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神經退化性老化疾病研究團隊

神經退化性老化疾病研究團隊

主持人: 陳景宗教授

研究專長:  巴金森氏症、疼痛、憂鬱症、藥物成癮研究

 

研究團隊成員:

陳景宗老師、陸清松醫師、王鴻利老師、楊春茂老師、蕭穎聰老師、王俊傑醫師、周晟老師、黃榮棋老師、黃國正老師

 

研究架構圖:

 

研究計畫:

 

說明

老化是神經退化性疾病(Neurodegenerative diseases)的重要危險因子,神經退化性疾病佔老年人口的比例已經逐年增加,相對的醫療資源用在預防與治療與老年相關的神經疾病,也以同步的速度遞增;其中老年失智症(又稱為阿茲海默症;Alzheimers diseaseAD」)和帕金森氏症(Parkinson’s diseasePD」)無論是歐美或是我國,均是最常見的神經退化性疾病;隨著老年人口的快速增加,可以預期ADPD或其他神經退化性疾病將是未來影響全球醫療、經濟、家庭與社會的重要議題。欲思對神經退化性疾病的防制有所突破,必須從多方面的醫療與研究著手,才能收到預期的成效。有鑑於世界各國的醫療團隊不乏有卓越的阿茲海默氏症和帕金森氏症研究中心,本研究團隊建立的主要目的乃利用長庚大學醫、工與管理學院對神經老化疾病既有的研發基礎與長庚醫療體系龐大的資料庫做人力與資源的配合與整合,期能開發早期預警的生物指標(biomarker)、生物標記(biosignature)與開創神經退化性疾病特有的動物與細胞模式,提供基礎研究從事病變機轉或連結臨床疾病判斷和當做藥物測試平台;此外將藉由醫工與管理專才對健康老年人和神經退化病患的生理參數作數據整合與分析,提供臨床醫護未來對老年生活品質提升的重要依據。本研究團隊成立的初期是以神經退化性疾病的各研究平台建立為主要目標,目前業已開發出各種研究退化性疾病的細胞與動物模式,並積極與國際一流醫學研究團隊建立團隊合作關係,使本中心的神經科學群達到國際頂尖的水準,以培訓本中心基礎研究人才,達到卓越與國際化的目標。未來本中心的發展將參考國外研究退化性疾病的最新趨勢,擴充本研究團隊的動能與開發新的研究議題,以符合科研精進的精神與目的。

 

背景

神經退化性疾病是一個緩慢的病變過程,涉及遺傳與非遺傳的環境因素,經由共通性的病理變化造就最終的疾病表徵(disease phenotypes),瞭解疾病的起始原因和過程除可掌握病情的發展外,尚可發展出早期預警指標,以幫助病患改善生活品質,並節省社會醫療成本。在眾多的神經退化性疾病中,阿茲海默症和帕金森氏症的罹病人口最多,帶給家庭與社會上的壓力也最大,而背後的原因複雜,包括體內氧化壓力的上升、代謝症候群、免疫力下降導致的慢性感染和發炎因子在腦部的堆積等等因素。其中帕金森氏症患者腦部或因基因的突變或因外在環境因子的誘發,導致a-synuclein蛋白的堆積,形成Lewy body的病理結構,致使紋狀體內多巴胺神經末稍退化影響運動功能;而阿茲海默症患者在大腦皮質和海馬迴因為b-amyloid蛋白的不正常聚合而形成plague的病理結構,或是因為Tau蛋白質過度磷酸化而導致微管(microtubule)的崩散,這些病理變化最終造成患者的失智症與認知功能受損。有鑑於此,國內最龐大的醫療體系-長庚醫院業已成立相關的研究中心,針對失智症、帕金森氏症和運動功能障礙從事病理分析、臨床診斷與基礎研究。本校老化中心內的「神經退化性疾病研究團隊」在過去頂尖大學研究計畫的經費支助下成立,當時即與長庚醫院既有的醫療研究團隊以及「神經科學中心」充分合作,利用長庚醫療體系的病患基因檢體分析與分子影像檢析,與本校各個核心實驗室(蛋白質體中心、生醫影像中心、基因體中心、代謝體中心、生物資訊實驗室)的尖端研發平台,並配合「動物行為核心實驗室」的設立,得以縱深性的從生物指標的確認到動物模式的建立與臨床病例做關聯,達到相輔相成的成效,與基礎與臨床結合的目標。此外,本中心以早期預警的生物標記為主要研究目標,所獲得的資料將可與老化中心內其他研究團隊配合與合作,以建構起多方位的老年醫療研究中心,提升國民健康指數。

