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HBxとYAPの発現はHBV関連肝細胞癌の発生と進行を促進する
Get PDF新潟大学Niigata University博士（医学）Background: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) accounts for 10%-20% of the total HCC numbers. Its clinical features include the occurrence in the younger generation, large tumors, and poor prognosis. The contribution of hepatitis B virus X (HBx) protein in hepatocytes during activation of various oncogenic pathways has been reported. We aimed to assess the possible association between HBx and Yes-associated protein (YAP) expression in the liver tissue and the clinical features of HBV-related HCC. Methods: The relationship between HBx and YAP expression was examined in vivo using HCC tumor and peritumor tissues (n=55). The clinical information including tumor size, marker, and the prognosis was assessed with protein expressions. The in vitro gene expression analyses were conducted using HBx- and YAP-overexpressing HCC cell lines. Results: Among 19 cases of HBV-related, 17 cases of hepatitis C virus (HCV)-related, and 19 cases of nonviral-related HCC, the HBV-related tumor showed the largest size. The HBx-stained area in the tumor and peritumor tissue showed a significant correlation with tumor size and serum α-fetoprotein level. YAP expression was higher in HBV-related tumor tissue than in the peritumor tissue and HCV-related tumor. Additionally, HBx and YAP protein expressions are correlated and both expressions in the tumor contributed to the poor prognosis. An in vitro study demonstrated that HBx and YAP overexpression in the hepatocytes activate the various oncogenic signaling pathways. Conclusions: Our study demonstrated that YAP expression in the liver of HBV-infected patients might be the key factor in HBV-related HCC development and control of tumor-related features.Biochemistry and Biophysics Reports. 2022, 32, 101352.新大院博(医)第1106
非アルコール性脂肪性肝疾患モデルメダカの心筋病変に対する選択的PPARαモジュレーター、ナトリウム-グルコース共輸送体2阻害剤、スタチンの有効性の検討
Get PDF新潟大学Niigata University博士（医学）Objective: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic dysregulation and is linked with various cardiovascular complications, which often lead to poor prognostic outcomes. To develop a standard therapy for NAFLD and to urgently address its complications, the current study aimed to investigate the mechanisms of NAFLD-related heart disease and the therapeutic effects of drugs targeting various metabolic pathways. Methods: To explore the mechanism of NAFLD-related heart disease, a medaka model of high-fat diet-induced NAFLD was utilized. The gross structural, histological, and inflammatory changes in the myocardium were evaluated in a time-dependent manner. In addition, the therapeutic effects of medicines used for NAFLD treatment including, selective peroxisome proliferator-activated receptor α modulator (SPPARMα, pemafibrate), sodium-glucose cotransporter 2 (SGLT2) inhibitor (tofogliflozin), and statin (pitavastatin), and their combinations on heart pathology were evaluated. To determine the mechanisms underlying the therapeutic effects, the expression of genes related to liver inflammation was assessed via whole transcriptome sequencing analysis. Results: The fish with NAFLD-related heart injury presented with cardiomyocyte hypertrophy, which led to cardiac hypertrophy. This morphological change was caused by the infiltration of inflammatory cells, including macrophages and CD4- and CD8-positive lymphocytes, in the cardiac wall and the expression of transforming growth factor beta 1 in the cardiomyocytes. Further, the livers of the fish had upregulated expressions of senescence-associated secretory phenotype-related genes. Treatment with pemafibrate, tofogliflozin, and pitavastatin reduced these changes and, consequently, cardiomyopathy. Conclusion: Our results demonstrated that NAFLD-related heart disease was attributed to the senescence-associated secretory phenotype-induced inflammatory activity in the cardiac wall, which resulted in myocardial hypertrophy. Moreover, the effects of SPPARMα, SGLT2 inhibitor, and statin on NAFLD-related heart disease were evident in the medaka NAFLD model.Biochemical and Biophysical Research Communications. 2022, 625, 116-121.新大院博(医)第1109
