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1.
J Ethnopharmacol ; 246: 112231, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31520671

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Liangxue Tongyu Prescription (LTP) is a traditional Chinese medicine formula composed of 8 crude drugs that is widely used to treat acute intracerebral hemorrhage (AICH). AIM OF THE STUDY: To verify the efficacy of LTP on the survival time in the treatment of acute intracerebral hemorrhagic rats (AICHs), and to elucidate its network pharmacodynamic mechanism of multi-component, multi-target, and multi-signaling pathways. MATERIALS AND METHODS: Survival analysis was used to evaluate the survival time of AICH rats induced by different doses of collagenase and the efficacy of three doses of LTP in the treatment of AICH rats. The Kaplan-Meier curves for survival time were produced and compared with the Log-rank test and Wilcoxon (Gehan) χ2. Differential mRNA-seq combined with network pharmacology was used to disclose the network effect mechanism of LTP on AICH, and the obtained differential genes were mapped into the predictive empirical compound-target network model (ECT network model) and the empirical compound-target-pathogenesis (disease) network model (ECTP network model). RESULTS: The median survival time of four different doses of LTP-treated groups (0.00 g/kg, 5.78 g/kg, 11.55 g/kg, 23.10 g/kg) for adult AICH rats by 0.18 U collagenase was 14 h, 37 h, 150 h, and 51 h respectively, and the 7-day survival rates were 33.3%, 41.7%, 50.0%, and 38.5%, of which the medium-dose group (MD) had a longer survival time and higher survival rate. Through further validation experiments, the MD group had a better efficacy trend with a median survival time of 168 h vs 23 h in the model control group (MC) (Wilcoxon Gehan Test, χ2 = 3.478, P = 0.062). The transcriptomic analysis of mRNA showed that 583 significant differential genes were found between the MC and MD group and 7 key therapeutic targets regulated by 29 compounds in LTP on AICH were screened out by VCT and VCTP network model. These targets were involved in 5 regulatory models or pathways. CONCLUSION: Our study confirmed the exact efficacy of the LTP in the treatment of AICH and revealed the potential pharmacodynamic components and mode of action of the LTP on AICH. Using differential transcriptome of mRNA combined with network pharmacology, we screened out 29 chemical compounds as the potential effective ingredients of LTP which acted on 7 targets of AICH involving 5 pathological pathways, mainly including repairing the brain function defect, improving neural function, protecting blood-brain barrier from damage, reducing inflammatory factors, and inhibiting apoptosis. The present study not only provides a new explanation for the 'multi-component, multi-target, multi-pathway' effects of the LTP on AICH but also screened out some major compounds of LTP and their potential targets which will facilitate the development of new drugs for AICH.

2.
PLoS One ; 14(11): e0222077, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31693665

RESUMO

OBJECTIVES: To investigate the consistency of adverse events (AEs) and adverse drug reactions (ADRs) reported in the literature, monitoring and social media data. METHODS: Using one Chinese patent medicine-Cordyceps sinensis extracts (CSE) as an example, we obtained safety data from the national monitoring system (July 2002 to February 2016), literature (up to November 2016) and social media (May 2019). For literature data, we searched the Chinese National Knowledge Infrastructure Database (CNKI), WanFang database, Chinese Science and Technology Periodical Database (VIP), Chinese Biomedical Literature Database (SinoMed), PubMed, Embase and the Cochrane Library. Social media data was from the Baidu post bar and Sina micro-blog. Two authors independently screened the literature and extracted data by PRISMA Harms checklist was followed. AEs and ADRs were coded using the World Health Organization Adverse Reaction Terminology (WHO-ART). AEs and ADRs were grouped into thirty-one organ-system classes for comparisons. Frequencies, relative frequencies and rank were used as metrics. Radar chart was used to manifest the features of the distributions and proportions. RESULTS: 610 AEs reported in CFDA monitoring data were associated with CSE, of which 537 (88.03%) were suspected ADRs (10.49% certain). 5568 AEs were identified from 172 papers (63% RCTs, 37% other types of studies including case series, case reports, ADR monitoring reports and reviews), in which 86 (1.54%) were ADRs (1.54% certain). 15 AEs (0 certain ADR) were identified from social media. AEs, ADRs and their affected system-organ classes, looked largely similar, but different in every aspect when looking at details. Data from RCTs demonstrated the most disparity. CONCLUSIONS: In our study, the most prevalent AEs and ADRs, mainly gastro-intestinal system disorders including nausea, diarrhea and vomiting, in monitoring system were largely similar with those in literature and social media. But data from different sources varied if looked at details. Multiple data sources (the monitoring system, literature and social media) should be integrated to collect safety information of interventions. The distributions of AEs and ADRs from RCTs were least similar with the data from other sources. Our empirical proof is consistent with other similar studies.

