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1.
FASEB J ; : fj201801966RRR, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31689136

RESUMO

Macrophages and their initiation of acute inflammation have been defined to be functionally important in tissue repair and regeneration. In injury-induced production of macrophage migration inhibitory factor (MIF), which has been described as a pleiotropic protein that participates in multiple cellular and biologic processes, it is unknown whether it is involved in the regulation of macrophage events during the epimorphic regeneration. In the model of gecko tail amputation, the protein levels of gecko MIF (gMIF) have been determined to be significantly increased in the nerve cells of the spinal cord in association with the recruitment of macrophages to the lesion site. gMIF has been shown to interact with the CD74 receptor to promote the migration of macrophages through activation of Ras homolog gene family member A and to trigger inflammatory responses through MAPK signaling pathways. The determination of microsphere phagocytosis also indicated that gMIF could enhance macrophage phagocytosis. gMIF-mediated recruitment and activation of macrophages have been found to be necessary for gecko tail regeneration, as evidenced by the depletion of macrophages using clodronate liposomes. The results present a novel function of MIF during the epimorphic regeneration, which is beneficial for insights into its pleiotropic property.-Wang, Y., Wei, S., Song, H., Zhang, X., Wang, W., Du, N., Song, T., Liang, H., Chen, X., Wang, Y. Macrophage migration inhibitory factor derived from spinal cord is involved in activation of macrophages following gecko tail amputation.

2.
J Control Release ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31676386

RESUMO

As the demand for nutrients in malignant proliferation of tumors increases, the L-type amino acid transporter 1(LAT1) and amino acid transporter B0,+ (ATB0,+) of tumor cells are more highly expressed than normal cells which can be used as new targets for active targeting of cancer. However, drug delivery systems often require multi-target design to achieve simultaneous targeting of different receptors or transporters due to the heterogeneity of the tumor. Here we utilized triethylamine-sucrose octasulfate gradient to actively encapsulate irinotecan into the introliposomal aqueous phase. Targeted ability was achieved through inserting different amino acids modified polyethylene glycol monostearate into the liposomes, and found that glutamate-liposomes can be targeted to LAT1, lysine-liposomes can be targeted to ATB0,+, and inspiringly, tyrosine-liposomes can be simultaneously targeted to LAT1 and ATB0,+. The tyrosine-modified liposomes showed the highest cellular uptake in BxPC-3 and MCF-7 cells which were highly expressed both LAT1 and ATB0,+. Moreover, we validated their targeting capabilities and elucidated the transport mechanism of LAT1 and ATB0,+-mediated endocytosis. The tumor inhibition rate of tyrosine-modified liposomes greatly increased from 39% to 87% compared with commercially available liposomes loaded CPT-11(Onivyde®). Overall, it showed a good application prospect for efficient tumor therapy and industrial production.

3.
BMC Complement Altern Med ; 19(1): 272, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31638956

RESUMO

BACKGROUND: This study aimed to investigate the effect of the Phellinus linteus (Mesima) decoction on podocyte injury in a rat model of focal and segmental glomerulosclerosis (FSGS) and evaluate the potential mechanisms. METHODS: FSGS resembling primary FSGS in humans was established in rats by uninephrectomy and the repeated injection of doxorubicin. The FSGS rats were randomly divided into the model group, low-dose group of P. linteus decoction (PLD-LD), medium-dose group of P. linteus decoction (PLD-MD), and high-dose group of P. linteus decoction (PLD-HD). Blood and urine analysis were performed after 12 weeks and the molecular indicators of renal function and the renal pathological changes were examined. RESULTS: FSGS developed within 12 weeks in the test group and showed progressive proteinuria and segmental glomerular scarring. Urinary protein, serum creatinine, urea nitrogen, triglycerides and cholesterol were significantly reduced following the 12-week intervention with P.linteus decoction, especially in the PLD-LD group. Renal nephrin and podocin were markedly increased. Moreover, the pathological damage in the renal tissue was alleviated by the PLD-LD intervention. CONCLUSION: The P. linteus decoction alleviated the podocyte injury in the FSGS rat model, thus minimizing the progression of glomerular sclerosis and improving renal function.

