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1.
J Med Chem ; 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32233366

RESUMO

Rational designs of small-molecule inhibitors targeting protein-protein interfaces have met little success. Herein, we have designed a series of triazole derivatives with a novel scaffold to specifically intervene with the interaction of TLR8 homomerization. In multiple assays, TH1027 was identified as a highly potent and specific inhibitor of TLR8. Successful solution of the X-ray crystal structure of TLR8 in complex with TH1027 shed in-depth mechanistic insight of its binding mode, validating that TH1027 located between two TLR8 monomers and recognized an unconventional pocket thereby preventing TLR8 from activation. Further biological evaluations showed that TH1027 dose-dependently suppressed the TLR8-mediated inflammation responses in both human monocyte cell lines, peripheral blood mononuclear cells (PBMCs), and rheumatoid arthritis patient specimens, suggesting strong therapeutic potential against autoimmune diseases.

2.
Acc Chem Res ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32233400

RESUMO

ConspectusToll-like receptors (TLRs) are the "gatekeepers" of the immune system in humans and other animals to protect the host from invading bacteria, viruses, and other microorganisms. Since TLR4 was discovered as the receptor for endotoxin in the late 1990s, significant progress has been made in exploiting an understanding of the function of TLRs. The TLR-signaling pathway is crucial for the induction and progression of various diseases. Dysregulation of TLR signaling contributes to numerous pathological conditions, including chronic inflammation, sepsis, cancers, asthma, neuropathic pain, drug addiction, and autoimmune diseases. Therefore, manipulation of TLR signaling is promising to halt their activity in inflammatory diseases, to enhance their signaling to fight cancers, to modulate their role in autoimmune diseases, and to suppress them to treat drug addiction. TLR agonists have demonstrated great potential as antimicrobial agents and vaccine adjuvants, whereas TLR antagonists are being developed as reagents and drugs to dampen immune responses. Because of their pivotal potential therapeutic applications, fruitful small-molecule compounds and peptide fragments have been discovered, and many of them have advanced to various stages of clinical trials (though only two have been approved by the Food and Drug Administration (FDA): MPLA as a TLR4 agonist and imiquimod as a TLR7 agonist).In this Account, we focus on the progress in developing TLR signaling pathway modulators (mainly focused on the Yin and Wang laboratories) over the past decade and highlight the accomplishments and currently existing challenges in the development of TLR modulators. First, we briefly describe the members of the human TLR family along with their natural modulators. Second, we illustrate our endeavors to discover TLR-targeted agents using comprehensive approaches. Specifically, a discussion of identification and characterization of new chemical entities, determination of modes of action, and further applications is presented. For instance, the TLR3 antagonist was first discovered through in silico screening, and the inhibitory activity was confirmed in murine cells. Considering the glycosylation on TLR3, a new direction for TLR3 modulator design was pointed out to target asparagine glycosylation. We have particularly focused on the discovery of TLR4 antagonists and have assessed their great potential in the clinical treatment of drug addiction and alcohol use disorders. In addition, we discuss multiple other popular and robust techniques for modulator discovery. Not only small organic modulators but also stapled peptides and peptidomimetics will attract more and more attention in the future. Finally, current challenges, opportunities, and future perspectives for TLR-targeted agents are also discussed.

