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Signalling pathways in autism spectrum disorder:mechanisms and therapeutic implications

Signal Transduction and Targeted Therapy 2022年第8期7卷 2863-2898页

作者： Chen-Chen Jiang Li-Shan Lin Sen Long Xiao-Yan Ke Kohji fukunaga Ying-Mei Lu Feng Han International Joint Laboratory for Drug Target of Critical Illnesses Key Laboratory of Cardiovascular&Cerebrovascular MedicineSchool of PharmacyNanjing Medical UniversityNanjing 211166China Department of Physiology School of Basic Medical SciencesNanjing Medical UniversityNanjing 211166China Department of Pharmacy Hangzhou Seventh People’s HospitalMental Health Center Zhejiang University School of MedicineHangzhou 310013China Child Mental Health Research Center Nanjing Brain HospitalNanjing Medical UniversityNanjing 210029China Department of CNS Drug Innovation Graduate School of Pharmaceutical SciencesTohoku UniversitySendai 980-8578Japan Institute of Brain Science The Affiliated Brain Hospital of Nanjing Medical UniversityNanjing 210029China Gusu School Nanjing Medical UniversitySuzhou Municipal HospitalThe Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou 215002China

Autism spectrum disorder(ASD)is a prevalent and complex neurodevelopmental disorder which has strong genetic *** the rapidly rising incidence of autism,little is known about its aetiology,risk factors,and disease *** are currently neither validated biomarkers for diagnostic screening nor specific medication for *** the last two decades,there have been remarkable advances in genetics,with hundreds of genes identified and validated as being associated with a high risk for *** convergence of neuroscience methods is becoming more widely recognized for its significance in elucidating the pathological mechanisms of *** have been devoted to exploring the behavioural functions,key pathological mechanisms and potential treatments of ***,as we highlight in this review,emerging evidence shows that signal transduction molecular events are involved in pathological processes such as transcription,translation,synaptic transmission,epigenetics and immunoinflammatory *** involvement has important implications for the discovery of precise molecular targets for ***,we review recent insights into the mechanisms and clinical implications of signal transduction in autism from molecular,cellular,neural circuit,and neurobehavioural ***,the challenges and future perspectives are discussed with regard to novel strategies predicated on the biological features of autism.

关键词： mechanisms spectrum behaviour

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Donepezil rescues the medial septum cholinergic neurons via nicotinic ACh receptor stimulation in olfactory bulbectomized mice

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Advances in Alzheimer's Disease 2013年第4期2卷 161-170页

作者： Yui Yamamoto Kohji fukunaga Department of Pharmacology Graduate School of Pharmaceutical Science Tohoku University Sendai Japan

Olfactory bulbectomy (OBX) causes cognitive dysfunction by degeneration of cholinergic neurons in the medial septum. Here, we define an involvement of nicotinic acetylcholine receptor (nAChR) in neuroprotective effect of donepezil in the septum neurons of OBX mice. Neuroprotective effects on the medial septal cholinergic neurons were assessed after chronic donepezil administration in OBX mice. We also measured Akt and ERK phosphorylation to define the neuroprotective mechanism of donepezil. We found that treatment with donepezil (1 - 3 mg/kg) for 15 consecutive days completely rescued cholinergic neurons in the OBX mice with concomitant improved memory. Reduction of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation were restored by chronic donepezil administration (1 - 3 mg/kg) in OBX mouse medial septum. Both phosphorylated Akt and ERK immunoreactivities were localized in cell bodies of choline acetyltransferase (ChAT)-positive cholinergic cells in the medial septum. Enhancement of Akt and ERK phosphorylation seen following donepezil administration was totally blocked by pre-administration of mecamylamine (10 μM), a nicotinic acetylcholine receptor antagonist. Donepezil increases phosphorylation of Akt and ERK via nAChR stimulation in the medial septum cholinergic neurons. The Akt and ERK stimulation by donepezil is associated with its ability of neuroprotection in the medial septum and memory improvement.

关键词： Donepezil Neuroprotection Medial Septum Nicotinic Acetylcholine Receptors

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Two Forensic Autopsy Cases of Liposarcoma

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Journal of Forensic Science and Medicine 2016年第3期2卷 175-178页

作者： Kino Hayashi Kumiko Asakura Nao Miyashita Akihiko Hamamatsu Akio Shigeta Tatsushige fukunaga Tokyo Medical Examiner’s Office 1Specific Disease Control SectionBureau of Social Welfare and Public HealthTokyo Metropolitan GovernmentTokyoJapan

Primary liposarcoma outside thighs is *** present two forensic autopsy cases of clinically undiagnosed primary liposarcoma(Case 1:Mediastinum,Case 2:Mesentery).Case 1 was a thin male in his 60s who had a well‑differentiated liposarcoma(850 g,23 cm×20 cm×10 cm)in the superior *** 2 was a thin female in her 50s who had a pleomorphic liposarcoma(10 kg,40 cm×25 cm×11 cm)in the abdominal cavity with liver *** cause of death in Case 1 was airway obstruction due to liposarcoma of the neck;that in Case 2 was complications of liposarcoma with *** liposarcoma often appears in deeper tissue without pain,it will grow quite large before it is noticed.

