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Neuroscience Bulletin 2014年第1期30卷 21-32页

作者： Feng Jiang Li-Ming Hua Yun-Lu Jiao Pin Ye Jin Fu Zhi-Jun Cheng Gang Ding Yong-Hua Ji xinhua Hospital (chongming) Affiliated to shanghai Jiao Tong University School of Medicine shanghai chongming xinhua translational medical institute for cancer pain Lab of Neuropharmacology and Neurotoxicology Shanghai University

The mammalian target of rapamycin （mTOR） pathway is essential for maintenance of the sensitivity of certain adult sensory neurons. Here, we investigated whether the mTOR cascade is involved in scorpion envenomation-induced pain hypersensitivity in rats. The results showed that intraplantar injection of a neurotoxin from Buthus martensii Karsch, BmK I （10 pg）, induced the activation of mTOR, as well as its downstream molecules p70 ribosomal S6 protein kinase （p70 S6K） and eukaryotic initiation factor 4E-binding protein 1 （4E-BP1）, in lumbar 5-6 dorsal root ganglia neurons on both sides in rats. The activation peaked at 2 h and recovered 1 day after injection. Compared with the control group, the ratios of p-mTOR/p-p70 S6K/p-4E- BP1 in three types of neurons changed significantly. The cell typology of p-mTOR/p-p70 S6K/p-4E-BP1 immuno-reactive neurons also changed. Intrathecal administration of deforolimus, a specific inhibitor of mTOR, attenuated BmK I-induced pain responses （spontaneous flinching, paroxysmal pain-like behavior, and mechanical hypersensitivity）. Together, these results imply that the mTOR signaling pathway is mobilized by and contributes to experimental scorpion sting-induced pain.

关键词： BmK I mTOR p70 ribosomal S6 protein kinase 4E-binding protein 1 pain dorsal rootganglion

Epigallocatechin-3-gallate induces apoptosis, inhibits proliferation and decreases invasion of glioma cell

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Neuroscience Bulletin 2014年第1期30卷 67-73页

作者： Hong Li Zhe Li Ya-Ming Xu Yue Wu Kang-Kang Yu Can Zhang Yong-Hua Ji Gang Ding Fu-Xue Chen School of Life Sciences Shanghai University xinhua Hospital (chongming) Affiliated to shanghai Jiao Tong University medical School xinhua translational institute for cancer pain

Epigallocatechin-3-gallate （EGCG）, a major polyphenol in green tea, has been considered a potential therapeutic and chemopreventive agent for cancer. Glioma is a malignant tumor with high mortality but effective therapy has not yet been developed. In this study, we found that EGCG induced apoptosis in U251 glioma cells via the laminin receptor （molecular weight 67kDa） in a time- and dose-dependent manner, decreased their invasiveness and inhibited their proliferation. The mitogen-activated protein kinase pathway was shown to be involved in glioma cell apoptosis and proliferation. Furthermore, the mRNA levels of matrix metalloproteinase （MMP）-2 and MMP-9 were reduced after EGCG treatment. These results suggest that EGCG has important therapeutic effects with low toxicity and side-effects, and could be used in cancer chemoprevention.

关键词： glioma epigallocatechin-3-gallate proliferation apoptosis invasion

Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes

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Neuroscience Bulletin 2014年第4期30卷 697-710页

作者： Heng Zhang Hui Ji Zhirui Liu Yonghua Ji Xinmin You Gang Ding Zhijun Cheng Lab of Neuropharmacology and Neurotoxicology Shanghai University xinhua Hospital (chongming) Shanghai Jiaotong University School of Medicine xinhua translational institute for cancer pain

Bupivacaine ranks as the most potent and efficient drug among class I local anesthetics, but its high potential for toxic reactions severely limits its clinical use. Although bupivacaine-induced toxicity is mainly caused by substantial blockade of voltage-gated sodium channels （VGSCs）, how these hydrophobic molecules interact with the receptor sites to which they bind remains unclear. Navl.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacaine- triggered arrhythmia. Here, we investigated the effect of bupivacaine on Navl.5 within the clinical concentration range. The electrophysiological measurements on Navl.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltage- and concentration-dependent blockade on the peak of/Na and the half-maximal inhibitory dose was 4.51 pmol/L. Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Navl.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nay1.5 but also accelerated the development of its open-state slow inactivation. These results extend our knowledge of the action of bupivacaine on cardiac sodium channels, and therefore contribute to the safer and more efficient clinical use of bupivacaine.