3.
Brain Behav ; : e01459, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742933

RESUMO

OBJECTIVE: To evaluate different injury factors and pathological characteristics of the brain at different disease stages in toxic milk (TX) mice, an animal model of Wilson's disease (WD). METHODS: Thirty TX mice (10 each at 3, 6 and 12 months old) and 30 age-matched C57 mice were used in this study. Corrected phase (CP) values were determined from susceptibility-weighted images. Myelin content was determined by measuring inhibition optical density values of Luxol fast blue-stained sections. Neurofilament protein 68 kDa (NF68), ß-amyloid precursor protein (ß-APP), and myelin basic protein (MBP) levels, as well as copper and iron content, in brain nuclei of the TX mouse were evaluated. Gene amplification ratios for catalase (CAT), GSH peroxidase (GSH-PX), nitric oxide synthase (NOS), and superoxide dismutase (SOD) in mouse brain were also determined. RESULTS: Compared with C57 mice, neuronal cell counts were decreased in 12-months-old TX mice (p = .011). Myelin content was decreased in the lenticular nucleus (p = .029), thalamus (p = .030), and brainstem (p = .034) of 6-months-old TX mice; decreases in the corresponding nuclei (p = .044, .037, and .032, respectively) were also found in 12-months-old TX mice. MBP values were lower in the lenticular nucleus and thalamus (p = .027 and .016, respectively) of 6-months-old TX mice and in the corresponding nuclei (p = .24 and .040) of 12-months-old TX mice. NF-68 values were lower in the lenticular nucleus and thalamus (p = .034 and .037, respectively) of 6-months-old TX mice and in the corresponding nuclei (p = .006 and .012) of 12-months-old TX mice. ß-APP values were higher in the thalamus of 6-months-old (p = .037) and 12-months-old (p = .012) TX mice. Iron content was higher in the lenticular nucleus, thalamus, and cerebellum (p = .044, .038, and .029, respectively) of 6-months-old TX mice and in the corresponding nuclei (p = .017, .024, and .029) of 12-months-old TX mice. The NOS gene amplification multiple was higher (p = .039), whereas the SOD1 gene amplification multiple was lower (p = .041) in 12-months-old TX mice. There was no correlation between metal content or oxidation index and pathological index. CONCLUSIONS: The pathological characteristics of the brains of TX mice may differ at different ages. Different pathogenic factors, including copper and iron deposition and abnormal oxidative stress, are present at different stages.

4.
Urol Int ; : 1-6, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711059

RESUMO

BACKGROUND: The association between uric acid and kidney disease has been extensively investigated. Numerous studies have reported the association between circulating levels of uric acid and renal function. OBJECTIVES: To test, by the Mendelian randomization method, whether there is a causal association between circulating levels of uric acid and renal function. METHODS: In 989 participants, estimated glomerular filtration rate (eGFR) was calculated, the circulating level of uric acid was tested, and the uric acid polymorphism (rs11722228) was genotyped. RESULTS: After adjusting for age, gender, smoking history, alcohol intake, antihypertensive medication, body mass index, waist-to-hip ratio, and levels of urea nitrogen and creatinine, a significant allelic difference was found in uric acid levels for each genotype (p < 0.0001). Furthermore, the circulating levels of uric acid were negatively associated with eGFR after adjusting for cardiovascular risk factors and other potential confounders (p < 0.0001). Meanwhile, eGFR was significantly associated with the genotypes of rs11722228 (ß = -0.07; p = 0.02). CONCLUSIONS: Evidence from the Mendelian randomization approach implied a causal relationship between uric acid and renal function in an apparently healthy population.

