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Endoplasmic reticulum stress,autophagy,neuroinflammation,and sigma 1 receptors as contributors to depression and its treatment

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Neural Regeneration Research 2024年第10期19卷 2202-2211页

作者： Chika Fujii Charles F.Zorumski yukitoshi izumi Department of Psychiatry Washington University School of MedicineSt.LouisMOUSA Taylor Family Institute for Innovative Psychiatric Research Washington University School of MedicineSt.LouisMOUSA

The etiological factors contributing to depression and other neuropsychiatric disorders are largely undefined. Endoplasmic reticulum stress pathways and autophagy are well-defined mechanisms that play critical functions in recognizing and resolving cellular stress and are possible targets for the pathophysiology and treatment of psychiatric and neurologic illnesses. An increasing number of studies indicate the involvement of endoplasmic reticulum stress and autophagy in the control of neuroinflammation, a contributing factor to multiple neuropsychiatric illnesses. Initial inflammatory triggers induce endoplasmic reticulum stress, leading to neuroinflammatory responses. Subsequently, induction of autophagy by neurosteroids and other signaling pathways that converge on autophagy induction are thought to participate in resolving neuroinflammation. The aim of this review is to summarize our current understanding of the molecular mechanisms governing the induction of endoplasmic reticulum stress, autophagy, and neuroinflammation in the central nervous system. Studies focused on innate immune factors, including neurosteroids with anti-inflammatory roles will be reviewed. In the context of depression, animal models that led to our current understanding of molecular mechanisms underlying depression will be highlighted, including the roles of sigma 1 receptors and pharmacological agents that dampen endoplasmic reticulum stress and associated neuroinflammation.

关键词： allopregnanolone fluvoxamine ketamine neurosteroids postpartum depression quercetin

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Glyphosate as a direct or indirect activator of pro-inflammatory signaling and cognitive impairment

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Neural Regeneration Research 2024年第10期19卷 2212-2218页

作者： yukitoshi izumi Kazuko A.O'Dell Charles F.Zorumski Department of Psychiatry Washington University School of MedicineSt.LouisMOUSA Taylor Family Institute for Innovative Psychiatric Research Washington University School of MedicineSt.LouisMOUSA

Glyphosate-based herbicides are widely used around the world, making it likely that most humans have significant exposure. Because of habitual exposure, there are concerns about toxicity including neurotoxicity that could result in neurological, psychiatric, or cognitive impairment. We recently found that a single injection of glyphosate inhibits long-term potentiation, a cellular model of learning and memory, in rat hippocampal slices dissected 1 day after injection, indicating that glyphosate-based herbicides can alter cognitive function. Glyphosate-based herbicides could adversely affect cognitive function either indirectly and/or directly. Indirectly, glyphosate could affect gut microbiota, and if dysbiosis results in endotoxemia(leaky gut), infiltrated bacterial by-products such as lipopolysaccharides could activate pro-inflammatory cascades. Glyphosate can also directly trigger pro-inflammatory cascades. Indeed, we observed that acute glyphosate exposure inhibits long-term potentiation in rat hippocampal slices. Interestingly, direct inhibition of long-term potentiation by glyphosate appears to be similar to that of lipopolysaccharides. There are several possible measures to control dysbiosis and neuroinflammation caused by glyphosate. Dietary intake of polyphenols, such as quercetin, which overcome the inhibitory effect of glyphosate on long-term potentiation, could be one effective strategy. The aim of this narrative review is to discuss possible mechanisms underlying neurotoxicity following glyphosate exposure as a means to identify potential treatments.

关键词： cognitive impairment glyphosate microglia neuroinflammation roundup toll-like receptor 4 zinc chelation

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Neurosteroids as stress modulators and neurotherapeutics: lessons from the retina

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Neural Regeneration Research 2023年第5期18卷 1004-1008页

作者： yukitoshi izumi Makoto Ishikawa Toru Nakazawa Hiroshi Kunikata Kota Sato Douglas F.Covey Charles F.Zorumski Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research Washington University School of MedicineSt.LouisMOUSA Department of Ophthalmic Imaging and Information Analytics Tohoku University Graduate School of MedicineSendaiJapan Department of Ophthalmology Tohoku University Graduate School of MedicineSendaiJapan Department of Retinal Disease Control Tohoku University Graduate School of MedicineSendaiJapan Department of Advanced Ophthalmic Medicine Tohoku University Graduate School of MedicineSendaiJapan Department of Developmental Biology Washington University School of MedicineSt.LouisMOUSA

Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.