关键词： bupivacaine Nav1.5 voltage-dependentblockade inactivated state

Pharmacological kinetics of BmK AS, a sodium channel site 4-specific modulator on Na_v1.3

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Neuroscience Bulletin 2012年第3期28卷 209-221页

作者： Zhi-Rui Liu Jie Tao Bang-Qian Dong Gang Ding Zhi-Jun Cheng Hui-Qiong He Yong-Hua Ji Laboratory of Neuropharmacology and Neurotoxicology Shanghai University Shanghai 200444 China xinhua translational institute for cancer pain Chongming Shanghai 202151 China

Objective In this study, the pharmacological kinetics of Buthus martensi Karsch （BmK） AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Nav1.3 expressed in Xenopus oocytes. Methods Two-electrode voltage clamp was used to record the whole-cell sodium current. Results The peak currents of Nav1.3 were depressed by BmK AS over a wide range of concentrations （10, 100, and 500 nmol/L）. Most remarkably, BmK AS at 100 nmol/L hyperpolarized the voltage-dependence and increased the voltage-sensitivity of steady-state activation/inactivation. In addition, BmK AS was capable of hyperpolarizing not only the fast inactivation but also the slow inactivation, with a greater preference for the latter. Moreover, BmK AS accelerated the time constant and increased the ratio of recovery in Nav1.3 at all concentrations. Conclusion This study provides direct evidence that BmK AS facilitates steady-state activation and inhibits slow inactivation by stabilizing both the closed and open states of the Nav1.3 channel, which might result from an integrative binding to two receptor sites on the voltage-gated sodium channels. These results may shed light on therapeutics against Nav1.3-targeted pathology.

关键词： VGSC subtype Nav1.3 VGSC site 4-specific modulator BmKAS

SCN9A Epileptic Encephalopathy Mutations Display a Gain-offunction Phenotype and Distinct Sensitivity to Oxcarbazepine

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Neuroscience Bulletin 2020年第1期36卷 11-24页

作者： Shuzhang Zhang Zhiping Zhang Yuan Shen Yudan Zhu Kun Du Jingkang Guo Yonghua Ji Jie Tao institute of Biomembrane and Biopharmaceutics Shanghai UniversityShanghai 200444China Central Laboratory and Department of Neurology Putuo HospitalShanghai University of Traditional Chinese MedicineShanghai 200062China Department of Clinical Laboratory Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 202150China xinhua translational institute for cancer pain Xinhua Hospital Chongming BranchShanghai 202150China Putuo Clinical medical School Anhui Medical UniversityShanghai 200062China

Genetic mutants of voltage-gated sodium channels(VGSCs)are considered to be responsible for the increasing number of epilepsy *** research has indicated that mutations of one of the VGSC genes,SCN9A(Navl.7),result in febrile seizures and Dravet syndrome in *** these recent efforts,the electrophysiological basis of SCN9A mutations remains ***,we performed a genetic screen of patients with febrile seizures and identified a novel missense mutation of SCN9A(W1150R).Electrophysiological characterization of different SCN9A mutants in HEK293T cells,the previously-reported N641Y and K655R variants,as well as the newly-found W1150R variant,revealed that the current density of the W1150R and N641Y variants was significantly larger than that of the wild-type(WT)*** time constants of recovery from fast inactivation of the N641Y and K655R variants were markedly lower than in the WT *** W1150R variant caused a negative shift of the G-V curve in the voltage dependence of steady-state *** mutants displayed persistent currents larger than the WT *** addition,we found that oxcarbazepine(OXC),one of the antiepileptic drugs targeting VGSCs,caused a significant shift to more negative potential for the activation and inactivation in WT and mutant ***-induced inhibition of currents was weaker in the W1150R variant than in the ***,with administering OXC the time constant of the N641Y variant was longer than those of the other two SCN9A *** all,our results indicated that the point mutation W1150R resulted in a novel gain-of-function *** findings indicated that SCN9A mutants contribute to an increase in seizure,and show distinct sensitivity to OXC.

