Isoanticorpos/metabolismo , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
16.
Medicine (Baltimore) ; 96(25): e7205, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28640108

RESUMO

Previous study has identified that the genetic variants in the human leukocyte antigen (HLA)-DP/DQ region were strongly associated with hepatitis B virus (HBV) infection. But their roles in liver function recovery after hepatic transplantation were still obscure. This study aimed to investigate whether HLA-DP/DQ polymorphisms were associated with post-transplant etiologies and prognosis in Chinese liver transplant recipients.A total of 144 liver transplant recipients were enrolled, which were divided into 2 groups according to the transplant etiology: HBV-related disease and non-HBV-related disease. HBV-related disease includes 3 subgroups: liver cirrhosis, hepatocellular carcinoma, and progressive HBV hepatitis. Three single-nucleotide polymorphisms HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs7453920) were studied in all recipients by high-resolution melting curve analysis. Liver function indices (albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, direct bilirubin, total bilirubin) and coagulation indices (prothrombin time, platelet, international normalized ratio, fibrinogen) were routinely tested. After transplant, 10 recipients who were positive for HBsAg or with elevation in HBV virus load were regarded as HBV recurrence.No significant association of HLA-DP/DQ polymorphisms with HBV recurrence or transplant etiology was observed (P < .05). Recipients with HLA-DQ (rs7453920) AG and AA genotype had lower direct bilirubin levels than GG genotype individuals, especially on the 14th day after surgery (17.80 vs. 5.35, P  =  .038). Patients with A alleles displayed earlier liver function recovery than patients with G alleles (7 vs. 6 months). No significant correlation was shown in HLA-DP rs3077 and rs9277535 with HBV infection or liver function recovery (P < .05).Our study concluded that HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs7453920) were not significantly associated with HBV recurrence or HBV susceptibility, but HLA-DQ rs7453920 was related to prognosis of liver transplant recipients. HLA-DQ rs7453920 A might be used as an indicator of earlier recovery and better prognosis after transplantation.


Assuntos
Antígenos HLA-DP/genética , Antígenos HLA-DQ/genética , Hepatopatias/genética , Hepatopatias/cirurgia , Transplante de Fígado , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Hepatite B/genética , Hepatite B/cirurgia , Vírus da Hepatite B , Humanos , Hepatopatias/etiologia , Hepatopatias/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Carga Viral
17.
Pharmacogenet Genomics ; 27(1): 19-26, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27779570

RESUMO

OBJECTIVE: A genome-wide association study has identified several gene polymorphisms associated with loss of renal function. The effect of these variants on renal function in kidney transplant recipients receiving immunosuppressive treatment is unknown. MATERIALS AND METHODS: A cohort of 189 kidney transplant recipients and their living donors were recruited from West China Hospital of Sichuan University, on whom we assessed the association of five single nucleotide polymorphisms with renal function after kidney transplantation. RESULTS: Glomerular filtration rate estimated by serum creatinine was significantly higher in recipients carrying allograft with the A allele at rs17319721 in SHROOM3 (shroom family member 3) than those in the group with the GG genotype from month 1 to month 6 after transplantation (P=0.020). Covariate adjustment analysis showed that the variant at rs17319721 in SHROOM3 was an independent risk factor for renal dysfunction after the first month after transplantation (P=0.022). The estimated glomerular filtration rate was the lowest in recipients with allograft carrying both the A allele at rs17319721 in SHROOM3 and the CC genotype at rs1045642 in ABCB1 (P<0.05). CONCLUSION: The genetic variants in SHROOM3 and ABCB1 in donors were associated closely with renal function after kidney transplantation.


Assuntos
Creatinina/sangue , Imunossupressores/administração & dosagem , Rim/fisiopatologia , Proteínas dos Microfilamentos/genética , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , China , Feminino , Genótipo , Taxa de Filtração Glomerular , Humanos , Imunossupressores/farmacologia , Transplante de Rim , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Adulto Jovem
18.
Br J Clin Pharmacol ; 83(4): 812-822, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27753146