关键词： Forensic autopsy case mediastinal liposarcoma mesenteric liposarcoma

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Easy fixation effects the prevention of Peterson’s hernia and Roux stasis syndrome

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World Journal of Gastrointestinal Surgery 2020年第8期12卷 346-354页

作者： Jian-Zhong Wu Hajime Orita Shun Zhang Hiroyuki Egawa Yukinori Yube Sanae Kaji Shinichi Oka Tetsu fukunaga Department of Gastroenterology and Minimally Invasive Surgery Juntendo University School of MedicineJuntendo UniversityTokyo 1638001Japan Department of Gastroenterology Surgery Suzhou Ninth People’s HospitalNantong UniversitySuzhou 215000Jiangsu ProvinceChina Department of Surgery Tongji UniversityShanghai 200000China

BACKGROUND Laparoscopic distal gastrectomy(LDG)for gastric cancer has been progressed and popular in Japan,since it was first described in *** reconstruction methods can be adopted according to remnant stomach size,and balance of pros and ***-en-Y(R-Y)reconstruction is a one of standard options after *** complications include Petersen’s hernia and Roux stasis *** we report our ingenious attempt,fixation of Roux limb and duodenal stump,for decreasing the development of Petersen’s hernia and Roux stasis *** To develop a method to decrease the development of Petersen’s hernia and Roux stasis *** We performed ante-colic R-Y reconstruction after *** R-Y reconstruction,we fixed Roux limb onto the duodenal stump in a smooth *** this small improvement in Roux limb,Roux limb was placed to the right of the ligament of *** not only changed the anatomy of the Petersen’s defect,but it also kept a fluent direction of gastrointestinal anastomosis and avoided a cross-angle after jejunojejunostomy.31 patients with gastric cancer was performed this technique after R-Y *** parameters including clinicopathologic characteristics,perioperative outcomes,postoperative complication and follow-up data were *** The operative time was(308.0±84.6 min).This improvement method took about 10 ***(6.5%)patients experienced pneumonia and pancreatitis,*** patient required reoperation or *** patients were followed up for at least 3 year,and none of the patients developed postoperative complications related to internal hernia or Roux stasis *** This 10 min technique is a very effective method to decrease the development of Petersen’s hernia and Roux stasis syndrome in patients who undergo LDG.

关键词： Laparoscopy distal gastrectomy Roux-en-Y reconstruction Internal hernia Roux limb syndrome Gastric cancer

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Ferroelectricity in Layered Perovskites as a Model of Ultra-Thin Films

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World Journal of Condensed Matter Physics 2016年第3期6卷 224-243页

作者： Masanori fukunaga Masaki Takesada Akira Onodera Department of Physics Hokkaido University Sapporo Japan

The instability of thin ferroelectric films is discussed based on the close similarity of dielectric properties between bulk Bi-layered perovskites and thin BaTiO3 films. The dielectric properties of pseudo-two-dimensional layered perovskites suggest that the bulk layered ferroelectric is a good model of ultra-thin ferroelectric film with a few perovskite units, free from any misfit lattice strain. It seems plausible that the ferroelectric interaction is still prominent but shows a crossover from ferroelectric to antiferroelectric along the unique c-axis (perpendicular to the film plane);with decreasing thickness, the ferroelectricity appears within the plane, which results in so-called “canted ferroelectricity”. An extra relaxation mode induced by surface effect of thin films correlates with soft mode, which results in a new intermediate phase between the paraelectric and ferroelectric phases. These evidences may indicate no critical thickness even for ferroelectric ultra- thin films.

关键词： Ferroelectricity Layered Oxide Perovskite Thin Film Size Effect

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Effectiveness and safety of a laparoscopic training system combined with modified reconstruction techniques for total laparoscopic distal gastrectomy

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World Journal of Gastroenterology 2020年第13期26卷 1490-1500页

作者： Shun Zhang Hajime Orita Hiroyuki Egawa Ryota Matsui Suguru Yamauchi Yukinori Yube Sanae Kaji Toru Takahashi Shinichi Oka Noriyuki Inaki Tetsu fukunaga Department of Gastroenterology and Minimally Invasive Surgery Juntendo University HospitalTokyo 113-8431Japan Department of Gastrointestinal Surgery Shanghai East HospitalTongji UniversityShanghai 200120China Department of Surgery Juntendo Urayasu HospitalJuntendo UniversityChiba 2790021Japan