关键词： allopregnanolone autophagy enantiomers excitotoxicity gamma-aminobutyric acid type A receptors glaucoma optic nerve oxysterols

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Modification to poloidal charge exchange recombination spectroscopy measurement in JT-60U tokamak

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Chinese Physics B 2007年第11期16卷 3434-3442页

作者：丁伯江 Sakamoto Yoshiteru^b Miura yukitoshi^b Institute of Plasma Physics Chinese Academy of SciencesHefei230031China Japan Atomic Energy Agency Naka-machiNaka-gunIbaraki 311-0193Japan

With consideration of the effects of the atomic process and the sight line direction on the charge exchange re-combination spectroscopy （CXRS）, a code used to modify the poloidal CXRS measurement on Tokamak-60 Upgrade （JT-60U） in Japan Atomic Energy Research Institute is developed, offering an effective tool to modify the measurement and analyse experimental results further. The results show that the poloidal velocity of ion is overestimated but the ion temperature is underestimated by the poloidal CXRS measurement, and they also indicate that the effect of observation angle on rotation velocity is a dominant one in a core region （r/a 〈 0.65）, whereas in an edge region where the sight line is nearly normal to the neutral beam, the observation angle effect is very small. The difference between the modified velocity and the neoclassical velocity is not larger than the error in measurement. The difference inside the internal transport barrier （ITB） region is 2-3 times larger than that outside the ITB region, and it increases when the effect of excited components in neutral beam is taken into account. The radial electric field profile is affected greatly by the poloidal rotation term, which possibly indicates the correlation between the poloidal rotation and the transport barrier formation.

关键词： atomic process charge exchange recombination spectroscopy （CXRS） modification,plasma

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Relationship between ghrelin, Helicobacter pylori and gastric mucosal atrophy in hemodialysis patients

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World Journal of Gastroenterology 2016年第47期22卷 10440-10449页

作者： Hitomi Ichikawa Mitsushige Sugimoto yukitoshi Sakao Shu Sahara Naro Ohashi Akihiko Kato Ken Sugimoto Takahisa Furuta Akira Andoh Tadashi Sakao Hideo Yasuda First Department of Medicine Hamamatsu University School of Medicine Hamamastsu Shizuoka 431-3192 Japan Division of Digestive Endoscopy Shiga University of Medical Science Hospital Otsu Shiga 520-2192 Japan Hamana Clinic Hamana Clinic Hamamatsu Shizuoka 434-0037 Japan Blood Purification Unit Hamamatsu University School of Medicine Hamamastsu Shizuoka 431-3192 Japan Center for Clinical Research Hamamatsu University School of Medicine Hamamastsu Shizuoka 431-3192 Japan Department of Gastroenterology Shiga University of Medical Science HospitalOtsu Shiga 520-2192 Japan

AIM To investigate the relationship between plasma ghrelin level, Helicobacter pylori(H. pylori) infection status and the severity of atrophy in hemodialysis patients.METHODS One hundred eights patients who received hemodialysis and 13 non-hemodialysis H. pylori-negative controlsunderwent gastroduodenoscopy to evaluate the severity of gastric atrophy. Serum levels of pepsinogen(PG) were measured as serum markers of gastric atrophy. H. pylori infection was evaluated by anti-H. pylori IgG antibody, rapid urease test and culture test. We classified H. pylori infection status as non-infection, present infection and past infection. In addition, plasma acyl-ghrelin and desacyl-ghrelin levels were measured by enzyme-linked immunosorbent assay. RESULTS Infection rate of H. pylori was 45.4%(49/108). Acylghrelin level in the non-infection group(39.4 ± 23.0 fmol/ml) was significantly higher than in the past(23.4 ± 19.9 fmol/ml, P = 0.005) and present infection groups(19.5 ± 14.0 fmol/ml, P < 0.001). Furthermore, desacyl-ghrelin level in the non-infection group(353.2 ± 190.2 fmol/ml) was significantly higher than those in the past(234.9 ± 137.5 fmol/ml, P = 0.008) and present infection groups(211.8 ± 124.2 fmol/ml, P < 0.001). Acyl-ghrelin was positively correlated with the PG Ⅰ level and PG Ⅰ/Ⅱ ratio(|R| = 0.484, P < 0.001 and |R| = 0.403, P < 0.001, respectively). Both ghrelins were significantly decreased in accordance with the progress of endoscopic atrophy(both P < 0.001) and acyl-ghrelin was significantly lower in patients with mild, moderate and severe atrophy(24.5 ± 23.1 fmol/ml, 20.2 ± 14.9 fmol/ml and 18.3 ± 11.8 fmol/ml) than in those with non-atrophy(39.4 ± 22.2 fmol/ml, P = 0.039, P = 0.002 and P < 0.001, respectively).CONCLUSION In hemodialysis patients, plasma ghrelin level was associated with the endoscopic and serological severity of atrophy related to H. pylori infection.

