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Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis

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Journal of Pharmaceutical Analysis 2023年第10期13卷 1135-1152页

作者： Jia-Jia Zhang Chang-Geng Song Miao Wang Gai-Qin Zhang Bin Wang Xi Chen Peng Lin Yu-Meng Zhu Zhi-Chuan Sun Ya-Zhou Wang Jian-Li Jiang Ling Li Xiang-Min Yang Zhi-Nan Chen National Translational Science Center for Molecular Medicine&Department of Cell Biology Fourth Military Medical UniversityXi'an710032China Department of neurology Xijing HospitalFourth Military Medical UniversityXi'an710032China Key laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials ScienceNorthwest UniversityXi'an710032China Department of Neurosurgery Xi'an Daxing HospitalXi'an710032China Department of Neurobiology and Institute of Neurosciences Collaborative Innovation Center for Brain ScienceSchool of Basic MedicineFourth Military Medical UniversityXi'an710032China

Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/b-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knockdown.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/b-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy

关键词： Morphine tolerance Mu-opioid receptor Endocytosis Monoclonal antibody Physical dependence

Needle Sensation and Personality Factors Influence Therapeutic Effect of Acupuncture for Treating Bell＇s Palsy： A Secondary Analysis of a Multicenter Randomized Controlled Trial

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Chinese Medical Journal 2016年第15期129卷 1789-1794页

作者： Chen-Yan Zhang Sha-Bei Xu Bo Huang Peng Du Gui-Bin Zhang Xiang Luo Guang-Ying Huang Min-Jie Xie Zong-Kui Zhou Wei Wang School of Psychology Central China Normal University Wuhan Hubei 430079 China Key laboratory of Adolescent Cyberpsychology and Behavior (CCNU) Ministry of Education Wuhan Hubei 430079 China Department of neurology Tongji Hospital Tongji Medical CoLlege Huazhong University of Science and Technology Wuhan Hubei 430030 China Department of neurology Zhongshan Hospital Fudan University Shanghai 200032 China Department of neurology Xiangyang Hospital Affiliated to Hubei University of Medicine Xiangyang Hubei 441000 China Institute of Integrated Traditional Chinese and Western Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 China Key laboratory of Neurological Diseases of Chinese Ministry of Education Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 China

Background： It has not been solved what kind of needle sensation might influence outcomes of acupuncture treatment. Effects of personality factors on the therapeutic effect of acupuncture have not been investigated. This study aimed to find the effects of the traits of personality on the objective outcome when different acupuncture techniques were used in treating patients with Bell＇s palsy. Methods： We performed a secondary analysis of a prospective multicenter randomized controlled trial of acupuncture for Bell＇s palsy. Patients were randomly assigned to the de qi and control groups, respectively. The primary outcome was facial nerve function at month 6. The intensity of each needle sensation was rated by a visual analog scale. Psychosocial thctors were assessed by the pretreatment mediator questionnaire： 16 Personality Factor Questionnaire （16PF） was used tbr assessing personality factors and digit cancellation test for assessing attention. Results： After 6 months, patients in the de qi group had better facial function （adjusted odds ratio [OR]： 4.16, 95% confidence interval [CI]： 2.23-7.78）. Path analysis showed that intensity of needle sensation of fullness had direct effect on House-Brackmann （HB） score at month 6. In de qi group, the low HB score on day I （OR： 0.13, 95% （_7： 0.03-0.45） and the low Social Boldness score （OR： 0.63, 95% CI： 0.41-0.97） in 16PF were associated with better facial function. In control group, low HB score on day 1 （OR： 0.25, 95% CI： 0.13-0.50）, low Vigilance score （OR： 0.66, 95% CI： 0.50-0.88）, and high Tension score （OR： 1.41,95% CI： 1.12 1.77） in 16PF were related to better facial function. Conclusions： The needle sensation of fullness could predict better facial function and personality traits might influence outcomes of acupuncture treatment. Both of them should be considered seriously in acupuncture treatment and research.

