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1.
Anal Chem ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32043875

RESUMO

Large-scale top-down proteomics characterizes proteoforms in cells globally with high confidence and high throughput using reversed-phase liquid chromatography (RPLC)-tandem mass spectrometry (MS/MS) or capillary zone electrophoresis (CZE)-MS/MS. The false discovery rate (FDR) from the target-decoy database search is typically deployed to filter identified proteoforms to ensure high-confidence identifications (IDs). It has been demonstrated that the FDRs in top-down proteomics can be drastically underestimated. An alternative approach to the FDR can be useful for further evaluating the confidence of proteoform IDs after database search. We argue that predicting retention/migration time of proteoforms from the RPLC/CZE separation accurately and comparing their predicted and experimental separation time could be a useful and practical approach. Based on our knowledge, there is still no report in the literature about predicting separation time of proteoforms using large top-down proteomics datasets. In this pilot study, for the first time, we evaluated various semi-empirical models for predicting proteoforms' electrophoretic mobility (µef) using large-scale top-down proteomics datasets from CZE-MS/MS. We achieved a linear correlation between experimental and predicted µef of E. coli proteoforms (R2=0.98) with a simple semi-empirical model, which utilizes the number of charges and molecular mass of each proteoform as the parameters. Our modeling data suggest that the complete unfolding of proteoforms during CZE separation benefits the prediction of their µef. Our results also indicate that N-terminal acetylation and phosphorylation both decrease proteoforms' charge by roughly one charge unit.

2.
Nat Prod Res ; : 1-9, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000527

RESUMO

Four new rearranged eudesmane sesquiterpenoids, Lyciiterpenoids A-D (1-4), together with four known compounds (5-8) were isolated from the aqueous extract of Lycii Cortex. Their structures were elucidated by spectroscopic analysis, and the absolute configurations of compounds 1-4 were determined by the quantum chemical ECD calculations. The absolute configuration of 1 was further confirmed by X-ray crystallographic data analysis. All the isolated compounds were evaluated for their cytotoxicity against three human cancer cell lines (MCF-7, HepG2, and A549). However, no significant activities were detected even with a concentration up to 100 µM.

3.
Nat Commun ; 11(1): 475, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980622

RESUMO

We reported previously that acid-sensing ion channel 1a (ASIC1a) mediates acidic neuronal necroptosis via recruiting receptor-interacting protein kinase 1 (RIPK1) to its C terminus (CT), independent of its ion-conducting function. Here we show that the N-terminus (NT) of ASIC1a interacts with its CT to form an auto-inhibition that prevents RIPK1 recruitment/activation under resting conditions. The interaction involves glutamate residues at distal NT and is disrupted by acidosis. Expression of mutant ASIC1a bearing truncation or glutamate-to-alanine substitutions at distal NT causes constitutive cell death. The NT-CT interaction is further disrupted by N-ethylmaleimide-sensitive fusion ATPase (NSF), which associates with ASIC1a-NT under acidosis, facilitating RIPK1 interaction with ASIC1a-CT. Importantly, a membrane-penetrating synthetic peptide representing the distal 20 ASIC1a NT residues, NT1-20, reduced neuronal damage in both in vitro model of acidotoxicity and in vivo mouse model of ischemic stroke, demonstrating the therapeutic potential of targeting the auto-inhibition of ASIC1a for neuroprotection against acidotoxicity.