关键词： Acyl-ghrelin Desacyl-ghrelin Helicobacter pylori Hemodialysis Pepsinogen

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Evaluation of novel slim biopsy forceps for diagnosis of biliary strictures: Single-institutional study of consecutive 360 cases(with video)

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World Journal of Gastroenterology 2017年第35期23卷 6429-6436页

作者： Kenjiro Yamamoto Takayoshi Tsuchiya Takao Itoi Shujiro Tsuji Reina Tanaka Ryosuke Tonozuka Mitsuyoshi Honjo Shuntaro Mukai Kentaro Kamada Mitsuru Fujita Yasutsugu Asai yukitoshi Matsunami Yuichi Nagakawa Hiroshi Yamaguchi Atsushi Sofuni Department of Gastroenterology and Hepatology Tokyo Medical University Third Department of Surgery Tokyo Medical University Department of Pathology Tokyo Medical University

AIM To evaluate the feasibility and reliability of endoscopic transpapillary bile duct biopsy for the diagnosis of biliary strictures.METHODS A total of 360 patients(241 men) who underwent endoscopic retrograde cholangiopancreatography for biliary strictures with biopsy from April 2012 to March 2016 at Tokyo Medical University Hospital were retrospectively reviewed. This study was approved by our Institutional Review Board(No. 3516). Informed consent was obtained from all individual participants included in this study. The biopsy specimens were obtained using a novel slim biopsy forceps(Radial Jaw 4P, Boston Scientific, Boston, MA, United States).RESULTS The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 69.6%, 100%, 100%, 59.1%, and 78.8%, respectively. The sensitivity was 75.6% in bile duct cancer, 64% in pancreatic cancer, 61.1% in gallbladder cancer, and 57.1% in metastasis. In bile duct cancer, a lower sensitivity was observed for perihilar bile duct stricture(68.7%) than for distal bile duct stricture(83.1%). In terms of the stricture lengths of pancreatic cancer, gallbladder cancer, and metastasis, a longer stenosis resulted in a better sensitivity. In particular, there was a significant difference between pancreatic cancer and gallbladder cancer(P < 0.05). One major complication was perforation of the extrahepatic bile duct with bile leakage. CONCLUSION Endoscopic transpapillary biopsy alone using novel slim biopsy forceps is feasible and reliable, but restrictive. Biopsy should be performed in consideration of the stricture level, stricture length, and cancer type.

关键词： Endoscopic transpapillary biopsy Biopsy forceps Biliary stricture Bile duct cancer Endoscopic retrograde cholangiography

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New Indoor Accelerated Weathering Condition for Approximating Molecular Weight Distribution of Outdoor-Exposed LDPE

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Journal of Chemistry and Chemical Engineering 2015年第8期9卷 481-493页

作者： Takashl Miwa yukitoshi Takeshita Yuichi Akage Masamitsu Watanabe Masaaki Takaya Takashi Sawada NTT Device Technology Labs NTT Corporation 3-1 Morinosato-Wakamiya Atsugi-shi Kanagawa 2430198 Japan Technical Assistance and Support Center NIT East Corporation 1-2-5 kamata-honcho Ota-ku Tokyo 1440053 Japan

LDPE (low-density polyethylene) photo degraded through various accelerated weathering tests has the molecular weight distribution curves unlike that through outdoor exposure. The authors therefore developed new weathering test condition based on the existing accelerated weathering test using a xenon arc lamp. Samples of LDPE were photo degraded using various accelerated weathering test conditions and outdoor exposure. The physical properties and chemical structures of the photo degraded samples were studied through a tensile test, infrared spectroscopy, and gel chromatography. The authors found that the molecular weight distribution curve of a sample photo degraded using a xenon lamp at a higher BPT (black panel temperature) (73 °C) was more similar to that of an outdoor-exposed sample than that of a sample photo degraded at the standard BPT (63 °C). It is considered that higher temperature accelerates radical recombination, consequently recreating molecular enlargement similar to the outdoor-exposed sample. Multiple regression analysis using newly introduced Mp (peak-top molecular weight) and Mw (weight-average molecular weight) as explanatory variables was conducted, which successfully enabled the authors to provide a simple explanation for the decrease in polymer tensile strength.

