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1.
Hepatology ; 2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31677282

RESUMO

Free and bioavailable 25-hydroxyvitamin D (25OHD) are emerging measurements of vitamin D status. It remains unclear whether circulating free or bioavailable 25OHD are relevant to hepatocellular carcinoma (HCC) prognosis. Our aim was to test the hypothesis that bioavailable 25OHD may be a better serum biomarker of vitamin D status than total 25OHD on the association with HCC survival. We included 1031 newly diagnosed, previously untreated patients with HCC from the Guangdong Liver Cancer Cohort (GLCC) enrolled between September 2013 and April 2017. Serum total 25OHD levels were measured using an electrochemiluminescence immunoassay. Serum free 25OHD levels were measured using a two-step enzyme-linked immunosorbent assay. Bioavailable 25OHD levels were calculated from measured free 25OHD and albumin using a previously validated equation. Primary outcomes were liver cancer-specific (LCSS) and overall survival (OS). Cox proportional hazards models were performed to calculate the multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 726 days, 430 patients had deceased, including 393 deaths from HCC. In multivariable analyses, higher bioavailable 25OHD levels were significantly associated with better survival, independent of nonclinical and clinical prognostic factors including serum C-reactive protein, Barcelona Clinic Liver Cancer (BCLC) stage, and cancer treatment. The multivariable-adjusted HRs in the highest vs. lowest quartile of bioavailable 25OHD levels were 0.69 (95% CI: 0.51, 0.93; P for trend=0.014) for LCSS and 0.71 (95% CI: 0.53, 0.94; P for trend=0.013) for OS. In contrast, neither total nor free 25OHD levels were associated with LCSS or OS. CONCLUSION: Higher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in a population-based HCC cohort, suggesting a potential utility of bioavailable 25OHD in HCC prognosis.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31369714

RESUMO

Lysophosphatidic acid (LPA) is an important lipid molecule for signal transduction in cell proliferation. Although the effects of LPA on vascular smooth muscle (VSM) cell growth have been reported previously, the underlying mechanisms of its action are not fully understood. The present study was undertaken to investigate the effects of some inhibitors of different protein kinases and other molecular targets on LPA-induced DNA synthesis as well as gene expression in the aortic VSM cells. The DNA synthesis was studied by [3H]-thymidine incorporation method and the gene expression was investigated by real time PCR technique. It was observed that the LPA-induced DNA synthesis was attenuated by inhibitors of protein kinase C (PKC; staurosporine, calphostin C and bisindolylmaleimide), phosphoinositide 3-kinase (PI3K; wortmannin, and LY294002), and ribosomal p70S6 kinase (p70S6K; rapamycin). The inhibitors of guanine protein coupled receptors (GPCR; pertussis toxin), phospholipase C (PLC; U73122 and D609), and sodium-hydrogen exchanger (NHE; amiloride and dimethyl amiloride) were also shown to depress the LPA-induced DNA synthesis. Furthermore, gene expressions for PLC ß1 isoform, PKC δ and ε isoforms, casein kinase II ß isoform and endothelin-1A receptors were elevated by LPA. These results suggest that the LPA-induced proliferation of VSM cells is mediated through the activation of GPCR and multiple protein kinases as well as gene expressions of their some specific isoforms.

3.
J Org Chem ; 84(11): 7207-7218, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31070913

RESUMO

Diastereoselective α-amination of N- tert-butanesulfinyl imidates has been developed using N-aryl (or N- tert-butyl) N-diphenylphosphinyldiazenes as nitrogen sources. The chiral 1-azaenolates derived from imidates undergo nucleophilic addition with diazenes to give α-hydrazino imidates in good yields.

