Publications by authors named "Kenji Ono"

87 Publications

The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model.

Biomed Pharmacother 2021 Aug 21;140:111738. Epub 2021 May 21.

Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Background: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC.

Methods: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy.

Findings: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver.

Interpretation: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.
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http://dx.doi.org/10.1016/j.biopha.2021.111738DOI Listing
August 2021

Secretion of signal peptides via extracellular vesicles.

Biochem Biophys Res Commun 2021 Jun 5;560:21-26. Epub 2021 May 5.

Department of Brain Function, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan; Department of Molecular Pharmacokinetics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 464-8601, Japan.

Signal peptides (SPs) consist of short peptide sequences present at the N-terminal of newly synthesizing proteins and act as a zip code for the translocation of the proteins to the endoplasmic reticulum (ER). It was thought that the SPs are intracellularly degraded after translocation to the ER; however, recent studies showed cleaved SPs have diverse roles for controlling cell functions in auto- and/or intercellular manners. In addition, it still remains obscure how SP fragments translocate away from the site where they are produced. Extracellular vesicles (EV) are important for intercellular communication and can transport functional molecules to specific cells. In this study, we show that SPs are involved in EV from T-REx AspALP cells that were transfected with a human APP SP-inducible expression vector. There was no difference in the average particle size or particle concentration of EV collected from T-REx AspALP cells and T-REx Mock cells. When the SP content in the EV was examined by mass spectrometry, the C-terminal fragment of APP SP was identified in the exosomes (SEV) of T-REx AspALP cells. In our preparation of SEV fractions, no ER-specific proteins were detected; therefore, SPs may be included in SEV but not in the debris of degraded ER. This is the first indication that SPs are secreted from cells via EV.
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http://dx.doi.org/10.1016/j.bbrc.2021.04.073DOI Listing
June 2021

A case of pleuroperitoneal communication in which establishing a laparoscopic pneumoperitoneum was useful for the detection of a fistula.

Surg Case Rep 2021 Mar 5;7(1):64. Epub 2021 Mar 5.

Thoracic Surgery, Kokura Memorial Hospital, Asano, Kokurakita-ku, Kitakyushu, Fukuoka, 802-8555, Japan.

Background: Pleuroperitoneal communication (PPC) is rarely observed, accounting for 1.6% of all patients who undergo continuous ambulatory peritoneal dialysis (CAPD). Although there have been several reports concerning the management of this condition, we have encountered several cases in which control failed. We herein report a valuable case of PPC in which laparoscopic pneumoperitoneum with video-assisted thoracic surgery (VATS) was useful for supporting the diagnosis and treatment.

Case Presentation: The patient was a 58-year-old woman with chronic renal failure due to chronic renal inflammation who was referred to a nephrologist in our hospital to undergo an operation for the induction of CAPD. Post-operatively, she had respiratory failure, and chest X-ray and computed tomography (CT) showed right-sided hydrothorax that decreased when the injection of peritoneal dialysate was interrupted. Therefore, PPC was suspected, and she was referred to our department for surgical repair. We planned surgical treatment via video-assisted thoracic surgery. During the surgery, we failed to detect any lesions with thoracoscopy alone; we therefore added a laparoscopic port at her right-sided abdomen near the navel and infused CO gas into the abdominal cavity. On thoracoscopy, bubbles were observed emanating from a small pore at the central tendon of the diaphragm, which was considered to be the lesion responsible for the PPC. We closed it by suturing directly.

Conclusions: VATS with laparoscopic pneumoperitoneum should be considered as an effective method for inspecting tiny pores of the diaphragm, especially when the lesions responsible for PPC are difficult to detect.
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http://dx.doi.org/10.1186/s40792-021-01147-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933319PMC
March 2021

Voxel-based simulation of flow and temperature in the human nasal cavity.

Comput Methods Biomech Biomed Engin 2021 Mar 23;24(4):459-466. Epub 2020 Oct 23.

Graduate School of Engineering, Chiba University, Chiba, Japan.

