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1.
Epilepsy Res ; 176: 106728, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34339940

RESUMO

OBJECTIVE: The pharmacokinetics of lamotrigine exhibits age-related characteristics. Nevertheless, current evidence regarding the therapeutic range of lamotrigine has been derived almost exclusively from studies in adult patients, and the applicability of this therapeutic range to the pediatric population remains unclear. The purpose of this study was to establish the appropriate age-specific therapeutic ranges of lamotrigine corresponding to adequate clinical responses for patients with epilepsy. METHODS: This prospective cohort study of therapeutic drug monitoring included 582 Chinese epilepsy patients receiving lamotrigine monotherapy. Patients were divided into three age-related subgroups: (1) toddler and school-age group (2-12 years old, n = 168), (2) adolescent group (12-18 years old, n = 171), and (3) adult group (>18 years old, n = 243). Patients with a reduction in seizure frequency of 50 % or greater than baseline were defined as responders, and the remaining patients were non-responders. The relationship between lamotrigine serum concentrations and clinical response was assessed using multivariate logistic regression analysis. A receiver operating characteristic curve was generated to determine the representative cut-off values of lamotrigine trough levels, to distinguish responders from non-responders. The upper margin of the therapeutic range of lamotrigine was determined by developing concentration-effect curves for the three age-related subgroups. RESULTS: The median trough levels of lamotrigine were significantly higher in responders than in non-responders from all three age-related groups (P < 0.0001). Results of logistic regression analysis revealed that higher serum concentrations of lamotrigine predicted a higher probability that seizure frequency would be reduced by more than 50 % compared to baseline (adjusted odds ratio: 1.228, 95 % CI: 1.137-1.327; P < 0.0001), and younger children were less likely to be responders (adjusted odds ratio: 1.027, 95 % CI: 1.012-1.043; P = 0.001). Based on a trade-off between sensitivity and specificity, the optimal cut-off values for lamotrigine trough concentrations corresponding to clinical response were 3.29 mg/L, 2.06 mg/L, and 1.61 mg/L in the toddler and school-age group, adolescent group, and adult group, respectively. By reducing interpatient variability, the results of the concentration-effect curves suggested no additional clinical benefit from a continued increase of doses for lamotrigine concentrations exceeding 9.08 mg/L, 8.43 mg/L, and 10.38 mg/L in the toddler and school-age group, adolescent group, and adult group, respectively. In conclusion, the therapeutic ranges of lamotrigine trough concentrations corresponding to adequate clinical response were 3.29-9.08 mg/L in the toddler and school-age group, 2.06-8.43 mg/L in the adolescent group, and 1.61-10.38 mg/L in the adult group. CONCLUSIONS: The study determined age-specific therapeutic ranges corresponding to optimal clinical efficacy for lamotrigine. Our findings lay the foundation for catalyzing novel opportunities to optimize treatment and reduce therapeutic costs. Based on the age-specific therapeutic ranges identified in this study, individualized and cost-effective algorithms for lamotrigine treatment of epilepsy patients may be developed and validated in larger cohort studies of therapeutic drug monitoring.

2.
Nat Biomed Eng ; 5(8): 926-940, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34373601

RESUMO

Current protocols for the differentiation of human pluripotent stem cells (hPSCs) into chondrocytes do not allow for the expansion of intermediate progenitors so as to prospectively assess their chondrogenic potential. Here we report a protocol that leverages PRRX1-tdTomato reporter hPSCs for the selective induction of expandable and ontogenetically defined PRRX1+ limb-bud-like mesenchymal cells under defined xeno-free conditions, and the prospective assessment of the cells' chondrogenic potential via the cell-surface markers CD90, CD140B and CD82. The cells, which proliferated stably and exhibited the potential to undergo chondrogenic differentiation, formed hyaline cartilaginous-like tissue commensurate to their PRRX1-expression levels. Moreover, we show that limb-bud-like mesenchymal cells derived from patient-derived induced hPSCs can be used to identify therapeutic candidates for type II collagenopathy and we developed a method to generate uniformly sized hyaline cartilaginous-like particles by plating the cells on culture dishes coated with spots of a zwitterionic polymer. PRRX1+ limb-bud-like mesenchymal cells could facilitate the mass production of chondrocytes and cartilaginous tissues for applications in drug screening and tissue engineering.


