OBJECTIVE: To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS). METHODS: Fourteen apolipoprotein E-deficient (ApoE^-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE^-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot. RESULTS: Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE^-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE^-/- mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05). CONCLUSION Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.
Mice ; Animals ; Apelin ; Tissue Plasminogen Activator/metabolism* ; Quercetin/therapeutic use* ; AMP-Activated Protein Kinases/metabolism* ; Sirtuin 1/metabolism* ; Signal Transduction/physiology* ; Atherosclerosis/metabolism* ; Apolipoproteins E

OBJECTIVE: To establish a machine learning model to predict the risk of early neurological deterioration (END) based on the clinical and laboratory data of patients with acute ischemic stroke (AIS) before intravenous thrombolysis. METHODS: The clinical data of AIS patients who received intravenous thrombolytic with recombinant tissue plasminogen activator (rt-PA) at the Stroke Center of the First Hospital of Qinhuangdao City from January 2019 to July 2022 were retrospectively analyzed. Patients were divided into END group and non-END group according to whether END appeared after intravenous thrombolytic. Clinical data of patients at admission were collected, including demographic characteristics, clinical evaluation, comorbidification, drug use history, laboratory tests, etc. Univariate and multivariate Logistic regression analysis were performed to screen out the independent predictors of the END of AIS patients after intravenous thrombolytic. The study subjects were randomly divided into a training set and a test set in a 7 : 3 ratio. Four machine learning prediction models, including Logistic regression (LR), K-nearest neighbor (KNN), support vector machine (SVM) and random forest (RF), were established based on independent predictors. The receiver operator characteristic curve (ROC curve) was used to evaluate the predictive ability of each model in END. RESULTS: A total of 704 patients were enrolled, of whom 99 were identified as END and 605 as non-END. Univariate and multivariate Logistic regression analysis was used to screen out the National Institutes of Health stroke scale [NIHSS, odds ratio (OR) = 1.049, 95% confidence interval (95%CI) was 1.015-1.082, P = 0.004], systolic blood pressure (OR = 1.013, 95%CI was 1.004-1.022, P = 0.004), lymphocyte percentage (LYM%, OR = 0.903, 95%CI was 0.853-0.953, P < 0.001), platelet to lymphocyte ratio (PLR, OR = 1.007, 95%CI was 1.002-1.014, P = 0.013) were the independent predictors of END in AIS patients after intravenous thrombolysis. The area under the curve (AUC) of LR, KNN, SVM, and RF machine learning models in the test dataset were 0.789 (95%CI was 0.675-0.902), 0.797 (95%CI was 0.685-0.910), 0.851 (95%CI was 0.751-0.952) and 0.809 (95%CI was 0.699-0.919), respectively. The RF model had the highest sensitivity (95.7%). The accuracy (0.736), specificity (72.0%) and AUC of SVM model were the highest, and its overall prediction ability was better than the other three models. CONCLUSIONS Machine learning models have a potential role in early predicting the risk of END after intravenous thrombolysis in AIS patients, and can provide help in clinical decision-making for intravenous thrombolysis.
Humans ; Tissue Plasminogen Activator/therapeutic use* ; Ischemic Stroke/drug therapy* ; Brain Ischemia ; Retrospective Studies ; Thrombolytic Therapy ; Stroke ; Fibrinolytic Agents/therapeutic use*

Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability, which gravely burdens the global economy. Current relatively effective clinical treatments are limited to intravenous alteplase and thrombectomy. Even so, patients still benefit little due to the short therapeutic window and the risk of ischemia/reperfusion injury. It is therefore urgent to figure out the neuronal death mechanisms following ischemic stroke in order to develop new neuroprotective strategies. Regarding the pathogenesis, multiple pathological events trigger the activation of cell death pathways. Particular attention should be devoted to excitotoxicity, oxidative stress, and inflammatory responses. Thus, in this article, we first review the principal mechanisms underlying neuronal death mediated by these significant events, such as intrinsic and extrinsic apoptosis, ferroptosis, parthanatos, pyroptosis, necroptosis, and autophagic cell death. Then, we further discuss the possibility of interventions targeting these pathological events and summarize the present pharmacological achievements.
Brain Ischemia/pathology* ; Cell Death ; Humans ; Ischemic Stroke ; Reperfusion Injury/pathology* ; Stroke/pathology* ; Tissue Plasminogen Activator/therapeutic use*