 

目的

神經退化性疾病是一個緩慢的病變過程,涉及遺傳與非遺傳的誘發因子,經由共通性的病理變化造就最終的疾病表徵(disease phenotypes),瞭解疾病的起始原因除可掌握病情的發展外,並可發展出早期預警指標,幫助病患改善生活品質減緩疾病的發展過程,以節省整體社會醫療成本。在眾多的神經退化性疾病中,阿茲海默症和帕金森氏症的罹病人口最多,帶給家庭與社會上的壓力也最大;有鑑於此,本研究團隊成立的主要目的在於開發神經退化性疾病的各細胞與動物模式,以提供退化性疾病病變過程的機制研究、測試環境因子導致神經退化的原因與治療性藥物測試的平台,我們的利基在於長庚醫療體系已有神經科學中心、失智症中心與帕金森氏症研究中心,針對退化性疾病與運動功能障礙從事病理分析與臨床診斷,尤其利用遺傳分析與分子影像造影技術已成功的確認若干家族性病例的基因病變位點。本中心的成立除可利用本校既有的各核心實驗室的研發平台,配合臨床病例以開發出特有的退化性疾病動物與細胞模式,達到基礎與臨床結合的目標,以期最終能增進全民健康福祉。

 

方法

一)開發退化性疾病的生物指標或標記(biomarker/biosignature identification:利用帕金森氏症和失智症病患的基因、血液或其他生物檢體,配合長庚大學既有的分析平台:例如基因體學、次世代基因定序(NGS)、蛋白質體學、代謝質體學、分子及生醫影像和生物資訊等尖端的分析平台,綜合性與複合式的搜尋病變基因位點、早期預警生物指標或病變的生物標記以及腦病變過程的分子影像profile,提供臨床病變過程的追蹤與確認。此外,我們也藉由團隊中具光電專長的周晟教授利用高靈敏的SPR表面電漿技術偵測帕金森氏症血液中a-synuclein以及失智症患者血液中b-amyloid不正常蛋白質聚合體的形成,當作早期預警或疾病進展的生物指標。

(二)神經退化性疾病的細胞與動物模式研究(disease models):神經退化性疾病的成因包含諸多環境因子與基因的交互作用,藉由生物指標的開發、我國特有病變家族的基因型確定以及環境毒素(environmental toxin)的確認等先決條件,可供長庚實驗動物中心製作特定的失智症或帕金森氏症動物模式;並利用業已於HARC設立的動物行為及活性實驗室的測試平台做功能性評估;此外,藉由本團隊吳瓊媛老師先進的piggyBac iPS (induced pluripotent stem cell)技術,可以開發出疾病特有的細胞模式,供研究者了解病變的細胞生理過程和做藥物篩選平台;或是利用神經腫瘤細胞株予以發炎因子的刺激當作模擬神經細胞病變退化的細胞模式。這些動物和細胞模式的成功建立,對未來相關神經退化性疾病的諸多研究課題,進行系統性的機制探討。

(三)老年醫療的整合性生物資訊:神經退化性疾病發作前的各項生理參數往往可提供極有價值的醫療資訊,配合生物指標的偵測,作為疾病發作前的臨床預警。利用長庚醫、工、管經營「養生文化村」既有的研發經驗導入失智症與退化性疾病的研究群,將可提供老化研究重要的資訊平台。充分運用Dr. E觀念做非侵入性檢測、無線追蹤日常生活作息、人際活動、飲食與生理參數,提供未來老化研究與退化性疾病發展的重要參考數據。

(四)推動國際合作機制:本研發團隊建立的另一目標就是藉由提升研發深度以達國際頂尖研究的水準,已利推動國際合作。團隊內的神經內科陸清松醫師長期與荷蘭鹿特丹(Rotterdam, NetherlandsErasmus醫學中心有研究合作,將分析有關帕金森氏症家族性病變的特定致病基因,此外生醫影像團隊也參與多項的國際廠商合作,在這樣的基礎上我們未來將持續推動進行以深化合作基礎,對本團隊的研究國際化將具有正面的意義。

 

 

主要成果

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Chang YF, Chao CH, Lin LY, Tsai CH, Chou C, Lee YJ (2014). Determination of urine cofilin-1 level in acute kidney injury using a high-throughput localized surface plasmon-coupled fluorescence biosensor. J Biomed Opt 19(1): 011004.