Assuntos
Proteínas de Homeodomínio/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Pluripotentes/citologia , Animais , Técnicas de Cultura de Células/métodos , Diferenciação Celular , Condrócitos/citologia , Condrócitos/metabolismo , Condrócitos/transplante , Condrogênese , Doenças do Colágeno/terapia , Meios de Cultura/química , Proteínas de Homeodomínio/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Pluripotentes/metabolismo , Polímeros/química , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Antígenos Thy-1/metabolismo , Engenharia Tecidual
3.
Pharmacol Res ; 169: 105610, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857625

RESUMO

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes encoding LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82 L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109 L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41 ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413 L/h. In addition, the UGT2B7 rs4356975 C > T and ABCB1 rs1128503 A > G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = -30.899 vs. -20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33-50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33-66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

4.
J Immunol ; 206(6): 1140-1150, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33526439

RESUMO

Intestinal microbiota are closely related to host physiology. Over the long course of evolution and interaction, both commensal bacteria and their host have evolved multiple strategies to adapt to each other. However, in invertebrates, the regulatory mechanism of intestinal microbiota homeostasis is largely unknown. In the current study, a digestive tract-specific C-type lectin, designated as CTL33, was identified because of its abundance and response to bacteria in the intestine of kuruma shrimp (Marsupenaeus japonicus). Silencing of CTL33 expression led directly to intestinal dysbiosis, tissue damage, and shrimp death. CTL33 could facilitate biofilm formation by the intestinal bacteria. This function originated from its unique architecture, with a lectin domain responsible for bacteria recognition and a coiled coil region that mediated CTL33 dimerization and cross-linked the bacteria into a biofilm-like complex. By mediating the formation of a biofilm, CTL33 promoted the establishment of intestinal bacteria in intestine and maintained the homeostasis of the microbiota. Thus, to our knowledge, we demonstrated a new mechanism of C-type lectin-mediated biofilm formation by intestinal bacteria, providing new insights into intestinal homeostasis regulation in invertebrates.


Assuntos
Proteínas de Artrópodes/metabolismo , Bactérias/imunologia , Microbioma Gastrointestinal/imunologia , Lectinas Tipo C/metabolismo , Penaeidae/imunologia , Animais , Proteínas de Artrópodes/genética , Biofilmes , Disbiose/genética , Disbiose/imunologia , Disbiose/microbiologia , Técnicas de Silenciamento de Genes , Homeostase/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Lectinas Tipo C/genética , Penaeidae/metabolismo , Penaeidae/microbiologia , Domínios Proteicos
5.
Thromb Haemost ; 121(7): 900-912, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33421964

RESUMO

Exercise training influences the risk of vascular thrombosis in patients with peripheral arterial disease (PAD). Mitochondrial functionalities in platelets involve the cellular bioenergetics and thrombogenesis. This study aimed to elucidate the effect of cycling exercise training (CET) on platelet mitochondrial bioenergetics in PAD patients. Forty randomly selected patients with PAD engaged in general rehabilitation (GR) with CET (i.e., cycling exercise at ventilation threshold for 30 minute/day, 3 days/week) (GR + CET, n = 20) or to a control group that only received GR course (n = 20) for 12 weeks. Systemic aerobic capacity and platelet mitochondrial bioenergetics that included oxidative phosphorylation (OXPHOS) and electron transport system (ETS) were measured using automatic gas analysis and high-resolution respirometry, respectively. The experimental results demonstrated that GR + CET for 12 weeks significantly (1) elevated VO2peak and lowered VE-VCO2 slope, (2) raised resting ankle-brachial index and enhanced cardiac output response to exercise, (3) increased the distance in 6-minute walk test and raised the Short Form-36 physical/mental component scores, and (4) enhanced capacities of mitochondrial OXPHOS and ETS in platelets by activating FADH2 (complex II)-dependent pathway. Moreover, changes in VO2peak levels were positively associated with changes in platelet OXPHOS and ETS capacities. However, no significant changes in systemic aerobic capacity, platelet mitochondrial bioenergetics, and health-related quality of life (HRQoL) occurred following GR alone. Hence, we conclude that CET effectively increases the capacities of platelet mitochondrial bioenergetics by enhancing complex II activity in patients with PAD. Moreover, the exercise regimen also enhanced functional exercise capacity, consequently improving HRQoL in PAD patients.