4.
Stroke ; : STROKEAHA119026872, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597550

RESUMO

Background and Purpose- Stroke and Alzheimer disease are 2 major causes of neurological disability in aged people and shared overlapping predictors. In recent prospective studies, high Lp(a) [lipoprotein(a)] level is associated with high risk of stroke but low risk of Alzheimer disease. Whether this reflects a causal association remains to be established. The aim of this study is to examine the causal associations of Lp(a) concentrations on ischemic stroke, ischemic stroke subtypes, and Alzheimer disease. Methods- We used 9 single-nucleotide polymorphisms associated with Lp(a) concentrations as instrumental variables. Summary-level data on ischemic stroke and its subtypes were obtained from the Multiancestry Genome-Wide Association Study of Stroke consortium with European individuals ≤446 696 individuals. Summary-level data on Alzheimer disease were obtained from the International Genomics of Alzheimer Project With European individuals ≤54 162 individuals. Two-sample Mendelian randomization (MR) estimates were calculated with inverse-variance weighted, penalized inverse-variance weighted, simple median, weighted median, and MR Pleiotropy Residual Sum and Outlier approaches, and MR-Egger regression was used to explore pleiotropy. Results- Genetically predicted 1-SD log-transformed increase in Lp(a) concentrations was associated with a substantial increase in risk of large artery stroke (odds ratio, 1.20; 95% CI, 1.11-1.30; P<0.001) and a reduce in risk of small vessel stroke (odds ratio, 0.92; 95% CI, 0.88-0.97; P=0.001) and Alzheimer disease (odds ratio, 0.94; 95% CI, 0.91-0.97; P<0.001) using inverse-variance weighted method. No significant association was observed for total ischemic stroke or cardioembolic stroke. MR-Egger indicated no evidence of pleiotropic bias. Results were broadly consistent in sensitivity analyses using penalized inverse-variance weighted, simple median, weighted median, and MR Pleiotropy Residual Sum and Outlier approaches accounting for potential genetic pleiotropy or outliers. Conclusions- This study provides evidence to support that high Lp(a) concentrations was causally associated with an increased risk of large artery stroke but a decreased risk of small vessel stroke and Alzheimer disease. The mechanism underlying the double-edged sword effect of Lp(a) concentrations on neurological system requires further investigation.

5.
J Am Heart Assoc ; 8(20): e012052, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31595836

RESUMO

Background The impact of estimated glomerular filtration rate (eGFR) on clinical short-term outcomes after stroke thrombolysis with tissue plasminogen activator remains controversial. Methods and Results We analyzed 18 320 ischemic stroke patients who received intravenous tissue plasminogen activator at participating hospitals in the Chinese Stroke Center Alliance between June 2015 and November 2017. Multivariate logistic regression models were used to evaluate associations between eGFR (<45, 45-59, 60-89, and ≥90 mL/min per 1.73 m2) and in-hospital mortality and symptomatic intracerebral hemorrhage, adjusting for patient and hospital characteristics and the hospital clustering effect. Of the 18 320 patients receiving tissue plasminogen activator, 601 (3.3%) had an eGFR <45, 625 (3.4%) had an eGFR 45 to 59, 3679 (20.1%) had an eGFR 60 to 89, and 13 415 (73.2%) had an eGFR ≥90. As compared with eGFR ≥90, eGFR values <45 (6.7% versus 0.9%, adjusted odds ratio, 3.59; 95% CI, 2.18-5.91), 45 to 59 (4.0% versus 0.9%, adjusted odds ratio, 2.00; 95% CI, 1.18-3.38), and 60 to 89 (2.5% versus 0.9%, adjusted odds ratio, 1.67; 95% CI, 1.20-2.34) were independently associated with increased odds of in-hospital mortality. However, there was no statistically significant association between eGFR and symptomatic intracerebral hemorrhage. Conclusions eGFR was associated with an increased risk of in-hospital mortality in acute ischemic stroke patients after treatment with tissue plasminogen activator. eGFR is an important predictor of poststroke short-term death but not of symptomatic intracerebral hemorrhage.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31580705