6.
J Knee Surg ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31683347

RESUMO

The main purpose of this article is to provide an up-to-date systematic review and meta-analysis comparing functional outcomes of total knee arthroplasty using either computer navigation (NAV-TKA) or conventional methods (CON-TKA) from the latest assemblage of evidence. This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. All Level I and II randomized controlled trials (RCTs) in PubMed, EMBASE, and Cochrane that compared functional outcomes after NAV- and CON-TKA were included in the review. Selected end points for random effects, pairwise meta-analysis included Knee Society Knee Score (KSKS), KS Function Score (KSFS), KS Total Score (KSTS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and range of motion at three arbitrary follow-up times. A total of 24 prospective RCTs comprising 3,778 knees were included from the initial search. At long-term follow-up (>5 years), NAV-TKA exhibited significantly better raw KSKS (p = 0.001) (low-quality evidence), contrary to CON-TKA, which reflected significantly better raw KSTS (p = 0.004) (high-quality evidence). While change scores (KSKS, WOMAC) from preoperative values favor CON-TKA at short-term (<6 months) and medium-term follow-up (6-60 months), long-term follow-up change scores in KSKS suggest the superiority of NAV-TKA over CON-TKA (p = 0.02) (very low-quality evidence). Overall, sizeable dispersion of nonstatistically significant functional outcomes in the medium term was observed to eventually converge in the long term, with less differences in functional outcome scores between the two treatment methods in short- and long-term follow-up. While raw functional outcome scores reflect no differences between NAV and CON-TKA, long-term follow-up change scores in KSKS suggest superiority of NAV-TKA over its conventional counterpart. Prospective studies with larger power are required to support the pattern of diminishing differences in functional outcome scores from medium- to long-term follow-up between the two modalities.

7.
Molecules ; 24(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694262

RESUMO

There is a continued need to develop new selective human monoamine oxidase (hMAO) inhibitors that could be beneficial for the treatment of neurological diseases. However, hMAOs are closely related with high sequence identity and structural similarity, which hinders the development of selective MAO inhibitors. "Three-Dimensional Biologically Relevant Spectrum (BRS-3D)" method developed by our group has demonstrated its effectiveness in subtype selectivity studies of receptor and enzyme ligands. Here, we report a series of novel C7-substituted coumarins, either synthesized or commercially purchased, which were identified as selective hMAO inhibitors. Most of the compounds demonstrated strong activities with IC50 values (half-inhibitory concentration) ranging from sub-micromolar to nanomolar. Compounds, FR1 and SP1, were identified as the most selective hMAO-A inhibitors, with IC50 values of 1.5 nM (selectivity index (SI) < -2.82) and 19 nM (SI < -2.42), respectively. FR4 and FR5 showed the most potent hMAO-B inhibitory activity, with IC50 of 18 nM and 15 nM (SI > 2.74 and SI > 2.82). Docking calculations and molecular dynamic simulations were performed to elucidate the selectivity preference and SAR profiles.

8.
BMJ Open ; 9(11): e030293, 2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31767583

RESUMO

INTRODUCTION: The best approach for choledocholithiasis remains a matter of debate. Choledocholithiasis is usually treated with endoscopic sphincterotomy (EST), laparoscopic common bile duct exploration (LCBDE) or laparoscopic transcystic common bile duct exploration (LTCBDE). Data pertaining to the clinical outcomes of these approaches in the management of patients with cholecysto-choledocholithiasis in China are limited. An analysis of the economic burden associated with these treatments is lacking. The Chinese REgistry Study on the Treatment of Cholecysto-Choledocholithiasis (CREST Choles) was designed to address these issues in a real-world setting. METHODS AND ANALYSIS: CREST Choles was an ambispective, multicenter, observational, open-cohort study. A total of 2700 patients undergoing one of the three treatments (EST+laparoscopic cholecystectomy (LC), LCBDE+LC and LTCBDE+LC) during the period from 1 January 2013 to 1 December 2018 at participating centres were enrolled in the study. Patients with gallstones and confirmed common bile duct stones were included. Data pertaining to demographics, disease history, procedural details, imaging features and follow-up were collected. Follow-up was conducted at least 6 months after enrolment in the study and annual follow-up will be conducted until December 2020. The primary outcome is the rate of adverse outcomes within 3 years postoperatively. Economic analysis (eg, incremental cost-effectiveness ratio) would be performed to compare expense across treatments. ETHICS AND DISSEMINATION: Ethical approval was obtained at all participating centres. The registry presented is the first attempt to comprehensively evaluate the cost of treatment for cholecysto-choledocholithiasis in China. Findings are expected to be available in 2020 and will facilitate clinical decision making in such cases. TRIAL REGISTRATION NUMBER: NCT02554097.