6.
Front Pharmacol ; 11: 751, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670054

RESUMO

Objective: To evaluate efficacy, safety, and economics profiles of intravenous levetiracetam (LEV) for status epilepticus (SE). Methods: We searched PubMed, Embase, the Cochrane Library, Clinicaltrials.gov, and OpenGrey.eu for eligible studies published from inception to June 12th 2019. Meta-analyses were conducted using random-effect model to calculate odds ratio (OR) of included randomized controlled trials (RCTs) with RevMan 5.3 software. Results: A total of 478 studies were obtained. Five systematic reviews (SRs)/meta-analyses, 9 RCTs, 1 non-randomized trial, and 27 case series/reports and 1 economic study met the inclusion criteria. Five SRs indicated no statistically significant difference in rates of seizure cessation when LEV was compared with lorazepam (LOR), phenytoin (PHT), or valproate (VPA). Pooled results of included RCTs indicated no statistically significant difference in seizure cessation when LEV was compared with LOR [OR = 1.04, 95% confidence interval (CI) 0.37 to 2.92], PHT (OR = 0.90, 95% CI 0.64 to 1.27), and VPA (OR = 1.47, 95% CI 0.81 to 2.67); and no statistically significant difference in seizure freedom within 24 h compared with LOR [OR = 1.83, 95% CI 0.57 to 5.90] and PHT (OR = 1.08, 95% CI 0.63 to 1.87). Meanwhile, LEV did not increase the risk of mortality during hospitalization compared with LOR (OR = 1.03, 95% CI 0.31 to 3.39), PHT (OR = 0.89, 95% CI 0.37 to 2.10), VPA (OR = 1.28, 95% CI 0.32 to 5.07), and placebo (plus clonazepam, OR = 0.73, 95% CI 0.16 to 3.38). LEV had lower need for artificial ventilation (OR = 0.23, 95% CI 0.06 to 0.92) and a lower risk of hypotension (OR = 0.15, 95% CI 0.03 to 0.84) compared to LOR. A trend of lower risk of hypotension and higher risk of agitation was found when LEV was compared with PHT. Case series and case report studies indicated psychiatric and behavioral adverse events of LEV. Cost-effectiveness evaluations indicated LEV as the most cost-effective non-benzodiazepines anti-epileptic drug (AED). Conclusions: LEV has a similar efficacy as LOR, PHT, and VPA for SE, but a lower need for ventilator assistance and risk of hypotension, thus can be used as a second-line treatment for SE. However, more well-conducted studies to confirm the role of intravenous LEV for SE are still needed.

7.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-20159756

RESUMO

On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesized that the anti-VEGF drug bevacizumab might be beneficial for treating Covid-19 patients. We recruited 26 patients from 2-centers (China and Italy) with confirmed severe Covid-19, with respiratory rate [≥] 30 times/min, oxygen saturation [≤] 93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O2 ratio (PaO2/FiO2) >100mmHg and [≤] 300 mmHg, and diffuse pneumonia confirmed by chest radiological imaging. This trial was conducted from Feb 15 to April 5, 2020, and followed up for 28 days. Relative to comparable control patients with severe Covid-19 admitted in the same centers, bevacizumab showed clinical efficacy by improving oxygenation and shortening oxygen-support duration. Among 26 hospitalized patients with severe Covid-19 (median age, 62 years, 20 [77%] males), bevacizumab plus standard care markedly improved the PaO2/FiO2 ratios at days 1 and 7 (elevated values, day 1, 50.5 [4.0,119.0], p<0.001; day 7, 111.0 [85.0,165.0], p<0.001). By day 28, 24 (92%) patients showed improvement in oxygen-support status, 17 (65%) patients were discharged, and none showed worsen oxygen-support status nor died. Significant reduction of lesion areas and ratios were shown in chest CT or X-ray analysis within 7 days. Of 14 patients with fever, body temperature normalized within 72 hours in 13 (93%) patients. Lymphocyte counts in peripheral blood were significantly increased and CRP levels were markedly decreased as shown in available data. Our findings suggested bevacizumab plus standard care was highly beneficial for treating patients with severe Covid-19. Clinical efficacy of bevacizumab warrants double blind, randomized, placebo-controlled trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04275414, URL: https://clinicaltrials.gov/ct2/show/NCT04275414.

