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1.
Cell Prolif ; : e12736, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31828859

RESUMO

Scoliosis, a complex three-dimensional deformity of the spine with the Cobb angle (a measure of the spinal lateral curvature) >10 degree, encompasses a spectrum of pathologies, including congenital, idiopathic, syndromic and neuromuscular aetiologies. The pathogenesis is multifactorial involving both environmental and genetic factors but the exact cellular and molecular mechanisms of disease development remain largely unknown. Emerging evidence showed that non-coding RNAs (ncRNAs), namely microRNAs, long ncRNAs and circular RNAs, are deregulated in many orthopaedic diseases, including scoliosis. Importantly, these deregulated ncRNAs functionally participate in the initiation and progression of scoliosis. Here, we review recent progress in ncRNA research on scoliosis.

2.
Ann Intern Med ; 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31869834

RESUMO

Background: Preliminary data suggest that preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) may improve risk prediction in patients undergoing noncardiac surgery. Objective: To determine whether preoperative NT-proBNP has additional predictive value beyond a clinical risk score for the composite of vascular death and myocardial injury after noncardiac surgery (MINS) within 30 days after surgery. Design: Prospective cohort study. Setting: 16 hospitals in 9 countries. Patients: 10 402 patients aged 45 years or older having inpatient noncardiac surgery. Measurements: All patients had NT-proBNP levels measured before surgery and troponin T levels measured daily for up to 3 days after surgery. Results: In multivariable analyses, compared with preoperative NT-proBNP values less than 100 pg/mL (the reference group), those of 100 to less than 200 pg/mL, 200 to less than 1500 pg/mL, and 1500 pg/mL or greater were associated with adjusted hazard ratios of 2.27 (95% CI, 1.90 to 2.70), 3.63 (CI, 3.13 to 4.21), and 5.82 (CI, 4.81 to 7.05) and corresponding incidences of the primary outcome of 12.3% (226 of 1843), 20.8% (542 of 2608), and 37.5% (223 of 595), respectively. Adding NT-proBNP thresholds to clinical stratification (that is, the Revised Cardiac Risk Index [RCRI]) resulted in a net absolute reclassification improvement of 258 per 1000 patients. Preoperative NT-proBNP values were also statistically significantly associated with 30-day all-cause mortality (less than 100 pg/mL [incidence, 0.3%], 100 to less than 200 pg/mL [incidence, 0.7%], 200 to less than 1500 pg/mL [incidence, 1.4%], and 1500 pg/mL or greater [incidence, 4.0%]). Limitation: External validation of the identified NT-proBNP thresholds in other cohorts would reinforce our findings. Conclusion: Preoperative NT-proBNP is strongly associated with vascular death and MINS within 30 days after noncardiac surgery and improves cardiac risk prediction in addition to the RCRI. Primary Funding Source: Canadian Institutes of Health Research.

3.
Anesth Analg ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31764163

RESUMO

Electroencephalographic (EEG) monitoring to indicate brain state during anesthesia has become widely available. It remains unclear whether EEG-guided anesthesia influences perioperative outcomes. The sixth Perioperative Quality Initiative (POQI-6) brought together an international team of multidisciplinary experts from anesthesiology, biomedical engineering, neurology, and surgery to review the current literature and to develop consensus recommendations on the utility of EEG monitoring during anesthesia. We retrieved a total of 1023 articles addressing the use of EEG monitoring during anesthesia and conducted meta-analyses from 15 trials to determine the effect of EEG-guided anesthesia on the rate of unintentional awareness, postoperative delirium, neurocognitive disorder, and long-term mortality after surgery. After considering current evidence, the working group recommends that EEG monitoring should be considered as part of the vital organ monitors to guide anesthetic management. In addition, we encourage anesthesiologists to be knowledgeable in basic EEG interpretation, such as raw waveform, spectrogram, and processed indices, when using these devices. Current evidence suggests that EEG-guided anesthesia reduces the rate of awareness during total intravenous anesthesia and has similar efficacy in preventing awareness as compared with end-tidal anesthetic gas monitoring. There is, however, insufficient evidence to recommend the use of EEG monitoring for preventing postoperative delirium, neurocognitive disorder, or postoperative mortality.