3.
PLoS One ; 15(1): e0227544, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31917827

RESUMO

AIM: A total of 241 patients with chronic HCV infection were recruited to investigate the association between liver fibrosis and PLT counts, as well as with MPV, PDW and P-LCR indices. METHODS: The determination of PLT indices was carried out using a Sysmex XT-1800i automated hematology analyzer. Serological tests for HA, LN, C-IV and PIIINP were performed in 210 patients. The liver stiffness was measured in 69 patients by transient elastography (FibroScan). RESULTS: The analysis showed that the four serum fibrosis markers were negatively correlated with PLT counts, but positively correlated with the MPV, PDW and P-LCR values. Moreover, a similar pattern was found after analyzing the FibroScan measurements, which were negatively correlated with PLT counts, but positively correlated with MPV, PDW and P-LCR values. We subdivided the HCV-infected patients into mild and advanced fibrosis groups. The PLT counts were significantly decreased and the MPV, PDW and P-LCR values were significantly increased in the advanced fibrosis group when compared with the mild fibrosis group. CONCLUSIONS: Our results demonstrate that not only the PLT counts but also the MPV, PDW and P-LCR indices significantly correlate with liver fibrosis in HCV-infected patients. Therefore, these indices may be useful laboratory measures for evaluating liver fibrosis progression.

4.
J Cell Physiol ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31967324

RESUMO

Retention after treatment and effective anchorage control are two essential factors in orthodontics. Our study aimed to explore the effects of fucoidan on orthodontic tooth movement (OTM) and the involvement of macrophages. We established a murine OTM model to test the effect of fucoidan administration. We found that mice injected with fucoidan had a deceleration in OTM and a higher bone mineral density. Moreover, fucoidan increased the proportion of F4/80+ CD206+ macrophages and promoted the messenger RNA expression of Arg-1, CD206, and IL-10 at both in vivo and in vitro levels. In addition, macrophages showed lower expression of TNF-α, IL-1ß, and IL-6 and a decrease in F4/80+ CD11c+ cells. Mechanistically, the level of phosphorylated STAT3 was elevated in unpolarized and restorative macrophages after treatment with fucoidan. Taken together, our findings suggest that fucoidan treatment inhibits OTM and enhances the stability of teeth after movement by promoting restorative macrophages through the STAT3 pathway.

5.
BMC Genomics ; 21(1): 62, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959122

RESUMO

BACKGROUND: The APETALA2/ethylene responsive factor (AP2/ERF) superfamily members are transcription factors that regulate diverse developmental processes and stress responses in plants. They have been identified in many plants. However, little is known about the AP2/ERF superfamily in longan (Dimocarpus longan Lour.), which is an important tropical/subtropical evergreen fruit tree that produces a variety of bioactive compounds with rich nutritional and medicinal value. We conducted a genome-wide analysis of the AP2/ERF superfamily and its roles in somatic embryogenesis (SE) and developmental processes in longan. RESULTS: A genome-wide survey of the AP2/ERF superfamily was carried out to discover its evolution and function in longan. We identified 125 longan AP2/ERF genes and classified them into the ERF (101 members), AP2 (19 members), RAV (four members) families, and one Soloist. The AP2 and Soloist genes contained one to ten introns, whereas 87 genes in the ERF and RAV families had no introns. Hormone signaling molecules such as methyl jasmonate (MeJA), abscisic acid (ABA), gibberellin, auxin, and salicylic acid (SA), and stress response cis-acting element low-temperature (55) and defense (49) boxes also were identified. We detected diverse single nucleotide polymorphisms (SNPs) between the 'Hong He Zi' (HHZ) and 'SI JI MI' (SJM) cultivars. The number of insertions and deletions (InDels) was far fewer than SNPs. The AP2 family members exhibited more alternative splicing (AS) events in different developmental processes of longan than members of the other families. Expression pattern analysis revealed that some AP2/ERF members regulated early SE and developmental processes in longan seed, root, and flower, and responded to exogenous hormones such as MeJA, SA, and ABA, and 2,4-D, a synthetic auxin. Protein interaction predictions indicated that the Baby Boom (BBM) transcription factor, which was up-regulated at the transcriptional level in early SE, may interact with the LALF/AGL15 network. CONCLUSIONS: The comprehensive analysis of molecular evolution and expression patterns suggested that the AP2/ERF superfamily may plays an important role in longan, especially in early SE, and in seed, root, flower, and young fruit. This systematic analysis provides a foundation for further functional characterization of the AP2/ERF superfamily with the aim of longan improvement.