深在性真菌感染症診断における新規β-D-グルカン測定試薬の、既存の測定試薬4種との比較による有効性の検討
Get PDF新潟大学Niigata University博士（医学）Background Each of the currently available (1→3)-β-D-glucan (BDG) measurement kits follows a different measurement method and cut-off value. Comparisons of diagnostic performance for invasive fungal infections (IFIs) are desirable. Additionally, ecological considerations are becoming increasingly important in the development of new measurement kits. Methods The plasma BDG levels in clinical samples were measured using the following currently available kits: the Fungitec G test MKII, the Fungitec G test ES, Fungitell, the β-Glucan test Wako, and the newly developed Wako kit (Wako-Eu). Wako-Eu uses a pre-treatment solution that conforms to European regulations for the registration, evaluation, authorisation, and restriction of chemicals. The values obtained for the samples using each kit were studied and compared. Results Of the 165 patients evaluated, 12 had IFIs, including pneumocystis pneumonia, aspergillosis, and candidiasis. BDG values obtained using the kits were moderately correlated with each other. Clinical diagnoses of the evaluated cases indicated that 21 false positives were diagnosed by at least one kit. The sensitivity of the Fungitell kit was relatively low, but those of the other four were over 90%. The specificity was above 90% for all kits. For positive predictive value, the Wako and the Wako-Eu methods were superior to the others owing to fewer false positive results. Conclusions The newly developed Wako-Eu method, which considers ecological concerns, shows diagnostic performance equivalent to that of its predecessor. To improve the diagnostic accuracy of IFIs, it is necessary to interpret the results carefully, giving due consideration to the characteristics of each measurement kit.PLOS ONE. 2021, 16(8), e0255172.新大院博(医)第1122
ミャンマーにおける小児ウイルス性急性下気道感染症の臨床像とその転帰
Get PDF新潟大学Niigata University博士（医学）Background: Acute lower respiratory infection (ALRI) remains the leading cause of death in children worldwide, and viruses have been the major cause of ALRI. In Myanmar, ALRI is associated with high morbidity and mortality in children, and detailed information on ALRI is currently lacking. Methods: This prospective study investigated the viral aetiologies, clinical manifestations, and outcomes of ALRI in hospitalised children aged 1 month to 12 years at the Yankin Children Hospital, Yangon, Myanmar from May 2017 to April 2019. The sample size was set to 300 patients for each year. Two nasopharyngeal swabs were obtained for the patients with suspected viral ALRI; one for rapid tests for influenza and respiratory syncytial virus (RSV), and the other for real-time PCR for the 16 ALRI-causing viruses. Pneumococcal colonization rates were also investigated using real-time PCR. Clinical information was extracted from the medical records, and enrolled patients were categorised by age and severity for comparison. Results: Among the 5463 patients admitted with a diagnosis of ALRI, 570 (10.4%) were enrolled in this study. The median age of the patients was 8 months (interquartile range, 4-15 months). The most common symptoms were cough (93%) and difficulty in breathing (73%), while the most common signs of ALRI were tachypnoea (78%) and chest indrawing (67%). A total of 16 viruses were detected in 502 of 570 patients' samples (88%), with RSV B (36%) and rhinovirus (28%) being the most commonly detected. Multiple viruses were detected in 221 of 570 samples (37%) collected from 570 patients. Severe ALRI was diagnosed in 107 of 570 patients (19%), and RSV B and human rhinovirus were commonly detected. The mortality rate was 5%; influenza virus A (29%) and RSV B (21%) were commonly detected, and stunting and lack of immunization were frequently observed in such cases. Additionally, 45% (259/570) of the patients had pneumococcal colonization. Conclusions: Viral ALRI in hospitalised children with a median of 8 months has significant morbidity and mortality rates in Myanmar. RSV and rhinovirus were the most commonly detected from nasopharyngeal swabs, while influenza virus and RSV were the most frequently associated with fatal cases.BMC Infectious Diseases. 2022, 22, 350.新大院博(医)第1130