Chang YF, Tsao KC, Liu YC, Chen YC, Yu PC, Huang YC, et al (2015). Diagnosis of human metapneumovirus in patients hospitalized with acute lower respiratory tract infection using a metal-enhanced fluorescence technique. J Virol Methods 213: 151-156.

Chao CH, Chang YF, Chen HC, Lin LY, Yu PC, Chang YS, et al (2012). Detection of urine cofilin-1 from patients hospitalized in the intensive care unit using the metal-enhanced fluorescence technique. Sensor Actuat B-Chem 173: 184-190.

Chao KT, Tsao HH, Weng YH, Hsiao IT, Hsieh CJ, Wey SP, et al (2012). Quantitative analysis of binding sites for 9-fluoropropyl-(+)-dihydrotetrabenazine ([(1)(8)F]AV-133) in a MPTP-lesioned PD mouse model. Synapse 66(9): 823-831.

Chen CY, Weng YH, Chien KY, Lin KJ, Yeh TH, Cheng YP, et al (2012). (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell death and differentiation 19(10): 1623-1633.

Chen HT, Chen JC (2015). Role of the ventral tegmental area in methamphetamine extinction: AMPA receptor-mediated neuroplasticity. Learn Mem 22(3): 149-158.

Chen HT, Ruan NY, Chen JC, Lin TY (2012). Dopamine D2 receptor-mediated Akt/PKB signalling: initiation by the D2S receptor and role in quinpirole-induced behavioural activation. ASN Neuro 4(6): 371-382.

Cheng ML, Wang CH, Shiao MS, Liu MH, Huang YY, Huang CY, et al (2015). Metabolic disturbances identified in plasma are associated with outcomes in patients with heart failure: diagnostic and prognostic value of metabolomics. J Am Coll Cardiol 65(15): 1509-1520.

Chi PL, Chen YW, Hsiao LD, Chen YL, Yang CM (2012). Heme oxygenase 1 attenuates interleukin-1beta-induced cytosolic phospholipase A2 expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts. Arthritis and rheumatism 64(7): 2114-2125.

Chiu CC, Yeh TH, Lai SC, Wu-Chou YH, Chen CH, Mochly-Rosen D, et al (2015). Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. Experimental Neurology 263: 244-253.

Chou AH, Chen SY, Yeh TH, Weng YH, Wang HL (2011). HDAC inhibitor sodium butyrate reverses transcriptional downregulation and ameliorates ataxic symptoms in a transgenic mouse model of SCA3. Neurobiol Dis 41(2): 481-488.

Chou AH, Chen YL, Chiu CC, Yuan SJ, Weng YH, Yeh TH, et al (2015). T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse. Neuropharmacology 99: 308-317.

Chou AH, Chen YL, Hu SH, Chang YM, Wang HL (2014). Polyglutamine-expanded ataxin-3 impairs long-term depression in Purkinje neurons of SCA3 transgenic mouse by inhibiting HAT and impairing histone acetylation. Brain research 1583: 220-229.

Chou AH, Lin AC, Hong KY, Hu SH, Chen YL, Chen JY, et al (2011). p53 activation mediates polyglutamine-expanded ataxin-3 upregulation of Bax expression in cerebellar and pontine nuclei neurons. Neurochem Int 58(2): 145-152.

Chou JS, Chen CY, Chen YL, Weng YH, Yeh TH, Lu CS, et al (2014). (G2019S) LRRK2 causes early-phase dysfunction of SNpc dopaminergic neurons and impairment of corticostriatal long-term depression in the PD transgenic mouse. Neurobiol Dis 68: 190-199.

Hsiao IT, Huang CC, Hsieh CJ, Hsu WC, Wey SP, Yen TC, et al (2012). Correlation of early-phase 18F-florbetapir (AV-45/Amyvid) PET images to FDG images: preliminary studies. Eur J Nucl Med Mol Imaging 39(4): 613-620.

Hsiao IT, Weng YH, Hsieh CJ, Lin WY, Wey SP, Kung MP, et al (2014). Correlation of Parkinson disease severity and 18F-DTBZ positron emission tomography. JAMA Neurol 71(6): 758-766.