RESUMO

Objectives: Large sample and high-quality evidence to evaluate the preliminary safety of the mobilizations and massage for cervical vertigo are not yet available. Thus, the present study aimed to investigate the comparative effectiveness and preliminary safety of Shi-style cervical mobilizations (SCM) compared with traditional massage (TM) in cervical vertigo patients. Design: A prospective, multicenter, open-label, randomized, controlled clinical trial with a 1:1 allocation ratio. Settings: Five academic medical centers. Subjects: A total of 360 adult patients with a diagnosis of cervical vertigo. Interventions: The patients were randomly allocated to either an SCM (n = 180) or TM (n = 180) group. The patients were treated during six sessions over 2 weeks. The primary outcome was the Dizziness Handicap Inventory (DHI) total scale score, and secondary outcomes included the DHI subscales, Chinese version of the Short-Form 36 Health Survey (CSF-36), and adverse events (AEs). Outcomes were assessed in the short term at 2 weeks, 1 month, and 3 months, and in the intermediate term at 6 months after randomization. Results: Significant changes were observed from the baseline in the DHI total scale and subscales at 2 weeks and 1, 3, and 6 months in both groups (all p < 0.05). However, the differences between the two groups were not significant (all p > 0.05). Furthermore, we noted significant changes from the baseline in SF-36 scores at 2 weeks in both groups (all p < 0.05), whereas CSF-36 scores were not significantly higher in the SCM group (all p > 0.05) compared with the TM group. No serious AEs were reported in either of the two groups. Conclusions: No differences in outcomes were detected between the SCM and TM groups in terms of treatment of cervicogenic dizziness. Efficacy trials are required to determine whether the improvement observed for each treatment was causally related to the interventions.

7.
Appl Opt ; 58(22): 6085-6090, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31503929

RESUMO

Recently, orbital angular momentum (OAM) beams have been applied in underwater optical communication (UWOC) to build a high-capacity communication link. However, a wave-front-sensitive OAM beam suffers significant distortion due to oceanic turbulence (OT), resulting in considerable intermodal crosstalk that degrades the UWOC performance. Herein, we propose and demonstrate an adaptive optics (AO)-based correction approach with a phase retrieval algorithm (PRA) to compensate for the distorted OAM beams induced by OT. In a simulation, an OT model with the random phase screen method is utilized. Two PRAs, the Gerchberg-Saxton algorithm (GSA) and the hybrid input-output algorithm (HIOA), are utilized to reconstruct the distorted phase-front of the OAM beam. The simulation results illustrate that the PRA-based AO approach can effectively compensate for the distorted OAM beam and improve the bit error rate performance in an oceanic channel. Additionally, the compensation performance of HIOA-based AO is superior to that of GSA-based AO in terms of convergence performance. This work verifies the feasibility and validity of a PRA-based AO approach in underwater turbulence optical communication and provides new insights into the OAM underwater communication system.

8.
Am J Pathol ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31539516

RESUMO

NF-κB signals through canonical RelA/p50 and noncanonical RelB/p52 pathways. The RelA/p50 is involved in basal and inflammatory lymphangiogenesis. However, the role of RelB/p52 in lymphatic vessel biology is unknown. Herein, we investigated changes in lymphatic vessels (LVs) in mice deficient in noncanonical NF-κB signaling and the function of RelB in lymphatic endothelial cells (LECs). LVs were examined in Relb-/-, p52-/-, or control mice, and the gene expression profiles in LECs with RelB knockdown. Relb-/-, but not p52-/-, mice exhibited multiple LV abnormalities. They include the following: i) increased capillary vessel diameter, ii) reduced smooth muscle cell (SMC) coverage of mature vessels, iii) leakage, and iv) loss of active and passive lymphatic flow. Relb-/- mature LVs had thinner vessel walls, more apoptotic LECs and SMCs, and fewer LEC junctions. RelB knockdown LECs had decreased growth, survival, and adhesion, and dysregulated signaling pathways involving these cellular events. These results suggest that Relb-/- mice have abnormal LVs, mainly in mature vessels with reduced SMC coverage, leakage, and loss of contractions. RelB knockdown in LECs leads to reduced growth, survival, and adhesion. RelB plays a vital role in LEC-mediated LV maturation and function.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31529371