BACKGROUND Total laparoscopic distal gastrectomy(TLDG)is increasing due to some advantages over open surgery,which has generated interest in gastrointestinal ***,TLDG is technically demanding especially for lymphadenectomy and gastrointestinal *** the course of training,trainee surgeons have less chances to perform open gastrectomy compared with that of senior *** To evaluate an appropriate,efficient and safe laparoscopic training procedures suitable for trainee *** Ninety-two consecutive patients with gastric cancer who underwent TLDG plus Billroth I reconstruction using an augmented rectangle technique and involving trainees were *** trainees were taught a laparoscopic view of surgical anatomy,standard operative procedures and practiced essential laparoscopic *** TLDG procedure was divided into regional lymph node dissections and gastrointestinal reconstruction for analyzing trainee *** surgical outcomes were compared between trainees and trainers to clarify the feasibility and safety of TLDG performed by *** curves were used to assess the utility of our training *** Five trainees performed a total of 52 TLDGs(56.5%),while 40 TLDGs were conducted by two trainers(43.5%).Except for depth of invasion and pathologic stage,there were no differences in clinicopathological *** performed more D2 gastrectomies than *** total operation time was significantly longer in the trainee *** time spent during the lesser curvature lymph node dissection and the Billroth I reconstruction were similar between the two *** difference was found in postoperative complications between the two *** learning curve of the trainees plateaued after five TLDG *** Preparing trainees with a laparoscopic view of surgical anatomy,standard operative procedures and practice in essential laparoscopic skills enabled trainees to perform TLDG sa

关键词： Gastric cancer Total laparoscopic gastrectomy Education system Trainees Augmented rectangle technique Standard procedure

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4K时代中日胃肠微创外科交流与协作

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中华消化外科杂志 2020年第11期19卷 1151-1153页

作者：福长洋介癌研有明医院消化中心普通外科日本东京135-8550

随着腹腔镜设备光学技术的发展,手术画面的质量获得较大提高,从而推动了日本胃肠肿瘤微创手术质量迅速提高。2017年《中华消化外科杂志》编辑委员会组织中国和日本的胃肠外科学专家成功举办“4K时代中日胃肠微创手术标准解读交流会”,... 详细信息

随着腹腔镜设备光学技术的发展,手术画面的质量获得较大提高,从而推动了日本胃肠肿瘤微创手术质量迅速提高。2017年《中华消化外科杂志》编辑委员会组织中国和日本的胃肠外科学专家成功举办“4K时代中日胃肠微创手术标准解读交流会”,希望通过会议交流、推广、普及中国与日本在腹腔镜胃肠微创手术领域的医疗技术。通过参加会议,笔者团队展示4K腹腔镜保留自主神经的胃肠肿瘤根治术等手术方式,介绍日本内镜外科学会腹腔镜技术认定制度,并与中国外科医师在手术技术要点和肿瘤学质量方面进行深入探讨,由此进一步推进中日胃肠微创外科交流与协作。

关键词：胃肿瘤肠肿瘤 4K分辨率交流腹腔镜检查

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Microsphere embolism-induced protein tyrosine nitration mediates the disruption of blood-brain barrier in the rat brain

Microsphere embolism-induced protein tyrosine nitration medi...

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第十五届国际药理学大会

作者： Yasufumi Shirasaki Kohji fukunaga Department of Pharmacology Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan New Product Research Laboratories Ⅱ Daiichi Pharmac eutical Co.Ltd.TokyoJapan Department of Pharmacology Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan New Product Research Laboratories Ⅱ Daiichi Pharmac eutical Co.Ltd.TokyoJapan

＜正＞ Brain ischemic injury elicits cerebral microvascular injury and results in blood -brain barrier (BBB disruption,which exacerbates the postischemic edema. The precise molecular mechanisms underlying ischemia - induced BBB disruption remain unclear. We here determine whether peroxynitrite formation in the vascular endothe lial cells （ECs） mediates BBB disruption after microsphere embolism （ME） ischemia in rat. The present study indicated that eNOS expression was significantly up - regulated in the brain microvessels 2-48 hours after ME. preceding disruption of BBB. In the vascular ECs. ME- induced eNOS expression was closely associated with protein tyrosine nitration. Leakage of rabbit IgG was also evident around nitrotyrosine - immunoreactive microvessels. To support the idea of undesirable roles of eNOS overexpression. a novel calmodulin - dependent NOS inhibitor. DY - 9760e. significantly inhibits protein tyrosine nitration after ME. Taken together. ME - induced eNOS expression and subsequently peroxynitrite formation in the vascular ECs likely accounts for the ischemia - induced BBB disruption.