Objective: To compare the efficacy and safety of pro-urokinase and reteplase in the treatment of patients with acute ST elevation myocardial infarction (STEMI). Methods: STEMI patients, who received intravenous thrombolytic therapy in Henan STEMI registry between September 2016 and August 2018, were eligible for this study. A total of 5479 patients from 66 hospitals were screened and patients were divided into pro-urokinase group (n=638) and reteplase group (n=702) according to thrombolytic drugs. Data including patient demographics, risk factors, medical histories, patient information at admission, in-hospital treatment, time delays, and clinical events were collected. The clinical recanalization rate, in-hospital mortality, in-hospital death or treatment withdrawal, in-hospital main adverse cardiovascular and cerebrovascular events (MACCE, death or treatment withdrawal, congestive heart failure, reinfarction and ischemic stroke) and post-thrombolysis bleeding were compared between the two groups. Bleeding events were evaluated with Bleeding Academic Research Consortium (BARC) criteria. Results: The median age [61.8 (53.2, 69.0) vs. 62.6 (52.1, 69.8), P=0.833] or the proportion of women [23.0% (147/638) vs. 25.1% (176/702), P=0.385] were similar between the pro-urokinase and reteplase groups. Clinical recanalization rates were similar between the pro-urokinase and reteplase groups [82.1% (524/638) vs. 84.9% (596/702), P=0.172], and there was no difference in the median time from onset to thrombolysis [194.5 (135.0,290.0) min vs. 190 (126.0,292.0) min, P=0.431] and the median recanalization time [95 (67.5,120.0) min vs. 95 (71.0,119.0) min, P=0.561] between the two groups. There was no significant difference in in-hospital mortality [5.5% (35/638) vs. 5.1% (36/702), P =0.770], in-hospital all-cause mortality, treatment withdrawal [8.9% (57/638) vs.7.7% (54/702), P=0.410], and in-hospital MACCE [13.0% (83/638) vs. 10.4% (73/702), P=0.137] between pro-urokinase and reteplase groups. However, the incidence of post-thrombolysis bleeding was significantly higher in reteplase group than in pro-urokinase group [7.8% (55/702) vs. 3.8% (24/638), P=0.002]. Further analysis found that the incidence of oral bleeding and the BARC grades 1-2 bleeding were significantly higher in reteplase group than in pro-urokinase group, whereas the incidence of cerebral hemorrhage was similar between the two groups [0.6% (4/638) vs. 0.4% (3/702), P=0.715]. The comparison of efficacy and safety outcomes between the two groups after adjusting for baseline characteristics using general linear mixed models was consistent with those before the adjustment. There was no significant difference in in-hospital mortality, in-hospital death or treatment withdrawal, in-hospital MACCE after adjusting for baseline characteristics and post-thrombolysis bleeding between the two groups. Conclusions: Pro-urokinase and reteplase have similar clinical efficacy in the treatment of STEMI. In terms of safety, the incidence of cerebral hemorrhage is similar, while the incidence of BARC grades 1-2 bleeding and oral bleeding is higher in reteplase group than in pro-urokinase group, which has no impact on in-hospital outcomes.
Female ; Fibrinolytic Agents/therapeutic use* ; Hospital Mortality ; Humans ; Myocardial Infarction/drug therapy* ; Recombinant Proteins ; ST Elevation Myocardial Infarction/drug therapy* ; Thrombolytic Therapy ; Tissue Plasminogen Activator ; Treatment Outcome ; Urokinase-Type Plasminogen Activator