关键词： 16 Personality Factor Questionnaire Bell＇s Palsy De Qi Needle Sensation

Antiplatelet Therapy in Acute Mild-Moderate Ischemic Stroke(ATAMIS):a parallel,randomised,open-label,multicentre,prospective study

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Stroke & Vascular neurology 2018年第4期3卷 263-267页

作者： Xiaowen Hou Xiaoqiu Li Xinhong Wang Huisheng Chen Department of neurology General Hospital of Shen-Yang Military RegionShenyangChina

Background A recent study shows that dual antiplatelet therapy with clopidogrel plus aspirin is superior to aspirin monotherapy for minor stroke,which is defined as a National Institutes of Health Stroke Scale(NIHSS)score of≤3.However,acute mild-moderate ischaemic stroke(4≤NIHSS≤10)still needs aggressive antiplatelet intervention to prevent deterioration and recurrence of stroke.The efficacy and safety of dual antiplatelet therapy versus aspirin monotherapy in the population are not clear.A multicentre clinical trial is designed to evaluate the efficacy and safety of clopidogrel plus aspirin therapy versus aspirin monotherapy within 48 hours of symptom onset of mild-moderate ischaemic stroke.Methods/Design The study is a randomised,open-label,multicentre,prospective trial with a target enrolment of 2700 patients from 60 centres in Northeast China.A treatment allocation identification number to each enrolled patient will be provided by a random number generator.The follow-up time for the clopidogrel plus aspirin and aspirin monotherapy groups is 90 days.The primary efficacy endpoint is a stroke progression event,which is defined as≥4 point increase in the NIHSS score in 48 hours.The second efficacy endpoints include new ischaemic stroke within 90 days,change in the NIHSS score within 14 days,modified Rankin Scale score on day 90 and other vascular or death events within 90 days.The safety endpoints include mucocutaneous haemorrhage,organ haemorrhage and intracranial haemorrhage,adverse events and severe adverse events.χ^(2)test,t-test(or Mann-Whitney test),survival analysis and Cox proportional hazards models will be conducted.The findings of the study may provide an important evidence for clinical practice for these patients.Discussion The trial will be conducted under a rational design and will provide valuable evidence on the appropriate treatment for this population.Ethics and dissemination The study was reviewed and approved by the Ethics Committee of the General Hospital of Shen-Yang Military Region(no K(201

关键词： prospective centre random

Nerve biopsy findings contribute to diagnosis of multiple mononeuropathy: 78% of findings support clinical diagnosis

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Neural Regeneration Research 2015年第1期10卷 112-118页

作者： Ying-shuang Zhang A-ping Sun Lu Chen Rong-fang Dong Yan-feng Zhong Jun Zhang Department of neurology Peking University Third Hospital Department of Pathology Peking University Health Science Center

Multiple mononeuropathy is an unusual form of peripheral neuropathy involving two or more nerve trunks. It is a syndrome with many different causes. We reviewed the clinical, electrophysi- ological and nerve biopsy findings of 14 patients who suffered from multiple mononeuropathy in our clinic between January 2009 and June 2013. Patients were diagnosed with vasculitic neurop- athy （n = 6）, perineuritis （n = 2）, chronic inflammatory demyelinating polyradiculoneuropathy （n = 2） or Lewis-Sumner syndrome （n = 1） on the basis of clinical features, laboratory data, elec- trophysiological investigations and nerve biopsies. Two patients who were clinically diagnosed with vasculitic neuropathy and one patient who was clinically diagnosed with chronic inflamma- tory demyelinating polyradiculoneuropathy were not confirmed by nerve biopsy. Nerve biopsies confirmed clinical diagnosis in 78.6% of the patients （11/14）. Nerve biopsy pathological diagno- sis is crucial to the etiological diagnosis of multiple mononeuropathy.

关键词： nerve regeneration peripheral nerve regeneration multiple mononeuropathy asym-metrical sensory-motor polyneuropathy systemic vasculitic neuropathy nonsystemic vasculiticneuropathy perineuritis inflammatory demyelinating polyradiculoneuropathy Lewis-Sumner syn-drome sural nerve biopsy skin biopsy peripheral nervous system

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缺血性卒中血流再通时代的脑细胞保护新策略

Science Bulletin 2022年第23期67卷 2372-2375页

作者：吴迪李明 Marc Fisher 吉训明 Department of neurology and China-America Institute of Neuroscience Xuanwu HospitalCapital Medical UniversityBeijing 100053China Bejing Institute of Brain Disorders Capital Medical UniversityBeijing 100053China Departmentof neurology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBoston 02215USA

Acute ischemic stroke (AIS) treatment has been advanced by the development of recanalization therapies, especially endovascular thrombectomy. Thrombectomy has led to a better prognosis at 90 d not only in stroke patients because of large-vessel occlusion in the proximal anterior cerebral circulation, but also in those due to basilar-artery occlusion [1]. Thus, the number of eligible patients for revascularization will continue to increase.