关键词： Voltage-gated sodium channel SCN9A Epilepsy Electrophysiological function Oxcarbazepine Sensitivity Introduction

Distribution and Functional Characteristics of Voltage-Gated Sodium Channels in Immature Cochlear Hair Cells

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Neuroscience Bulletin 2020年第1期36卷 49-65页

作者： You Zhou Chenchen Xia Manli Yi Xueling Wang Hao Wu Yonghua Ji Department of Otolaryngology-Head and Neck Surgery Ninth People’s HospitalShanghai Jiaotong University School of MedicineShanghai 200125China Ear institute Shanghai Jiaotong University School of MedicineShanghai 200125China shanghai Key Laboratory of translational Medicine on Ear and Nose Diseases Shanghai 200125China Laboratory of Neuropharmacology and Neurotoxicology Shanghai UniversityShanghai 200444China translational institute for cancer pain Xinhua Hospital Chongming BranchShanghai 202150China

Voltage-gated sodium channels(VGSCs)are transiently expressed in cochlear hair cells before hearing onset and play an indispensable role in shaping spontaneous *** this study,we showed that Na^+currents shaped the spontaneous action potentials in developing mouse inner hair cells(IHCs)by decreasing the time required for the membrane potential to reach the action-potential *** immature IHCs,we identified 9 known VGSC subtypes(***-l.9ot),among which Navl.7a was the most highly expressed subtype and the main contributor to Na+currents in developing hair *** recordings of two cochlea-specific Navi.7 variants(CbmNavl.7a and CbmNavl.7b)revealed a novel loss-of-function mutation(C934R)at the extracellular linker between segments 5 and 6 of domain *** addition,post-transcriptional modification events,such as alternative splicing and RNA editing,amended the gating properties and kinetic features of CbmNavl.7a(C934).These results provide molecular and functional characteristics of VGSCs in mammalian IHCs and their contributions to spontaneous physiological activity during cochlear maturation.

关键词： Cochlear hair cell Spontaneous action potential Voltage-gated sodium channel Post-transcriptional modification Gating property Introduction

Up-Regulation of Akt and Nav1.8 in BmK I-Induced pain

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Neuroscience Bulletin 2018年第3期34卷 539-542页

作者： Guokun Zhou Yunlu Jiao You Zhou Shichao Qin Jie Tao Feng Jiang Zhi-Yong Tan Yong-Hua Ji Lab of Neuropharmacology and Neurotoxicology Shanghai University Shanghai 200444 China xinhua translational institute for cancer pain Shanghai 202150 China Department of Pharmacology and Toxicology and Stark Neurosciences Research institute Indiana University School of Medicine Indianapolis IN 46202 USA

Dear Editor,As the key contributor to the rising phase of action potentials in dorsal root ganglion（DRG）neurons,voltagegated sodium channels（VGSCs）are important in physiological and pathological pain *** instance,... 详细信息

关键词： Akt In Up-Regulation of Akt and Nav1.8 in BmK I-Induced pain

Modulatory effects of bufalin,an active ingredient from toad venom on voltagegated sodium channels

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Modulatory effects of bufalin,an active ingredient from toad...