4.
Br J Nutr ; 121(12): 1376-1388, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30935429

RESUMO

Existing data on folate status and hepatocellular carcinoma (HCC) prognosis are scarce. We prospectively examined whether serum folate concentrations at diagnosis were associated with liver cancer-specific survival (LCSS) and overall survival (OS) among 982 patients with newly diagnosed, previously untreated HCC, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study between September 2013 and February 2017. Serum folate concentrations were measured using chemiluminescent microparticle immunoassay. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95 % CI by sex-specific quartile of serum folate. Compared with patients in the third quartile of serum folate, patients in the lowest quartile had significantly inferior LCSS (HR = 1·48; 95 % CI 1·05, 2·09) and OS (HR = 1·43; 95 % CI 1·03, 1·99) after adjustment for non-clinical and clinical prognostic factors. The associations were not significantly modified by sex, age at diagnosis, alcohol drinking status and Barcelona Clinic Liver Cancer (BCLC) stage. However, there were statistically significant interactions on both multiplicative and additive scale between serum folate and C-reactive protein (CRP) levels or smoking status and the associations of lower serum folate with worse LCSS and OS were only evident among patients with CRP > 3·0 mg/l or current smokers. An inverse association with LCSS were also observed among patients with liver damage score ≥3. These results suggest that lower serum folate concentrations at diagnosis are independently associated with worse HCC survival, most prominently among patients with systemic inflammation and current smokers. A future trial of folate supplementation seems to be promising in HCC patients with lower folate status.

5.
Chem Commun (Camb) ; 55(26): 3777-3780, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30864606

RESUMO

Products derived from the reaction between N-tert-butanesulfinyl imidates and acylsilanes can be tuned by choosing appropriate bases and solvents. Here we show that in the presence of NaHMDS/THF, addition of enolized N-tert-butanesulfinyl imidates to acylsilanes and subsequent [1,2]-Brook rearrangement generate ß-silyloxy anion intermediates that undergo intramolecular cyclization to afford polysubstituted cyclopropanes. In the presence of tBuOK/toluene, the reaction generates ß-silyloxy imidates as the protonation products of the ß-silyloxy anion intermediates. Both reactions are highly diastereoselective.

6.
J Org Chem ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30407820

RESUMO

A diastereoselective α-fluorination of N- tert-butanesulfinyl imidates was developed. Deprotonation of N- tert-butanesulfinyl imidates with lithium hexamethyldisilazide generates aza-enolates that can be intercepted, with excellent diastereocontrol, by the inexpensive electrophilic fluorinating agent NFSI. This protocol was applied to the preparation of synthetically useful trans-2-fluoro-cyclohexamine with high enantiomeric purity (99.5% ee).

7.
Urology ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30471367

RESUMO

OBJECTIVE: To explore new therapies for castration-resistant prostate cancer (CRPC) to improve patients' quality of life and extend life. MATERIALS AND METHODS: The synthesis, morphology analysis, phase analysis, spectral analysis and photothermal conversion test were referenced to our previous articles. Then NIR-light-driven CuS nanoplates to inhibit the growth of prostate cancer cells in vivo and in vitro was carried out. Transmission electron microscope, mCherry-LC3 syncytial virus labelling, acridine orange staining and autophagy protein were used to detect the autophagy caused by CuS nanoplates and chloroquine was used to inhibit the process of autophagy. RESULTS: The CuS nanoplates prepared in this study feature low cytotoxicity, simple preparation and high photothermal conversion efficiency. Driven by 980nm near-infrared light, CuS nanoplates could inhibit the growth of prostate cancer cells in vivo and in vitro, while triggering the autophagy and cytoprotection of prostate cancer cells. CONCLUSIONS: CuS nanoplates are a kind of commendable photothermal therapy agent in CRPC treating. Autophagy inhibition enhances the photothermal efficiency of CuS nanoplates, which indicates favorable application prospects in the treatment of advanced prostate cancer.

8.
Int J Cancer ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30426509

RESUMO

Copper and zinc are essential micronutrients, whose imbalance may be involved in the development and progression of cancer. However, the role of copper and/or zinc imbalance in the prognosis of hepatocellular carcinoma (HCC) is currently unclear. Our objective was to investigate the association between serum levels of copper, zinc and their ratio (copper/zinc) at diagnosis with HCC survival. We included 989 patients with incident HCC in this prospective cohort study, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study within 30 days of diagnosis between September 2013 and February 2017. Serum copper and zinc were measured using inductively coupled plasma mass spectrometry. Primary outcomes were liver cancer-specific survival (LCSS) and overall survival (OS). Cox proportional hazards models were used to calculate the multivariable hazard ratios (HRs) and 95% confidence interval (CI). Higher serum copper levels were strongly associated with worse LCSS (Q4 vs. Q1: HR=1.87, 95% CI: 1.22-2.86; P<0.01 for trend) and OS (Q4 vs. Q1: HR=2.06, 95% CI: 1.36-3.11; P<0.01 for trend). The calculated copper/zinc ratio was positively associated with LCSS (Q4 vs. Q1: HR=1.31, 95% CI: 0.89-1.92; P=0.04 for trend) and OS (Q4 vs. Q1: HR=1.43, 95% CI: 0.99-2.08; P=0.01 for trend). No overall associations were observed between serum zinc levels and LCSS or OS in the entire cohort. The results suggest that higher serum copper and copper in relation to zinc levels (i.e., higher copper/zinc ratio) may be associated with worse HCC survival, but serum zinc levels may be not associated with HCC survival. This article is protected by copyright. All rights reserved.