6.
Oral Dis ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31958204

RESUMO

OBJECTIVE: As an extracellular vesicle, exosomes can release from virus-infected cells containing various viral or host cellular elements and could stimulate recipient's cellular response. Enterovirus 71 (EV71), a single-strand positive-sense RNA virus, is known to cause hand, foot, and mouth disease (HFMD) in children and bring about severe clinical diseases. METHODS: Separated the human oral epithelial cells (OE cells) from normal buccal mucosa through enzyme digestion. Performed a comprehensive miRNA profiling in exosomes from EV71-infected OE cells through deep small RNA-seq. Using the Human Antiviral Response RT Profiler PCR Array profiles to explore the interactions of innate immune signaling networks with exosomal miR-30a. Knocked out the MyD88 gene in macrophages using CRISPR/Cas9-mediated genome editing method. RESULTS: Our study demonstrated that the miR-30a was preferentially enriched in exosomes that released from EV71-infected human oral epithelial cells through small RNA-seq. We found that the transfer of exosomal miR-30a to macrophages could suppress type Ⅰ interferon response through targeting myeloid differentiation factor 88 (MyD88) and subsequently facilitate the viral replication. CONCLUSIONS: Exosomes released from EV71-infected OE cells selectively packaged high level of miR-30a that can be functionally transferred to the recipient macrophages resulted in targeting MyD88 and subsequently inhibited type I interferon production in receipt cells, thus promoting the EV71 replication.

7.
J Diabetes ; 12(3): 247-258, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31680450

RESUMO

BACKGROUND: G protein-coupled receptor kinase-2 (GRK2) has been shown as a key regulator of cardiac function, and the myocardial GRK2 levels are mirrored by the levels in peripheral blood mononuclear cells (PBMCs). In this study, we evaluated the myocardial and PBMCs GRK2 levels in early diabetic cardiomyopathy (DCM). METHODS: C57BL/KS-db/db male diabetic mice at 12 weeks of age, as the type 2 diabetes (T2DM) animal model of early DCM were evaluated. Forty-four T2DM patients with left ventricular diastolic dysfunction (LVDD), without evidence of hypertension, coronary artery diseases, congestive heart failure, and diabetic complications and without evidence of ischemia in a maximal treadmill exercise test, were recruited as the DM + LVDD group; 30 age-matched T2DM patients without LVDD were recruited as the DM control group. Left ventricular diastolic function was evaluated by cardiac tissue Doppler. The pseudonormal pattern of ventricular filling and E'/A' < 1 were regarded as LVDD. RESULTS: Compared to 8-week-old diabetic mice and 12-week-old control mice, GRK2-mRNA level and expression in myocardial tissues of 12-week-old diabetic mice were significantly increased, as well as the left ventricular wall thickness and systolic function. And the collagen volume fraction (CVF), collagen-3 expression, P53 expression, and cell apoptotic rate in the myocardium of 12-week-old diabetic mice elevated as well. The GRK2-mRNA level in PBMCs of DM with LVDD was significantly higher than in DM control without LVDD. CONCLUSIONS: GRK2 expression increased in the myocardial tissue and the PBMCs at the early stage of DCM. These data support further research on the role of GRK2 as the clinical biomarker for early DCM.