关键词：缺血性卒中 occlusion Acute

Impact of extended nursing model after multi-disciplinary treatment on young patient with post-stroke

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World Journal of Clinical Cases 2023年第14期11卷 3148-3157页

作者： Xiao-Yan Xu Zhi-Juan Pang Mei-Hui Li Kun Wang Jie Song Yue Cao Mao Fang Second Ward Department of NeurologyThe Second Affiliated Hospital of Qiqihar Medical CollegeQiqihar 161006Heilongjiang ProvinceChina Department of Rehabilitation Medicine The Second Affiliated Hospital of Qiqihar Medical CollegeQiqihar 161006Heilongjiang ProvinceChina

BACKGROUND Stroke has become one of the most serious life-threatening diseases due to its high morbidity,disability,recurrence and mortality rates.AIM To explore the intervention effect of multi-disciplinary treatment(MDT)extended nursing model on negative emotions and quality of life of young patients with post-stroke.METHODS A total of 60 young stroke patients who were hospitalized in the neurology department of our hospital from January 2020 to December 2021 were selected and randomly divided into a control group and an experimental group,with 30 patients in each group.The control group used the conventional care model and the experimental group used the MDT extended nursing model.After the inhospital and 3-mo post-discharge interventions,the differences in negative emotions and quality of life scores between the two groups were evaluated and analyzed at the time of admission,at the time of discharge and after discharge,respectively.RESULTS There are no statistically significant differences in the negative emotions scores between the two groups at admission,while there are statistically significant differences in the negative emotions scores within each group at admission and discharge,at discharge and post-discharge,and at discharge and post-discharge.In addition,the negative emotions scores were all statistically significant at discharge and after discharge when compared between the two groups.There was no statistically significant difference in quality of life scores at the time of admission between the two groups,and the difference between quality of life scores at the time of admission and discharge,at the time of discharge and post-discharge,and at the time of admission and post-discharge for each group of patients was statistically significant.CONCLUSION The MDT extended nursing mode can improve the negative emotion of patients and improve their quality of life.Therefore,it can be applied in future clinical practice and is worthy of promotion.

关键词： Multi-disciplinary treatment extended nursing model Young people with post-stroke Negative emotions Quality of life

Echinacoside Protects Against MPP+-Induced Neuronal Apoptosis via ROS/ATF3/CHOP Pathway Regulation

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Neuroscience Bulletin 2016年第4期32卷 349-362页

作者： Qing Zhao Xiaoyan Yang Dingfang Cai Ling Ye Yuqing Hou Lijun Zhang Jiwei Cheng Yuan Shen Kaizhe Wang Yu Bai Department of neurology Putuo HospitalShanghai University of Traditional Chinese Medicine Department of Emergency Internal Medicine Putuo HospitalShanghai University of Traditional Chinese Medicine laboratory of neurology Institute of Integrative MedicineZhongshan Hospital Fudan University Department of Integrative Medicine Zhongshan HospitalFudan University Center for Translational Neurodegeneration and Regenerative Therapy Shanghai Tenth People’s Hospital Affiliated with Tongji University School of Medicine Department of Immunology Tongji University School of Medicine