9.
Angew Chem Int Ed Engl ; 57(47): 15583-15586, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30255973

RESUMO

A diastereoselective [2,3] rearrangement of O-silyl N-sulfinyl N,O-ketene acetals derived from chiral N-acyl tert-butanesulfinamides was developed, giving α-sulfenyloxy carboxamides with excellent enantioselectivity. Enolization and subsequent silylation of N-acyl tert-butanesulfinamides initiate this aza variant of the Mislow-Evans rearrangement, in which the chirality at the sulfur atom in the rearrangement precursors is faithfully transferred to the α-carbon stereocenter of the products. The Ellman sulfinamide, often used as a chiral ammonia equivalent, can serve in this rearrangement as a chiral precursor for the asymmetric synthesis of α-oxygen-functionalized carboxamides.

10.
Microbiome ; 6(1): 172, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30249275

RESUMO

BACKGROUND: The metabolic syndrome (MetS) epidemic is associated with economic development, lifestyle transition and dysbiosis of gut microbiota, but these associations are rarely studied at the population scale. Here, we utilised the Guangdong Gut Microbiome Project (GGMP), the largest Eastern population-based gut microbiome dataset covering individuals with different economic statuses, to investigate the relationships between the gut microbiome and host physiology, diet, geography, physical activity and socioeconomic status. RESULTS: At the population level, 529 OTUs were significantly associated with MetS. OTUs from Proteobacteria and Firmicutes (other than Ruminococcaceae) were mainly positively associated with MetS, whereas those from Bacteroidetes and Ruminococcaceae were negatively associated with MetS. Two hundred fourteen OTUs were significantly associated with host economic status (140 positive and 74 negative associations), and 157 of these OTUs were also MetS associated. A microbial MetS index was formulated to represent the overall gut dysbiosis of MetS. The values of this index were significantly higher in MetS subjects regardless of their economic status or geographical location. The index values did not increase with increasing personal economic status, although the prevalence of MetS was significantly higher in people of higher economic status. With increased economic status, the study population tended to consume more fruits and vegetables and fewer grains, whereas meat consumption was unchanged. Sedentary time was significantly and positively associated with higher economic status. The MetS index showed an additive effect with sedentary lifestyle, as the prevalence of MetS in individuals with high MetS index values and unhealthy lifestyles was significantly higher than that in the rest of the population. CONCLUSIONS: The gut microbiome is associated with MetS and economic status. A prolonged sedentary lifestyle, rather than Westernised dietary patterns, was the most notable lifestyle change in our Eastern population along with economic development. Moreover, gut dysbiosis and a Western lifestyle had an additive effect on increasing MetS prevalence.

11.
Nat Med ; 24(12): 1940, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30250144

RESUMO

In the version of this article originally published, in the sentence "Applying the same approach to obesity (Fig. 2b), MetS (Fig. 2c) and fatty liver (Fig. 2d) yielded similar results," two figure panels were cited incorrectly. The data for obesity are in Fig. 2c, and the data for MetS are in Fig. 2b. The sentence has been updated with the correct citations in the print, PDF and HTML versions of the article.

12.
J Pharm Biomed Anal ; 161: 455-463, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30216794

RESUMO

Gentianopsis barbata, Halenia corniculata, and Gentianella acuta were widely distributed throughout China and commonly used in traditional Chinese medicine. However, owing to similar living environments and morphological features, locals often had trouble distinguishing between these three species. In this present study, chromatograms at 350 nm were obtained and the composition and content of their chemical compounds determined using HPLC-DAD/ESI-MS2. In total, 35 chemical compounds were detected, 32 of which were identified, 25 of which were xanthones, 6 flavonoids, and 1 chlorogenic acid. The 350 nm chromatograms of these three species displayed evident differences. The individual compounds and their occurrence and content in different parts of the plant within different species were included in our results. This basic data will be useful for future pharmacological study. The total compositions of flavonoids and xanthones were approximately comparable in G. barbata and H. corniculata. Meanwhile, xanthones were predominant in G. acuta. From the perspective of chemical compound compositions, the leaf is recommended as the most valuable medicinal section for each of these three species.