8.
J Cell Physiol ; 235(5): 4804-4813, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31637730

RESUMO

Alternative splicing (AS) is critically associated with tumorigenesis and patient's prognosis. Here, we systematically analyzed survival-associated AS signatures in oral squamous cell carcinoma (OSCC) and evaluated their prognostic predictive values. Survival-related AS events were identified by univariate and multivariate Cox regression analyses using OSCC data from the TCGA head neck squamous cell carcinoma data set. The Percent Spliced In calculated by SpliceSeq from 0 to 1 was used to quantify seven types of AS events. A predictive model based on AS events was constructed by least absolute shrinkage and selection operator Cox regression assay and further validated using a training-testing cohort design. Patient survival was estimated using the Kaplan-Meier method and compared with Log-rank test. The receiver operating characteristics curve area under the curves was used to evaluate the predictive abilities of these predictive models. Furthermore, gene-gene interaction networks and the splicing factors (SFs)-AS regulatory network was generated by Cytoscape. A total of 825 survival-related AS events within 719 genes were identified in OSCC samples. The integrative predictive model was better at predicting outcomes of patients as compared to those models built with the individual AS event. The predictive model based on three AS-related genes also effectively predicted patients' survival. Moreover, seven survival-related SFs were detected in OSCC including RBM4, HNRNPD, and HNRNPC, which have been linked to tumorigenesis. The SF-AS network revealed a significant correlation between survival-related AS genes and these SFs. Our findings revealed a systemic portrait of survival-associated AS events and the splicing network in OSCC, suggesting that AS events might serve as novel prognostic biomarkers and therapeutic targets for OSCC.

9.
Neurocrit Care ; 32(1): 104-112, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31549349

RESUMO

BACKGROUND: Accurate prediction of malignant brain edema (MBE) after stroke is paramount to facilitate close monitoring and timely surgical intervention. The Enhanced Detection of Edema in Malignant Anterior Circulation Stroke (EDEMA) score was useful to predict potentially lethal malignant edema in Western populations. We aimed to validate and modify it to achieve a better predictive value for MBE in Chinese patients. METHODS: Of ischemic stroke patients consecutively admitted in the Department of Neurology, West China Hospital between January 2010 and December 2017, we included patients with anterior circulation stroke, early signs of brain edema on computed tomography within 24 h of onset, and admission National Institutes of Health Stroke Scale (NIHSS) score ≥ 8. MBE was defined as the development of signs of herniation (including decrease in consciousness and/or anisocoria), accompanied by midline shift ≥ 5 mm on follow-up imaging. The EDEMA score consisted of five parameters: glucose, stroke history, reperfusion therapy, midline shift, and cistern effacement. We created a modified score by adding admission NIHSS score to the original EDEMA score. The discrimination of the score was assessed by the area under the receiver operating characteristics curve (AUC). Calibration was assessed by Hosmer-Lemeshow test and calibration plot. We compared the discrimination of the original and modified score by AUC, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Clinical usefulness of the two scores was compared by plotting net benefits at different threshold probabilities in the decision curve analysis. RESULTS: Of the 478 eligible patients (mean age 67.3 years; median NIHSS score 16), 93 (19%) developed MBE. The EDEMA score showed moderate discrimination (AUC 0.72, 95% confidence interval [CI] 0.67-0.76) and good calibration (Hosmer-Lemeshow test, P = 0.77). The modified score showed an improved discriminative ability (AUC 0.80, 95% CI 0.76-0.84, P < 0.001; NRI 0.67, 95% CI 0.55-0.78, P < 0.001; IDI 0.07, 95% CI 0.06-0.09, P < 0.001). Decision curves showed that the modified score had a higher net benefit than the original score in a range of threshold probabilities lower than 60%. CONCLUSIONS: The original EDEMA score showed an acceptable predictive value for MBE in Chinese patients. By adding the admission NIHSS score, the modified score allowed for a more accurate prediction and clinical usefulness. Further validation in large cohorts of different ethnicities is needed to confirm our findings.