第十四届生物毒素毒理学术大会暨第一届生物毒素——从生存适应到转化医学专题学术会议

作者： Yudan Zhu Feng Jiang Jian Xu Peihao Yin Jie Tao Department of Central Laboratory and Neurosurgery Putuo HospitalShanghai University of Traditional Chinese Medicine xinhua Hospital (chongming) Affiliated to shanghai Jiao Tong University School of Medicine Shanghai Chongming Xinhua Translational Medical Institute for Cancer Pain

Chan-su(toad venom) has been used as an analgesic agent in China from ancient to modern ***,a non-peptide toxin extracted from toad venom,is considered as one of the analgesic *** molecular mechanism underlying the anti-nociceptive effects of bufalin remains unclear so *** the present study,we investigated the pharmacological effects of bufalin on painrelated ion channels as well as animal models through patch clamp,calcium imaging and animal behavior *** the whole-cell recording,bufalin caused remarkable suppressive effect on the peak currents of voltage-gated sodium channels(VGSCs) of dorsal root ganglion neuroblastomas(ND7-23 cell) in a dose-dependent *** prompted the voltage-dependent activation and induced a negative shift on the fast inactivation of *** recovery kinetics of VGSCs were significantly slowed and recovery proportion were reduced after administering *** bufalin produced insignificant effect not only on voltage-dependent Kv4.2,Kv4.3 and BK channels heterologously expressed in HEK293 T cells,but also on the capsaicin and allyl isothiocyanate(AITC)induced Ca2+***’s more,bufalin could observably relieve formalin-induced spontaneous flinching and licking response as well as carrageenan-induced thermal and mechanical hyperalgesia in dose-dependent manner,which was in agreement with the results of in vitro *** present results suggest that the remarkable anti-nociceptive effects produced by bufalin are probably ascribed to its specific regulation on voltage-gated sodium *** inhibited the VGSCs in a dose-dependent manner,which provide references for the optimal dose selection of analgesia drugs.

关键词： voltage-gated sodium channels bufalin dose dependent inhibition anti-nociceptive effects ND7-23 cell

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Skeletal organoids

Biomaterials translational 2024年第4期5卷 390-410页

作者： Chen Zhang Yingying Jing Jianhua Wang Zhidao Xia Yuxiao Lai Long Bai Jiacan Su Organoid Research Center Institute of Translational MedicineShanghai UniversityShanghaiChina National Center for translational Medicine(shanghai)SHU Branch Shanghai UniversityShanghaiChina School of Medicine Shanghai UniversityShanghaiChina Department of Orthopaedics Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Centre for Nanohealth Swansea University Medical SchoolSwansea UniversitySwanseaUK Centre for translational Medicine Research&Development Institute of Biomedical and Health EngineeringShenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong ProvinceChina Wenzhou institute of shanghai University WenzhouZhejiang ProvinceChina

The skeletal system,composed of bones,muscles,joints,ligaments,and tendons,serves as the foundation for maintaining human posture,mobility,and overall biomechanical ***,with ageing,chronic overuse,and acute injuries,conditions such as osteoarthritis,intervertebral disc degeneration,muscle atrophy,and ligament or tendon tears have become increasingly prevalent and pose serious clinical *** disorders not only result in pain,functional loss,and a marked reduction in patients’quality of life but also impose substantial social and economic *** treatment modalities,including surgical intervention,pharmacotherapy,and physical rehabilitation,often do not effectively restore the functionality of damaged tissues and are associated with high recurrence rates and long-term complications,highlighting significant limitations in their ***,there is a strong demand to develop novel and more effective therapeutic and reparative *** technology,as a three-dimensional micro-tissue model,can replicate the structural and functional properties of native tissues in vitro,providing a novel platform for in-depth studies of disease mechanisms,optimisation of drug screening,and promotion of tissue *** recent years,substantial advancements have been made in the research of bone,muscle,and joint organoids,demonstrating their broad application potential in personalised and regenerative ***,a comprehensive review of current research on skeletal organoids is still ***,this article aims to present an overview of the definition and technological foundation of organoids,systematically summarise the progress in the construction and application of skeletal organoids,and explore future opportunities and challenges in this field,offering valuable insights and references for researchers.

关键词： applications construction strategies organoids skeletal system