4.
Cell Prolif ; 52(6): e12704, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31621141

RESUMO

Intervertebral disc degeneration (IDD) is a common cause of low back pain, which inflicts more global disability than any other condition. Although IDD was deemed to be a natural process that comes with ageing, a growing body of evidence suggested that both genetic and environmental factors could modify the development of IDD. In this connection, aberrant function of nucleus pulposus cells has been implicated in IDD pathogenesis. Circular RNAs are a novel class of endogenous non-coding RNAs that play crucial regulatory roles in diverse cellular processes. Recently, deregulation of circRNAs in nucleus pulposus cells was found to functionally participate in IDD development. In this review, we summarize the current knowledge regarding the deregulation of circRNAs in IDD in relation to their actions on nucleus pulposus cell functions, including cell proliferation, apoptosis and extracellular matrix synthesis/degradation. The potential clinical utilities of circRNAs as therapeutic targets for the management of IDD are also discussed.

5.
Heart Asia ; 11(2): e011155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565074

RESUMO

Objectives: This meta-analysis and systematic review seeks to compare both characteristic parameters and procedural outcomes of atrial fibrillation (AF) catheter ablation in patients under general anaesthesia (GA)/deep sedation and mild/moderate sedation. Background: Catheter ablation has become a widely applied intervention for treating symptomatic AF and arrhythmias that are refractory to medical therapy. It can be conducted through from mild sedation to GA. Methods: PubMed and Embase were searched up to July 2018 for randomised controlled trials, cohort and observational studies that assessed the outcomes of catheter ablation under GA/deep sedation or mild/moderate sedation. Nine studies were included in this meta-analysis after screening with the inclusion and exclusion criteria. Heterogeneity between studies and publication bias was evaluated by I2 index and Egger's regression, respectively. Results: Our meta-analysis found catheter AF ablation with GA/deep sedation to be associated with reduced risk of recurrence (RR: 0.79, 95% CI 0.56 to 1.13, p=0.20) and complications (RR: 0.95, 95% CI 0.64 to 1.42, p=0.82), though statistically insignificant. In terms of procedural parameters, there was no significant difference between the two groups for both procedural time (SMD: -0.13, 95% CI -0.90 to 0.63, p=0.74) and fluoroscopy time (SMD: -0.41, 95% CI -1.40 to 0.58, p=0.41). Univariate meta-regression did not reveal any covariates as a moderating factor for complication and recurrence risk. Conclusion: Apart from an increased likelihood of procedural success, ablation by GA/deep sedation was found to be non-significantly different from the mild/moderate sedation approach in both procedural parameters and outcome measures.

6.
Lancet ; 394(10212): 1907-1914, 2019 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645286

RESUMO

BACKGROUND: An association between increasing anaesthetic depth and decreased postoperative survival has been shown in observational studies; however, evidence from randomised controlled trials is lacking. Our aim was to compare all-cause 1-year mortality in older patients having major surgery and randomly assigned to light or deep general anaesthesia. METHODS: In an international trial, we recruited patients from 73 centres in seven countries who were aged 60 years and older, with significant comorbidity, having surgery with expected duration of more than 2 h, and an anticipated hospital stay of at least 2 days. We randomly assigned patients who had increased risk of complications after major surgery to receive light general anaesthesia (bispectral index [BIS] target 50) or deep general anaesthesia (BIS target 35). Anaesthetists also nominated an appropriate range for mean arterial pressure for each patient during surgery. Patients were randomly assigned in permuted blocks by region immediately before surgery, with the patient and assessors masked to group allocation. The primary outcome was 1-year all-cause mortality. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000632897, and is closed to accrual. FINDINGS: Patients were enrolled between Dec 19, 2012, and Dec 12, 2017. Of the 18 026 patients screened as eligible, 6644 were enrolled, randomly assigned to treatment or control, and formed the intention-to-treat population (3316 in the BIS 50 group and 3328 in the BIS 35 group). The median BIS was 47·2 (IQR 43·7 to 50·5) in the BIS 50 group and 38·8 (36·3 to 42·4) in the BIS 35 group. Mean arterial pressure was 3·5 mm Hg (4%) higher (median 84·5 [IQR 78·0 to 91·3] and 81·0 [75·4 to 87·6], respectively) and volatile anaesthetic use was 0·26 minimum alveolar concentration (30%) lower (0·62 [0·52 to 0·73] and 0·88 [0·74 to 1·04], respectively) in the BIS 50 than the BIS 35 group. 1-year mortality was 6·5% (212 patients) in the BIS 50 group and 7·2% (238 patients) in the BIS 35 group (hazard ratio 0·88, 95% CI 0·73 to 1·07, absolute risk reduction 0·8%, 95% CI -0·5 to 2·0). Grade 3 adverse events occurred in 954 (29%) patients in the BIS 50 group and 909 (27%) patients in the BIS 35 group; and grade 4 adverse events in 265 (8%) and 259 (8%) patients, respectively. The most commonly reported adverse events were infections, vascular disorders, cardiac disorders, and neoplasms. INTERPRETATION: Among patients at increased risk of complications after major surgery, light general anaesthesia was not associated with lower 1-year mortality than deep general anaesthesia. Our trial defines a broad range of anaesthetic depth over which anaesthesia may be safely delivered when titrating volatile anaesthetic concentrations using a processed electroencephalographic monitor. FUNDING: Health Research Council of New Zealand; National Health and Medical Research Council, Australia; Research Grant Council of Hong Kong; National Institute for Health and Research, UK; and National Institutes of Health, USA.