The nasal airway is an extremely complex structure, therefore grid generation for numerical prediction of airflow in the nasal cavity is time-consuming. This paper describes the development of a voxel-based model with a Cartesian structured grid, which is characterized by robust and automatic grid generation, and the simulation of the airflow and air-conditioning in an individual human nasal airway. Computed tomography images of a healthy adult nose were used to reconstruct a virtual three-dimensional model of the nasal airway. Simulations of quiet restful inspiratory flow were then performed using a Neumann boundary condition for the energy equation to adequately resolve the flow and heat transfer. General agreements of airflow patterns, which were a high-speed jet posterior to the nasal valve and recirculating flow that occupied the anterior part of the upper cavity, and temperature distributions of the airflow and septum wall were confirmed by comparing measurements with numerical simulation results.
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http://dx.doi.org/10.1080/10255842.2020.1836166DOI Listing
March 2021

Unusual giant multilocular mesothelial cyst of mediastinum.

Surg Case Rep 2020 Oct 1;6(1):249. Epub 2020 Oct 1.

Thoracic Surgery, Kokura Memorial Hospital, Asano, Kokurakita-ku, Kitakyushu-shi, Fukuoka, 802-8555, Japan.

Background: Intrathoracic mesothelial cysts are congenital lesions induced by the abnormal development of the pericardial coelom. There have been a few reports of giant mesothelial cyst of the superior mediastinum, but the preferred treatment remains a controversial topic. We herein report a rare case of successful removal of giant mesothelial cyst that was incidentally detected during a medical checkup.

Case Presentation: A 53-year-old man with a feeling of mild chest tightness was referred to our hospital for the evaluation of an abnormal shadow of the mediastinum on chest X-ray. Computed tomography showed a multilocular, homogenous, large cyst in the superior mediastinum measuring 18 cm in size without contrast enhancement and with spotty calcification, and magnetic resonance imaging showed a low intensity on T1-weighted images and high intensity on T2-weighted images. Therefore, a cystic thymoma, thymic cyst, lymphangioma, cystic teratoma or pericardial cyst was suspected as the preoperative diagnosis. Despite mild symptoms, the patient underwent total thymectomy under median sternotomy for an appropriate diagnosis and treatment. The pathological diagnosis was giant multilocular mesothelial cyst.

Conclusions: Intrathoracic mesothelial cyst is a benign cyst and generally asymptomatic, but can sometimes induce critical chest clinical symptoms if untreated, depending on its size. In our case, complete surgical resection and a detailed pathological evaluation was effective for making the appropriate diagnosis and delivering treatment. In addition, an immunohistological evaluation is effective for diagnosing mesothelial cysts when it is difficult to distinguish the cyst from other cystic lesions.
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http://dx.doi.org/10.1186/s40792-020-01011-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527379PMC
October 2020

Multifocal cholesterol granulomas of the anterior mediastinum.

Surg Case Rep 2020 Jul 28;6(1):182. Epub 2020 Jul 28.

Thoracic surgery, Kokura Memorial Hospital, Asano, Kokurakita-ku, Kitakyushu-shi, Fukuoka, 802-8555, Japan.

Background: Cholesterol granuloma in the mediastinum is rarely observed, accounting for 1% of all mediastinum tumors. There have been only a few reports of multifocal cholesterol granulomas of the thymus. We herein report a rare case of multifocal cholesterol granuloma in the thymus that was incidentally detected during follow-up of an aortic aneurysm.

Case Presentation: The patient was a 70-year-old man with dyslipidemia and hypertension who was referred to our hospital to undergo an operation for chest aortic aneurysm. Preoperative computed tomography (CT) showed 4 lesions in the anterior mediastinum measuring up to 4 cm in size with slight contrast enhancement and spotty calcification. Therefore, a thymoma, bronchogenic cyst, or lymphangioma were considered as the preoperative diagnosis. The patient underwent total thymectomy under thoracotomy followed by aortic arch replacement for the aortic aneurysm. The pathological diagnosis was multifocal cholesterol granulomas in the thymus.

Conclusions: Cholesterol granulomas should be included in the differential diagnosis of cystic tumor in the mediastinum, especially in patients with basal disease such as dyslipidemia and hypertension, which may lead to aortic aneurysm. Furthermore, complete surgical resection and a detailed histological evaluation are important for the accurate diagnosis and treatment.
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http://dx.doi.org/10.1186/s40792-020-00943-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387393PMC
July 2020

Chemical sequential extraction of O horizon samples from Fukushima forests: Assessment for degradability and radiocesium retention capacity of organic matters.

J Environ Radioact 2020 Sep 5;220-221:106306. Epub 2020 Jun 5.

Center for Forest Restoration and Radioecology, Forestry and Forest Products Research Institute, 1 Matsunosato, Tsukuba, Ibaraki, 305-8687, Japan.

