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Wilson's disease: Prospective developments towards new therapies

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World Journal of Gastroenterology 2017年第30期23卷 5451-5456页

作者： Giusy Ranucci Roman Polishchuck Raffaele Iorio Department of translational Medical Science Section of Pediatric University Federico Ⅱ Telethon institute of Genetics and medicine

Wilson's disease(WD) is an autosomal recessive disorder of copper metabolism, caused by mutations in the ATP7 B gene. A clear demand for novel WD treatment strategies has emerged. Although therapies using zinc salts and copper chelators can effectively cure WD, these drugs exhibit limitations in a substantial pool of WD patients who develop intolerance and/or severe side effects. Several lines of research have indicated intriguing potential for novel strategies and targets for development of new therapies. Here, we review these new approaches, which comprise correction of ATP7 B mutants and discovery of new compounds that circumvent ATP7B-deficiency, as well as cell and gene therapies. We also discuss whether and when these new therapeutic strategies will be translated into clinical use, according to the key requirements for clinical trials that remain to be met. Finally, we discuss the hope for the current rapidly developing research on molecular mechanisms underlying WD pathogenesis and for the related potential therapeutic targets to provide a solid foundation for the next generation of WD therapies that may lead to an effective, tolerable and safe cure.

关键词： ATP7B Stem cell-derived hepatocyte like cells Methanobactin Heat shock protein 70 p38 JNK Correctors translational medicine Precision medicine

Neonatal Maternal Deprivation Followed by Adult Stress Enhances Adrenergic Signaling to Advance Visceral Hypersensitivity

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Neuroscience Bulletin 2019年第1期35卷 4-14页

作者： Wan-Jie Du Shufen Hu Xin Li Ping-An Zhang Xinghong Jiang Shan-Ping Yu Guang-Yin Xu Laboratory for translational Pain medicine Institute of NeuroscienceSoochow UniversitySuzhou 215123China Center for translational medicine The Zhangjiagang Affiliated Hospital of Soochow UniversityZhangjiagang 215600China Department of Anesthesiology Emory University School of MedicineAtlantaGA 30307USA

The pathophysiology of visceral pain in patients with irritable bowel syndrome remains largely *** previous study showed that neonatal maternal deprivation(NMD) does not induce visceral hypersensitivity at the age of 6 weeks in rats. The aim of this study was to determine whether NMD followed by adult stress at the age of 6 weeks induces visceral pain in rats and to investigate the roles of adrenergic signaling in visceral pain. Here we showed that NMD rats exhibited visceral hypersensitivity 6 h and 24 h after the termination of adult multiple stressors(AMSs). The plasma level of norepinephrine was significantly increased in NMD rats after AMSs. Whole-cell patch-clamp recording showed that the excitability of dorsal root ganglion(DRG) neurons from NMD rats with AMSs was remarkably increased. The expression of β_2 adrenergic receptors at the protein and mRNA levels was markedly higher in NMD rats with AMSs than in rats with NMD alone. Inhibition of β_2 adrenergic receptors with propranolol or butoxamine enhanced the colorectal distention threshold and application of butoxamine also reversed the enhanced hypersensitivity of DRG neurons. Overall,our data demonstrate that AMS induces visceral hypersensitivity in NMD rats, in part due to enhanced NE-β_2 adrenergic signaling in DRGs.

关键词： Irritable bowel syndrome Dorsal root ganglion Norepinephrine Visceral pain Stress

An epigenetic view of developmental diseases: new targets, new therapies

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World Journal of Pediatrics 2016年第3期12卷 291-297页

作者： Pei Xie Li-Qun Zang Xue-Kun Li Qiang Shu institute of Genetics College of Life SciencesZhejiang University Children's Hospital Zhejiang University School of Medicine institute of translational medicine School of MedicineZhejiang University

Background:Function of epigenetic modifications is one of the most competitive fields in life *** the past several decades,it has been revealed that epigenetic modifications play essential roles in development and diseases including developmental *** the present review,we summarize the recent progress about the function of epigenetic regulation,especially DNA and RNA modifi cations in developmental *** sources:Original research articles and literature reviews published in PubMed-indexed ***:DNA modifications including methylation and demethylation can regulate gene expression,and are involved in development and multiple diseases including Rett syndrome,Autism spectrum disorders,congenital heart disease and cancer,*** methylation and demethylation play important roles in RNA processing,reprogramming,circadian,and neuronal activity,and then modulate ***:DNA and RNA modifications play important roles in development and diseases through regulating gene *** components could serve as novel targets for the treatment of developmental diseases.