7.
Environ Sci Pollut Res Int ; 26(33): 34421-34429, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31637615

RESUMO

Circular RNAs (circRNAs) are an important class of non-coding RNAs partly by acting as microRNA sponges. Growing evidence indicates that air pollution exposure during pregnancy could lead to congenital defects in the offspring. In this study, using circRNAs sequencing, we profiled differentially expressed circRNAs in rat embryos exposed to a high concentration (> 200 µg/m3) of fine particulate matter (PM2.5) in utero. Compared with the control embryos whose mothers were reared in clean air, 25 and 55 circRNAs were found to be downregulated and upregulated, respectively, in the air pollution-exposed group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of circRNA-coexpressed genes indicated that segmentation, brain development, and system development together with lysine degradation, Rap1 signaling pathway, and adrenergic signaling were deregulated by in utero air pollution exposure. We also identified the central role of three circRNAs, namely circ_015003, circ_030724, and circ_127215 in the circRNA-microRNA interaction network. These data suggested that circRNA deregulation might play a crucial role in the development of air pollution-associated congenital malformations.

9.
J Cell Mol Med ; 23(11): 7717-7725, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31557384

RESUMO

Air pollution has been a serious public health issue over the past few decades particularly in developing countries. Air pollution exposure during pregnancy poses potential threat to offspring as the deleterious substances might pass through placenta to alter foetal development. A growing number of studies have demonstrated that long non-coding RNAs (lncRNAs) participate in the development of many diseases, including congenital defects. Here, we used RNA sequencing to identify differentially expressed lncRNAs in air pollution-exposed rat embryos compared with control group. Our data suggested that 554 lncRNAs (216 up-regulated and 338 down-regulated) were significantly differentially expressed in the air pollution-exposed embryos. Moreover, potential cellular functions of these deregulated lncRNAs were predicted via KEGG signal pathway/GO enrichment analyses, which suggested the possible involvements of neurological process, sensory perception of smell and the G-protein signalling pathway. Furthermore, potential functional network of deregulated lncRNAs and their correlated mRNAs in the development of congenital spinal abnormality was established. Our data suggested that lncRNAs may play a vital role in the pathophysiology of air pollution-exposed congenital spinal malformation.

10.
Semin Cell Dev Biol ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31408699

RESUMO

Autophagy is a conserved intracellular degradation process enclosing the bulk of cytosolic components for lysosomal degradation to maintain cellular homeostasis. Accumulating evidences showed that a specialized form of autophagy, known as xenophagy, could serve as an innate immune response to defend against pathogens invading inside the host cells. Correspondingly, infectious pathogens have developed a variety of strategies to disarm xenophagy, leading to a prolonged and persistent intracellular colonization. In this review, we first summarize the current knowledge about the general mechanisms of intracellular bacterial infections and xenophagy. We then focus on the ongoing battle between these two processes.