RESUMO

Liposomal drug delivery has become an established technology platform to deliver dual drugs to produce synergistic effects and reduce the adverse effects of traditional chemotherapy. Gambogic acid (GA) and retinoic acid (RA) are both effective anticancer components, but their low water-solubility (gambogic acid < 0.0050 mg/mL, retinoic acid 0.0048 < mg/mL) makes it difficult to load both drugs into the liposomes actively using the conventional method. We have successfully used solvent-assisted active loading technology (SALT) to load the insoluble drugs into the internal water phase via water-miscible organic solvent. Gambogic acid and retinoic acid co-encapsulated liposomes (weight ratio of GA to RA = 1:2, GRL) exhibited the strongest synergistic effect; combination index (CI) was 0.614 in 4T1 cells. Our studies demonstrated that GRL had uniform droplet size of about 130 nm, high stability, and controlled release behavior. GRL outperformed gambogic acid and retinoic acid solution (GRS) in pharmacokinetic profiles for a longer half-life and increased AUC. Comparing to GRS, GL, and RL, GRL showed increased cytotoxicity and apoptosis in 4T1 cells and showed the strongest anti-tumor ability in the in vivo anti-tumor efficacy. Overall, the SALT was a promising method to active loading poorly soluble drugs into liposomes, and the results showed GRL possessed a great potential for use in synergistic anticancer therapy.

10.
Chin Med J (Engl) ; 132(17): 2053-2058, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31403970

RESUMO

BACKGROUND: Both cortical and cortical-subcortical (cortex-involved) lesions are typically associated with embolic stroke, of which atrial fibrillation (AF) is the common cause. The aim of this study was to find out the associations between cortex-involved stroke, vascular risk factors, and the subtypes (discovery time and duration) of AF. METHODS: This was an imaging study of the China Atrial Fibrillation Screening in Acute Ischemic Stroke Patients (CRIST) trial. Between October 2013 and June 2015, 1511 acute ischemic stroke or transient ischemic attack (TIA) patients within 7 days after stroke onset at 20 Chinese hospitals were enrolled in this prospective, multicenter cohort, cross-sectional study. The final analysis of this sub-study included 243 patients with AF with required magnetic resonance imaging (MRI) sequences. AF was diagnosed by 6-day Holter monitoring and classified by duration of 24 h. Two stroke specialists blinded to the clinical information reviewed MRI (diffusion-weighted MRI). The third stroke specialists, also blinded to the clinical information, assessed the conflicts. Adjusted large artery atherosclerosis as confounding factor, the associations between cortex-involved lesions, vascular risk factors, and the subtype of AF were evaluated by univariate and multivariate regression analyses. RESULTS: Of 243 acute ischemic stroke patients with AF, 190 were known AF and 53 were newly detected AF. There were 28 patients with AF persistent >24 h and 25 persistent ≤24 h in newly detected AF. Patients with newly detected AF were likely to have a fewer history of stroke or TIA (16.98% vs. 36.31%, P = 0.008) and lower fasting blood glucose (5.91 ±â€Š1.83 mmol/L vs. 6.75 ±â€Š3.83 mmol/L, P = 0.030) than patients with known AF. Among these 243 patients, 102 (41.98%) patients were with cortex-involved lesions. Cortex-involved lesions were significantly related to newly detected AF persistent >24 h (odds ratio [OR]: 4.517, 95% confidence interval [CI]: 1.490-13.696, P = 0.008), proteinuria (OR: 3.431, 95% CI: 1.530-7.692, P = 0.021), and glycosylated hemoglobin (OR: 0.632, 95% CI: 0.464-0.861, P = 0.004). CONCLUSIONS: Compared to previously known AF, newly detected AF persistent >24 h was associated with cortex-involved ischemic stroke. CLINICAL TRIAL REGISTRATION: NCT02156765, https://clinicaltrials.gov/ct2/show/record/NCT02156765.