关键词： congenital heart disease development DNA modifi cation 5-hydroxymethylcytosine neurological disorders RNA modifi cation

Underlying mechanisms and clinical potential of circRNAs in glioblastoma

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Oncology Research 2023年第4期31卷 449-462页

作者： LEI ZHANG YUAN ZHANG HUIJUAN GAO XIN LI PEIFENG LI institute for translational medicine The Affiliated Hospital of Qingdao UniversityQingdao UniversityQingdao266021China

Glioblastoma(GBM)is the most malignant form of glioma and is difficult to diagnose,leading to high mortality *** RNAs(circRNAs)are noncoding RNAs with a covalently closed loop *** are involved in various pathological processes and have been revealed to be important regulators of GBM *** exert their biological effects by 4 different mechanisms:serving as sponges of microRNAs(miRNAs),serving as sponges of RNA binding proteins(RBPs),modulating parental gene transcription,and encoding functional *** the 4 mechanisms,sponging miRNAs is *** good stability,broad distribution and high specificity make circRNAs promising biomarkers for GBM *** this paper,we summarized the current understanding of the characteristics and action mechanisms of circRNAs,illustrated the underlying regulatory mechanisms of circRNAs in GBM progression and explored the possible diagnostic role of circRNAs in GBM.

关键词： CircRNAs GBM Underlying mechanisms Clinical value

Chemokine and chemotactic signals in dendritic cell migration

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Cellular & Molecular Immunology 2018年第4期15卷 346-352页

作者： Laura Tiberio Annalisa Del Prete Tiziana Schioppa Francesca Sozio Daniela Bosisio Silvano Sozzani Department of Molecular and translational medicine University of BresciaBresciaItaly Humanitas Clinical and Research institute Rozzano-MilanoItaly

Dendritic cells (DCs) are professional antigen-presenting cells responsible for the activation of specific T-cell responses and for thedevelopment of immune tolerance. Immature DCs reside in peripheral tissues and specialize in antigen capture, whereas matureDCs reside mostly in the secondary lymphoid organs where they act as antigen-presenting cells. The correct localization of DCs isstrictly regulated by a large variety of chemotactic and nonchemotactic signals that include bacterial products, DAMPs (dangerassociated molecular patterns), complement proteins, lipids, and chemokines. These signals function both individually and inconcert, generating a complex regulatory network. This network is regulated at multiple levels through different strategies, such assynergistic interactions, proteolytic processing, and the actions of atypical chemokine receptors. Understanding this complexscenario will help to clarify the role of DCs in different pathological conditions, such as autoimmune diseases and cancers and willuncover new molecular targets for therapeutic interventions.

关键词： generating network mostly

Preparation of ^(188)Re-HEDP lyophilized kit for instant bone metastases therapy

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Nuclear Science and Techniques 2014年第6期25卷 48-53页

作者：杨志朱华李囡马云霞张岩 Key Laboratory of Carcinogenesis and translational Research (Ministry of Education) Department of Nuclear Medicine Peking University Cancer Hospital & Institute

Hydroxyethylidene diphosphonate(HEDP) was prepared and labeled with rhenium-188. Its lyophilized kit was developed for instant preparing of188Re-HEDP.188Re-HEDP showed high focile uptake in normal mice(> 30% ID/g at carrier co-injection) in BABLC/SPF mice. High quality single photon emission computed tomography(SPECT) image of New Zealand rabbit was obtained at 4 h after intravenous injection of 74 MBq radiotracer. The lyophilized HEDP kit affords the new opportunity for routine clinical application in bone metastases therapy.

关键词：试剂盒冻干制备治疗即时放射性示踪剂 HEDP 静脉注射

Upregulation of Spinal Voltage-Dependent Anion Channel 1 Contributes to Bone Cancer Pain Hypersensitivity in Rats

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Neuroscience Bulletin 2017年第6期33卷 711-721页

作者： Xiangpeng Kong Jinrong Wei Diyu Wang Xiaoju Zhu Youlang Zhou Shusheng Wang Guang-Yin Xu Guo-Qin Jiang Jiangsu Key Laboratory of translational Research and Therapy for Neuro-Psychiatric Diseases and institute of Neuroscience The Second Affiliated Hospital Soochow University Center for translational medicine Affiliated Zhangjiagang Hospital of Soochow University

Voltage-dependent anion channel 1（VDAC1） is thought to contribute to the progression of tumor development. However, whether VDAC1 contributes to bone cancer pain remains unknown. In this study, we found that the expression of VDAC1 was upregulated in the L2–5 segments of the spinal dorsal horn at 2 and 3 weeks after injection of tumor cells into the tibial cavity. Intrathecal injection of a VDAC1 inhibitor significantly reversed the pain hypersensitivity and reduced the over-expression of Toll-like receptor 4（TLR4）. Intrathecal injection of minocycline, an inhibitor of microglia, also attenuated the pain hypersensitivity of rat models of bone cancer *** results suggest that VDAC1 plays a significant role in the development of complicated cancer pain, possibly by regulating the expression of TLR4.