4.
Biomaterials ; 235: 119765, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31991338

RESUMO

Cancer starvation therapy based on catalytic chemistry of glucose oxidase (GOx) offers great potential for multimodal treatment, benefiting from both nutrition shutting-off and the oxidization product hydrogen peroxide (H2O2). Herein, further optimization of such combined therapy was achieved by a cascade Nano-reactor, which was constructed by incorporating GOx into a bio-mimic upconversion nanosystem. The cascade began when GOx was delivered into tumor sites through homotypic targeting, facilitating selective starving of cancer cells and H2O2 generation. Then, upon 980 nm laser excitation, the 470 nm light emitted by upconversion nanoparticles (NaYF4: Yb, Tm) photolyzed H2O2 into hydroxyl radical for phototherapy, superior to direct photolysis by blue light with limited tissue penetration depth. Meanwhile, the 800 nm emission of UCNPs was used to track the in vivo fate and tumor targeting ability of the Nano-reactor. Radionuclide imaging further confirmed the targeting of the Nano-reactor to subcutaneous 4T1 tumor and lung metastasis. Significantly enhanced therapeutic efficacy of this cascade starvation-phototherapy was validated in vitro and in vivo, suggesting the Nano-reactor as a smart, simple and strong system for cancer multimodal therapy.

5.
J Proteome Res ; 19(2): 864-872, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31917576

RESUMO

Ankylosing spondylitis (AS) is a systemic, chronic, and inflammatory rheumatic disease that affects 0.2% of the population. Current diagnostic criteria for disease activity rely on subjective Bath Ankylosing Spondylitis Disease Activity Index scores. Here, we aimed to discover a panel of serum protein biomarkers. First, tandem mass tag (TMT)-based quantitative proteomics was applied to identify differential proteins between 15 pooled active AS and 60 pooled healthy subjects. Second, cohort 1 of 328 humans, including 138 active AS and 190 healthy subjects from two independent centers, was used for biomarker discovery and validation. Finally, biomarker panels were applied to differentiate among active AS, stable AS, and healthy subjects from cohort 2, which enrolled 28 patients with stable AS, 26 with active AS, and 28 healthy subjects. From the proteomics study, a total of 762 proteins were identified and 46 proteins were up-regulated and 59 proteins were down-regulated in active AS patients compared to those in healthy persons. Among them, C-reactive protein (CRP), complement factor H-related protein 3 (CFHR3), α-1-acid glycoprotein 2 (ORM2), serum amyloid A1 (SAA1), fibrinogen γ (FG-γ), and fibrinogen ß (FG-ß) were the most significantly up-regulated inflammation-related proteins and S100A8, fatty acid-binding protein 5 (FABP5), and thrombospondin 1 (THBS1) were the most significantly down-regulated inflammation-related proteins. From the cohort 1 study, the best panel for the diagnosis of active AS vs healthy subjects is the combination of CRP and SAA1. The area under the receiver operating characteristic (ROC) curve was nearly 0.900, the sensitivity was 0.970%, and the specificity was 0.805% at a 95% confidence interval from 0.811 to 0.977. Using 0.387 as the cutoff value, the predictive values reached 92.00% in the internal validation set (62 with active AS vs 114 healthy subjects) and 97.50% in the external validation phase (40 with active AS vs 40 healthy subjects). From the cohort 2 study, a panel of CRP and SAA1 can differentiate well among active AS, stable AS, and healthy subjects. For active AS vs stable AS, the area under the ROC curve was 0.951, the sensitivity was 96.43%, the specificity was 88.46% at a 95% confidence interval from 0.891 to 1, and the coincidence rate was 92.30%. For stable AS vs healthy humans, the area under the ROC curve was 0.908, the sensitivity was 89.29%, the specificity was 78.57% at a 95% confidence interval from 0.836 to 0.980, and the coincidence rate was 83.93%. For active AS vs healthy subjects, the predictive value was 94.44%. The results indicated that the CRP and SAA1 combination can potentially diagnose disease status, especially for active or stable AS, which will be conducive to treatment recommendation for patients with AS.