11.
Biochem Biophys Res Commun ; 518(2): 325-330, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421824

RESUMO

Exosomes are a type of extracellular vesicles derived from cells and mediators of intercellular communication. Different cell types have their own unique exosomes for exchanging information. We previously found that SASH1, a tumor suppressor, was lowly expressed or absent in glioma tissues and glioma C6 cells, but the structure and function of the corresponding exosomes had been unclear. Hence, we aimed to investigate whether exosomes generated from normal glial cells and glioma cells form different protein patterns and whether those derived from normal glial cells affect SASH1 expression in glioma cells. We collected exosomes from astrocytes and C6 cells and identified their exosomal proteins through mass spectrometry. We also performed gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses, whose results showed that both the total and unique exosomal proteins from each cell type were similar. Moreover, the KEGG analysis revealed different clusters of unique exosomal proteins in glial cells and glioma cells. In the normal glial cells, the top clusters were mainly involved in processes with RNA transcripts and proteins, whereas in glioma cells the clusters were attributed to PI3K-Akt signaling, cell adhesion, and cancer-related pathways. Western blot analysis showed that HMGB1 exists in exosomes derived from cultured astrocytes, although its expression was higher in glioma C6 cells. Furthermore, we found that exosomes extracted from astrocytes could increase SASH1 expression in C6 cells (P = 0.040), whereas those derived from HMGB1-depleted astrocytes could not (P = 0.6133). The expression levels of SASH1 decreased after the addition of extracellular recombinant HMGB1 protein, whereas that of TLR4 increased. Our study is the first to demonstrate that HMGB1 plays different roles depending on its form: as an extracellular protein, HMGB1 decreases SASH1 expression, but as an exosomal protein, HMGB1 increases SASH1 expression. Nevertheless, the mechanism, which partly depends on the TLR4 pathway, behind these opposing effects requires further study. Our novel findings on the structure-dependent roles of the cytokine HMGB1 in promoting or inhibiting cancer provide a fresh insight into the interactions of cancer cells with the microenvironment.

12.
J Med Chem ; 62(17): 7708-7721, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31393124

RESUMO

The cyclic dipeptides generally present lower affinity toward intestinal oligopeptide transporter 1 (PEPT1) than the linear dipeptides. JBP485 (cyclo(l-Hyp-l-Ser)) is a low-affinity substrate of PEPT1 with poor oral bioavailability. However, JBP923 (l-Hyp-l-Ser) is a high-affinity substrate of PEPT1 with high oral absorption. We hypothesize that the bioactivatable pseudo-tripeptidization prodrug strategy is promising to increase the affinity of cyclic dipeptides toward PEPT1. To test our hypothesis, we design five amino acid ester prodrugs of JBP485. Compared with JBP485, the optimal prodrug (JBP485-3-CH2-O-valine, J3V) demonstrates improved affinity of PEPT1, oral bioavailability in rats and beagle dogs. Moreover, J3V can dose-dependently protect against liver injury. Additionally, J3V is stable in the gastrointestinal tract, beneficial to the PEPT1-mediated membrane transport, and is bioactivated in the enterocytes and hepatic cells, essential to elicit its bioactivity. In summary, the bioactivatable pseudo-tripeptidization strategy shows potential in increasing affinity of PEPT1 to enhance oral bioavailability of cyclic dipeptides.