关键词： Cancer-induced pain Spinal dorsal horn Voltage-dependent anion channel 1 Toll-like receptor 4 Microglia

Prognostic value of interim ^(18)F-FDG PET/CT in diffuse large B-cell lymphoma

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Chinese Journal of Cancer Research 2013年第1期25卷 95-101页

作者： Zhitao Ying Xuejuan Wang Yuqin Song Wen Zheng Xiaopei Wang Yan Xie Ningjing Lin Meifeng Tu Lingyan Ping Weiping Liu Lijuan Deng Chen Zhang Zhi Yang Jun Zhu Key Laboratory of Carcinogenesis and translational Research (Ministry of Education) Department of LymphomaPeking University Cancer Hospital & Institute Key Laboratory of Carcinogenesis and translational Research (Ministry of Education) Department of Nuclear MedicinePeking University Cancer Hospital & Institute

Objective： Diffuse large B-cell lymphoma （DLBCL） is a heterogeneous disease. The prognostic factor currently used is not accurate enough to predict the outcomes of patients with DLBCL. The prognostic significance of interim PET/CT in DLBCL remains controversial. The aim of this study is to determine the predictive value of interim 18F-FDG PET/CT after first-line treatment in patients with DLBCL. Methods： Thirty-two patients with DLBCL underwent baseline, interim and post-treatment lSF-FDG PET/CT scans. Imaging results were analyzed for the survival of patients via software SPSS 13.0, retrospectively. Results： Thirty-one of the 32 patients were treated with R-CHOP regimen, and interim 18F-FDG PET/CT of 24 patients was performed after 2 cycles of treatment. After a median follow-up period of 16.7 months, the 2-year progression-free survival （PFS） rates were significantly different between the groups above and below SUVmax CUt-Off value of 2.5 （P=0.039）. No significant differences were found in the 2-year PFS rates if SUVm, cut-offvalues were set as 2.0 and 3.0, respectively （P=0.360; P=0.113）. Conclusions： Interim PET/CT could predict the prognosis of DLBCL patients with the SUVmax cut-off value of 2.5, but more clinical data should be concluded to confirm this conclusion.

关键词： Fludeoxy-glucose F18 lyrnphoma large cell diffuse prognosis standard utility value

Ginkgo biloba exocarp extracts inhibits metastasis and its effects on TGF-β1/ERK1/2/MMP-9 signaling pathway in B16-F10 melanoma

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中国药理学与毒理学杂志 2019年第10期 884-885页

作者： LUO Cheng-rong WANG Meng-meng GAO Yan-qi CHEN Hua-sheng XU Ai-hua institute of translational medicine Medical CollegeYangzhou University

OBJECTIVE To study the inhibition and mechanism of Ginkgo biloba exocarp extracts（GBEE）for the metastasis of B16-F10 melanoma in C57 BL/6 J mice. METHODS The metastasis model of B16-F10 in C57BL/6J mice was set up. The C57 BL/6 J mice were randomly separated into these groups: positive control,model control, normal control and GBEE treatment groups, n=10. The mice in positive group wereintraperitoneal（ip） injectioncis-dichlorodiamineplatinum（Ⅱ） at a dose of 5 mg·kg-1, twice a day for 7 d; model group and normal group were both intragastric gavage（ig） normal saline（NS） in a volume of 0.1 m L/10 g, once a day for17 d; the GBEE treatment groups were respectively ig GBEE 50, 100 and 200 mg · kg-1, once a day for 17 *** the administration, the lung tissue was removed and the lung surface metastasis was observed; the rate of lung metastasis and anti-metastasis were calculated;the degree of lung metastasis was observed by HE staining; in vitro, the effect of GBEE on the migration rate of B16-F10 cel s was detected by wound healing test; Western Blot was used to detect the expression of TGF-β1, ERK1/2,p-ERK1/2 and MMP-9 protein in B16-F10 cel s. RESULTS In vivo, we discovered that GBEE(50, 100, 200 mg·kg-1)cansuppress tumor lung metastasis of B16-F10 melanoma in C57 BL/6 J mice in a dose-dependent way. In vitro, we found that GBEE(20, 40, 80 mg·L-1) can significantly inhibit B16-F10 cells treated for 24 h and 48 h migration in a time-and concentration-dependent way. GBEE(20, 40,80 mg ·L-1) can suppressed TGF-β1, p-ERK1/2/ERK1/2 and MMP-9 protein expression level in a concentrationdependent way. CONCLUSION GBEE significantly inhibit the metastasis of B16-F10 melanoma, and its mechanism of action is related to the inhibition of extracellular matrix degradation and cell migration through the TGF-β1/ERK1/2/MMP-9 signaling pathway.

关键词： GBEE metastasis B16-F10 TGF-β1/ERK1/2/MMP-9