关键词： DY-9760e peroxynitrite ischemia blood - brain barrier

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Useful detection of CD147 (EMMPRIN) for pathological diagnosis of early hepatocellular carcinoma in needle biopsy samples

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World Journal of Gastroenterology 2007年第21期13卷 2913-2917页

作者： Satoshi Mamori Keisuke Nagatsuma Tomokazu Matsuura Kiyoshi Ohkawa Hiroshi Hano Masaharu fukunaga Masato Matsushima Yoshifumi Masui Nao Fushiya Hiroshi Onoda Yasuyuki Searashi Ichiro Takagi Hisao Tajiri Division of Gastroenterology and Hepatology Department of Internal MedicineThe Jikei University School of MedicineTokyo 105-8461Japan Department of Laboratory Medicine The Jikei University School of MedicineTokyo 105-8461Japan Department of Biochemistry 1 The Jikei University School of MedicineTokyo 105-8461Japan Department of Pathology The Jikei University School of MedicineTokyo 105-8461Japan Department of Pathology The Jikei University School of MedicineThe Daisan HospitalTokyo 105-8461Japan Division of Clinical Research and development The Jikei University School of MedicineTokyo 105-8461Japan

AIM:To make clear whether CD147 (EMMPRIN) expression in pathological tumor samples with a fine-needle aspiration biopsy is useful for pathological diagnosis of early hepatocellular carcinoma (HCC). METHODS:Twenty-two patients (15 men and 7 women; median age 68 years,range 56-81 years) underwent a liver tissue biopsy in order to make a diagnosis of HCC. Paraffin-embedded liver biopsy tissue samples from 22 patients were stained with anti-CD147 antibody,murine monoclonal antibody 12C3 (MAb12C3) for immunohistochemical analysis. An immunohistochemical analysis of CD147 was performed and the degree of staining compared between tumor and non-tumor tissue. In addition,the degree of staining within tumor tissue was compared according to a number of clinicopathological variables. RESULTS:The degree of staining of CD147 was significantly higher in tumor tissues than non-tumor tissues,even in tumors less than 15 mm in *** expression of this protein was significantly elevated in HCC tissue specimens from patients with a low value of serum AST and γ-GTP.

关键词： CD147 serves potentially as apathological target for cancer detection of early HCC.

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Rivastigmine Restores 5-HT<sub>1A</sub>Receptor Levels in the Hippocampus of Olfactory Bulbectomized Mice

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Advances in Alzheimer's Disease 2014年第3期3卷 128-136页

作者： Muhammad Rashedul Islam Shigeki Moriguchi Hideaki Tagashira Kohji fukunaga Department of Pharmacology Graduate School of Pharmaceutical Sciences Tohoku University Sendai Japan

Rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, is used for symptomatic treatment of patients with mild to moderately severe dementia in Alzheimer’s disease (AD) patients. In the present study, we found that 5-HT1A receptor (5-HT1AR) is downregulated, whereas 5-HT2A receptor (5-HT2AR) is upregulated in the hippocampal dentate gyrus (DG) and CA1 region by olfactory bulbectomy (OBX) in mice. Furthermore, chronic treatment with rivastigmine (1.0 mg/kg) for 2 weeks starting 2 weeks after OBX operation restored the decreased 5-HT1AR and the increased 5-HT2AR levels. To determine whether cholinergic receptor stimulation by rivastigmine is involved in the rivastigmine-induced regulation of 5-HTR levels, we treated the mice with mecamylamine (2.5 mg/kg), or atropine (5.0 mg/kg) with rivastigmine (1.0 mg/kg) once a day for 2 weeks. Notably, the rivastigmine-induced 5-HT1AR upregulation was eliminated by mecamylamine but not by atropine treatments. On the other hand, the restored 5-HT2AR level by rivastigmine was not affected by either mecamylamine or atropine. Treatment with 8-OH-DPAT, a selective 5-HT1AR agonist improved the decreased 5-HT1AR and the increased 5-HT2AR levels in OBX mice. On the other hand, treatment with TCB-2, a potent 5-HT2AR agonist had no effects on the 5-HT1AR and 5-HT2AR dysregulation in OBX mice. Taken together, nicotinic acetylcholine receptor (nAChR) stimulation mediates rivastigmine-induced upregulation of 5-HT1AR. Therefore, we speculate that the increased ACh levels by rivastigmine can stimulate nAChR located on serotonergic nerve terminals and stimulate 5-HT1AR by the enhanced 5-HT release in the hippocampus. The 5-HT1AR stimulation likely mediates the improvement of 5-HT1AR levels as auto-receptor in OBX hippocampus.

关键词： Rivastigmine 5-HT1A Receptor 5-HT2A Receptor Nicotinic Acetylcholine Receptor Olfactory Bulbectomized Mice

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