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| 1 | Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection显示文摘Missense mutations in Leucine-Rich Repeat Kinase 2(LRRK2)cause the majority of familial and some sporadic forms of Parkinson’s disease(PD).The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity,promoting the development of LRRK2 kinase inhibitors as therapeutics.Many potent and specific small-molecule LRRK2 inhibitors have been reported with promise.However,nearly all inhibitors are ATP competitive—some with unwanted side effects and unclear clinical outcome—alternative types of LRRK2 inhibitors are lacking.Herein we identify 5′-deoxyadenosylcobalamin(AdoCbl),a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity.Multiple assays show that AdoCbl directly binds LRRK2,leading to the alterations of protein conformation and ATP binding in LRRK2.STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain.Furthermore,we provide evidence that AdoCbl modulates LRRK2 activity through disrupting LRRK2 dimerization.Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue,and prevents neurotoxicity in cultured primary rodent neurons as well as in transgenic C.elegans and D.melanogaster expressing LRRK2 disease variants.Finally,AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models.Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism,which can be harnessed to develop new LRRK2-based PD therapeutics in the future. | Adam Schaffner Xianting Li Yacob Gomez-Llorente Emmanouela Leandrou Anna Memou Nicolina Clemente Chen Yao Farinaz Afsari Lianteng Zhi Nina Pan Keita Morohashi Xiaoluan Hua Ming-Ming Zhou Chunyu Wang Hui Zhang Shu G.Chen Christopher J.Elliott Hardy Rideout Iban Ubarretxena-Belandia Zhenyu Yue | 2019 | Cell Research2019，29，4： | 7 |
| 2 | Des-gamma-carboxy prothrombin as an important prognostic indicator in patients with small hepatocellular carcinoma显示文摘AIM:To clarify the effect of a high des-gamma-carboxy prothrombin (DCP) level on the invasiveness and prognosis of small hepatocellular carcinoma. METHODS: Among 142 consecutive patients with known DCP levels, who underwent hepatectomy because of hepatocellular carcinoma, 85 patients met the criteria for small hepatocellular carcinoma, i.e. one ≤ 5 cm sized single tumor or no more than three ≤ 3 cm sized tumors. RESULTS: The overall survival rate of the 142 patients was 92.1% for 1 year, 69.6% for 3 years, and 56.9% for 5 years. Multivariate analysis showed that microscopic vascular invasion (P = 0.03) and serum DCP ≥ 400 mAU/mL (P = 0.02) were independent prognostic factors. In the group of patients who met the criteria for small hepatocellular carcinoma, DCP ≥ 400 mAU/mL was found to be an independent prognostic factor for recurrence-free (P = 0.02) and overall survival (P = 0.0005). In patients who did not meet the criteria, the presence of vascular invasion was an independent factor for recurrence-free (P = 0.02) and overall survivals (P = 0.01). In 75% of patients with small hepatocellular carcinoma and high DCP levels, recurrence occurred extrahepatically. CONCLUSION: For small hepatocellular carcinoma, a high preoperative DCP level appears indicative fortumor recurrence. Because many patients with a high preoperative DCP level develop extrahepatic recurrence, it is necessary to screen the whole body. | Kenichi Hakamada Norihisa Kimura Takuya Miura Hajime Morohashi Keinosuke Ishido Masaki Nara Yoshikazu Toyoki Shunji Narumi Mutsuo Sasaki | 2008 | World Journal of Gastroenterology2008，14，9： | 4 |
| 3 | Basic helix-loop-helix transcription factors DEC1 and DEC2 regulatethe paclitaxel-induced apoptotic pathway of MCF-7 human breast cancer cells显示文摘 | Yunyan Wu Fuyuki Sato Ujjal Bhawal Takeshi Kawamoto Katsumi Fujimoto Mitsuhide Noshiro Satoko Morohashi Yukio Kato Hiroshi Kijima | 2011 | International Journal of Molecular Medicine2011，，4： | 3 |