10.
Acta Neurol Scand ; 141(3): 193-201, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31598961

RESUMO

Hyperdense middle cerebral artery sign (HMCAS) on admitting to neuroimaging is reported to have prognostic value for poor outcomes after thrombolysis, while evidence from studies comprising a sufficiently large sample size is limited. To detect prognostic predictors after thrombolysis could help improve therapeutic clinical strategies for acute ischemic stroke. We included prospective and retrospective studies of stroke patients that were treated with intravenous thrombolysis, in which functional outcomes (ie, a modified Rankin scale [mRS]) and systematic intracranial hemorrhage (sICH) were assessed in relation to HMCAS during pretreatment head CT. Random-effects models were used to calculate pooled risk ratios (RR) of poor outcomes and sICH for HMCAS patients as compared to patients without HMCAS. Eleven studies permitted identification of 11 818 patients. The risk of poor outcome at 3 months in the HMCAS-positive group was 1.56-fold the negative group (RR, 1.56; 95% CI 1.50-1.62; P < .001). The sICH risk when comparing both groups was found to be non-significant. Sensitivity analysis regarding studies performing thrombolysis within 3 hours also exhibited significant differences in their functional outcomes (RR, 1.56, 95% CI 1.49-1.62; P < .001) in patients with HMCAS as compared to non-HMCAS patients, although this was true for sICH risk. The presence of HMCAS on pretreatment CT predicts a poor outcome at 3 months after intravenous thrombolysis, while its relationship with the incidence of sICH was found to have no statistic value. Our study implies that more aggressive treatment should be considered for HMCAS patients.

11.
J Chem Theory Comput ; 16(1): 510-527, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31751129

RESUMO

We examine the ability of six molecular dynamics (MD) force fields (Amber ff14SB, Amber ff99SBnmr1, Amber ff03ws, OPLS-AA/L, OPLS-AA/M, and CHARMM36) to reproduce conformational ensembles of the central alanine in GAG and AAA in a way that is consistent with five (GAG) or six (AAA) J coupling constants and amide I' profiles. MD-derived Ramachandran plots for all six force fields under study differ from those obtained by the Gaussian fit to experimental data in three major ways: (i) the polyproline II (pPII) basin in the Ramachandran plot is too concentrated, (ii) the antiparallel ß (aß) basin is overpopulated, and (iii) the transitional ß (ßt) basin is underpopulated. Amber ff14SB outperforms the other five MD force fields and yields the highest pPII populations of the central alanine residue in GAG (55%) and AAA (63%), in good agreement with the predictions of the Gaussian model (59 and 76%). The analysis of the hydration layer around the central alanine residue reveals considerable reorientation of water molecules and reduction in both the average number of water molecules and the average number of water-water hydrogen bonds when glycines (in GAG) are replaced by alanines (in AAA), elucidating water-mediated nearest neighbor effects on alanine's conformational dynamics.

12.
J Org Chem ; 85(3): 1579-1600, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31829590

RESUMO

Cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) (cGAS), a cytosolic DNA sensor, plays an important role in the type I interferon response. DNA from either invading microbes or self-origin triggers the enzymatic activity of cGAS. Aberrant activation of cGAS is associated with various autoimmune disorders. Only one selective probe exists for inhibiting cGAS in cells, while others are limited by their poor cellular activity or specificity, which underscores the urgency for discovering new cGAS inhibitors. Here, we describe the development of new small-molecule human cGAS (hcGAS) inhibitors (80 compounds synthesized) with high binding affinity in vitro and cellular activity. Our studies show CU-32 and CU-76 selectively inhibit the DNA pathway in human cells but have no effect on the RIG-I-MAVS or Toll-like receptor pathways. CU-32 and CU-76 represent a new class of hcGAS inhibitors with activity in cells and provide a new chemical scaffold for designing probes to study cGAS function and development of autoimmune therapeutics.

13.
Mol Psychiatry ; 25(3): 603-613, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29915376

RESUMO

Presenilin-1 (PSEN1) is the catalytic subunit of the γ-secretase complex, and pathogenic mutations in the PSEN1 gene account for the majority cases of familial AD (FAD). FAD-associated mutant PSEN1 proteins have been shown to affect APP processing and Aß generation and inhibit Notch1 cleavage and Notch signaling. In this report, we found that a PSEN1 mutation (S169del) altered APP processing and Aß generation, and promoted neuritic plaque formation as well as learning and memory deficits in AD model mice. However, this mutation did not affect Notch1 cleavage and Notch signaling in vitro and in vivo. Taken together, we demonstrated that PSEN1S169del has distinct effects on APP processing and Notch1 cleavage, suggesting that Notch signaling may not be critical for AD pathogenesis and serine169 could be a critical site as a potential target for the development of novel γ-secretase modulators without affecting Notch1 cleavage to treat AD.