麻酔ラットにおける中枢性ムスカリン受容体を介したアトロピンの水誘発嚥下の促通効果
Get PDF新潟大学Niigata University博士（歯学）Anticholinergic medication causes impaired swallowing with hyposalivation. However, the underlying mechanisms by which these drugs modulate the swallowing reflex remain unclear. This study investigated the effects of the muscarinic acetylcholine receptor (mAChR) nonspecific antagonist atropine on the initiation of swallowing. Experiments were performed on 124 urethane-anesthetized rats. A swallow was evoked by either topical laryngeal application of a small amount of distilled water (DW), saline, citric acid, or capsaicin; upper airway distention with a continuous airflow; electrical stimulation of the superior laryngeal nerve (SLN); or focal microinjection of N-methyl-D-aspartate (NMDA) into the lateral region of the nucleus of the solitary tract (L-nTS). Swallows were identified by electromyographic bursts of the digastric and thyrohyoid muscles. Either atropine, the peripheral mAChR antagonist methylatropine, or antagonists of mAChR subtypes M1-M5 were intravenously delivered. Atropine at a dose of 1 mg/kg increased the number of DW-evoked swallows compared with baseline and did not affect the number of swallows evoked by saline, citric acid, capsaicin, or upper airway distention. Methylatropine and M1-M5 antagonists did not significantly change the number of DW-evoked swallows. Bilateral SLN transection completely abolished DW-evoked swallows, and atropine decreased the swallowing threshold of SLN electrical stimulation. Finally, microinjection of NMDA receptor antagonist AP-5 into the L-nTS inhibited DW-evoked swallows, and atropine facilitated the initiation of swallowing evoked by NMDA microinjection into this region. These results suggest that atropine facilitates DW-evoked swallows via central mAChR actions. NEW & NOTEWORTHY Atropine facilitated the distilled water (DW)-evoked swallows in anesthetized rats. Atropine decreased the swallowing threshold evoked by electrical stimulation of the superior laryngeal nerve, which is a primary sensory nerve for the initiation of DW-evoked swallows. Atropine facilitated the swallows evoked by N-methyl-D-aspartate microinjection into the lateral region of the nucleus of the solitary tract, which is involved in the DW-evoked swallows. We speculate that atropine facilitates the DW-evoked swallows via central muscarinic receptor actions.American Journal of Physiology Gastrointestinal and Liver Physiology. 2023, 325(2), G109-G121.新大院博(歯)第551
Blood-Brain Barrier Abnormalities in Multiple System Atrophy : Focus on Claudin-5
Get PDF新潟大学Niigata University博士（医学）多系統萎縮症（Multiple system atrophy，MSA）は，自律神経障害，錐体外路徴候，小脳性運動失調を様々な程度で来たす稀な神経変性疾患であり，病理学的にはリン酸化 α-synuclein 陽性のオリゴデンドロサイト胞体内封入体（glial cytoplasmic inclusion: GCI）により特徴づけられる．近年，MSA では成熟オリゴデンドロサイトのみならず，その前駆細胞（oligodendrocyte precursor cell，OPC）も疾病機序に関わる可能性が指摘されている．一方，毛細血管の近傍に存在するOPC は，血液脳関門（blood-brain barrier，BBB），特に血管内皮細胞のタイトジャンクション維持に重要な役割を果たすと報告されている．これらの報告から，MSA ではOPC を介して血液脳関門が障害されると仮説を立て，この検証を目的として，MSA剖検例を対象とした病理学的研究を行った．MSAの主要病変である運動野において直径10μm 以下の毛細血管に注目し，タイトジャンクション構成タンパク質claudin-5 を免疫組織化学により定量化した．その結果，白質・皮質のいずれにおいても，claudin-5 定量値は，MSA では正常対照と比較し有意に低下していた．BBB 機能低下の指標となるfibrinogen の血管外漏出を定量化したところ，白質・皮質のいずれにおいても，MSA では正常対照と比較し有意に高値であった．さらに剖検脳組織を透明化し，光シート型顕微鏡で観察したところ，MSA の運動野白質・皮質ではIgG が血管外に漏出していた．またMSA では，OPC マーカーであるneuron-glial antigen（NG2）に陽性の細胞を毛細血管近傍に認め，これらの一部では胞体内にリン酸化α-synucleinが蓄積していた．以上より，MSA の運動野白質・皮質では，タイトジャンクション構成タンパク質の発現低下によりBBB の機能が低下することが明らかにされた．この要因として，毛細血管近傍のOPC にリン酸化α-synuclein が沈着し，それらのタイトジャンクション維持機構が障害された可能性が考えられた．新大院博（医）第1156
正弦波位相変調法を用いた光渦の位相分布計測に関する研究