8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(3): 967-971, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32552966

RESUMO

OBJECTIVE: To study the clinical effects of preoperative autologous blood donation (PABD) in selective general surgery. METHODS: Paired study was performed in PABD group with 70 PABD cases screened from selective general surgery during the period from November 2017 to August 2018 in our hospital, and the control group included 70 cases without preoperative autologous blood donation, the baseline data before surgery were not significantly different. The transfusion quantities of allogeneic RBC and plasma, the levels of perioperative hemoglobin and platelets, the time and expense of hospitalization were compared between two groups. RESULTS: The levels of Hb and Plt in PABD group before and after blood collection were determined as follows: 138.26±14.73 g/L vs 127.52±13.36 g/L (P<0.05) and (221.67±52.86)×109/L vs (198.35±52.65)×109/L (P>0.05) respectively. The analysis of allo-RBC and allo-plasma transfusion in PABD group and control group showed that: the quantity of allogeneic RBC transfusion was 0.20±0.71 U and 0.89±0.97 U, and the quantity of allogeneic plasma transfusion was 30.43±100.81 ml and 106.52±152.61 ml (P<0.05) respectirdy during perioperation. The comparison results of preoperative Hb and plt in PABD group and control group were 135.65±14.16 g/L vs 134.15±11.98 g/L and (270.36±58.28)×109/L vs (271.67±65.02) ×109/L respectively. The levels of postoperative Hb and plt in PABD group and control group were 120.24±14.40 g/L vs 121.20±14.30 g/L at 1 d after operation, and (241.80±63.58)×109/L vs (241.30±69.11)×109/L at 1 d after operation respectively; 123.15±13.80 g/L vs 121.65±14.33 g/L at 3 d after operation and (251.26±72.94)×109/L vs (255.54±73.85)×109/L at 3 d after operation; 122.78±13.92 g/L and 122.00±13.82 g/L (before discharge) and (262.50±80.96)×109/L and (264.56±71.08)×109/L (before discharge, platelet). These data were not statistically different (P>0.05). The hospitalization time was 14.84±3.37 days and 14.84±2.24 days, respectively, without statistical difference (P>0.05) in two groups. The expenses of hospitalization and the blood transfusion in two groups were 50627.27±9889.45 RMB and 50979.43±8195.00 RMB; 354.39±362.57 RMB and 684.02±425.53 RMB (P<0.05). CONCLUSION: The application of PABD reduces the use of allogeneic blood and costs for patients undergoing selective surgery with blood losts of 1000 ml.


Assuntos
Doadores de Sangue , Transfusão de Sangue Autóloga , Transfusão de Componentes Sanguíneos , Transfusão de Sangue , Humanos , Plasma
9.
Respiration ; 99(6): 500-507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32485723

RESUMO

BACKGROUND: The predictors and airway morphological changes during the development of postintubation tracheal stenosis (PITS) have not been well elucidated. OBJECTIVES: To elucidate the validation of endobronchial optical coherence tomography (EB-OCT) in assessing the airway morphological changes in PITS. METHODS: We performed oral endotracheal intubation in 12 beagles to establish the PITS model. EB-OCT was performed respectively before modeling and on the 1st, 7th, and 12th day after extubation in 9 canines, and was conducted consecutively in 3 canines during the development of PITS. Histological findings and the thickness and gray-scale value of the tracheal wall assessed by EB-OCT measurements were analyzed and compared. RESULTS: The tracheal wall edema, granulation tissue proliferation, cartilage destruction in PITS, and airway wall thickening detected by EB-OCT were in concordance with the histopathological measurements. The consecutive EB-OCT observation of the airway structure demonstrated the tracheal wall thickness significantly increased from 344.41 ± 44.19 µm before modeling to 796.67 ± 49.75 µm on the 9th day after modeling (p < 0.05). The airway wall gray-scale values assessed by EB-OCT decreased from 111.19 ± 14.71 before modeling to 74.96 ± 4.08 on the 9th day after modeling (p < 0.05). The gray-scale value was negatively correlated with the airway wall thickness (r = -0.945, p = 0.001). CONCLUSION: The EB-OCT imaging, in concordance with the histopathological finding, was validated for assessing the airway morphological changes during the development of PITS. The EB-OCT evaluation of cartilage damage and gray-scale value measurement might help predict the development and prognosis of PITS.