14.
Circ Cardiovasc Qual Outcomes ; 12(12): e005610, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31830825

RESUMO

BACKGROUND: Little is known about long-term trends in outcomes of patients with ischemic stroke in China. We aimed to assess longitudinal trends in these outcomes over the past 15 years in China and explore possible factors behind the trends. METHODS AND RESULTS: Patients with ischemic stroke admitted to the Department of Neurology at West China Hospital were prospectively and consecutively enrolled in a central registry since 2002, and the present study analyzed data from those admitted to hospital within 7 days of stroke during the period 2002 to 2016. Patients were binned into three 5-year intervals for temporal analysis. Death, disability, and death/disability at 3 and 12 months after stroke were compared among the time intervals across the entire sample and in subsets stratified by age (<65 or ≥65 years). To explore the possible factors related to the trends in outcomes, interaction between the factors and time on outcomes was entered separately into the multivariable logistic regression model. Of 6462 patients with ischemic stroke in the final analysis, 3837 (59.4%) were men, and mean age was 64.2 years (SD, 13.7). Mean age at stroke onset and National Institutes of Health Stroke Scale score at admission decreased significantly during the 15-year period (P<0.001). Between 2002 to 2006 and 2012 to 2016, cumulative incidences declined significantly for death at 3 months (from 9.6% to 6.4%), disability at 3 months (from 36.8% to 28.7%), and death/disability at 3 months (from 42.9% to 33.3%), as well as for death at 12 months (from 15.9% to 10.7%), disability at 12 months (from 23.2% to 17.6%), and death/disability at 12 months (from 35.4% to 26.4%; all P<0.001). The decreases in disability and death/disability at 3 and 12 months between 2002 to 2006 and 2012 to 2016 remained significant after adjusting for confounders, and the results were similar for the entire cohort and for subgroups of patients <65 or ≥65 years. Only interactions of National Institutes of Health Stroke Scale score on admission and time period (2012-2016) were found to significantly correlate with disability and death/disability at 3 and 12 months (all P≤0.03). CONCLUSIONS: Our study from a large medical center in southwest China suggests that since 2002, risks of disability and death/disability at 3 and 12 months after ischemic stroke have declined. This appears to be due, at least in part, to a significant decline in National Institutes of Health Stroke Scale score on admission, which may reflect greater public awareness of stroke detection, willingness to seek medical attention, and ease of access to healthcare infrastructure. The factors behind this apparent improvement require further study.

15.
J Med Chem ; 62(22): 10221-10244, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31687820

RESUMO

Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines, and guanosine analogues. Substantial evidence is present linking chronic inflammation mediated specifically by TLR7 to the progression of autoimmunity. We identified a new TLR7/8 dual inhibitor (1) and a TLR8-specific inhibitor (2) based on our previous screen targeting TLR8. Compound 1, bearing a benzanilide scaffold, was found to inhibit TLR7 and TLR8 at low micromolar concentrations. We envisioned making modifications on the benzanilide scaffold of 1 resulting in a class of highly specific TLR7 inhibitors. Our efforts led to the discovery of a new TLR8 inhibitor (CU-115) and identification of a TLR7/8 dual inhibitor (CU-72), bearing a distinct diphenyl ether skeleton, with potential for TLR7 selectivity optimization. Given the role of TLR8 in autoimmunity, we also optimized the potency of 2 and developed a new TLR8 inhibitor bearing a 1,3,4-oxadiazole motif.