6.
Acta Pharmacol Sin ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949292

RESUMO

Metrnl is a newly identified secreted protein highly expressed in the intestinal epithelium. This study aimed to explore the role and mechanism of intestinal epithelial Metrnl in ulcerative colitis. Metrnl-/- (intestinal epithelial cell-specific Metrnl knockout) mice did not display any phenotypes of colitis under basal conditions. However, under administration of 3% dextran sodium sulfate (DSS) drinking water, colitis was more severe in Metrnl-/- mice than in WT mice, as indicated by comparisons of body weight loss, the presence of occult or gross blood per rectum, stool consistency, shrinkage in the colon, intestinal damage, and serum levels of inflammatory factors. DSS-induced colitis activated autophagy in the colon. This activation was partially inhibited by intestinal epithelial Metrnl deficiency, as indicated by a decrease in Beclin-1 and LC3-II/I and an increase in p62 in DSS-treated Metrnl-/- mice compared with WT mice. These phenomena were further confirmed by observation of autophagosomes and immunofluorescence staining for LC3 in epithelial cells. The autophagy-related AMPK-mTOR-p70S6K pathway was also activated in DSS-induced colitis, and this pathway was partially blocked by intestinal epithelial Metrnl deficiency, as indicated by a decrease in AMPK phosphorylation and an increase in mTOR and p70S6K phosphorylation in DSS-treated Metrnl-/- mice compared with WT mice. Therefore, Metrnl deficiency deteriorated ulcerative colitis at least partially through inhibition of autophagy via the AMPK-mTOR-p70S6K pathway, suggesting that Metrnl is a therapeutic target for ulcerative colitis.

7.
J Neurochem ; : e14971, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31976561

RESUMO

Acid sensing ion channel 1a (ASIC1a) is well-known to play a major pathophysiological role during brain ischemia linked to acute acidosis of ~ pH 6, while its function during physiological brain activity, linked to much milder pH changes, is still poorly understood. Here, by performing live cell imaging utilizing Na+ and Ca2+ sensitive and spatially specific fluorescent dyes, we investigated the role of ASIC1a in cytosolic Na+ and Ca2+ signals elicited by a mild extracellular drop from pH 7.4 to 7.0 and how these affect mitochondrial Na+ and Ca2+ signaling or metabolic activity. We show that in mouse primary cortical neurons, this small extracellular pH change triggers cytosolic Na+ and Ca2+ waves that propagate to mitochondria. Inhibiting ASIC1a with Psalmotoxin 1 (PcTX1) or ASIC1a gene knockout blocked not only the cytosolic but also the mitochondrial Na+ and Ca2+ signals. Moreover, physiological activation of ASIC1a by this pH shift enhances mitochondrial respiration and evokes mitochondrial Na+ signaling even in digitonin - permeabilized neurons. Altogether our results indicate that ASIC1a is critical in linking physiological extracellular pH stimuli to mitochondrial ion signaling and metabolic activity and thus is an important metabolic sensor.

8.
Nat Commun ; 11(1): 158, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919416

RESUMO

Regulating the fluorescent properties of organic small molecules in a controlled and dynamic manner has been a fundamental research goal. Although several strategies have been exploited, realizing multi-color molecular emission from a single fluorophore remains challenging. Herein, we demonstrate an emissive system by combining pyrene fluorophore and acylhydrazone units, which can generate multi-color switchable fluorescent emissions at different assembled states. Two kinds of supramolecular tools, amphiphilic self-assembly and γ-cyclodextrin mediated host-guest recognition, are used to manipulate the intermolecular aromatic stacking distances, resulting in the tunable fluorescent emission ranging from blue to yellow, including a pure white-light emission. Moreover, an external chemical signal, amylase, is introduced to control the assembly states of the system on a time scale, generating a distinct dynamic emission system. The dynamic properties of this multi-color fluorescent system can be also enabled in a hydrogel network, exhibiting a promising potential for intelligent fluorescent materials.