10.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-20031666

RESUMO

ObjectiveThe coronavirus disease 2019 (COVID-19) - a novel and highly infectious pneumonia - has now spread across China and beyond for over four months. However, its psychological impact on patients is unclear. We aim to examine the prevalence and associated risk factors for psychological morbidities and fatigue in patients with confirmed COVID-19 infection. MethodsAmidst the disease outbreak, 41 out of 105 COVID-19 patients in a local designated hospital in China were successfully assessed using a constellation of psychometric questionnaires to determine their psychological morbidities and fatigue. Several potential biopsychosocial risk factors (including pre-existing disabilities, CT severity score of pneumonia, social support, coping strategies) were assessed through multivariable logistic regression analyses to clarify their association with mental health in patients. Results43.9% of 41 patients presented with impaired general mental health, 12.2% had post-traumatic stress disorder (PTSD) symptoms, 26.8% had anxiety and/or depression symptoms, and 53.6% had fatigue. We did not find any association between pneumonia severity and psychological morbidities or fatigue in COVID-19 patients. However, high perceived stigmatization was associated with an increased risk of impaired general mental health and high perceived social support was associated with decreased risk. Besides, negative coping inclination was associated with an increased risk of PTSD symptoms; high perceived social support was associated with a decreased risk of anxiety and/or depression symptoms. ConclusionsPsychological morbidities and chronic fatigue are common among COVID-19 patients. Negative coping inclination and being stigmatized are primary risk factors while perceived social support is the main protective factor.

11.
Biochem Biophys Res Commun ; 526(1): 213-217, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32204914

RESUMO

The Cre-loxP recombination system is widely used to generate genetically modified mice for biomedical research. Recently, a highly efficient photoactivatable Cre (PA-Cre) based on reassembly of split Cre fragments has been established. This technology enables efficient DNA recombination that is activated upon blue light illumination with spatiotemporal precision. In this study, we generated a tTA-dependent photoactivatable Cre-loxP recombinase knock-in mouse model (TRE-PA-Cre mice) using a CRISPR/Cas9 system. These mice were crossed with ROSA26-tdTomato mice (Cre reporter mouse) to visualize DNA recombination as marked by tdTomato expression. We demonstrated that external noninvasive LED blue light illumination allows efficient DNA recombination in the liver of TRE-PA-Cre:ROSA26-tdTomato mice transfected with tTA expression vectors using hydrodynamic tail vein injection. The TRE-PA-Cre mouse established here promises to be useful for optogenetic genome engineering in a noninvasive, spatiotemporal, and cell-type specific manner in vivo.


Assuntos
Técnicas de Introdução de Genes , Engenharia Genética , Genoma , Integrases/metabolismo , Optogenética , Animais , Sequência de Bases , DNA/genética , Feminino , Luz , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais , Tetraciclina/farmacologia
12.
Neuropsychiatr Dis Treat ; 16: 397-406, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103959

RESUMO

Objective: To investigate the effect of recombinant adenovirus-mediated HIF-1 alpha (HIF-1α) on the expression of vascular endothelial growth factor (VEGFA) and HIF-1α in hypoxic brain microvascular endothelial cells (BMEC) in rats. Methods: Primary cultured rat BMEC in vitro were treated without or with either recombinant adenovirus-mediated hypoxia-inducible factor-1 alpha (AdHIF-1α) or recombinant adenovirus empty vector (Ad) in the presence of CoCl2 (simulating hypoxia conditions), or were grown under normoxia conditions. The expression of VEGFA and HIF-1α was analyzed at 12h, 24h, 48h and 72h incubation time, respectively. We also accessed a GEO dataset of stroke to analyze in vivo the alteration of HIF-1α and VEGFA expression, and the correlations between HIF-1α, VEGFA and CD31 mRNA levels in vascular vessels after stroke. Results: VEGFA and HIF-1α expression were significantly higher in at each time point in the AdHIF-1α than other groups (p<0.05), whereas the Ad group and hypoxia group, showed no statistically significant difference (p>0.05). Moreover, VEGFA and HIF-1α levels were significantly higher in BMEC under hypoxia conditions than normoxia conditions (p <0.05). Both HIF-1α and VEGFA expression significantly increased after stroke in vivo with 1.30 and 1.57 fold-change in log2, respectively. There were significantly positive associations between HIF-1α, VEGFA and CD31 mRNA levels in vivo after stroke. Conclusion: Hypoxia-induced HIF-1α and VEGFA expression in vascular vessels, and recombinant AdHIF-1α could up-regulate VEGFA, and enhance HIF-1ααlevels in BMEC in vitro, which may play an important role in the recovery of stroke.