16.
J Food Sci Technol ; 56(11): 4879-4890, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31741512

RESUMO

Grape skin can be considered as an excellent and inexpensive source of polyphenol antioxidant compounds. A high-efficiency accelerated solvent extraction (ASE) method was developed for antioxidant polyphenols from grape skin. A three-factors three-level Box-Behnken design by response surface methodology was employed for optimization of extraction parameters in terms of total phenolic content, total anthocyanins content and antioxidant activity. The optimized condition was ethanol concentration of 48.80%, temperature of 50.79 °C and extraction time of 14.82 min. Under these conditions, the highest yields of polyphenol, the total phenolic content (15.24 mg GAE/g), total anthocyanins content (346.68 mg CGE/100 g) in grape skin, were obtained with significant antioxidant properties by DPPH, ABTS and FRAP assays. Moreover, the extracts from various grape skins by ASE, possessed ten main antioxidant polyphenols with the highest concentration of p-hydroxybenzoic acid and malvidin-3-O-glucoside. Compared with conventional solvent extraction, ASE extracted more amounts of polyphenols, exhibited more extraction level with shorter time and higher reproducibility.

17.
Brain Behav ; 9(10): e01426, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31566920

RESUMO

BACKGROUND AND PURPOSE: Intravenous thrombolysis (IVT) has become the standard treatment for acute ischemic stroke within 4.5 hr after symptoms onset. However, a fraction of patients would develop early neurological deterioration (END) after IVT. The aim of our study was to explore the utility of neutrophil-lymphocyte ratio (NLR) in predicting END. METHODS: From October 2016 to March 2018, 342 consecutive patients with thrombolytic therapy were prospectively enrolled in this study. Blood cell counts were sampled in stroke emergency room before IVT. END was defined as a National Institutes of Health Stroke Scale score increase of ≥4 points within 24 hr after IVT. Multiple regression analysis was used to investigate the potential risk factors of END. We also performed receiver operating characteristic curve analysis and nomogram analysis to assess the overall discriminative ability of the NLR in predicting END. RESULTS: Of the 342 patients, 86 (25.1%) participants were identified with END. Univariate logistic regression analysis demonstrated that patients with NLR in the third tertile, compared with the first tertile, were more likely to have END (odds ratio, 9.783; 95% confidence interval [CI], 4.847-19.764; p = .001). The association remained significant even after controlled for potential confounders. Also, a cutoff value of 4.43 for NLR was detected in predicting post-thrombolysis END with a sensitivity of 70.9% and a specificity of 79.3% (area under curve, 0.779; 95% CI, 0.731-0.822). Furthermore, our established nomogram indicated that higher NLR was an indicator of post-thrombolysis END (c-index was 0.789, p < .001). CONCLUSIONS: This study showed that elevated level of NLR may predict post-thrombolysis END in ischemic stroke patients.

18.
J Orthop Surg Res ; 14(1): 307, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511005

RESUMO

BACKGROUND: Osteoarthritis (OA) is the common chronic degenerative joint bone disease that is mainly featured by joint stiffness and cartilage degradation. Icariin (ICA), an extract from Epimedium, has been preliminarily proven to show anti-osteoporotic and anti-inflammatory effects in OA. However, the underlying mechanisms of ICA on chondrocytes need to be elucidated. METHODS: LPS-treated chondrocytes and monosodium iodoacetate (MIA)-treated Wistar rats were used as models of OA in vitro and in vivo, respectively. LDH and MTT assays were performed to detect cytotoxicity and cell viability. The expression levels of NLRP3, IL-1ß, IL-18, MMP-1, MMP-13, and collagen II were detected by qRT-PCR and Western blotting. The release levels of IL-1ß and IL-18 were detected by ELISA assay. Caspase-1 activity was assessed by flow cytometry. Immunofluorescence and immunohistochemistry were used to examine the level of NLRP3 in chondrocytes and rat cartilage, respectively. The progression of OA was monitored with hematoxylin-eosin (H&E) staining and safranin O/fast green staining. RESULTS: ICA could suppress LPS-induced inflammation and reduction of collagen formation in chondrocytes. Furthermore, ICA could inhibit NLRP3 inflammasome-mediated caspase-1 signaling pathway to alleviate pyroptosis induced by LPS. Overexpression of NLRP3 reversed the above changes caused by ICA. It was further confirmed in the rat OA model that ICA alleviated OA by inhibiting NLRP3-mediated pyroptosis. CONCLUSION: ICA inhibited OA via repressing NLRP3/caspase-1 signaling-mediated pyroptosis in models of OA in vitro and in vivo, suggesting that ICA might be a promising compound in the treatment of OA.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Flavonoides/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Osteoartrite/tratamento farmacológico , Piroptose/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Colágeno/biossíntese , Avaliação Pré-Clínica de Medicamentos/métodos , Flavonoides/uso terapêutico , Inflamassomos/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Piroptose/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
19.
J Agric Food Chem ; 67(41): 11508-11517, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31538478

