2-Methyl-5H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine, an edaravone analog, exerts neuroprotective effects against acute ischemic injury via inhibiting oxidative stress

Oxidative stress plays an indispensable role in the pathogenesis of cerebral ischemia.Inhibiting oxidative stress has been considered as an effective approach for stroke treatment.Edaravone,a free radical scavenger,has been shown to prevent cerebral ischemic injury.However,the clinical efficacy of edaravone is limited because it has a low scavenging activity for superoxide anions（O_2-（·-））.Here,we report that 2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine,a novel small-molecule compound structurally related to edaravone,showed a stronger inhibitory effect on oxidative stress in vitro.In vivo,2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine reversed transient middle cerebral artery occlusion-induced dysfunctions of superoxide dismutases and malondialdehyde,two proteins crucial for oxidative stress,suggesting a strengthened antioxidant system.Moreover,2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine decreased blood brain barrier permeability.Then,we found that 2-methyl-5 Hbenzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine had a stronger neuroprotective effect than edaravone.More importantly,2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine decreased not only infarct size and neurological deficits in the acute phase but also modified neurological severity score and escape latency in Morris water maze task in the delayed period,indicating enhanced neuroprotection,sensorimotor function and spatial memory.Together,these findings suggest that 2-methyl-5 H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine could be a preferable option for stroke treatment.

年龄≤40岁的乳腺恶性叶状肿瘤患者临床特征及预后影响因素

目的:探讨年龄≤40岁的乳腺恶性叶状肿瘤(malignant phyllodes tumors,MPTs)患者临床特征及预后因素。方法:回顾性分析2006年1月至2020年10月188例于天津医科大学肿瘤医院收治的乳腺MPTs患者的临床资料,按照年龄≤40岁和年龄>40岁分为年轻组54例和年长组134例。采用χ^(2)检验或Fisher确切概率法、Kaplan–Meier法、Cox比例风险回归模型进行统计学分析。结果:年轻组乳腺MPTs患者5年和10年无复发生存(recurrence-free survival,RFS)率分别为55.8%和46.6%。年轻组患者的肿瘤直径>5 cm占59.3%(32/54)、年长组的占35.8%(48/134),两组比较差异具有统计学意义(P=0.031);年轻组患者的手术切缘<1 cm和术后化疗的比例分别为50.0%(27/54)和20.4%(11/54),较年长组的35.8%(48/134)和7.5%(10/134)高(P=0.048,P=0.024);年轻组中的患者行肿块切除术且保证手术切缘≥1 cm与乳腺全乳切除术相比,RFS差异无统计学意义(P=0.410)。Cox比例风险回归模型多因素分析显示,年龄(P=0.034)和手术切缘(P<0.001)是影响术后RFS的独立预后因素。结论:年龄和手术切缘影响乳腺MPTs预后,年龄≤40岁患者较>40岁预后更差,对于年龄≤40岁患者在保证手术切缘至少1 cm情况下行肿块切除术可行。

Application for Optimization of New Soft Magnetic Material Motor by Taguchi Method

The application of new soft magnetic materials in permanent magnet motor can effectively reduce the loss of motor and improve the efficiency of motor. Taguchi method is a local multivariable and multi-objective optimization method widely used in various engineering problems, which can effectively improve the efficiency of engineering optimization. In this paper, based on a 25 kW, 1700 r/min three-phase permanent magnet motor, the relevant motor model is established in the finite element simulation software, and the relevant simulation analysis is carried out. Combined with Taguchi method optimization, the local optimal structure scheme is obtained. Through optimization, the motor can maintain high efficiency, reduce the cogging torque of the motor by 53.45%, reduce the torque ripple by 36.79%, and increase the torque generated by the permanent magnet per unit mass by 21.42%. Through this optimization, the overall performance of the motor has been significantly improved. The research content of this paper verifies the feasibility of the application of Taguchi method in the optimization of new soft magnetic material motor, provides a new idea for the optimization design of new soft magnetic material motor, and also provides a certain reference for the local multi-objective optimization of the electromagnetic structure of other similar motors.

Preclinical evaluation of ZL006-05,a new antistroke drug with fast-onset antidepressant and anxiolytic effects

Background Poststroke depression and anxiety,independent predictor of poor functional outcomes,are common in the acute phase of stroke.Up to now,there is no fast-onset antidepressive and anxiolytic agents suitable for the management of acute stroke.ZL006-05,a dual-target analgesic we developed,dissociates nitric oxide synthase from postsynaptic density-95 while potentiatesα2-containingγ-aminobutyric acid type A receptor.This study aims to determine whether ZL006-05 can be used as an antistroke agent with fast-onset antidepressant and anxiolytic effects.Methods Photothrombotic stroke and transient middle cerebral artery occlusion were induced in rats and mice.Infarct size was measured by TTC(2,3,5-Triphenyltetrazolium chloride)staining or Nissl staining.Neurological defects were assessed by four-point scale neurological score or modified Neurological Severity Scores.Grid-walking,cylinder and modified adhesive removal tasks were conducted to assess sensorimotor functions.Spatial learning was assessed using Morris water maze task.Depression and anxiety were induced by unpredictable chronic mild stress.Depressive behaviours were assessed by tail suspension,forced swim and sucrose preference tests.Anxiety behaviours were assessed by novelty-suppressed feeding and elevated plus maze tests.Pharmacokinetics,toxicokinetics and long-term toxicity studies were performed in rats.Results Administration of ZL006-05 in the acute phase of stroke attenuated transient and permanent ischaemic injury and ameliorated long-term functional impairments significantly,with a treatment window of 12 hours after ischemia,and reduced plasminogen activato-induced haemorrhagic transformation.ZL006-05 produced fast-onset antidepressant and anxiolytic effects with onset latency of 1 hour in the normal and CMS mice,had antidepressant and anxiolytic effects in stroke mice.ZL006-05 crossed the blood-brain barrier and distributed into the brain rapidly,and had a high safety profile in toxicokinetics and long-term toxicological studies.Conclusion ZL006-05 is a new neuroprotectant with fast-onset antidepressant and anxiolytic effects and has translational properties in terms of efficacy,safety and targeting of clinical issues.

Phase Evolution of Cu--S System in Ethylene Glycol Solution： the Effect of Anion and PVP on the Transformation of Thiourea

The transformation mechanisms of thiourea in ethylene glycol solution was systematically investigated in this report, which shows the transformation process is influenced by the anion （NO3-, CI-, Br-） and polyvinylpyrroli- done （PVP）. Thiourea （tu） isomerizes into ammonium thiocyanate when NO3- is present, regardless of the existence of PVP. For CI-, thiourea coordinates with copper anion to form [Cu（tu）]Clol/2H20 complex whether PVP is pre- sent. When it comes to Br-, thiourea hydrolyzes in the cooperation of PVP or coordinates with copper anion to form [Cu（tu）Br]. 1/2H20 complex without PVP. The different transformation routes will lead to different phase evolution of the Cu--S system. This work may provide a new understanding of the transformation of thiourea in ethylene glycol solution. The optical properties of the as-prepared copper sulfides exhibit significant stoichiometry- dependent features which may have potential applications in semiconductor photovoltaic devices.