9.
Nat Cell Biol ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31768048

RESUMO

Redox balance, an essential feature of healthy physiological steady states, is regulated by circadian clocks, but whether or how endogenous redox signalling conversely regulates clockworks in mammals remains unknown. Here, we report circadian rhythms in the levels of endogenous H2O2 in mammalian cells and mouse livers. Using an unbiased method to screen for H2O2-sensitive transcription factors, we discovered that rhythmic redox control of CLOCK directly by endogenous H2O2 oscillations is required for proper intracellular clock function. Importantly, perturbations in the rhythm of H2O2 levels induced by the loss of p66Shc, which oscillates rhythmically in the liver and suprachiasmatic nucleus (SCN) of mice, disturb the rhythmic redox control of CLOCK function, reprogram hepatic transcriptome oscillations, lengthen the circadian period in mice and modulate light-induced clock resetting. Our findings suggest that redox signalling rhythms are intrinsically coupled to the circadian system through reversible oxidative modification of CLOCK and constitute essential mechanistic timekeeping components in mammals.

10.
Stem Cell Res ; 41: 101610, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775087

RESUMO

Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme in the HDAC family. The HDAC6 has been shown to play important roles in several biological processes. Meanwhile, it is also an attractive therapeutic target for a variety of diseases. However, the mechanism of HDAC6 function is not fully understood yet, and it is still lacking highly specific targeted drugs. Here, we generated a homozygous HDAC6 knockout human embryonic stem cell (hESC) line, WAe009-A-21 by the CRISPR/Cas9-based gene editing method. The WAe009-A-21 cell line does not express HDAC6 protein, while maintaining normal 46, XX karyotype, pluripotency, and trilineage differentiation potential.

11.
Life Sci ; 239: 116886, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31678286

RESUMO

Enterochromaffin (EC) cell is the main cell type that responsible for 5-hydroxytryptamine (5-HT) synthesis, storage and release of the gut. Intestinal 5-HT play a key role in visceral sensation, intestinal motility and permeability, EC cell hyperplasia and increased 5-HT bioavailability in the gut have been found to be involved in the symptoms generation of irritable bowel syndrome and inflammatory bowel disease. EC cells originate from intestinal stem cells, the interaction between proliferation and differentiation signals on intestinal stem cells enable EC cell number to be regulated in a normal level. This review focuses on the impact factors, pathogenesis mechanisms, and therapeutic clues for intestinal EC cells hyperplasia, and showed that EC cell hyperplasia was observed under the condition of physiological stress, intestinal infection or intestinal inflammation, the disordered proliferation and/or differentiation of intestinal stem cells as well as their progenitor cells all contribute to the pathogenesis of intestinal EC cell hyperplasia. The altered intestinal niche, i.e. increased corticotrophin releasing factor (CRF) signal, elevated nerve growth factor (NGF) signal, and Th2-dominant cytokines production, has been found to have close correlation with intestinal EC cell hyperplasia. Currently, CRF receptor antagonist, nuclear factor-κB inhibitor, and NGF receptor neutralizing antibody have been proved useful to attenuate intestinal EC cell hyperplasia, which may provide a promising clue for the therapeutic strategy in EC cell hyperplasia related diseases.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31618514