9.
Nat Prod Res ; : 1-9, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31928366

RESUMO

Three new compounds (1-3), together with six known compounds (4-9), were isolated from the ethyl acetate fraction of ethanol extract of the aerial parts of Justicia gendarussa Burm.f. All of these known compounds were isolated from the plant for the first time. Their structures including absolute configurations were elucidated on the basis of HR-ESI-MS, NMR spectroscopic analyses, single crystal X-ray diffraction and comparison with the literatures. Compounds 1-9 were tested for their antioxidant and anti-inflammatory activities. Compounds 5 and 8 showed the antioxidant activities with IC50 values of 28.61 ± 1.56 and 22.55 ± 1.38 µM, respectively. Compounds 2 and 3 showed anti-inflammatory activity in LPS-induced RAW 264.7 macrophages with the IC50 values of 20.95 ± 1.11 and 16.50 ± 1.04 µM, respectively.

10.
J Cell Mol Med ; 2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31930674

RESUMO

Hepatitis B virus (HBV) is a human hepatotropic virus. However, HBV infection also occurs at extrahepatic sites, but the relevant host factors required for HBV infection in non-hepatic cells are only partially understood. In this article, a non-hepatic cell culture model is constructed by exogenous expression of four host genes (NTCP, HNF4α, RXRα and PPARα) in human non-hepatic 293T cells. This cell culture model supports HBV entry, transcription and replication, as evidenced by the detection of HBV pgRNA, HBV cccDNA, HBsAg, HBeAg, HBcAg and HBVDNA. Our results suggest that the above cellular factors may play a key role in HBV infection of non-hepatic cells. This model will facilitate the identification of host genes that support extrahepatic HBV infection.

11.
J Telemed Telecare ; 26(1-2): 3-13, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30153767

RESUMO

INTRODUCTION: Telehealth intervention has been proposed as a sustainable and innovative intervention approach to Parkinson's disease (PD) patients, but there are still conflicting results in the literature about its effect. This study aimed to evaluate the efficacy of telehealth intervention for PD patients. METHODS: PubMed, EMBASE, CENTRAL and China National Knowledge Infrastructure (CNKI) were searched from the inception to June 2018 for randomized controlled trials (RCTs) and cohort studies, without language restrictions. When feasible, data were statistically pooled for meta-analysis using Review Manager 5.3. Otherwise, narrative summaries were used. RESULTS: Twenty-one studies were included. With respect to PD severity, compared with usual care, telehealth intervention was beneficial in lowering motor impairment of PD patients significantly (mean difference (MD) = -2.27, 95% confidence interval (95% CI) -4.25 to -0.29, p = 0.02), rather than mental status (MD = -0.98, 95% CI -2.61 to 0.65, p = 0.24), activities of daily living (MD = -1.51, 95% CI -4.91 to 1.89, p = 0.38) and motor complications (MD = -0.36, 95% CI -1.31 to 0.59, p = 0.46). Telehealth intervention did not lead to significant reduction in quality of life (standardized mean difference (SMD) = 0.04, 95% CI -0.20 to 0.28, p = 0.76), depression (SMD = -0.12, 95% CI -0.37 to 0.13, p = 0.34), cognition (MD = 0.37, 95% CI -0.34 to 1.09, p = 0.31) and balance (MD = 0.09, 95% CI -2.49 to 2.66, p = 0.95). DISCUSSION: Telehealth intervention is an effective option for individuals with PD to improve their motor impairment. Further well-designed studies are warranted to confirm our findings.