Ischemic stroke is a major health crisis causing high mortality and morbidity. The key treatment relies on the rapid intervention to dissolve thrombus, to reduce bleeding side effect and re-canalize clotted blood vessels using clot lysis drugs. Tissue plasminogen activator (tPA) is the only FDA-approved drug for ischemic stroke, but it has many limitations in clinical use. In recent years, the development of thrombolytic drugs and treatment strategies based on tPA has been progressed rapidly. Here we review the recent progress in this field, including the contributions from us and others, to promote the future development of novel thrombolytic drugs.
Brain Ischemia/drug therapy* ; Fibrinolytic Agents/therapeutic use* ; Humans ; Research/trends* ; Stroke/drug therapy* ; Thrombolytic Therapy/trends* ; Tissue Plasminogen Activator/therapeutic use*

To study the effect of modified Buyang Huanwu Decoction on the hemorrhagic transformation after intravenous thrombolysis of recombinant tissue type plasminogen activator(rt-PA) in patients with super early(onset time<4. 5 h) cerebral infarction. From March 2016 to July 2018,at the brain disease zone of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine,212 cases of super early cerebral infarction were selected and divided into two group according to the randomized complete blocks designs: control group(106 cases) and traditional Chinese medicine group(106 cases). The control group was treated with rt-PA intravenous thrombolysis,while the traditional Chinese medicine group was treated with modified Buyang Huanwu Decoction in addition to the therapy of the control group. Both groups were treated for 14 days. Neurological deficit score,serum matrix metalloproteinase-9(MMP-9),neuron specific enolase(NSE),vascular endothelial growth factor(VEGF) and plasma cellular fibronectin(c-FN) levels,the incidence of hemorrhagic transformation,clinical efficacy and adverse drug reactions before and after treatment were compared between the two groups. According to the findings,at the 14 thday after treatment,the rank sum test of the grade data showed that the clinical efficacy of the traditional Chinese medicine group was better than that of the control group(Z =-2. 033,P = 0. 042); on the basis of χ2 test,the total efficiency of the traditional Chinese medicine group was higher than that of the control group(χ2= 4. 895,P =0. 027); the hemorrhagic transformation rate of the traditional Chinese medicine group was lower than that of the control group within14 days of treatment(χ2= 3. 962,P = 0. 047). MMP-9 levels in the traditional Chinese medicine group were lower than those in the control group at the 3 rd,5 th,7 th,10 th,14 thd after treatment(t =-2. 474,-3. 022,-5. 163,-6. 998,-9. 821; P = 0. 014,0. 003,0,0,0). The improvement of c-FN,NSE,VEGF and NIHSS scores in the traditional Chinese medicine group was superior to that of the control group after 14 days of treatment(t =-2. 343,-3. 187,-2. 129,-3. 105; P = 0. 020,0. 002,0. 034,0. 002). No obvious adverse reactions of modified Buyang Huanwu Decoction were observed during 14 days of treatment. Modified Buyang Huanwu Decoction could reduce the expressions of MMP-9,c-FN,NSE and VEGF after rt-PA intravenous thrombolysis in patients with super early cerebral infarction,and decrease the hemorrhagic transformation rate after thrombolysis,with high safety.
Cerebral Infarction ; drug therapy ; Drugs, Chinese Herbal ; therapeutic use ; Fibronectins ; blood ; Humans ; Matrix Metalloproteinase 9 ; blood ; Medicine, Chinese Traditional ; Phosphopyruvate Hydratase ; blood ; Recombinant Proteins ; therapeutic use ; Thrombolytic Therapy ; Tissue Plasminogen Activator ; therapeutic use ; Vascular Endothelial Growth Factor A ; blood