Echinacoside （ECH） is protective in a mouse model of Parkinson＇ s disease （PD） induced by 1-methyl-4- phenylpyridinium ion （MPP＋）. To investigate the mechanisms involved, SH-SYSY neuroblastoma ceils were treated with MPP＋ or a combination of MPP＋ and ECH, and the expression of ATF3 （activating transcription factor 3）, CHOP （C/EBP-homologous protein）, SCNA （synuclein alpha）, and GDNF （glial cell line-derived neurotrophic factor） was assessed. The results showed that ECH significantly improved cell survival by inhibiting the generation of MPP＋-induced reactive oxygen species （ROS）. In addition, ECH suppressed the ROS and MPP＋- induced expression of apoptotic genes （ATF3, CHOP, and SCNA）. ECH markedly decreased the MPP＋-induced cas- pase-3 activity in a dose-dependent manner. ATF3- knockdown also decreased the CHOP and cleaved caspase- 3 levels and inhibited the apoptosis induced by MPP＋. Interestingly, ECH partially restored the GDNF expression that was down-regulated by MPP＋. ECH also improved dopaminergic neuron survival during MPP＋ treatment and protected these neurons against the apoptosis induced by MPTP. Taken together, these data suggest that the ROS/ ATF3/CHOP pathway plays a critical role in mechanisms by which ECH protects against MPP＋-induced apoptosis in PD.

关键词： Echinacoside Parkinson＇s disease 1-Methyl-4-phenylpyridinium ion. Reactive oxygen species ATF3 CHOP

A 65-year-old man with infratentorial diffuse encephalopathy and hydrocephalus

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Chinese Medical Journal 2011年第11期124卷 1758-1760页

作者： FENG Yan-qing GUO Ning LIU Jun-xiu LAI Rong CHEN Xi HUANG Fan Department of neurology First Affiliated Hospital of Sun Yat-senUniversity Guangzhou Guangdong 510080 China

Tuberculous encephalopathy （TBE） is an important diagnosis in countries with a high prevalence of tuberculosis. TBE is a life-threatening condition but rarely reported in the modern literature. We reported a case of a man with extensive parenchymal lesions involving the brainstem and right cerebellar hemisphere that resolved after treatment. The clinical, laboratory and pathological features of this case are highlighted and the pathogenesis is discussed.

关键词： tuberculous encephalopathy hydrocephalus

Fatigue correlates with sleep disturbances in Parkinson disease

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Chinese Medical Journal 2021年第6期134卷 668-674页

作者： Xiang-Yang Cao Jin-Ru Zhang Yun Shen Cheng-Jie Mao Yu-Bing Shen Yu-Lan Cao Han-Ying Gu Fen Wang Chun-Feng Liu Department of neurology and Suzhou Clinical Research Center of Neurological Disease The Second Affiliated Hospital of Soochow UniversitySuzhouJiangsu 215004China Department of neurology The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai’anHuai’anJiangsu 223002China Jiangsu Key laboratory of Neuropsychiatric Diseases and Institute of Neuroscience Soochow UniversitySuzhouJiangsu 215123China Department of Psychiatry Johns Hopkins University School of MedicineBaltimoreMDUSA

Background: Many Parkinson disease (PD) patients complain about chronic fatigue and sleep disturbances during the night. The objective of this study is to determine the relationship between fatigue and sleep disturbances by using polysomnography (PSG) in PD patients.Methods: Two hundred and thirty-two PD patients (152 with mild fatigue and 80 with severe fatigue) were recruited in this study. Demographic information and clinical symptoms were collected. Fatigue severity scale (FSS) was applied to evaluate the severity of fatigue, and PSG was conducted in all PD patients. FSS ≥4 was defined as severe fatigue, and FSS <4 was defined as mild fatigue. Multivariate logistic regression and linear regression models were used to investigate the associations between fatigue and sleep disturbances.Results: Patients with severe fatigue tended to have a longer duration of disease, higher Unified Parkinson Disease Rating Scale score, more advanced Hoehn and Yahr stage, higher daily levodopa equivalent dose, worse depression, anxiety, and higher daytime sleepiness score. In addition, they had lower percentage of rapid eye movement (REM) sleep (P = 0.009) and were more likely to have REM sleep behavior disorder (RBD) (P = 0.018). Multivariate logistic regression analyses found that the presence of RBD and proportion of REM sleep were the independent predictors for fatigue. After the adjustment of age, sex, duration, body mass index, severity of disease, scores of Hamilton Rating Scale for Depression, Hamilton Anxiety Rating Scale, and other sleep disorders, proportion of REM sleep and degree of REM sleep without atonia in patients with PD were still associated with FSS score.Conclusion: Considering the association between fatigue, RBD, and the altered sleep architecture, fatigue is a special subtype in PD and more studies should be focused on this debilitating symptom.

关键词： Fatigue Parkinson disease Polysomnography Sleep behavior disorder