12.
J Hazard Mater ; 386: 121663, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31784133

RESUMO

Exposure to polycyclic aromatic hydrocarbons and phthalates are linked to lung function decline and altered relative telomere length (RTL) accompanying with oxidative stress and inflammatory events in human body. However, limited data are available about impacts of co-exposure of PAHs and phthalates on lung function and RTL. We conducted a pilot study with repeated measures during the winter of 2014 and summer of 2015 in Wuhan city, China. Participants took part in the measures of lung function, RTL, urinary monohydroxylated-PAHs (OH-PAHs) and phthalate metabolites over three consecutive days in each season. Linear mixed-effect (LME) models and Bayesian kernel machine regression (BKMR) were used to analyze the relations of OH-PAHs or phthalate metabolites with lung function or RTL. LME models showed the negative associations of 3-day average of hydroxyphenanthrene (2 + 3-, 4-OHPhe) or 1-hydroxypyrene with FEV1, 3-day average of 2 + 3-OHPhe with FVC. BKMR models revealed the negative relation of eight OH-PAHs with FEV1, FVC or RTL; nine phthalate metabolites may counteract an overall effect of eight OH-PAHs on FEV1, FVC or RTL. The findings indicated that urinary phthalate metabolites may counteract the negative association of urinary OH-PAHs on FEV1 or FVC, which may be partially linked to shorter RTL regarding biological aging.

13.
Environ Pollut ; 257: 113509, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31767236

RESUMO

Evidence is available about the associations of phthalates or their metabolites with blood lipids, however, the mixture effects of multiple phthalate metabolites on blood lipid traits remain largely unknown. In this pilot study, 106 individuals at three age groups of <18, 18- and ≥60 years were recruited from the residents (n = 1240) who were randomly selected from two communities in Wuhan city, China. The participants completed the questionnaire survey and physical examination as well as provided urine samples in the winter of 2014 and the summer of 2015. We measured urinary levels of nine phthalate metabolites using a high-performance liquid chromatography-tandem mass spectrometry. We estimated the associations of individual phthalate metabolite with blood lipid traits by linear mixed effect (LME) models, and assessed the overall association of the mixture of nine phthalate metabolites with blood lipid traits using Bayesian kernel machine regression (BKMR) models. LME models revealed the negative association of urinary mono-2-ethylhexyl phthalate (MEHP) with total cholesterol (TC) as well as of urinary mono-benzyl phthalate or urinary MEHP with low density lipoprotein cholesterol (LDL-C). BKMR models revealed the negative overall association of the mixture of nine phthalate metabolites with TC or LDL-C, and DEHP metabolites (especially MEHP) had a greater contribution to TC or LDL-C levels than non-DEHP metabolites. The findings indicated the negative overall association of the mixture of nine phthalate metabolites with TC or LDL-C. Among nine phthalate metabolites, MEHP was the most important component for the changes of TC or LDL-C levels, implying that phthalates exposure may disrupt lipid metabolism in the body.

14.
Autophagy ; 16(3): 531-547, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31204559

RESUMO

Mutations in the macroautophagy/autophagy gene WDR45 cause ß-propeller protein-associated neurodegeneration (BPAN); however the molecular and cellular mechanism of the disease process is largely unknown. Here we generated constitutive wdr45 knockout (KO) mice that displayed cognitive impairments, abnormal synaptic transmission and lesions in several brain regions. Immunohistochemistry analysis showed loss of neurons in prefrontal cortex and basal ganglion in aged mice, and increased apoptosis in prefrontal cortex, recapitulating a hallmark of neurodegeneration. Quantitative proteomic analysis showed accumulation of endoplasmic reticulum (ER) proteins in KO mouse. At the cellular level, accumulation of ER proteins due to WDR45 deficiency resulted in increased ER stress and impaired ER quality control. The unfolded protein response (UPR) was elevated through ERN1/IRE1 or EIF2AK3/PERK pathway, and eventually led to neuronal apoptosis. Suppression of ER stress or activation of autophagy through MTOR inhibition alleviated cell death. Thus, the loss of WDR45 cripples macroautophagy machinery in neurons and leads to impairment in organelle autophagy, which provides a mechanistic understanding of cause of BPAN and a potential therapeutic strategy to treat this genetic disorder.Abbreviations: 7-ADD: 7-aminoactinomycin D; ASD: autistic spectrum disorder; ATF6: activating transcription factor 6; ATG: autophagy-related; BafA1: bafilomycin A1; BCAP31: B cell receptor associated protein 31; BPAN: ß-propeller protein-associated neurodegeneration; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CDIPT: CDP-diacylglycerol-inositol 3-phosphatidyltransferase (phosphatidylinositol synthase); DDIT3/CHOP: DNA-damage inducible transcript 3; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GFP: green fluorescent protein; HIP: hippocampus; HSPA5/GRP78: heat shock protein family A (HSP70) member 5; KO: knockout; LAMP1: lysosomal-associated membrane 1; mEPSCs: miniature excitatory postsynaptic currents; MG132: N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal; MIB: mid-brain; MTOR: mechanistic target of rapamycin kinase; PCR: polymerase chain reaction; PFA: paraformaldehyde; PFC: prefrontal cortex; PRM: parallel reaction monitoring; RBFOX3/NEUN: RNA binding protein, fox-1 homolog [C. elegans] 3; RTN3: reticulon 3; SEC22B: SEC22 homolog B, vesicle trafficking protein; SEC61B: SEC61 translocon beta subunit; SEM: standard error of the mean; SNR: substantia nigra; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; Tm: tunicamycin; TMT: tandem mass tag; TUDCA: tauroursodeoxycholic acid; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UPR: unfolded protein response; WDR45: WD repeat domain 45; WT: wild type; XBP1: X-box binding protein 1.