RESUMO

Tiopronin, as a novel thiol-containing nucleophile, was introduced for depolymerizing polymeric proanthocyanidins from grape seed into catechins and three new proanthocyanidin-tiopronin degradation products: (+)-catechin-4ß-S-tiopronin methyl ester (CT), (-)-epicatechin-4ß-S-tiopronin methyl ester (ECT), and (-)-epicatechin gallate-4ß-S-tiopronin methyl ester (ECGT). A Box-Behnken design was employed to optimize degradation conditions based on single-factor experiments to obtain target products. Each of the new degradation compounds was isolated by the high-speed counter-current chromatography combined with semipreparative high performance liquid chromatography in large amounts, and then, their structures were identified by 1H NMR, 13C NMR, 2D-NMR, as well as mass spectrometry analysis. The absolute configurations were further confirmed by comparison between the calculated electronic circular dichroism and experimental spectra. Further evaluation of antibacterial activities of these compounds showed that CT and ECT possessed more inhibiting capacity against Staphylococcus aureus and Escherichia coli than parent compound catechin and epicatechin. However, ECGT has no bacteriostatic capacity against these two bacteria.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Catequina/química , Distribuição Contracorrente/métodos , Extrato de Sementes de Uva/isolamento & purificação , Extrato de Sementes de Uva/farmacologia , Proantocianidinas/isolamento & purificação , Proantocianidinas/farmacologia , Tiopronina/química , Antibacterianos/química , Cromatografia Líquida de Alta Pressão , Escherichia coli/efeitos dos fármacos , Extrato de Sementes de Uva/química , Proantocianidinas/química , Sementes/química , Espectrometria de Massas por Ionização por Electrospray , Staphylococcus aureus/efeitos dos fármacos , Vitis/química
20.
Front Neurol ; 10: 945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31555200

RESUMO

Studies suggest that microRNAs that regulate expression of matrix metalloproteinase (MMP)-9 may be involved in hemorrhagic transformation (HT) after cardioembolic stroke, so we examined whether such microRNAs could predict HT in acute cardioembolic stroke patients. Blood samples were prospectively collected from patients who later experienced HT (n = 29) or did not (n = 29), and the samples were assayed for eight microRNAs identified as related to MMP-9 based on three microRNA databases. Expression levels of these microRNAs were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in 28 of the 58 patients, 14 of whom suffered HT and 14 of whom did not. Four differentially expressed miRNAs were identified: hsa-miR-21-5p, hsa-miR-206, hsa-miR-491-5p, and hsa-miR-3123. Subsequent qRT-PCR analysis of these four miRNAs across all 58 patients showed that levels of miR-21-5p, miR-206, and miR-3123 were significantly higher in patients with HT than in those without HT, while expression of miR-491-5p was similar between the two groups. The area under the receiver operating characteristic curve for predicting HT was 0.677 (95% CI 0.535-0.818) for miR-21-5p, 0.687 (95% CI 0.543-0.830) for miR-206, and 0.661 (95% CI 0.512-0.810) for miR-3123. Our results suggest that these three microRNAs may be prognostic markers for HT after cardioembolic stroke, which should be verified by future studies with large samples.

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