Hsiao IT, Weng YH, Lin WY, Hsieh CJ, Wey SP, Yen TC, et al (2014). Comparison of 99mTc-TRODAT-1 SPECT and 18 F-AV-133 PET imaging in healthy controls and Parkinson's disease patients. Nucl Med Biol 41(4): 322-329.

Hsieh HL, Chi PL, Lin CC, Yang CC, Yang CM (2014). Up-regulation of ROS-dependent matrix metalloproteinase-9 from high-glucose-challenged astrocytes contributes to the neuronal apoptosis. Mol Neurobiol 50(2): 520-533.

Hsieh HL, Lin CC, Chan HJ, Yang CM (2012a). c-Src-dependent EGF receptor transactivation contributes to ET-1-induced COX-2 expression in brain microvascular endothelial cells. J Neuroinflammation 9: 152.

Hsieh HL, Lin CC, Hsiao LD, Yang CM (2013). High glucose induces reactive oxygen species-dependent matrix metalloproteinase-9 expression and cell migration in brain astrocytes. Mol Neurobiol 48(3): 601-614.

Hsieh HL, Lin CC, Shih RH, Hsiao LD, Yang CM (2012). NADPH oxidase-mediated redox signal contributes to lipoteichoic acid-induced MMP-9 upregulation in brain astrocytes. J Neuroinflammation 9: 110.

Hua MY, Yang HW, Liu HL, Tsai RY, Pang ST, Chuang KL, et al (2011). Superhigh-magnetization nanocarrier as a doxorubicin delivery platform for magnetic targeting therapy. Biomaterials 32(34): 8999-9010.

Huang CL, Wu-Chou YH, Lai SC, Chang HC, Yeh TH, Weng YH, et al (2011). Contribution of glucocerebrosidase mutation in a large cohort of sporadic Parkinson's disease in Taiwan. Eur J Neurol 18(10): 1227-1232.

Huang CY, Chen YL, Li AH, Lu JC, Wang HL (2014). Minocycline, a microglial inhibitor, blocks spinal CCL2-induced heat hyperalgesia and augmentation of glutamatergic transmission in substantia gelatinosa neurons. J Neuroinflammation 11: 7.

Huang HM, Hsiao IT (2016). Accelerating an Ordered-Subset Low-Dose X-Ray Cone Beam Computed Tomography Image Reconstruction with a Power Factor and Total Variation Minimization. PLoS One 11(4): e0153421.

Huang KL, Lin KJ, Ho MY, Chang YJ, Chang CH, Wey SP, et al (2012). Amyloid deposition after cerebral hypoperfusion: evidenced on [(18)F]AV-45 positron emission tomography. J Neurol Sci 319(1-2): 124-129.

Kung MP, Weng CC, Lin KJ, Hsiao IT, Yen TC, Wey SP (2012). Amyloid plaque imaging from IMPY/SPECT to AV-45/PET. Chang Gung Med J 35(3): 211-218.

Lan MY, Chang YY, Yeh TH, Lai SC, Liou CW, Kuo HC, et al (2014). High frequency of SPG4 in Taiwanese families with autosomal dominant hereditary spastic paraplegia. BMC Neurol 14: 216.

Lan MY, Yeh TH, Chang YY, Kuo HC, Sun HS, Lai SC, et al (2015). Clinical and genetic analysis of Taiwanese patients with hereditary spastic paraplegia type 5. Eur J Neurol 22(1): 211-214.

Lao CL, Lu CS, Chen JC (2013). Dopamine D3 receptor activation promotes neural stem/progenitor cell proliferation through AKT and ERK1/2 pathways and expands type-B and -C cells in adult subventricular zone. Glia 61(4): 475-489.

Lin CC, Hsieh HL, Chi PL, Yang CC, Hsiao LD, Yang CM (2014). Upregulation of COX-2/PGE2 by ET-1 mediated through Ca2+-dependent signals in mouse brain microvascular endothelial cells. Mol Neurobiol 49(3): 1256-1269.

Lin CC, Hsieh HL, Liu SW, Tseng HC, Hsiao LD, Yang CM (2015). BK Induces cPLA2 Expression via an Autocrine Loop Involving COX-2-Derived PGE2 in Rat Brain Astrocytes. Mol Neurobiol 51(3): 1103-1115.