To investigate how radiocesium (Cs) is retained in the O horizon via interactions with organic matter, we collected O horizon samples in Japanese cedar (Cryptomeria japonica) and konara oak (Quercus serrata) forest sites in Fukushima during the 8 years following the Fukushima Dai-ichi Nuclear Power Plant accident. To assess degradability and Cs retention capacity of organic matter, we conducted chemical sequential extraction with organic solvent and sulfuric acid, collecting the following fractions: organic solvent extractives (Fraction 1), acid-soluble carbohydrates (Fraction 3), and acid-insoluble residue (Fraction 4). In all samples, across sampling years and sites, Cs content in Fractions 1, 3, and 4, as a proportion of the total Cs content, was 0.0-23.6%, 18.4-42.9%, and 44.8-76.0%, respectively. Generally, Cs is considered to be electrostatically bound to organic matter and relatively mobile, making it easily extractable by sulfuric acid treatment. However, we observed a relatively high proportion of Cs in Fraction 4, suggesting strong retention of Cs and their immobility in the O horizon. Complex organic matter such as lignin or tannin may contribute this retention. We also noted that some part of Cs may be also retained by clay minerals in the O horizon. Although organic matter in Fractions 1 and 3 is considered to decompose faster than that in Fraction 4, over the observation period the Cs proportion and net rate of decrease in Cs content (in total and in each fraction) remained nearly constant. This result implies that decomposition of organic matter and the consequent release of bound Cs may be partly compensated by additional input of Cs from the canopy and Cs recycling by soil microorganisms. Our study highlights the potential role of organic matter in the O horizon as a temporary reservoir of Cs and a driver of the Cs cycle in forest ecosystems.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106306DOI Listing
September 2020

Superior vena cava replacement combined with venovenous shunt for thymic carcinoma.

Int J Surg Case Rep 2020 6;72:104-107. Epub 2020 Jun 6.

Thoracic Surgery, Kokura Memorial Hospital, Kitakyushu, Japan.

Introduction: Advanced-stage thymic malignancies are a heterogeneous group of mediastinal tumors that include thymoma and thymic carcinoma infiltrating the surrounding thoracic structures. When the tumor infiltrates the superior vena cava (SVC), radical resection can be selectively achieved via en bloc SVC resection and its prosthetic conduit replacement. We herein report a case of SVC replacement for thymic carcinoma en bloc radical resection.

Case Presentation: A 75-year-old Japanese man presented at our hospital due to progressive dyspnea and edema of his face and upper extremities. CT showed a 55 × 40 × 38-mm tumor located at the anterior mediastinum lesion. This tumor had invaded the superior vena cava and both brachiocephalic veins. We performed surgical resection for the thymic carcinoma located at the mediastinum that invaded the superior vena cava and both brachiocephalic veins. The surgery was performed through a full median sternotomy and transmanubrial approach without using an artificial heart and lung. The tumor involved the SVC, right brachiocephalic vein (RBCV) and left brachiocephalic vein (LBCV). We performed SVC replacement for thymic carcinoma en bloc radical resection.

Discussion: This report has two important implications. First, a venovenous shunt (VVS) from the distal LBCV to the right auricle was very useful and safe before performing an SVC complete clamp. The second implication of our study was that using a PTFE with a large inner diameter may prevent thrombus occlusion.

Conclusions: We experienced SVC replacement for thymic carcinoma en bloc radical resection. We were able to safely performed this surgery using our usual approach.
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http://dx.doi.org/10.1016/j.ijscr.2020.05.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298324PMC
June 2020

A minimally invasive and safe surgical approach to resect anterior superior sulcus tumors.

Int J Surg Case Rep 2020 28;68:148-150. Epub 2020 Feb 28.

Thoracic Surgery, Kokura Memorial Hospital, Kitakyushu-shi, Japan.

Introduction: Superior sulcus tumors (SSTs) are a wide range of tumors invading a section of the apical chest wall called the thoracic inlet. The unique characteristics of SSTs lie in the anatomy of the region where these tumors occur. For this reason, a surgical approach to treating these tumors is technically demanding, and complete resection may be difficult to accomplish.

Case Presentation: A 71-year-old Japanese man presented at our hospital due to left anterior chest pain and an abnormal chest CT scan showing a 40 × 33 × 30-mm tumor located in the left anterior apex of the thoracic inlet. This tumor had invaded the first and second rib and was located near the subclavian vein. There was no significant distant metastasis. Therefore, we performed surgical resection. The surgical procedure included three steps. First, we performed VATS observation via the left thoracic cavity. Second, via the transmanubrial approach, we obtained tumor-free margins of the anterior cervical structures. Third, through VATS in the left lateral decubitus position, we performed left upper lobectomy and mediastinal lymph node dissection. This surgery was successful, with no postoperative complications.