13.
Aging (Albany NY) ; 11(15): 5807-5816, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31422381

RESUMO

In this study we tested whether vascular aging is associated with the risk of first stroke in the Kailuan cohort, a community-based Chinese cohort. For participants aged ≥ 50 years, healthy vascular aging (HVA) was defined as an absence of hypertension and a brachial-ankle pulse wave velocity < the mean + 2 standard deviations, which was determined from a reference sample of healthy participants aged < 30 years. The primary outcome was first stroke (ischemic or hemorrhagic). In total, 11,474 participants were enrolled. The prevalence of HVA decreased from 36.0% in participants aged 50-59 years to 4.7% in those aged ≥ 70 years. During a median follow-up of 3.3 years, the incidence of first stroke was 0.5% in the HVA group but was 2.6% in the Non-HVA group. After adjusting for confounding variables, HVA was associated with a 0.32-fold lower risk of first stroke compared to the Non-HVA group (95% confidence interval, 0.18-0.56; p < 0.001). It thus appears that HVA reduced the risk of first stroke in a community-based Chinese population. This suggests that evaluation of vascular aging as part of public health screening may be useful for stroke risk assessment.

14.
Hypertens Res ; 42(11): 1776-1782, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31451721

RESUMO

Blood pressure (BP) fluctuates widely during the acute phase of stroke. Compared to single BP assessment, patterns of BP over time may have greater power in predicting stroke outcome. This study aims to investigate the effect of BP fluctuation patterns on stroke outcomes in acute ischemic stroke (IS) patients. IS patients within 24 h of onset registered in the BOSS registry between 2012 and 2014 were analyzed. Fluctuation of BP was predefined as the change trend in systolic BP (SBP) from Day 1 to Day 7 after onset and was used to divide patients into groups with sustained high SBP (≥160 mmHg) during the first 7 days (C1); rapid (C2: within the first 2 days) or delayed (C3: after 2 days) decline from high (≥160 mmHg) to low (<160 mmHg); consistently low SBP (C4); and elevation from low to high (C5). The primary stroke outcome was defined as a modified Rankin Scale score ≥3 at 3 months after onset. Of 1,095 IS patients, C1 (n = 90) had the highest risk of poor outcome (23.3%), while C2 (n = 198, risk = 11.6%) and C4 (n = 650, risk = 12.2%) had the lowest risk. C2 and C4 had a significant reduction in poor outcome risk when compared to C1, even after adjustment for average BP and BP variability (BPV) during the first 7 days (adjusted odds ratio[OR]C2 = 0.32, 95% CI: 0.12-0.80; ORC4 = 0.37, 95% CI: 0.14-0.97). The BP fluctuation pattern in the acute phase of IS might be a useful predictive parameter for functional outcome independent of average BP and BPV.

15.
J Clin Hypertens (Greenwich) ; 21(10): 1534-1541, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468708

RESUMO

Using data from the Blood Pressure and Clinical Outcome in TIA or Ischemic Stroke (BOSS) study, we aim to test the applicability and feasibility of stroke secondary prevention recommendations from the 2017 American College of Cardiology/American Heart Association guideline. Patients were categorized based on their blood pressure (BP) status at 3 months. The nonhypertension group was defined as those without a diagnosis of hypertension. The other patients were further divided into three subgroups according to office BP measured at 3-month visit (BP <130/80, 130-139/80-89, and ≥140/90 mm Hg). The primary outcome was any stroke within one year. The associations between BP status and 1-year prognosis (recurrent stroke, recurrent stroke/TIA, and poor functional outcome [modified Rankin scale score 3-6]) were estimated. Among 2341 IS/TIA patients, additional 1056 patients were classified as uncontrolled hypertension at the 90-day visit according to the new guidelines. Adjusted hazard/odds ratios (95% confidence intervals [CI]) for recurrent stroke in BP <130/80, 130-139/80-89, and ≥140/90 compared with nonhypertension group were 2.42 (95% CI: 0.87-6.76), and 4.30 (95% CI: 1.73-10.70), respectively. The prevalence of hypertension and uncontrolled BP among BOSS study population was substantially higher based on the new guidelines. BP of 130-139/80-89 did not show the worsened clinical outcomes compared with people without hypertension. Our study adds to the growing uncertainty about secondary prevention BP goal for IS/TIA patients.