RESUMO

Aculenes are a unique class of norsequiterpenes (C14 ) that are produced by Aspergillus aculeatus. The nordaucane skeleton in aculenes A-D may be derived from an ent-daucane precursor through demethylation, however, the enzymes involved remain unexplored. We identified the biosynthetic gene cluster and characterized the biosynthetic pathway based on gene inactivation, feeding experiments, and heterologous reconstitution in Saccharomyces cerevisiae and Aspergillus oryzae. We discovered that three cytochrome P450 monoxygenases are required to catalyze the stepwise demethylation process. AneF converts the 12-methyl group into a carboxylic acid and AneD installs the 10-hydroxy group for later tautomerization and stabilization. Finally, AneG installs an electron-withdrawing carbonyl group at the C-2 position, which triggers C-12 decarboxylation to yield the nordaucane skeleton. Additionally, a terpene cyclase (AneC) was found that forms a new product (dauca-4,7-diene).

13.
Environ Microbiol ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600864

RESUMO

Myxococcus xanthus kills susceptible bacteria using myxovirescin A (TA) during predation. However, whether prey cells in nature can escape M. xanthus by developing resistance to TA is unknown. We observed that many field-isolated Bacillus licheniformis strains could survive encounters with M. xanthus, which was correlated to their TA resistance. A TA glycoside was identified in the broth of predation-resistant B. licheniformis J32 co-cultured with M. xanthus, and a glycosyltransferase gene (yjiC) was up-regulated in J32 after the addition of TA. Hetero-expressed YjiC-modified TA to a TA glucoside (TA-Gluc) by conjugating a glucose moiety to the C-21 hydroxyl group, and the resulting compound was identical to the TA glycoside present in the co-culture broth. TA-Gluc exhibited diminished bactericidal activity due to its weaker binding with LspA, as suggested by in silico docking data. Heterologous expression of the yjiC gene conferred both TA and M. xanthus-predation resistance to the host Escherichia coli cells. Furthermore, under predatory pressure, B. licheniformis Y071 rapidly developed predation resistance by acquiring TA resistance through the overexpression of yjiC and lspA genes. These results suggest that M. xanthus predation resistance in B. licheniformis is due to the TA deactivation by glucosylation, which is induced in a predator-mediated manner.

14.
J Chem Inf Model ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31652060

RESUMO

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, which is arguably the most important family of drug target. With the technology breakthroughs in X-ray crystallography and cryo-electron microscopy, more than 300 GPCR-ligand complex structures have been publicly reported since 2007, covering about 60 unique GPCRs. Such abundant structural information certainly will facilitate the structure-based drug design by targeting GPCRs. In this study, we have developed a fragment-based computational method for designing novel GPCR ligands. We first extracted the characteristic interaction patterns (CIPs) on the binding interfaces between GPCRs and their ligands. The CIPs were used as queries to search the chemical fragments derived from GPCR ligands, which were required to form similar interaction patterns with GPCR. Then, the selected chemical fragments were assembled into complete molecules by using the AutoT&T2 software. In this work, we chose ß-adrenergic receptor (ß-AR) and muscarinic acetylcholine receptor (mAChR) as the targets to validate this method. Based on the designs suggested by our method, samples of 63 compounds were purchased and tested in a cell-based functional assay. A total of 15 and 22 compounds were identified as active antagonists for ß2-AR and mAChR M1, respectively. Molecular dynamics simulations and binding free energy analysis were performed to explore the key interactions (e.g., hydrogen bonds and π-π interactions) between those active compounds and their target GPCRs. In summary, our work presents a useful approach to the de novo design of GPCR ligands based on the relevant 3D structural information.

16.
Urolithiasis ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616985

RESUMO

This study assesses the feasibility and effectiveness of using a three-dimensional (3D) printing model for preoperative planning in the treatment of full staghorn stones, specifically in the selection of the most optimal calyx for puncture. Twelve patients were enrolled in this trial. A preoperative CT taken in prone position was performed on each of the patients. 3D models were reconstructed using digital imaging and 3D printers. Three identical models were printed for each patient. Three puncture sites from the upper-, middle-, and lower-pole calyces of the kidney models were selected for simulation of percutaneous nephrolithotomy. The stone-free rates were recorded after each of the simulations. The puncture site that yielded the maximum SFR was translated to the patient for the actual procedure. CT was performed postoperatively on both patients and simulation models. The SFR of patients and simulation models was compared. Correlation analysis and consistency analysis suggested that there was a high degree of consistency between patients and 3D-printed models. The Pearson product-moment correlation coefficient r for the postoperative stone volume of the patients (PoSVP) and postoperative stone volume of the models (PoSVM) was 0.972 (P < 0.001, 95% CI = 0.900-0.992). The Bland-Altman plot of PoSVP to PoSVM showed an icon of 95% consistency 205.8(- 725.5 ~ 1137.1), and 100% of the points were within the 95% limits of agreement. 3D-printed models can potentially be used for preoperative planning in the treatment of full staghorn stones, especially in the selection of the most optimal calyx for puncture.