13.
Nat Med ; 24(10): 1532-1535, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30150716

RESUMO

Dysbiosis, departure of the gut microbiome from a healthy state, has been suggested to be a powerful biomarker of disease incidence and progression1-3. Diagnostic applications have been proposed for inflammatory bowel disease diagnosis and prognosis4, colorectal cancer prescreening5 and therapeutic choices in melanoma6. Noninvasive sampling could facilitate large-scale public health applications, including early diagnosis and risk assessment in metabolic7 and cardiovascular diseases8. To understand the generalizability of microbiota-based diagnostic models of metabolic disease, we characterized the gut microbiota of 7,009 individuals from 14 districts within 1 province in China. Among phenotypes, host location showed the strongest associations with microbiota variations. Microbiota-based metabolic disease models developed in one location failed when used elsewhere, suggesting that such models cannot be extrapolated. Interpolated models performed much better, especially in diseases with obvious microbiota-related characteristics. Interpolation efficiency decreased as geographic scale increased, indicating a need to build localized baseline and disease models to predict metabolic risks.

14.
J Org Chem ; 83(17): 10580-10588, 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30010340

RESUMO

A diastereoselective α-sulfenylation of chiral α-aryl/alkyl N- tert-butanesulfinyl imidates has been developed. Suitable sulfur electrophiles can be used as sulfenylating reagents to intercept aza-enolates generated from imidate deprotonation, giving α-thiofunctionalized imidates in good yields with high diastereocontrol. This protocol for C-S bond formation can efficiently synthesize enantioenriched 1,2-sulfanyl amine derivatives such as sulconazole.

15.
Can J Physiol Pharmacol ; 96(10): 1017-1021, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29847734

RESUMO

The effects of CO2 water-bath therapy on the hind limb of diabetic animals with or without peripheral ischemia were examined. Diabetes was induced in rats by administering streptozotocin (65 mg·kg-1), and the animals were then divided into 3 groups. After 4 weeks, peripheral ischemia was induced by ligation of the femoral artery for 2 weeks in 2 groups (diabetic ischemic) of diabetic rats, whereas the femoral artery was not occluded in the third group (diabetic). All these animals were subjected to water-bath therapy (with or without CO2 mixing; 20 min·day-1 for 5 days·week-1) for a period of 4 weeks. Both peak and mean flows, unlike minimal flow, in diabetic ischemic limbs were increased about a twofold by CO2 water-bath treatment. Morphological examination of hind limb tissue sections revealed about a twofold increase in the small artery count in diabetic ischemic animals upon CO2 water-bath treatment. These results indicate that CO2 water-bath therapy augments the blood flow and development of angiogenesis in the skeletal muscle of diabetic ischemic animals and thus may be of some benefit for the treatment of peripheral arterial disease in diabetes.

16.
Chem Commun (Camb) ; 54(23): 2882-2885, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29493693

RESUMO

A dimethyl phosphite-mediated addition of α-keto N-tert-butanesulfinyl imidates to nitrosoarenes was developed. Nitrosoarenes were successfully used as electrophiles to trap aza-enolate intermediates that were generated from nucleophilic addition of deprotonated phosphite to α-keto N-tert-butanesulfinyl imidates and following phospha-Brook rearrangement, allowing efficient construction of ketonitrones with excellent (Z)-geometries.

17.
Org Lett ; 20(4): 1236-1239, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29405721

RESUMO

Diastereoselective α-hydroxylation using molecular oxygen has been achieved with chiral α-alkyl N-tert-butanesulfinyl imidates and α-aryl N'-tert-butanesulfinyl amidines. The aza-enolates generated from deprotonation of imidates/amidines can be intercepted by O2 with excellent diastereocontrol and subsequently transformed into α-hydroxylation products in the presence of the reductant trimethyl phosphite.