16.
Mol Immunol ; 114: 369-377, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31450182

RESUMO

The prevalence of IgE-mediated food allergy is increasing in the whole wide world which often causes skin and gastrointestinal tract symptoms, or even fatal anaphylactic shock. However, the evaluation of food allergens remains difficult, and the mechanism of food allergy is still not fully clear. To study the gene expression profile in food allergy animal models and identify the regulatory mechanism of the crucial genes, two administration routes were used to build animal models in our study. OVA-specific IgE and IL-4 levels were tested by ELISA, transcriptome profiling was carried out by microarray, and the regulatory mechanism of the highest expressed gene was studied in the primary spleen cells. We found that activation-induced cytidine deaminase (Aicda) is the highest expressed gene in the allergic mice, IL-21 can dramatically enhance the expression of Aicda in the lymph node microenvironment, and IL-17A can promote this effect significantly though it has only limited influence by itself. At last, we illuminated that the promotion of IL-21 on Aicda is partially through STAT3. In summary, our results suggest that IL-21 and IL-17A may play important role in the expression of Aicda as well as food allergy.

17.
JAMA Neurol ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31424481

RESUMO

Importance: Dual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about the optimal duration of dual antiplatelet therapy for minor stroke or TIA. Objective: To obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA. Design, Setting, and Participants: This analysis pooled individual patient-level data from 2 large-scale randomized clinical trials that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor stroke or high-risk TIA. The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial enrolled patients at 114 sites in China from October 1, 2009, to July 30, 2012. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial enrolled patients at 269 international sites from May 28, 2010, to December 19, 2017. Both were followed up for 90 days. Data analysis occurred from November 2018 to May 2019. Interventions: In the 2 trials, patients with minor stroke or high-risk TIA were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset. Main Outcomes and Measures: The primary efficacy outcome was a major ischemic event (ischemic stroke, myocardial infarction, or death from ischemic vascular causes). The primary safety outcome was major hemorrhage. Results: The study enrolled 5170 patients (CHANCE) and 4881 patients (POINT). Analysis included individual data from 10 051 patients (5016 in the clopidogrel-aspirin treatment group and 5035 in the control group) with a median age of 63.2 (interquartile range, 55.0-72.9) years; 6106 patients (60.8%) were male. Clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (328 of 5016 [6.5%] vs 458 of 5035 [9.1%]; hazard ratio [HR], 0.70 [95% CI, 0.61-0.81]; P < .001), mainly within the first 21 days (263 of 5016 [5.2%] vs 391 of 5035 [7.8%]; HR, 0.66 [95% CI, 0.56-0.77]; P < .001), but not from day 22 to day 90. No evidence of heterogeneity of treatment outcome across trials or prespecified subgroups was observed. Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was nonsignificant. Conclusions and Relevance: In this analysis of the POINT and CHANCE trials, the benefit of dual antiplatelet therapy appeared to be confined to the first 21 days after minor ischemic stroke or high-risk TIA.