11.
Cancer Prev Res (Phila) ; 12(10): 653-666, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31431500

RESUMO

Chemoprevention is cost-effective for colorectal cancer when targeted at intermediate- or high-risk populations. Bufalin is a cardiac glycoside extracted from the traditional Chinese medicine (TCM) "Chan Su," which has been used as an anticancer agent. On the basis of the relative safety of bufalin, we investigated whether bufalin could act as a chemoprophylactic agent to prevent colon tumorigenesis in two murine models, namely colitis-associated colorectal cancer and Apc germline mutation-developed colorectal cancer. Our results revealed that long-term (12-16 weeks) administration of low-dose bufalin (0.5 mg/kg) effectively suppressed tumorigenesis in both colorectal cancer models, accompanied by attenuated epithelial cell proliferation (reduced bromodeoxyuridine incorporation, lower levels of cyclin A, cyclin D1, cyclin E, and cyclin-dependent kinases-2/4, and higher levels of p21 and p27) and promoted apoptosis (increased TUNEL positivity and caspase-3/9 cleavages, reduced levels of Bcl-2, Bcl-xL and survivin, and increased levels of Bax and Bak). Bufalin also suppressed the expression of proinflammatory mediators [reduced levels of cyclooxygenase-2, tumor TNFα, IL1ß, IL6, C-X-C motif chemokine ligand (CXCL)-1, CXCL-2, and CXCL-5] in the colitis-associated colorectal cancer model. These effects were associated with the inhibition of oncogenic NF-κB and PI3K/Akt pathways. Our findings unveil a novel chemoprophylactic action of bufalin in colorectal cancer in vivo and provided efficacy data and mechanistic evidence for further clinical evaluation of this TCM compound for colorectal cancer chemoprevention in individuals at risk of colorectal cancer.

12.
BMC Cancer ; 19(1): 649, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266475

RESUMO

BACKGROUND: Prognostication of patients with colorectal cancer (CRC) currently relies on tumor-node-metastasis (TNM) staging but clinical outcomes of patients of the same histoclinical stage are heterogeneous. It is therefore imperative to devise novel molecular tests to stratify CRC patients. Our previous work demonstrated that eukaryotic elongation factor-2 kinase (EEF2K) is a tumor suppressor in CRC. Herein, we investigated EEF2K expression in CRC and determined its relationship with clinicopathological parameters. METHODS: Quantitative RT-PCR and Westerns blots were used to examine EEF2K expression in primary tumor and the adjacent non-tumor tissues of CRC patients (n = 20). Kaplan-Meier curves and Cox regression analysis were used to assess the association between clinical outcomes of CRC patients and EEF2K protein expression determined by immunohistochemistry on tissue microarray (n = 151). RESULTS: EEF2K was significantly downregulated at both mRNA and protein levels in tumors of CRC patients. Univariate Cox regression analysis revealed that CRC patients with high tumor grade, advanced TNM staging and low EEF2K expression were associated with worse overall survival. Multivariate analysis further demonstrated that low EEF2K expression was an independent factor for predicting poorer overall survival in CRC patients (p = 0.014; Hazard ratio = 2.951; 95% confidence interval: 1.240-7.024). The 5-year survival rate was 82.8% in the EEF2K-high-expression group versus 63.9% in the EEF2K-low-expression group (p = 0.0118). The association of overall survival with EEF2K expression in CRC patients was verified in The Cancer Genome Atlas (TCGA) cohort. CONCLUSIONS: EEF2K is downregulated in CRC and its expression can be employed as a prognostic marker for CRC patients independent of TNM staging.


Assuntos
Neoplasias do Colo/metabolismo , Quinase do Fator 2 de Elongação/metabolismo , Neoplasias Retais/metabolismo , Idoso , Colo/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Regulação para Baixo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/metabolismo , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Reto/metabolismo , Análise de Regressão , Taxa de Sobrevida , Resultado do Tratamento , Proteínas Supressoras de Tumor
13.
Eur Heart J ; 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31237939