Get PDF新潟大学Niigata University博士（工学）The vortex beam (VB) with a helix wavefront has a wide range of applications in optical manipulation and information processing. In the past decades, some research on the vortex phenomenon had remarkable development and the research on VB has gradually become an important branch of modern optics. The spiral wavefront of VB is characterized by characteristics phase of exp(ilθ) with the topological charge of l and the azimuth angle of θ. The unique spiral phase structure presents a hollow bright ring in the intensity distribution of VB and yields a phase singularity in the optical axis with the undefine phase and amplitude of zero. Because of the helix wavefront, each photon of VB possesses the orbital angular momentum (OAM), given by hl, related to the topological charge, where the h is the Planck constant. Considering the unique property of OAM, the VB has a wide range of applications in optical tweezers and information processing. For example, the focused VB generating the electric field gradient force can be used for capturing particle, making it rotate around the optical axis of VB. In addition, the property of OAM can be used for fabricating the chiral micro-scale structures materials as well. In the optical communication field, the OAM can have been used as an alternative degree of freedom for multiplexing modulation, thereby enlarging the capacity of optical communication, which is also referred to as mode/spatial-division multiplexing. Given these applications using the feature of the VB, the phase distribution of a wavefront of VB, which is related to the topological charge, is the one of most crucial parameters. Therefore, investigation of the property of VB and proposing the phase measurement method of VB are significant for these applications using the VB. Main research and innovations of this thesis are as follows: (1) Investigation of the property of vortex beam. The VB with the spiral phase structure is derived from wave equation under the condition paraxial approximation. Due to the spiral wavefront, each photon of VB possessing the OAM that has many applications in optical tweezers and optical communication. In the experiment, the common VB has mainly two types for Laguerre-Gaussian and Bessel beams. Considering these applications, the generation of high quality of VB is essential and the general methods of generating VB is mainly classified to Laser mode modulation and phase element. (2) Sinusoidal phase modulation method Phase measurement of the VB as well as estimation of the topological charge are significant for these applications. Some methods of phase measurement of VB have been proposed. Nevertheless, these methods have some obvious disadvantage due to the complex experimental configuration and data processing. Therefore, the Sinusoidal phase modulation method is proposed to measure the phase profile of vortex wavefront based the interferometric measurement technique with the high measurement accuracy and the simple data processing method. Due to more convenient configuration and straightforward calibration, the SPM is excellent method for phase measurement of VB. (3) Estimation method of topological charge The topological charge of VB is the one of most crucial parameters as well and defined by the maximum variation in phase distribution of the VB along to the azimuth angle. Hence, the continuous variation of phase along to azimuth angle in wrapped phase was used for estimating the topological charge. However, due to the discontinuous phase distribution in wrapped phase distribution of VB, it may lead to the enormous measurement error. For obtaining the continuous phase distribution of VB, the phase unwrapping method based on polar coordinates used for estimating the topological charge can distinguish the position of phase singularity and phase step, with high measurement accuracy. (4) Reduction of effect of phase singularity The phase singularity with an undefined phase and amplitude of zero must be reduced or eliminated in advance. Because of the intensity in the position of phase singularity being far small from other pixel of intensity of VB, the suitable threshold value of measured intensity of VB was defined to reduce the part of phase singularity only that the above the threshold value of intensity is highlighted.新大院博(工)第541