INTRODUCTION: Telestroke allows for remote determination of suitability for treatment with thrombolysis in patients with acute ischaemic stroke. However, this approach is time-dependent and most centres have yet to achieve the recommended treatment times. We describe a quality improvement initiative aimed at improving the telestroke workflow and treatment times at our centre. METHODS: A multidisciplinary workgroup comprising clinicians, stroke case managers and radiology staff was formed to oversee the initiative. A phase-by-phase review of the existing workflow was done to identify the reasons for delay. Phase-specific measures were then introduced to address these delays, and a data-monitoring system was established to track the impact of these measures. The initiatives were implemented through four Plan-Do-Study-Act cycles. The door-to-needle (DTN) times for thrombolysis and clinical outcomes before and after the interventions were compared. RESULTS: A total of 104 patients were evaluated. The median DTN time improved from 96 minutes to 78 minutes post implementation of initiatives (p = 0.003). Fewer patients had symptomatic intracranial haemorrhages (8.5% vs. 24.2%; p = 0.03), and more patients had improvements in their National Institutes of Health Stroke Scale score (47.9% vs. 25.0%; p = 0.031) after the initiatives were introduced. CONCLUSION The quality improvement initiative resulted in a reduction in median DTN time. Our approach allowed for a systematic method to resolve delays within the telestroke workflow. This initiative is part of an ongoing effort aimed at providing thrombolysis safely to eligible patients in the shortest possible time.
Adult ; Aged ; Aged, 80 and over ; Emergency Service, Hospital ; organization & administration ; Female ; Humans ; Interprofessional Relations ; Intracranial Hemorrhages ; prevention & control ; Male ; Middle Aged ; Quality Improvement ; Severity of Illness Index ; Singapore ; Stroke ; therapy ; Telemedicine ; methods ; organization & administration ; standards ; Thrombolytic Therapy ; methods ; Time ; Tissue Plasminogen Activator ; therapeutic use ; Treatment Outcome

BACKGROUNDPrevention of osteonecrosis (ON) has seldom been addressed. The purpose of this study was to evaluate the effect of resveratrol on preventing steroid-induced ON in rabbits.

METHODSSeventy-two rabbits were divided into four groups: (1) NEC (ON) group: thirty rabbits were treated with lipopolysaccharide (LPS) once, then with methylprednisolone (MPS) daily for 3 days; (2) PRE (prevention) group: thirty rabbits were given one dose of LPS, then MPS daily for 3 days, and resveratrol on day 0 and daily for 2 weeks; (3) RES (resveratrol) group: six rabbits were given resveratrol for 2 weeks but without LPS/MPS; (4) CON (control) group: six rabbits were given alcohol for 2 weeks but without LPS/MPS. Levels of plasma tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), thrombomodulin (TM), vascular endothelial growth factor (VEGF), maximum enhancement (ME) by magnetic resonance imaging, and ON incidence were evaluated.

RESULTSThe PRE group had a lower ON incidence than the NEC group, but with no significant differences at 2 weeks and 12 weeks. The RES and CON groups did not develop ON. TM and VEGF were significantly higher in the NEC group compared with the PRE group at weeks 1, 2, and 4 (TM: 1 week, P = 0.029; 2 weeks, P = 0.005; and 4 weeks, P = 0.047; VEGF: 1 week, P = 0.039; 2 weeks, P = 0.021; 4 weeks, P = 0.014), but the difference disappeared at 12 weeks. The levels of t-PA and PAI-1 were not significantly different between the NEC and PRE groups. The TM, t-PA, PAI-1, and VEGF concentrations in the RES and CON groups did not change over time. Compared to the baseline, ME in the NEC group decreased significantly (P = 0.025) at week 1, increased significantly (P = 0.021) at week 2, and was decreased at week 12. The variance was insignificant in the PRE group.

CONCLUSIONSResveratrol may improve blood supply to bone in a rabbit model of ON of the femoral head via anti-inflammatory effects to protect the vascular endothelium and reduce thrombosis.

Animals ; Disease Models, Animal ; Femur Head Necrosis ; chemically induced ; prevention & control ; Lipopolysaccharides ; toxicity ; Magnetic Resonance Imaging ; Methylprednisolone ; toxicity ; Plasminogen Activator Inhibitor 1 ; blood ; Rabbits ; Stilbenes ; pharmacology ; therapeutic use ; Thrombomodulin ; blood ; Tissue Plasminogen Activator ; blood ; Vascular Endothelial Growth Factor A ; blood

OBJECTIVETo investigate factors related to hemorrhagic transformation and favorable outcomes in wake-up ischemic stroke (WUIS) patients undergoing intravenous thrombolytic therapy.