RESUMO

AIMS: To determine the 1-year risk of stroke and other adverse outcomes in patients with a new diagnosis of perioperative atrial fibrillation (POAF) after non-cardiac surgery. METHODS AND RESULTS: The PeriOperative ISchemic Evaluation (POISE)-1 trial evaluated the effects of metoprolol vs. placebo in 8351 patients, and POISE-2 compared the effect of aspirin vs. placebo, and clonidine vs. placebo in 10 010 patients. These trials included patients with, or at risk of, cardiovascular disease who were undergoing non-cardiac surgery. For the purpose of this study, we combined the POISE datasets, excluding 244 patients who were in atrial fibrillation (AF) at the time of randomization. Perioperative atrial fibrillation was defined as new AF that occurred within 30 days after surgery. Our primary outcome was the incidence of stroke at 1 year of follow-up; secondary outcomes were mortality and myocardial infarction (MI). We compared outcomes among patients with and without POAF using multivariable adjusted Cox proportional hazards models. Among 18 117 patients (mean age 69 years, 57.4% male), 404 had POAF (2.2%). The stroke incidence 1 year after surgery was 5.58 vs. 1.54 per 100 patient-years in patients with and without POAF, adjusted hazard ratio (aHR) 3.43, 95% confidence interval (CI) 2.00-5.90; P < 0.001. Patients with POAF also had an increased risk of death (incidence 31.37 vs. 9.34; aHR 2.51, 95% CI 2.01-3.14; P < 0.001) and MI (incidence 26.20 vs. 8.23; aHR 5.10, 95% CI 3.91-6.64; P < 0.001). CONCLUSION: Patients with POAF have a significantly increased risk of stroke, MI, and death at 1 year. Intervention studies are needed to evaluate risk reduction strategies in this high-risk population.

14.
JAMA ; 321(18): 1788-1798, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31087023

RESUMO

Importance: Unrecognized obstructive sleep apnea increases cardiovascular risks in the general population, but whether obstructive sleep apnea poses a similar risk in the perioperative period remains uncertain. Objectives: To determine the association between obstructive sleep apnea and 30-day risk of cardiovascular complications after major noncardiac surgery. Design, Setting, and Participants: Prospective cohort study involving adult at-risk patients without prior diagnosis of sleep apnea and undergoing major noncardiac surgery from 8 hospitals in 5 countries between January 2012 and July 2017, with follow-up until August 2017. Postoperative monitoring included nocturnal pulse oximetry and measurement of cardiac troponin concentrations. Exposures: Obstructive sleep apnea was classified as mild (respiratory event index [REI] 5-14.9 events/h), moderate (REI 15-30), and severe (REI >30), based on preoperative portable sleep monitoring. Main Outcomes and Measures: The primary outcome was a composite of myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation, and stroke within 30 days of surgery. Proportional-hazards analysis was used to determine the association between obstructive sleep apnea and postoperative cardiovascular complications. Results: Among a total of 1364 patients recruited for the study, 1218 patients (mean age, 67 [SD, 9] years; 40.2% women) were included in the analyses. At 30 days after surgery, rates of the primary outcome were 30.1% (41/136) for patients with severe OSA, 22.1% (52/235) for patients with moderate OSA, 19.0% (86/452) for patients with mild OSA, and 14.2% (56/395) for patients with no OSA. OSA was associated with higher risk for the primary outcome (adjusted hazard ratio [HR], 1.49 [95% CI, 1.19-2.01]; P = .01); however, the association was significant only among patients with severe OSA (adjusted HR, 2.23 [95% CI, 1.49-3.34]; P = .001) and not among those with moderate OSA (adjusted HR, 1.47 [95% CI, 0.98-2.09]; P = .07) or mild OSA (adjusted HR, 1.36 [95% CI, 0.97-1.91]; P = .08) (P = .01 for interaction). The mean cumulative duration of oxyhemoglobin desaturation less than 80% during the first 3 postoperative nights in patients with cardiovascular complications (23.1 [95% CI, 15.5-27.7] minutes) was longer than in those without (10.2 [95% CI, 7.8-10.9] minutes) (P < .001). No significant interaction effects on perioperative outcomes were observed with type of anesthesia, use of postoperative opioids, and supplemental oxygen therapy. Conclusions and Relevance: Among at-risk adults undergoing major noncardiac surgery, unrecognized severe obstructive sleep apnea was significantly associated with increased risk of 30-day postoperative cardiovascular complications. Further research would be needed to assess whether interventions can modify this risk.