Disucussion: This surgical approach was effective and safe for treating a superior sulcus tumor located the anterior apex of the thoracic inlet. Next, VATS lobectomy is minimally invasive and safe after the transmanubrial approach for managing anterior superior sulcus tumor.

Conclusion: We experienced a case of locally advanced superior sulcus tumor located at the anterior apex of the thoracic inlet and performed complete resection.
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http://dx.doi.org/10.1016/j.ijscr.2020.02.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058854PMC
February 2020

Two extremely rare cases of extrapleural hematoma.

Surg Case Rep 2019 Dec 16;5(1):200. Epub 2019 Dec 16.

Thoracic Surgery, Kokura Memorial Hospital, Asano, Kokurakita-ku, Kitakyushu-shi, Fukuoka, 802-8555, Japan.

Background: Extrapleural hematoma is uncommon. However, according to the size of hematoma and/or the progression of anemia, surgical treatment to control bleeding might be necessary because a huge hematoma can cause ventilator and circulatory disturbances to press heart and lung. We present two unusual cases of huge extrapleural hematoma in an anticoagulated patient with no apparent history of trauma or otherwise traumatic episodes.

Case Presentation: Case 1: A 78-year-old man presented to our emergency department with pain in his right shoulder and disturbance of consciousness. He had no apparent history of trauma. Computed tomography (CT) of the chest revealed the presence of a huge lens-like encapsulated lesion measuring 220 × 90 mm in the right thoracic cavity. These findings all supported a diagnosis of extrapleural hematoma with hemothorax. Case 2: A 73-year-old man was brought to our hospital by ambulance after bruising his back in his house. CT of the chest revealed the presence of a huge lens-like encapsulated lesion measuring 230 × 70 mm in the left thoracic cavity. Hemorrhagic effusion was obtained by thoracocentesis, and the lesion was suspected of being a hematoma. In both two cases, we performed video-assisted thoracic surgery (VATS), which was minimally invasive and effective. These two patients were cured and discharged smoothly after surgery.

Conclusions: We reported two rare cases of extrapleural hematoma. This disease requires close attention when it manifests in patients undergoing anticoagulation therapy. Regarding treatment, VATS was particularly effective in these cases.
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http://dx.doi.org/10.1186/s40792-019-0760-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915188PMC
December 2019

Novel Oxindole-Curcumin Hybrid Compound for Antioxidative Stress and Neuroprotection.

ACS Chem Neurosci 2020 01 18;11(1):76-85. Epub 2019 Dec 18.

NAGARAGAWA Research Center, API Co., Ltd. , Gifu 502-0071 , Japan.

Oxidative stress plays an important role in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The oxindole compound GIF-2165X-G1 is a hybrid molecule composed of the oxindole skeleton of the neuroprotective compound GIF-0726-r and the polyphenolic skeleton of the antioxidant curcumin. We previously reported that novel oxindole derivatives such as GIF-0726-r and GIF-2165X-G1 prevent endogenous oxidative stress-induced cell death in mouse hippocampal HT22 cells. In this study, we present a detailed investigation of the effect of GIF-2165X-G1 on endogenous oxidative stress in HT22 cells in comparison with GIF-0726-r and curcumin. GIF-2165X-G1 exhibited more potent neuroprotective activity than GIF-0726-r or curcumin and had less cytotoxicity than that observed with curcumin. Both GIF-0726-r and GIF-2165X-G1 were found to have ferrous ion chelating activity similar to that exhibited by curcumin. GIF-2165 X-G1 and curcumin induced comparable antioxidant response element transcriptional activity. Although the induction of heme oxygenase-1, an antioxidant response element-regulated gene product, was much stronger in curcumin-treated cells than in GIF-2165X-G1-treated cells, it turned out that the induction of heme oxygenase-1 is dispensable for neuroprotection. These results demonstrate that the introduction of the polyphenol skeleton of curcumin to the oxindole GIF-0726-r improves neuroprotective features. Furthermore, intrastriatal injection of GIF-2165X-G1 alleviated apomorphine-induced rotation and prevented dopaminergic neuronal loss in a 6-hydroxydopamine mouse model of Parkinson's diseases. Collectively, our novel findings indicate that the novel oxindole compound GIF-2165X-G1 serves to delay the progression of Parkinson's disease by suppressing oxidative stress.
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http://dx.doi.org/10.1021/acschemneuro.9b00619DOI Listing
January 2020

Voxel-based modeling of airflow in the human nasal cavity.