17.
Complement Ther Clin Pract ; 37: 109-114, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31622811

RESUMO

BACKGROUND: As clinical trials evaluating the efficacy of traditional Chinese medicine (TCM) therapies have increased, several empirical studies have shown that the quality of TCM trials is generally low in terms of risk of bias. This qualitative study aimed to investigate the factors influencing the quality of TCM clinical trials to provide strategic advice on trial quality improvement. METHODS: One focus group with clinical trial auditors (n = 4) and six in-depth semi-structured interviews with clinical research organization managers (n = 2), lecturers and researchers in TCM academic institutions (n = 2), a chief physician in a TCM oncology department and a PhD candidate specialized in non-pharmaceutical TCM interventions were conducted. The interviews were audio-recorded, transcribed verbatim and thematically analyzed. RESULTS: Factors that influenced the quality of TCM clinical trials emerged with the following 6 themes: trial design; trialists/participants; trial conducting; TCM specified problems; trial monitoring, and finally societal influences. The lack of expertise and time inputs of the trialists were repeatedly mentioned. Methodological difficulties experienced when conducting TCM trials including calculating sample size, analyzing the efficacy of TCM decoctions with multiple ingredients, blinding in trials investigating non-pharmaceutical TCM interventions were highlighted. Interviewees agreed that third-party monitoring can help improving trial quality and improve participant welfare, may accelerate recruiting processes and increase compliance; however more comprehensive regulations and funding requirements would be needed. CONCLUSIONS: This study identified real-life issues influencing the quality of TCM clinical trials from design to reporting. In addition to mandatory training for TCM trial designers and coordinators, more effective institutional oversight is required. Future studies should explore specific measures to address the methodological problems in TCM trials and explore how the quality of TCM trials can affect further evidence synthesis and clinical practice.

18.
Cancer Sci ; 110(11): 3533-3542, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31489722

RESUMO

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors in the urinary system. Surgical intervention is the preferred treatment for ccRCC, but targeted biological therapy is required for postoperative recurrent or metastatic ccRCC. Autophagy is an intracellular degradation system for misfolded/aggregated proteins and dysfunctional organelles. Defective autophagy is associated with many diseases. Mul1 is a mitochondrion-associated E3 ubiquitin ligase and involved in the regulation of divergent pathophysiological processes such as mitochondrial dynamics, and thus affects the development of various diseases including cancers. Whether Mul1 regulates ccRCC development and what is the mechanism remain unclear. Histochemical staining and immunoblotting were used to analyze the levels of Mul1 protein in human renal tissues. Statistical analysis of information associated with tissue microarray and The Cancer Genome Atlas (TCGA) database was conducted to show the relationship between Mul1 expression and clinical features and survival of ccRCC patients. Impact of Mul1 on rates of cell growth and migration and autophagy flux were tested in cultured cancer cells. Herein we show that Mul1 promoted autophagy flux to facilitate the degradation of P62-associated protein aggresomes and adipose differentiation-related protein (ADFP)-associated lipid droplets and suppressed the growth and migration of ccRCC cells. Levels of Mul1 protein and mRNA were significantly reduced so that autophagy flux was likely blocked in ccRCC tissues, which is potentially correlated with enhancement of malignancy of ccRCC and impairment of patient survival. Therefore, Mul1 may promote autophagy to suppress the development of ccRCC.