18.
BMC Complement Altern Med ; 19(1): 191, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362725

RESUMO

BACKGROUND: Wnt/ß-catenin signaling pathway is closely related to osteoarthritis. In our preliminary study, ß-catenin conditional activation (cAct) mice that specifically over-express ß-catenin gene in cartilage chondrocyte exhibits osteoarthritis-like phenotype in the lumbar disc and knee joint. Therefore, we used the mice to model FJ-OA and test the potential curative effect of Velvet Antler Polypeptide (VAP) on this mice model. METHODS: We tested the effect of VAP on ß-catenin conditional activation mice, and used Cre negative littermates as controls. Micro-CT, histology and histomorphometry analysis were performed to evaluate the curative effect of VAP on mice facet joint-like phenotype. Expression of ß-catenin and collagen II was detected by immunohistochemistry (IHC) and western-blot., MMP13, ADAMTS4 and ADAMTS5 was detected by immunofluorescence (IF). RT-PCR analysis was preformed to detect mRNA expression of cartilage degrading enzymes, such as MMP13, ADAMTS4 and ADAMTS5. RESULTS: Results of micro-CT (µCT) analysis showed that VAP could partially reverse lumbar disc osteophyte formation observed in ß-catenin(ex3)Col2ER mice. Histology data revealed VAP partially improved facet joint cartilage tissue invades. Histomorphometry analysis showed an increase in total cartilage area after VAP treatment. IHC show that VAP reduced ß-catenin protein levels and moderately up-regulated collagen II protein levels. RT-PCR and IF data showed that VAP down-regulated the expression of extracellular matrix synthesis (ECM) degradation enzymes MMP13, ADAMTS4 and ADAMTS5. CONCLUSION: Taken together, VAP may modulate ECM by inhibits MMP13, ADAMTS4 and ADAMTS5 via Wnt /ß-catenin signaling pathway. Velvet Antler Polypeptide may be a potential medicine for FJ-OA.

19.
Neurol Res ; 41(10): 893-899, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31328681

RESUMO

Objectives: Although statin therapy is associated with lower recurrence in patients with acute ischaemic stroke, data-evaluating associations between inpatient statin use and stroke recurrence in diabetic patients after acute stroke onset are limited. Methods: This study was based on population data from the Chinese National Stroke Registry. Patients with acute ischaemic stroke and no history of statin therapy were selected. Individuals treated regularly with any type or dosage of statins during acute hospitalization were defined as having inpatient statin therapy. The subjects were divided into two groups according to statin use status during acute hospitalization. Multivariate logistic regression analysis was used to analyse the associations between statin use and stroke recurrence in patients with or without diabetes. Results: A total of 11,429 patients, 2341 (20.48%) with diabetes, were selected for analysis. Statin therapy during hospitalization was documented in 4982 (43.59%). Logistic analysis showed no significant associations between inpatient statin use and stroke recurrence in diabetic subjects at 3 months (OR = 0.90, 95% CI = 0.69-1.16, P = 0.40) or 1 year (OR = 0.92, 95% CI = 0.74-1.16, P = 0.48), but statin use was significantly associated with lower recurrence in non-diabetic patients at both 3 months (OR = 0.80, 95% CI = 0.69-0.92, P = 0.002) and 1 year (OR = 0.82, 95% CI = 0.72-0.93, P = 0.002) after discharge. Conclusion: Inpatient statin use was associated with lower stroke recurrence in non-diabetic patients after acute ischaemic stroke, but no definite association between inpatient statin use and stroke recurrence in patients with diabetes mellitus was found.

20.
Nanomedicine ; 21: 102066, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351237

RESUMO

A single nanodrug delivery system for combined delivery of paclitaxel and doxorubicin that integrates high co-loading efficiency, synchronous co-delivery of combined drugs, controllable drug release, and maintains the drug combination at fixed synergistic ratios has been proven to be challenging. Here, we report a redox dual-responsive prodrug nanosystem consisting of a paclitaxel-doxorubicin heterodimeric prodrug with a thioether bond linkage to effectively co-deliver two therapeutic drugs. The heterodimeric prodrug could self-assemble into uniform nanoaggregates containing DSPE-PEG2K with a precise drug co-loading ratio in water, and possessed a high co-loading content. We demonstrated that this nanosystem provided strong synergistic effects in MCF-7 and 4 T1 cells. In vivo, this nanosystem results in a long blood circulation, high accumulation in the tumor, and significant inhibition of tumor growth in BALB/c mice bearing 4 T1 tumors. Such a simple, safe, and efficient heterodimeric prodrug nanosystem exhibits great potential for clinical translation in future combination chemotherapy treatments.

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