Assuntos
Doenças Cardiovasculares/etiologia , Complicações Pós-Operatórias/etiologia , Apneia Obstrutiva do Sono/complicações , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Idoso , Doenças Cardiovasculares/mortalidade , Feminino , Humanos , Hipóxia/complicações , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polissonografia , Complicações Pós-Operatórias/mortalidade , Estudos Prospectivos , Fatores de Risco , Apneia Obstrutiva do Sono/diagnóstico
15.
J Cell Mol Med ; 23(8): 4883-4890, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31140726

RESUMO

Spinal cord injury (SCI) may lead to persistent locomotor dysfunction and somatosensory disorders, which adversely affect the quality of life of patients and cause a significant economic burden to the society. The efficacies of current therapeutic interventions are still far from satisfaction as the secondary damages resulting from the complex and progressive molecular alterations after SCI are not properly addressed. Recent studies revealed that long non-coding RNAs (lncRNAs) are abundant in the brain and might play critical roles in several nervous system disorders. At the cellular level, lncRNAs have been shown to regulate the expression of protein-coding RNAs and hence participate in neuronal death, demyelination and glia activation. Notably, SCI is characterized by these biological processes, suggesting that lncRNAs could be novel modulators in the pathogenesis of SCI. This review describes recent progresses in the lncRNA transcriptome analyses and their molecular functions in regulating SCI progression.

16.
Theranostics ; 9(6): 1651-1665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037129

RESUMO

Rationale: Brain-derived neurotrophic factor (BDNF) is a key mediator in the development of chronic pain. Sortilin is known to interact with proBDNF and regulate its activity-dependent secretion in cortical neurons. In a rat model of inflammatory pain with intraplantar injection of complete Freund's adjuvant (CFA), we examined the functional role of proBDNF-sortilin interaction in dorsal root ganglia (DRG). Methods: Expression and co-localization of BDNF and sortilin were determined by immunofluorescence. ProBDNF-sortilin interaction interface was mapped using co-immunoprecipitation and bimolecular fluorescence complementation assay. The analgesic effect of intrathecal injection of a synthetic peptide interfering with proBDNF-sortilin interaction was measured in the CFA model. Results: BDNF and sortilin were co-localized and their expression was significantly increased in ipsilateral L4/5 DRG upon hind paw CFA injection. In vivo adeno-associated virus-mediated knockdown of sortilin-1 in L5 DRG alleviated pain-like responses. Mapping by serial deletions in the BDNF prodomain indicated that amino acid residues 71-100 supported the proBDNF-sortilin interaction. A synthetic peptide identical to amino acid residues 89-98 of proBDNF, as compared with scrambled peptide, was found to interfere with proBDNF-sortilin interaction, inhibit activity-dependent release of BDNF in vitro and reduce CFA-induced mechanical allodynia and heat hyperalgesia in vivo. The synthetic peptide also interfered with capsaicin-induced phosphorylation of extracellular signal-regulated kinases in ipsilateral spinal cord of CFA-injected rats. Conclusions: Sortilin-mediated secretion of BDNF from DRG neurons contributes to CFA-induced inflammatory pain. Interfering with proBDNF-sortilin interaction reduced activity-dependent release of BDNF and might serve as a therapeutic approach for chronic inflammatory pain.

17.
Medicine (Baltimore) ; 98(19): e15526, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083198

RESUMO

BACKGROUND: Despite introducing novel analgesics, pain management for spine surgery remains a challenge. Multimodal pain control has recently gained popularity in surgical spine care. We proposed a novel management approach using multimodal cocktail analgesics. Injection to skin surrounding surgical incision site will be given perioperatively. This study evaluates the safety and efficacy of cocktail analgesic injection on pain management following lumbar spinal fusion surgery. METHODS: Thirty-six patients with degenerative lumbar spinal diseases on the waiting list for lumbar spinal fusion surgery will be recruited. Patients will be randomly assigned to receive either cocktail analgesic injection or sterile saline before surgical wound closure. All patients will routinely receive postoperative intravenous patient-controlled analgesia (IV-PCA) with sufentanil on an as-needed basis without a basal dose. The primary outcome is perceived pain intensity as measured by visual analog pain score. Secondary outcomes include sufentanil consumption, time to first use of IV-PCA, rescue analgesics consumption, and the presence of adverse effects. Findings of this interventional trial will provide novel evidence supporting the superior effect of cocktail analgesic injection during surgery. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-17013094.