13.
Aging (Albany NY) ; 11(24): 12733-12753, 2019 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-31884423

RESUMO

Here we study the effects of differentiated embryonic chondrocyte gene 1(DEC1) deficiency on midbrain dopaminergic(DA) neurons in the substantia nigra pars compacta(SNpc) through behavioral, histological and molecular analysis. We have found that compared to the age-matched WT mice, DEC1 deficient mice show a decrease in locomotor activity and motor coordination, which shows the main features of Parkinson's disease(PD). But there is no significant difference in spatial learning and memory skills between WT and DEC1 KO mice. Compared to the age-matched WT mice, DEC1 deficient mice exhibit the loss of DA neurons in the SNpc and reduction of dopamine and its metabolites in the striatum. The activated caspase-3 and TH/TUNEL+ cells increase in the SNpc of 6- and 12-month-old DEC1 KO mice compared to those of the age-matched WT mice. But we haven't found any NeuN/TUNEL+ cell increase in the hippocampus of the above two types of mice at the age of 6 months. Furthermore, DEC1 deficiency leads to a significant inhibition of PI3K/Akt/GSK3ß signaling pathway. Additionally, LiCl could rescue the DA neuron loss of midbrain in the 6-month-old DEC1 KO mice. Taken together, the loss of DA neurons in the DEC1 deficient mice potentially involves the downregulation of PI3K/Akt/GSK3ß signaling.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas de Homeodomínio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Envelhecimento , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Feminino , Glicogênio Sintase Quinase 3 beta/genética , Proteínas de Homeodomínio/genética , Masculino , Camundongos , Camundongos Knockout , Degeneração Neural/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética
14.
Chest ; 156(5): 915-925, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31265836

RESUMO

BACKGROUND: The anatomic location of small airways, the distribution of airway cartilage, and their correlation with ageing have not been well elucidated. The objective of this article was to explore the morphologic characteristics of small airways in vivo, and how airway structural changes correlate with age using endobronchial optical coherence tomography (EB-OCT). METHODS: We recruited 112 subjects with peripheral pulmonary nodules. Participants underwent CT scan, spirometry, and EB-OCT measurements. We measured the airway internal diameter, the inner area (Ai), the airway wall area percentage (Aw%), and the thickness of airway cartilage. EB-OCT airway structural characteristics at different age intervals were analyzed, and the association between airway morphology and age was evaluated. RESULTS: Of the small airways, 47.3% originated from the seventh generation of bronchi. Cartilage was uniformly present in the third to sixth generation of bronchi, despite a decreasing proportion of cartilage from the seventh to ninth generation of bronchi (92.4%, 54.5%, and 26.8%, respectively). The thickness of airway cartilage progressively decreased with older age. In subjects 40 to 54 years of age, Ai from the third to sixth generation correlated positively with age (r = 0.577, P < .001). Both Ai from the third to sixth generation and Ai from the seventh to ninth generation correlated negatively with age in subjects 55 to 69 years of age (r = -0.374, P = .021 and r = -0.410, P = .011). Aw% from the third to sixth generation and Aw% from the seventh to ninth generation did not correlate significantly with age. CONCLUSIONS: Small airways are mainly located at the seventh generation, where cartilaginous structures are present despite reduced distribution in more distal airways, and the thickness decreased in older age. Reduction in luminal area of medium-to-small airways might be the morphologic changes associated with ageing (ie, > 55 years of age).


Assuntos
Envelhecimento/fisiologia , Remodelação das Vias Aéreas , Brônquios/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Adulto , Idoso , Brônquios/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
15.
Talanta ; 203: 1-8, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31202313

RESUMO

Lysosomes generally maintain the weak acidic microenvironment, to ensure highly efficient activity and functions of hydrolytic enzymes and proteins. Aberrations of the lysosomal pH may result in cellular functional changes and influence human physiology, possibly causing serious diseases. Small-molecular fluorescent probes based imaging techniques capable of providing information on target locations are considerably appreciated. Herein, by reducing the size of the typical lysosome targetable group 4-(2-aminoethyl) morpholine, we rationally designed a rhodamine analogue probe Ly-HN2AM with N-Aminomorpholine as the ring-closed switch and the lysosome targetable moiety for visualizing lysosomal pH changes. With the benefit of constructing multi-pentacyclic intramolecular hydrogen bond when binding with the H+, Ly-HN2AM gives a highly sensitive response towards pH values ranging from 4.79 to 6.07, with a remarkable higher pKa 5.35 over the typical 4-(2-aminoethyl) morpholine modified probes. The new probe was successfully applied to visualize pH value changes in lysosome-associated physiological and pathological processes with excellent photostability and low cytotoxicity, indicating the potential applications of lysosome specific bioimaging.