关键词：分子量分布加速老化试验户外曝晒 LDPE 室内低密度聚乙烯多元回归分析分布曲线

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Water Absorption and Degraded Stress Relaxation Behavior in Water-Borne Anticorrosive Urethane/Epoxy Coatings

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Journal of Chemistry and Chemical Engineering 2015年第2期9卷 75-89页

作者： yukitoshi Takeshita Ethan Becker Seizo Sakata Takuya Kamisho Takashi Miwa Takashi Sawada NTT Energy and Environment Systems Laboratories Nippon Telegraph and Telephone Corporation Tokyo 180-8585 Japan Chemistry and Engineering Physics University of Wiseonsin-Platteville W15 3818 USA

The kinetics of water absorption in water-borne anticorrosive urethane/epoxy coatings, which were actually introduced in the industrial field, are studied. It is found that the high water affinity of a water-borne coating supports a higher saturated water content, M∞, and helps to facilitate absorption D. The three parameters of stretched exponential function called the William-Watt equation, Eo, τ, and β, are determined to fit the degraded stress relaxation behavior in the water absorption process because this function quantitatively describes the relaxing ability and has been successfully used by a number of researchers. An increasing in the water content is shown to correlate strongly with a decrease in Eo and β early in the absorption process between Mt/M∞ = 0 and Mt/M∞ ≈ 0.5. The adhesive characteristics of the coatings are correlated with water content, and shown to exhibit higher cohesive failure in coating epoxies under saturated conditions. This suggests that water interferes with the intermolecular bonding between polymer chains which degrades the bulk materials ability to diffuse stress concentrations and reduces its overall strength.

关键词：应力松弛行为水性聚氨酯环氧树脂涂料防腐吸水性指数函数佛罗里达州环氧涂料

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Surgical Resection of a Rapidly Growing Giant Pericardial Cyst: A Case Report

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International Journal of Clinical Medicine 2012年第6期3卷 554-558页

作者： Masanori Yokoba Chiaki Kusanagi Naomi Kuroudu yukitoshi Satoh Noriyuki Masuda Masato Katagiri Department of Clinical Laboratories Kitasato University Kitasato Japan Department of Pulmonary Medicine Kitasato University Kitasato Japan Department of Thoracic Surgery Kitasato University Hospital Kitasato Japan

We report here a case of a patient who underwent surgical resection of a giant pericardial cyst that was growing rapidly, causing anterior chest pain. An asymptomatic 56-year-old woman underwent a complete medical checkup in a health-care center. Her chest X-ray showed an unusually large bulge on the left cardiac border, and she was referred to our hospital. The chest X-ray taken 2 years ago in another hospital showed similar bulge on the same left cardiac border, but it was noticeably smaller. Chest CT revealed a 9.5 × 4.5 cm pericardial cyst within the anterolateral aspect of the left cardiac border. The CT number of the mass was approximately 15 - 20 HU. The mass also showed slight hyperintensity on T1-weighted MR images and hyperintensity on T2-weighted MR images. Four weeks later, she experienced anterior chest pain for the first time, and the chest X-ray and CT showed an increase in the size of the pericardial cyst. The CT number of the mass increased to approximately 30 - 40 HU. The cyst was successfully removed by video-assisted thoracic surgery. The pericardial cyst was diagnosed as benign according to the results of histopathology. We conclude that the rapid growth of the pericardial cyst was caused by intracystic hemorrhage that originated from vascularized connective tissue in the cyst wall.

关键词： Pericardial Cyst Intracystic Hemorrhage Video-Assisted Thoracic Surgery Mediastinal Mass

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A Rare Case of Cervical Dumbbell Meningioma with the C2 Spinous Process Preservation

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Open Journal of Orthopedics 2016年第4期6卷 98-102页

作者： Tatsuya Sato Takatoshi Okuda Tsuyoshi Saito Ikuho Yonezawa Shingo Onda yukitoshi Shimamura Kei Yoshikawa Hiromitsu Takano Kazuo Kaneko Department of Orthopedic Surgery Juntendo University School of Medicine 2-1-1 Hongo Tokyo Japan Department of Human Pathology Juntendo University School of Medicine 2-1-1 Hongo Tokyo Japan

Dumbbell growth is often observed in schwannoma but rarely in meningioma. In particular, the occurrence of dumbbell meningioma at the cervical cord level in Japan is markedly rare. We reported an elderly case with sym... 详细信息

关键词： Dumbbell Meningioma Spinous Process Preservation Cervical Spine Spinal Tumor Spinal Surgery

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