15.
Sci Total Environ ; 702: 135056, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31731128

RESUMO

Limited researches are available on seasonal variation of inhalation exposure of polycyclic aromatic hydrocarbons (PAHs) and its cancer risk assessment in China. We recruited 20 fresh postgraduates and measured outdoor and indoor (dormitories, offices and laboratories) daily PM2.5 concentrations in four seasons (seven consecutive days in every season) during 2014 -2015, calculated daily potential doses of personal exposure to total Benzo[a]pyrene equivalent concentration (BaPeq) in the microenvironments based on the total BaPeq and the time-activity patterns, and estimated incremental lifetime cancer risk (ILCR) using Monte Carlo method. Daily average concentrations of PM2.5-bound ∑PAHs on the campus ranked from high to low were winter, autumn, spring, summer in the dormitories and offices. Daily average concentration of PM2.5-bound ∑PAHs were higher in indoor environments than outdoor in the same season, except for that of PM2.5-bound ∑PAHs in laboratories in the winter. Median values of ILCR in both sexes from high to low were winter (men vs. women: 5.35e-9 vs. 4.96e-9), spring (3.71e-9 vs. 4.00e-9), autumn (2.92e-9 vs. 3.02e-9), summer (1.71e-9 vs. 1.87e-9). Indoor and outdoor PM2.5-bound PAHs concentrations showed seasonal and spatial variations. The ILCR value for PM2.5-bound PAHs was higher in women than in men.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental , Exposição por Inalação/estatística & dados numéricos , Material Particulado/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Adulto , China/epidemiologia , Humanos , Neoplasias/epidemiologia , Medição de Risco , Estações do Ano
16.
BMJ Open ; 9(11): e032417, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31784442