Assuntos
Autofagia , Carcinoma de Células Renais/enzimologia , Neoplasias Renais/enzimologia , Mitocôndrias/enzimologia , Ubiquitina-Proteína Ligases/metabolismo , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Rim/enzimologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Proteólise , Proteínas de Ligação a RNA/metabolismo , Ubiquitina-Proteína Ligases/análise
19.
J Agric Food Chem ; 67(41): 11498-11507, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31544455

RESUMO

Proanthocyanidins (PAs) possess superior antioxidant properties and nutritious value, however, low bioavailability and stability limit their applications. Here, we developed a novel method to encapsulate PA dimers successfully into horse spleen apoferritin (apoHSF) using a disassembly/reassembly method based on pH change. The PA-HSF nanoparticles were characterized using fluorescence spectroscopy, transmission electron microscopy, circular dichroism, and high-performance liquid chromatography. One apoferritin cage could approximately encapsulate 25.6 molecules of the PA dimer. The results showed that the encapsulation of the PA dimers protected it from the damage of oxidants and temperature below room temperature would be an appropriate condition for HSF-578 solution storage. Moreover, HepG2 cell monolayer absorption and adhesion analyses indicated that the PA dimers encapsulated within apoHSF cages were more efficient in transport. In addition, it was indicated that the PA-HSF nanoparticles had higher cellular antioxidant activity. The novel strategy provided in this study indicates that the protein cage structures like ferritin have potential to be applied in the field of food nutrition.


Assuntos
Antioxidantes/química , Antioxidantes/metabolismo , Apoferritinas/química , Composição de Medicamentos/métodos , Proantocianidinas/química , Proantocianidinas/metabolismo , Animais , Disponibilidade Biológica , Transporte Biológico , Cromatografia Líquida de Alta Pressão , Dimerização , Células Hep G2 , Cavalos , Humanos
20.
Sci Total Environ ; 693: 133628, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31377374

RESUMO

Environmental amenities and disamenities of urban rivers and their capitalization in property prices have been a major subject of empirical investigation in the hedonic price method (HPM) literature for several decades. Primary studies across the globe have nonetheless adopted varying valuation scenarios and modelling approaches. And systematic variation has been shown in homeowners' marginal willingness-to-pay (WTP) for urban rivers' amenities and disamenities, ranging between -12.2% and 63.58% price premium. To identify which valuation scenarios, socio-economic variables, and modelling characteristics might affect the quantification of urban rivers' impacts on property values, we conducted a very first meta-analysis of existing evidence to extract additional information concerning the heterogeneity in WTP estimates pertaining to urban rivers' environmental amenities and disamenities. A total of 53 observations from 30 primary studies that adopted HPM to provide WTP estimates for three prominent valuation scenarios, i.e., proximity, view and water quality, were synthesized using a random effects model. Our meta-analysis results revealed several important factors in explaining the heterogeneity in empirical WTP estimates pertaining to urban rivers' environmental amenities/disamenities. First, while all three valuation scenarios could capture urban rivers' impacts on residential property values, river view was associated with the greatest premium, followed by river water quality, and river proximity the least. Second, we found that WTP estimates were significantly higher after the year of 2000, indicating the widespread and successful river restoration and rehabilitation projects in the 21st century has driven up homeowners' environmental perception and appreciation of urban rivers' amenities, especially their clear depreciation of negative environmental disamenities, to a high level. Third, our results showed that homeowners' valuation of urban rivers was not sensitive to the macro-geographical locations of their residences, suggesting a universal overall appreciation/depreciation of urban rivers across varying cultures and societies. Instead, household income level and population density should be systematically controlled if value transfer across countries is necessary. The findings of this meta-analysis could help refine urban rivers' attributes to be incorporated into HPM studies so as to adequately quantify people's sophisticated valuation of intertwined amenities and disamenities. On the practical front, our results supported two arguments from a very utilitarian point of view. First, it appears that the visual impacts might be prioritized for river restoration projects, such as through careful revegetation of riparian areas using native species. This could harbor rich diversity of ecological functions and in the meantime maximize environmental amenities that homeowners would like to pay for. And second, cost-effective river restoration in urbanized contexts should be prioritized in densely populated areas over places with relatively low population densities. This approach might maximize the number of people who can enjoy rivers for a given budget.

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