Assuntos
Analgesia/métodos , Analgésicos/administração & dosagem , Vértebras Lombares/cirurgia , Fusão Vertebral , Protocolos Clínicos , Humanos
18.
J Cell Mol Med ; 23(6): 4290-4300, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30973211

RESUMO

Impaired autophagic degradation of intracellular lipids is causally linked to the development of non-alcoholic steatohepatitis (NASH). Pharmacological agents that can restore hepatic autophagic flux could therefore have therapeutic potentials for this increasingly prevalent disease. Herein, we investigated the effects of polydatin, a natural precursor of resveratrol, in a murine nutritional model of NASH and a cell line model of steatosis. Results showed that oral administration of polydatin protected against hepatic lipid accumulation and alleviated inflammation and hepatocyte damage in db/db mice fed methionine-choline deficient diet. Polydatin also alleviated palmitic acid-induced lipid accumulation in cultured hepatocytes. In both models, polydatin restored lysosomal function and autophagic flux that were impaired by NASH or steatosis. Mechanistically, polydatin inhibited mTOR signalling and up-regulated the expression and activity of TFEB, a known master regulator of lysosomal function. In conclusion, polydatin ameliorated NASH through restoring autophagic flux. The polydatin-regulated autophagy was associated with inhibition of mTOR pathway and restoration of lysosomal function by TFEB. Our study provided affirmative preclinical evidence to inform future clinical trials for examining the potential anti-NASH effect of polydatin in humans.

19.
J Cell Physiol ; 234(10): 17896-17904, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30883755

RESUMO

Air pollution exposure has been increasing extensively and there are evidence suggesting that exposure to air pollution during pregnancy can lead to congenital defects in the offspring. Recent findings suggested that microRNAs (miRNAs) might play important roles in the pathogenesis of developmental defects. However, the miRNAs profile pattern in the air pollution-exposed embryos remains unknown. RNA sequencing was performed to determine the differentially expressed miRNAs in the rat embryos (gestation day 9) with or without air pollution exposure. The potential functions and the associated mechanisms of these differentially expressed miRNAs were determined using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analyses. The regulatory networks of mRNA-miRNA interactions were also reconstructed. As compared with the control group, a total of 291 miRNAs were differentially expressed in the rat embryos from the air pollution-exposed group, in which 204 and 87 miRNAs were significantly downregulated and upregulated, respectively. These miRNAs were predicted to deregulate mitotic spindle organization, cellular respiration, glycolate metabolism, and proteasome. Extensive regulation of target genes by miR-346, miR-504, miR-214-3p and miR-1224 was also predicted. Our results suggested that miRNAs may play crucial roles in the pathogenesis of air pollution-induced congenital spinal defects through deregulating multiple biological processes.

20.
Anesthesiology ; 130(5): 756-766, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30870165

RESUMO

BACKGROUND: Perioperative hypotension is associated with cardiovascular events in patients having noncardiac surgery. It is unknown if the severity of preexisting coronary artery disease determines susceptibility to the cardiovascular risks of perioperative hypotension. METHODS: In this retrospective exploratory analysis of a substudy of an international prospective blinded cohort study, 955 patients 45 yr of age or older with history or risk factors for coronary artery disease underwent coronary computed tomographic angiography before elective inpatient noncardiac surgery. The authors evaluated the potential interaction between angiographic findings and perioperative hypotension (defined as systolic blood pressure less than 90 mmHg for a total of 10 min or more during surgery or for any duration after surgery and for which intervention was initiated) on the composite outcome of time to myocardial infarction or cardiovascular death up to 30 days after surgery. Angiography assessors were blinded to study outcomes; patients, treating clinicians, and outcome assessors were blinded to angiography findings. RESULTS: Cardiovascular events (myocardial infarction or cardiovascular death within 30 days after surgery) occurred in 7.7% of patients (74/955), including in 2.7% (8/293) without obstructive coronary disease or hypotension compared to 6.7% (21/314) with obstructive coronary disease but no hypotension (hazard ratio, 2.51; 95% CI, 1.11 to 5.66; P = 0.027), 8.8% (14/159) in patients with hypotension but without obstructive coronary disease (hazard ratio, 3.85; 95% CI, 1.62 to 9.19; P = 0.002), and 16.4% (31/189) with obstructive coronary disease and hypotension (hazard ratio, 7.34; 95% CI, 3.37 to 15.96; P < 0.001). Hypotension was independently associated with cardiovascular events (hazard ratio, 3.17; 95% CI, 1.99 to 5.06; P < 0.001). This association remained in patients without obstructive disease and did not differ significantly across degrees of coronary disease (P value for interaction, 0.599). CONCLUSIONS: In patients having noncardiac surgery, perioperative hypotension was associated with cardiovascular events regardless of the degree of coronary artery disease on preoperative coronary computed tomographic angiography.

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