RESUMO

AIMS: Elderly transplant recipients have a lower incidence of acute rejection, and a higher risk to die from infectious complications. A potential cause may be differences in the pharmacokinetics (PK) or pharmacodynamics (PD) of the immunosuppressive drugs they are taking. This study was designed to comprehensively evaluate the influence of age on the PK and PD of mycophenolic acid (MPA). METHODS: In this study the PK and PD of MPA was studied in 26 elderly and 54 younger renal transplant recipients treated with mycophenolate mofetil and tacrolimus. Patients were sampled repetitively, both before and during the first 6 months after kidney transplantation. Age-related variability in MPA PK, baseline IMPDH activity, as well as MPA-induced IMPDH inhibition were studied. RESULTS: The IMPDH activity pre-transplantation did not differ between elderly and younger patients. Neither IMPDH activity pre-transplantation nor maximum IMPDH inhibition was significantly correlated with the patients' age. The area under the MPA plasma concentration-time curve (AUC0-12h ) and the area under the effect (IMPDH activity)-time curve (AEC0-12h ) from 0 to 12 h were also not significantly different between the two groups. We found no significant differences in EC50 and Emax between elderly and younger patients. CONCLUSIONS: Age did not significantly affect the PK or PD of MPA. It is unlikely that the lower incidence of acute rejection in elderly patients, or the higher risk to die from a severe infection in elderly patients is due to different handling of MPA in the elderly.


Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Ácido Micofenólico/administração & dosagem , Adulto , Fatores Etários , Idoso , Área Sob a Curva , Feminino , Humanos , IMP Desidrogenase/antagonistas & inibidores , IMP Desidrogenase/metabolismo , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/farmacologia , Tacrolimo/administração & dosagem , Fatores de Tempo , Transplantados , Adulto Jovem
19.
Autophagy ; 12(9): 1560-74, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27310765

RESUMO

Macroautophagy/autophagy plays an important role against pathogen infection in mammals and plants. However, little has been known about the role of autophagy in the interactions of insect vectors with the plant viruses, which they transmit. Begomoviruses are a group of single-stranded DNA viruses and are exclusively transmitted by the whitefly Bemisia tabaci in a circulative manner. In this study, we found that the infection of a begomovirus, tomato yellow leaf curl virus (TYLCV) could activate the autophagy pathway in the Middle East Asia Minor 1 (MEAM1) species of the B. tabaci complex as evidenced by the formation of autophagosomes and ATG8-II. Interestingly, the activation of autophagy led to the subsequent degradation of TYLCV coat protein (CP) and genomic DNA. While feeding the whitefly with 2 autophagy inhibitors (3-methyladenine and bafilomycin A1) and silencing the expression of Atg3 and Atg9 increased the viral load; autophagy activation via feeding of rapamycin notably decreased the amount of viral CP and DNA in the whitefly. Furthermore, we found that activation of whitefly autophagy could inhibit the efficiency of virus transmission; whereas inhibiting autophagy facilitated virus transmission. Taken together, these results indicate that TYLCV infection can activate the whitefly autophagy pathway, which leads to the subsequent degradation of virus. Furthermore, our report proves that an insect vector uses autophagy as an intrinsic antiviral program to repress the infection of a circulative-transmitted plant virus. Our data also demonstrate that TYLCV may replicate and trigger complex interactions with the insect vector.


Assuntos
Autofagia , Begomovirus , Hemípteros/virologia , Adenina/análogos & derivados , Adenina/química , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Primers do DNA , Feminino , Genômica , Gossypium , Insetos Vetores/virologia , Masculino , Doenças das Plantas/virologia , Sirolimo/química
20.
Pharmacogenomics ; 17(3): 249-57, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26784512

RESUMO

AIM: Determine the effect of genetic variants of donors and recipients on early renal function and tacrolimus pharmacokinetics in kidney transplant recipients. PATIENTS & METHODS: We measured CYP3A5 (6986A>G), ABCB1 (3435C>T, 2677G>T/A, 1236C>T) genetic polymorphisms in 120 renal transplant recipients and donors by high-resolution melting curve analysis. The renal function and tacrolimus trough concentrations were analyzed. RESULTS: The genotype of CYP3A5 (6986A>G) in recipients showed strong influence on tacrolimus pharmacokinetics. The ABCB1 3435 CC genotype in donor was significantly associated with lower estimated glomerular filtration in recipients within 1 month (p < 0.05) and correlated with delayed creatinine recovery (p = 0.007). CONCLUSIONS: ABCB1 3435 CC genotype in donor influences early renal function and creatinine recovery in tacrolimus-treated kidney transplant recipients.


Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Rim/efeitos dos fármacos , Doadores Vivos , Tacrolimo/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Creatinina/sangue , Citocromo P-450 CYP3A/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Rim/fisiopatologia , Masculino , Polimorfismo de Nucleotídeo Único
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