METHODSClinical data of 600 patients undergoing multimodal image-guided intravenous recombinant tissue plasminogen activator (rt-PA) therapy in Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine center from May 2009 to May 2015 were retrospectively analyzed. Among 600 patients, 68 were diagnosed as WUIS including 17 cases aged 80 or older. Hemorrhagic transformation within the first 24 h after thrombolysis was assessed according to ECASS II criteria. Favorable outcome was defined as three-month modified Rankin Scale (mRS) 0-3. Univariate and binary logistic regression were used to analyze the risk factors of hemorrhagic transformation and poor clinical outcomes in WUIS patients.

RESULTSUnivariate analysis showed that WUIS patients aged ≥ 80 years had a lower rate in males (41.2% vs 76.5%, P=0.007), smokers (11.8% vs 43.1%, P=0.019) and favorable outcome (52.9% vs 78.4%, P=0.043); and a higher rate of cardiac embolism (64.7% vs 35.3%, P=0.034) compared with those aged <80 years. Binary logistic regression showed that age was not an independent risk factor for favorable outcome (OR=0.524, 95% CI:0.141-1.953, P=0.336) or hemorrhagic transformation (OR=1.039, 95% CI: 0.972-1.111, P=0.262).

CONCLUSIONOlder age is not related to the favorable outcome or hemorrhagic transformation in WUIS patients undergoing multimodal image-guided intravenous thrombolytic therapy.

Administration, Intravenous ; Age Factors ; Aged ; Aged, 80 and over ; Brain Ischemia ; diagnosis ; drug therapy ; Female ; Fibrinolytic Agents ; administration & dosage ; therapeutic use ; Humans ; Male ; Recombinant Proteins ; administration & dosage ; therapeutic use ; Retrospective Studies ; Risk Factors ; Stroke ; diagnosis ; drug therapy ; Thrombolytic Therapy ; Tissue Plasminogen Activator ; administration & dosage ; therapeutic use ; Treatment Outcome

OBJECTIVETo assess brush sign (BS) on susceptibility-weighted imaging (SWI) in prediction of hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS) after intravenous thrombolysis(IVT).

METHODSPatients with acute cerebral ischemic stroke, who had major cerebral artery occlusion (internal carotid artery, middle cerebral artery M1 and M2), treated with intravenous recombinant tissue plasminogen activator (rt-PA) from August 2009 to October 2014 in the Second Affiliated Hospital, Zhejiang University School of Medicine, were enrolled in the study. All patients underwent SWI scanning. The asymmetry index (AI) was defined as the difference of intensity between ischemic and normal hemispheres on the SWI phase map; according to AI values patients were divided into 3 groups: BS=0(n=9), BS=1 (n=39) and BS=2 (n=18). The relationships between BS and HT and the clinical outcome among the 3 groups were analyzed.

RESULTSSixty-six patients aged 68 ± 13 years were included in the study, including 44 males (67%) and 22 females (33%), and 44 (67%) with acute ischemic stroke. The mean pre-treatment National Institutes of Health Stroke Scale (NIHSS) score was 13 (6-17), and the onset to needle time was (252 ± 88) min. Twenty-six (39.4%) patients had HT, including 18 cases (27.3%) with HI and 8 cases (12.1%) with PH; BS was observed more frequently in HT group than non-HT group. Binary logistic regression analysis showed that BS was independently associated with HT of patients with acute ischemic stroke following IVT (OR=2.589, 95% CI: 1.080-6.210, P=0.033). In those without reperfusion after IVT, patients with higher BS grade had higher HT rate (P=0.023).

CONCLUSIONBrush sign on SWI can be used for predicting hemorrhagic transformation after intravenous thrombolysis in patients with acute ischemic stroke.

Administration, Intravenous ; Aged ; Aged, 80 and over ; Brain Ischemia ; diagnosis ; drug therapy ; Carotid Artery, Internal ; pathology ; Diagnostic Imaging ; Female ; Humans ; Male ; Middle Aged ; Recombinant Proteins ; administration & dosage ; therapeutic use ; Stroke ; diagnosis ; drug therapy ; Thrombolytic Therapy ; Tissue Plasminogen Activator ; administration & dosage ; therapeutic use ; Treatment Outcome ; United States