Lin CC, Hsieh HL, Shih RH, Chi PL, Cheng SE, Chen JC, et al (2012). NADPH oxidase 2-derived reactive oxygen species signal contributes to bradykinin-induced matrix metalloproteinase-9 expression and cell migration in brain astrocytes. Cell Commun Signal 10(1): 35.

Lin CC, Hsieh HL, Shih RH, Chi PL, Cheng SE, Yang CM (2013). Up-regulation of COX-2/PGE2 by endothelin-1 via MAPK-dependent NF-kappaB pathway in mouse brain microvascular endothelial cells. Cell Commun Signal 11(1): 8.

Lin CC, Lee IT, Chi PL, Hsieh HL, Cheng SE, Hsiao LD, et al (2014). C-Src/Jak2/PDGFR/PKCdelta-dependent MMP-9 induction is required for thrombin-stimulated rat brain astrocytes migration. Mol Neurobiol 49(2): 658-672.

Lin CC, Lee IT, Wu WB, Liu CJ, Hsieh HL, Hsiao LD, et al (2013). Thrombin mediates migration of rat brain astrocytes via PLC, Ca(2)(+), CaMKII, PKCalpha, and AP-1-dependent matrix metalloproteinase-9 expression. Mol Neurobiol 48(3): 616-630.

Lin KJ, Hsiao IT, Hsu JL, Huang CC, Huang KL, Hsieh CJ, et al (2016). Imaging characteristic of dual-phase (18)F-florbetapir (AV-45/Amyvid) PET for the concomitant detection of perfusion deficits and beta-amyloid deposition in Alzheimer's disease and mild cognitive impairment. Eur J Nucl Med Mol Imaging 43(7): 1304-1314.

Lin YT, Kao SC, Day YJ, Chang CC, Chen JC (2016). Altered nociception and morphine tolerance in neuropeptide FF receptor type 2 over-expressing mice. European journal of pain 20(6): 895-906.

Lin YT, Liu TY, Yang CY, Yu YL, Chen TC, Day YJ, Chang CC, Huang GJ, Chen JC (2016). Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation. Psychoneuroendocrinology DOI: 10.1016/j.psyneuen.2016.05.014

Lin YT, Ro LS, Wang HL, Chen JC (2011). Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitro study. J Neuroinflammation 8: 126.

Liu HL, Chen PY, Yang HW, Wu JS, Tseng IC, Ma YJ, et al (2011). In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low-frequency-ultrasound-induced blood-brain barrier opening in swine. J Magn Reson Imaging 34(6): 1313-1324.

Liu HL, Yang HW, Hua MY, Wei KC (2012). Enhanced therapeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status. Neurosurg Focus 32(1): E4.

Lu CS, Lai SC, Wu RM, Weng YH, Huang CL, Chen RS, et al (2012). PLA2G6 mutations in PARK14-linked young-onset parkinsonism and sporadic Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet 159B(2): 183-191.

Meir YJ, Lin A, Huang MF, Lin JR, Weirauch MT, Chou HC, et al (2013). A versatile, highly efficient, and potentially safer piggyBac transposon system for mammalian genome manipulations. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27(11): 4429-4443.

Shih RH, Cheng SE, Hsiao LD, Kou YR, Yang CM (2011). Cigarette smoke extract upregulates heme oxygenase-1 via PKC/NADPH oxidase/ROS/PDGFR/PI3K/Akt pathway in mouse brain endothelial cells. J Neuroinflammation 8: 104.

Shih RH, Wang CY, Yang CM (2015). NF-kappaB Signaling Pathways in Neurological Inflammation: A Mini Review. Front Mol Neurosci 8: 77.

Su LC, Tian YC, Chang YF, Chou C, Lai CS (2014). Rapid detection of urinary polyomavirus BK by heterodyne-based surface plasmon resonance biosensor. J Biomed Opt 19(1): 011013.

Tang HY, Ho HY, Wu PR, Chen SH, Kuypers FA, Cheng ML, et al (2015). Inability to maintain GSH pool in G6PD-deficient red cells causes futile AMPK activation and irreversible metabolic disturbance. Antioxid Redox Signal 22(9): 744-759.

Ting CY, Fan CH, Liu HL, Huang CY, Hsieh HY, Yen TC, et al (2012). Concurrent blood-brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment. Biomaterials 33(2): 704-712.

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