RESUMO

INTRODUCTION: Postoperative nausea and vomiting (PONV) is among the most common adverse reactions following anaesthesia and surgery. Recent clinical studies have reported that the average incidence is about 30%, while in patients specifically undergoing neurosurgery, the incidence can be as great as 73%. Studies also suggest that its occurrence increases the risk of intracranial haematoma and haemorrhage. The objective of this study is to evaluate the effectiveness of intradermal thumbtack needle buried Neiguan (pericardium 6 (P6)) point therapy in the prevention of PONV in patients undergoing craniotomy under general anaesthesia. METHODS AND ANALYSIS: This is a single-centre, three-arm, randomised controlled trial. 180 participants are randomly assigned to either an acupuncture, intradermal thumbtack needle or control group in a 1:1:1 ratio. The P6 of the acupuncture group is punctured at both sides perpendicularly to a depth of 20 mm. Needles are retained for 30 min and stimulated every 10 min to maintain the de qi. The therapy includes two treatments; the acupuncture is administered immediately after and 24 hours after surgery. For the intradermal thumbtack needle group, the intradermal thumbtack needle is quickly inserted into the skin and embedded at P6 acupoints bilaterally. Patients and their families are asked to press the needlepoint with the onset of nausea, vomiting, bloating, pain and other reported discomforts. The needle is replaced after 24 hours. The therapy is administered immediately after and 24 hours after surgery. For the control group, no intervention is carried out. The incidence of PONV within 48 hours after craniotomy across the three groups is observed. Other observations include: (1) assessment of nausea score (severity of nausea) and pain score (visual analogue scale) 0-2, 2-6, 6-24 and 24-48 hours after craniotomy under general anaesthesia; (2) assessment of total rescue antiemetic dosage 0-48 hours after craniotomy under general anaesthesia; (3) length of hospital stay and (4) patient satisfaction score with PONV management. We will perform all statistical analysis following the intention-to-treat principle. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Bioethics Subcommittee of the West China Hospital, Sichuan University: the approval number is 2018 (number 231). Results will be expected to be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR1800017173.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31831364

RESUMO

BACKGROUND AND AIMS: High serum hepatocyte growth factor (HGF) levels increase the risk of ischemic stroke and are probably associated with outcomes after ischemic stroke. However, it remains unclear whether the association between HGF and ischemic stroke prognosis is modified by blood lipid status. METHODS AND RESULTS: Data were derived from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke), and we measured baseline serum HGF levels in 3027 ischemic stroke patients. The primary outcome was a combination of death and major disability (modified Rankin Scale score≥3) at 2 years after ischemic stroke. Blood lipid status could modify association between HGF and ischemic stroke prognosis (Pinteraction = 0.002). After multivariate adjustment, the odds ratios of primary outcome associated with the highest tertile of HGF were 2.13 (95% CI, 1.45-3.14; Ptrend<0.001) for patients with dyslipidemia and 0.81 (95% CI, 0.54-1.22; Ptrend = 0.310) for those with normal lipids. Adding HGF to conventional risk factors improved risk prediction for primary outcome in patients with dyslipidemia (net reclassification improvement: 24.28%, P < 0.001; integrated discrimination index: 0.43%, P = 0.022) but not in those with normal lipids. Secondary analyses further revealed that HDL-C was the main lipid component to modify the prognostic significance of serum HGF among ischemic stroke patients. CONCLUSIONS: There was a modified effect of blood lipid status on the association between serum HGF and ischemic stroke prognosis. Elevated serum HGF was associated with outcomes in ischemic stroke patients with dyslipidemia, especially low HDL-C. Further studies are warranted to replicate our findings and clarify the potential biological mechanisms.

18.
Nat Commun ; 10(1): 5566, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804482

RESUMO

Overexpressed Aurora-A kinase promotes tumor growth through various pathways, but whether Aurora-A is also involved in metabolic reprogramming-mediated cancer progression remains unknown. Here, we report that Aurora-A directly interacts with and phosphorylates lactate dehydrogenase B (LDHB), a subunit of the tetrameric enzyme LDH that catalyzes the interconversion between pyruvate and lactate. Aurora-A-mediated phosphorylation of LDHB serine 162 significantly increases its activity in reducing pyruvate to lactate, which efficiently promotes NAD+ regeneration, glycolytic flux, lactate production and bio-synthesis with glycolytic intermediates. Mechanistically, LDHB serine 162 phosphorylation relieves its substrate inhibition effect by pyruvate, resulting in remarkable elevation in the conversions of pyruvate and NADH to lactate and NAD+. Blocking S162 phosphorylation by expression of a LDHB-S162A mutant inhibited glycolysis and tumor growth in cancer cells and xenograft models. This study uncovers a function of Aurora-A in glycolytic modulation and a mechanism through which LDHB directly contributes to the Warburg effect.