| 4 | Tertiary Structure-Function Analysis Reveals the Pathogenic Signaling Potentiation Mechanism of Helicobacter pylori Oncogenic Effector CagA显示文摘 | Takeru Hayashi Miki Senda Hiroko Morohashi Hideaki Higashi Masafumi Horio Yui Kashiba Lisa Nagase Daisuke Sasaya Tomohiro Shimizu Nagarajan Venugopalan Hiroyuki Kumeta Nobuo N. Noda Fuyuhiko Inagaki Toshiya Senda Masanori Hatakeyama | 2012 | Cell Host & Microbe2012，，1： | 2 |
| 5 | A clinical evaluation oftitanium mini-implants as anchors for orthodontic intrusion inthe beagle dogs显示文摘 | Ohmae M Saito S Morohashi T | 2001 | Clin J Orthod2001，119，5： | 1 |
| 6 | Determination of seasonal and temporal variation in the provenance of dissolved cations in rain in Japan based on Sr and Pb isotopes显示文摘 | Nakano T Morohashi S Yasuda H | 2006 | Atmospheric Environment2006，40，38： | 1 |
| 7 | High complexation ability of thiacalixarene with transition metal ions: the effects of replacing methyene bridges of tetra(p-t-butyl)calix arenetetrol by epithio groups显示文摘 | Naoya Morohashi Fumitaka Narumi | 1998 | Bull Chem Soc Jpn1998，71，7： | 1 |
| 8 | Endosseous titanium implants as anchors formesiodistal tooth movement in beagle dog显示文摘 | Saito S Sugimoto N Morohashi T | 2000 | Am J Orthod2000，118，4： | 1 |
| 9 | Production of fertile somatic hybrid plants between Oriental hybrid lily and Lilium x formolongi显示文摘 | Horita M Morohashi H Komai F | 2003 | Planta2003，217，4： | 1 |
| 10 | A clinical and histological evaluation of titanium mini-implants as anchors for orthodontic intrusion in the beagle dog显示文摘 | Ohmae M Saito S Morohashi T | 2001 | Am J Orthod Dentofac Orthop2001，119，5： | 1 |
| 11 | A clinical and histo: logical evaluation of titanium mini-implant as anchors for orthodontic intrusion in the beagle dog显示文摘 | Ohmae M Saito S Morohashi T | 2001 | Am J Orthod Dentofacial Orthop2001，119，： | 1 |
| 12 | Isolation and characterization of a novel GRAS gene that regulates meiosis-associat- ed gene expression 显示文摘 | Morohashi K Minami M Takase H | 2003 | Journal of Biological Chemistry2003，278，20： | 1 |
| 13 | An endo-p-mannanase devel- ops exclusively in themicropylar endosperm of tomato seeds prior to radicle emergence显示文摘 | Nonogaki H Morohashi Y | 1996 | Plant Physiol1996，110，： | 1 |
| 14 | Cloning and characterization of a UV-B-inducible maize flavonol synthase 显示文摘 | Ferreyra M L F Rius S Emiliani J Pourcel L Feller A Morohashi K Casati P Grotewold E | 2010 | The Plant Journal2010，62，1： | 1 |
| 15 | A clinical and histological evaluation of titanium mini-implants as anchors for orthodontic intrusion in the beagle dog 显示文摘 | Ohmae M Saito S Morohashi T | 2001 | Am J Orthod Dentofacial Orthop2001，119，5： | 1 |
| 16 | Allograft inflammatory factor-1 regulates trinitrobenzene sulphonic acid-induced colitis显示文摘 | MOROHASHI T IWABUCHI K WATANO K | 2003 | Immunology2003，110，1： | 1 |
| 17 | 20 Gbiffs QPSK W-band (75-110 GHz) wireless link in flee space using radio-over-fiber technique 显示文摘 | KANNO A INAGAKI K MOROHASHI I | 2011 | IEICE Electronics Express2011，8，8： | 1 |
| 18 | Replacement of CH4in the hydrate by use of liquid CO2显示文摘 | OTA M MOROHASHI K ABE Y | 2005 | Energy Conversion and Management2005，46，11： | 1 |
| 19 | Endosseous titanium implants as anchors for mesiodistal tooth movement in the beagle dog 显示文摘 | Saito S Sugimoto N Morohashi T | 2000 | Am J Orthod Dentofaeial Orthop2000，118，6： | 1 |
| 20 | High complexation ability of thiacalixarene with transition metal ions the effects of replacing methylene bridges of tetra p-t-butylcalixarenetetrol by epithio groups显示文摘 | Iki N Morohashi N Miyano S | 1998 | Bulletin of the Chemical Society of Japan1998，71，7： | 1 |
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