Assuntos
Corantes Fluorescentes/química , Lisossomos/metabolismo , Morfolinas/química , Rodaminas/química , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Morfolinas/síntese química , Morfolinas/toxicidade , Rodaminas/síntese química , Rodaminas/toxicidade
16.
Biochem Biophys Res Commun ; 514(2): 386-392, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31047638

RESUMO

Acute liver injury seriously endangers human health. Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has antioxidative effects in addition to being widely used in the treatment of type 2 diabetes and was reported to ameliorate liver diseases. The aim of this study was to evaluate the hepatoprotective effects of liraglutide on carbon tetrachloride (CCl4)-induced acute liver injury in mice and to investigate the mechanisms involved in this protective effect. Male BALB/c mice were pre-treated with liraglutide (200 µg/kg/day) by hypodermic injection for 3 days before a 0.1% (v/v) CCl4 (10 ml/kg, dissolved in olive oil) intraperitoneal injection, or post-treated with liraglutide once immediately after a CCl4 intraperitoneal injection. The experimental data showed that liraglutide treatment significantly decreased the serum ALT and AST levels and ameliorated the liver histopathological changes induced by CCl4. In addition, liraglutide pre-treatment dramatically increased the number of proliferating cell nuclear antigen (PCNA)-positive hepatocytes and significantly reduced hepatocyte apoptosis after CCl4 treatment. As a consequence, liraglutide pre-treatment significantly prevented CCl4-induced malondialdehyde (MDA) production and increased the activity of the antioxidant superoxide dismutase (SOD) enzyme. In addition, liraglutide pre-treatment significantly ameliorated mitochondrial respiratory functions and ultrastructural features. Furthermore, liraglutide pre-treatment enhances the activation of the NRF2/HO-1 signaling pathway. In summary, liraglutide protects against CCl4-induced acute liver injury by protecting mitochondrial functions and inhibiting oxidative stress, which may partly involve the activation of NRF2/HO-1 signaling pathway.


Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Liraglutida/farmacologia , Substâncias Protetoras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
17.
Chem Commun (Camb) ; 55(37): 5359-5362, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30994651

RESUMO

Herein, we have fabricated gold nanorod graphitic nanocapsule (AuNR@G) doped poly(vinyl alcohol) (PVA)/chitosan (CS) hydrogels, which possessed highly efficient and stable photothermal antibacterial properties for both Gram-negative E. coli and Gram-positive S. aureus under the irradiation of a near-infrared laser.


Assuntos
Ouro/química , Hidrogéis/química , Raios Infravermelhos , Nanocápsulas/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/efeitos da radiação , Humanos , Hidrogéis/farmacologia , Álcool de Polivinil/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/efeitos da radiação
18.
Psychiatry Res ; 275: 86-93, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30884335

RESUMO

Major depressive disorder (MDD) is a recurrent, chronic mental illness. While music therapy has been established as an effective treatment for MDD patients, the effects of this therapy on brain function remain unclear. This research employed near-infrared spectroscopy (NIRS) to explore the effects of music therapy on brain activity in mild or moderate MDD patients and to illustrate the potential mechanism of music therapy. Methods: Fifteen MDD patients and fifteen healthy controls (HC) underwent neuropsychological evaluations and NIRS measurements. All participants were treated with continuous music therapy for 10 days. Subsequently, all individuals were evaluated with neuropsychological assessments and NIRS measurements again. Results: The verbal fluency task (VFT) performances of the participants yielded significantly higher scores after music therapy in terms of vegetables, four-footed animals and fruit blocks. After the music treatment, the NIRS data showed that the mean active oxy-Hb values of channels 21, 23, 19, and 41 were significantly increased in both the MDD and HC groups. The MDD group showed significant activation in the dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (VMPFC) after music therapy. The results indicate that music therapy could improve the brain function of MDD patients.