19.
Clin Cancer Res ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796514

RESUMO

PURPOSE: Emerging evidence indicates that castration-resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor (AR) or its V7 splice variant (AR-V7) and commonly becomes resistant to endocrine therapy. The aim of this work is to evaluate the function of a kinesin protein, KIF4A, in regulating AR/AR-V7 in prostate cancer endocrine therapy resistance. EXPERIMENTAL DESIGN: We examined KIF4A expression in clinical prostate cancer specimens by IHC. Regulated pathways were investigated by qRT-PCR, immunoblot analysis, immunoprecipitation, and luciferase reporter and chromatin immunoprecipitation (ChIP) assays. A series of functional analyses were conducted in cell lines and xenograft models. RESULTS: Examination of the KIF4A protein and mRNA levels in patients with prostate cancer showed that increased expression of KIF4A was positively correlated with androgen receptor (AR) levels. Patients with lower tumor KIF4A expression had improved overall survival and disease-free survival. Mechanistically, KIF4A and AR form an auto-regulatory positive feedback loop in prostate cancer: KIF4A binds AR and AR-V7 and prevents CHIP-mediated AR and AR-V7 degradation; AR binds the promoter region of KIF4A and activates its transcription. KIF4A promotes castration-sensitive and castration-resistant prostate cancer cell growth through AR- and AR-V7-dependent signaling. Furthermore, KIF4A expression is upregulated in enzalutamide-resistant prostate cancer cells, and KIF4A knockdown effectively reverses enzalutamide resistance and enhances the sensitivity of CRPC cells to endocrine therapy. CONCLUSIONS: These findings indicate that KIF4A plays an important role in the progression of CRPC and serves as a crucial determinant of the resistance of CRPC to endocrine therapy.

20.
Zhongguo Gu Shang ; 32(11): 1053-1057, 2019 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-31870056

RESUMO

OBJECTIVE: To explore clinical effect of infrared thermal imaging technology for the treatment of free anterolateral thigh perforator flap transplantation. METHODS: From June 2014 to June 2018, 31 patients with skin defect at various degrees treated by free anterolateral thigh perforator flap transplantation, including 21 males and 10 females aged from 16 to 59 years old with an average age of(35.3±1.5) years old, the courses of disease ranged from 2 to 4 weeks with an average of (1.8±0.6) weeks. The number of perforating branch, the position of the perforating branch, the perforating branch vitality detected by Doppler blood stream detector and parameters of thermal imaging image in order to guide design of skin flap, and compared results with the data of perforator arteries observed during the operation. RESULTS: Totally 52 branches of perforating arteries were detected by Doppler blood stream detector during operation, and 38 perforator branches were confirmed in operation, the accuracy rate was 73.1%. Thirty-eight branches of perforating arteries were detected by infrared thermography during operation, and 35 branches of perforating branches were confirmed in operation, the accuracy rate was 92.1%; there were statistical difference. The most dynamic perforating pivot found by Doppler blood stream detector was confirmed by intraoperative diagnosis, with an accuracy rate of 80.6%. The most dynamic perforating pivot found by infrared thermography is confirmed by intraoperative diagnosis, with an accuracy rate of 100%; there were statistical difference. Thirty-one flaps were survived without vascular crisis occurred. All patients were followed up from 6 to 18 months with an average of(10.7±1.2) months. The flaps survived with soft texture and good blood circulation, the defect was not bloated, the color of skin flap was basically the same as that of the normal skin, and the limbs appearance and function recovered well. CONCLUSIONS: Infrared infrared thermal imaging technology could be used as a new technology in localization of perforator artery in free anterolateral thigh perforator flap transplantation.


Assuntos
Retalho Perfurante , Procedimentos Cirúrgicos Reconstrutivos , Lesões dos Tecidos Moles , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Pele , Coxa da Perna , Adulto Jovem
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