18.
Arch Virol ; 163(4): 845-853, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29327237

RESUMO

Despite increased understanding of how viral infection is involved in asthma exacerbations, it is less clear which viruses are involved and to what extent they contribute to asthma exacerbations. Here, we sought to determine the prevalence of different respiratory viruses during asthma exacerbations. Systematic computerized searches of the literature up to June 2017 without language limitation were performed. The primary focus was on the prevalence of respiratory viruses, including AdV (adenovirus), BoV (bocavirus), CoV (coronavirus), CMV (cytomegalovirus), EnV (enterovirus), HSV (herpes simplex virus), IfV (influenza virus), MpV (metapneumovirus), PiV (parainfluenzavirus), RV (rhinovirus) and RSV (respiratory syncytial virus) during asthma exacerbations. We also examined the prevalence of viral infection stratified by age, geographic region, type of respiratory secretion, and detection method. Sixty articles were included in the final analysis. During asthma exacerbations, the mean prevalence of AdV, BoV, CoV, CMV, EnV, HSV, IfV, MpV, PiV, RV and RSV was 3.8%, 6.9%, 8.4%, 7.2%, 10.1%, 12.3%, 10.0%, 5.3%, 5.6%, 42.1% and 13.6%, respectively. EnV, MPV, RV and RSV were more prevalent in children, whereas AdV, BoV, CoV, IfV and PiV were more frequently present in adults. RV was the major virus detected globally, except in Africa. RV could be detected in both the upper and lower airway. Polymerase chain reaction was the most sensitive method for detecting viral infection. Our findings indicate the need to develop prophylactic polyvalent or polyvirus (including RV, EnV, IfV and RSV) vaccines that produce herd immunity and reduce the healthcare burden associated with virus-induced asthma exacerbations.


Assuntos
Asma/epidemiologia , Sistema Respiratório/virologia , Infecções Respiratórias/epidemiologia , Viroses/epidemiologia , Adenoviridae/patogenicidade , Adenoviridae/fisiologia , África/epidemiologia , Fatores Etários , Américas/epidemiologia , Ásia/epidemiologia , Asma/complicações , Asma/virologia , Coronavirus/patogenicidade , Coronavirus/fisiologia , Citomegalovirus/patogenicidade , Citomegalovirus/fisiologia , Enterovirus/patogenicidade , Enterovirus/fisiologia , Europa (Continente)/epidemiologia , Bocavirus Humano/patogenicidade , Bocavirus Humano/fisiologia , Humanos , Metapneumovirus/patogenicidade , Metapneumovirus/fisiologia , Prevalência , Vírus Sincicial Respiratório Humano/patogenicidade , Vírus Sincicial Respiratório Humano/fisiologia , Infecções Respiratórias/complicações , Infecções Respiratórias/virologia , Respirovirus/patogenicidade , Respirovirus/fisiologia , Rhinovirus/patogenicidade , Rhinovirus/fisiologia , Simplexvirus/patogenicidade , Simplexvirus/fisiologia , Viroses/complicações , Viroses/virologia
19.
Sci Rep ; 7(1): 15322, 2017 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-29127397

RESUMO

MicroRNAs (miRNAs) regulate biological pathways by inhibiting gene expression. However, most current analytical methods fail to consider miRNAs, when inferring functional or pathway activities. In this study, we developed a model called sPAGM to infer subpathway activities by integrating gene and miRNA expressions. In this model, we reconstructed subpathway graphs by embedding miRNA components, and characterized subpathway activity (sPA) scores by simultaneously considering the expression levels of miRNAs and genes. The results showed that the sPA scores could distinguish different samples across tumor types, as well as samples between tumor and normal conditions. Moreover, the sPAGM model displayed more specificities than the entire pathway-based analyses. This model was applied to melanoma tumors to perform a prognosis analysis, which identified a robust 55-subpathway signature. By using The Cancer Genome Atlas and independently verified data sets, the subpathway-based signature significantly predicted the patients' prognoses, which were independent of clinical variables. In the prognostic performance comparison, the sPAGM model was superior to the gene-only and miRNA-only methods. Finally, we dissected the functional roles and interactions of components within the subpathway signature. Taken together, the sPAGM model provided a framework for inferring subpathway activities and identifying functional signatures for clinical applications.

20.
J Org Chem ; 82(19): 10748-10755, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28910104

RESUMO

A single-flask reaction of silyllithium, α-keto N-tert-butanesulfinyl imidates and aldehydes has been developed for the diastereoselective synthesis of α,ß-dihydroxy acid derivatives. In this reaction, the nucleophilic addition of silyllithium to chiral α-keto imidates followed by silyl migration forms chiral aza-enolates, which react diastereoselectively with aldehydes. Subsequent [1,4]-O → O silyl migration affords α-substituted ß-(silyoxy)-α-hydroxy imidates.

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