Assuntos
Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/terapia , Hemodinâmica , Musicoterapia , Córtex Pré-Frontal/irrigação sanguínea , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Córtex Pré-Frontal/diagnóstico por imagem , Espectroscopia de Luz Próxima ao Infravermelho , Adulto Jovem
19.
J Magn Reson Imaging ; 49(6): 1704-1712, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30390401

RESUMO

BACKGROUND: Multiparameter, multimodality 18 F-FDG PET/MRI holds great potential for the diagnosis of cervical cancer based on the correlation between tumor glucose metabolism and imaging parameters. PURPOSE: To characterize the heterogeneity of tumor glucose metabolism by evaluating the correlation between 18 F-FDG uptake parameters and multiparametric functional MRI metrics in cervical carcinoma. STUDY TYPE: Retrospective. POPULATION: Fifty-four patients with cervical carcinoma. FIELD STRENGTH/SEQUENCE: Hybrid PET/MR (3T), multi-b DWI, and R2* mapping. ASSESSMENT: The maximum and mean standardized uptake values (SUVmax and SUVmean , respectively) from PET and functional MRI metrics (D, D*, f, and R2*) were obtained. Cervical carcinoma tissues also underwent HIF-1α, VEGF, and GLUT-1 immunohistochemical staining. STATISTICAL TESTS: Single-factor Spearman rank and Pearson correlation analysis and multiple linear regression (MLR) analysis were applied. RESULTS: R2*, D, and f have different degrees of correlation (moderate, weak, moderately strong correlation, respectively) with SUVmax and SUVmean (r = 0.530 and 0.527, and P < 0.001 for R2*; r = -0.292 and -0.291, and P < 0.05 for D; r = 0.539 and 0.520, and P < 0.001 for f, respectively). Immunohistochemical staining showed that HIF-1α expression has a moderate degree of correlation with R2* (r = 0.491; P < 0.001); GLUT-1 expression was significantly correlated with SUVmax and SUVmean (r = 0.633 and 0.622; P < 0.001), and VEGF expression had a moderately strong correlation with f (r = 0.457; P = 0.001). If SUVmax is the dependent variable, MLR yields an R-squared value after adjustment (adjusted R-squared) = 0.358, and F = 10.833 (P < 0.001), and the fitting linear equation is Y (SUVmax ) = 9.184 + 0.161X1 (R2*)+50.343X2 (f)-4.780 (D). Otherwise, MLR yields the adjusted R-squared = 0.342, and F = 10.187 (P < 0.001), and the linear regression equation is Y (SUVmean ) = 5.925 + 0.102X1 (R2*)+28.029X2 (f)-2.907X3 (D). DATA CONCLUSION: The functional MRI sequence parameters R2*, f, and D can provide information on the hypoxic condition, blood perfusion, and molecular diffusion of the tumor. 18 F-FDG PET/MR multi-imaging technique can be adopted to evaluate the heterogeneity of glucose metabolism in cervical carcinoma. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:1704-1712.


Assuntos
Carcinoma/diagnóstico por imagem , Glucose/metabolismo , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Neoplasias do Colo do Útero/diagnóstico por imagem , Adulto , Idoso , Feminino , Fluordesoxiglucose F18 , Transportador de Glucose Tipo 1/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pessoa de Meia-Idade , Imagem Multimodal , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Talanta ; 192: 128-134, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348367

RESUMO

Hypochlorous acid (HClO), one of the most important reactive oxygen species (ROS), is a potent antimicrobial agent for the immune system against invasive bacteria and a wide range of pathogens. Therefore, it is critical to develop sensitive and selective methods for visualization of HClO in biological samples. In this work, a two-photon fluorescent probe HN2-TP) with long-wavelength emission (far-red: 630 nm) based on rhodamine analogue for bioimaging HClO was developed. Owing to a specific HClO induced cyclization reaction, the new probe shows large fluorescence enhancement (about 106-fold), good linear range with high sensitivity (detection limit: 40 nM), high selectivity and fast response when monitoring HClO in vitro. More importantly, by successfully imaging HClO in living cells and tissues, this kind of two-photon fluorescent probe with long-wavelength emission is expected for accurate sensing in complex biosystems, which could eliminate undesired autofluorescence and self-absorption.


Assuntos
Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Fígado/química , Fótons , Animais , Proliferação de Células , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Estrutura Molecular , Células RAW 264.7 , Ratos
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