Comput Methods Biomech Biomed Engin 2019 Feb 18;22(3):331-339. Epub 2019 Feb 18.

a Graduate School of Engineering , Chiba University , Chiba , Japan.

This paper describes the simulation of airflow in human nasal airways using voxel-based modeling characterized by robust, automatic, and objective grid generation. Computed tomography scans of a healthy adult nose are used to reconstruct 3D virtual models of the nasal airways. Voxel-based simulations of restful inspiratory flow are then performed using various mesh sizes to determine the level of granularity required to adequately resolve the airflow. For meshes with close voxel spacings, the model successfully reconstructs the nasal structure and predicts the overall pressure drop through the nasal cavity.
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http://dx.doi.org/10.1080/10255842.2018.1555584DOI Listing
February 2019

Frankia communities at revegetating sites in Mt. Ontake, Japan.

Antonie Van Leeuwenhoek 2019 Jan 28;112(1):91-99. Epub 2018 Aug 28.

Department of Forest Soil, Forestry and Forest Products Research Institute, Matsunosato 1, Tsukuba, 305-8687, Japan.

In 1984 at Mt. Ontake in Japan, an earthquake caused a devastating landslide, and as a result, the vegetation on the south slope of the mountain was completely eliminated. In higher elevation (2000 m) areas, revegetation has not yet been completed even 30 years after the landslide. Revegetation progress throughout the area was heterogeneous. In the partially revegetated areas, actinorhizal plant species such as Alnus maximowiczii and Alnus matsumurae have been found. In the present study, we investigated the Frankia communities in the higher-elevation area using sequence analysis of the amplified nifH (dinitrogenase reductase) gene from nodule and soil samples collected in the disturbed region, undisturbed forest, and in the boundary between the disturbed region and the undisturbed forest. Phylogenetic analysis of partial nifH sequences revealed the presence of six clusters, each of which consisted of highly similar (> 99%) sequences. Four clusters showed significant sequence similarity to Frankia (three Alnus- and a Casuarina-infecting strains). Diversity in the Frankia community was relatively low-only one or two clusters were detected in a site. At most of the sampling sites, a dominant cluster in a nodule coincided with that in rhizosphere soil, indicating that community structure in the rhizosphere is a primary factor that determines occupancy in a nodule. No significant difference in community structure was observed between plant species. Diversity in the Frankia community varied depending on revegetation progress. Cluster A, which was the most dominant in the disturbed region, was likely to have invaded from undisturbed forest.
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http://dx.doi.org/10.1007/s10482-018-1151-4DOI Listing
January 2019

High-density lipoprotein suppresses tumor necrosis factor alpha production by mycobacteria-infected human macrophages.

Sci Rep 2018 04 30;8(1):6736. Epub 2018 Apr 30.

Department of Bacteriology, Niigata University School of Medicine, Niigata, Japan.

Immune responses to parasitic pathogens are affected by the host physiological condition. High-density lipoprotein (HDL) and low-density lipoprotein (LDL) are transporters of lipids between the liver and peripheral tissues, and modulate pro-inflammatory immune responses. Pathogenic mycobacteria are parasitic intracellular bacteria that can survive within macrophages for a long period. Macrophage function is thus key for host defense against mycobacteria. These basic facts suggest possible effects of HDL and LDL on mycobacterial diseases, which have not been elucidated so far. In this study, we found that HDL and not LDL enhanced mycobacterial infections in human macrophages. Nevertheless, we observed that HDL remarkably suppressed production of tumor necrosis factor alpha (TNF-α) upon mycobacterial infections. TNF-α is a critical host-protective cytokine against mycobacterial diseases. We proved that toll-like receptor (TLR)-2 is responsible for TNF-α production by human macrophages infected with mycobacteria. Subsequent analysis showed that HDL downregulates TLR2 expression and suppresses its intracellular signaling pathways. This report demonstrates for the first time the substantial action of HDL in mycobacterial infections to human macrophages.
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http://dx.doi.org/10.1038/s41598-018-24233-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928146PMC
April 2018

Inducible nitric oxide synthase during the late phase of sepsis is associated with hypothermia and immune cell migration.

Lab Invest 2018 05 14;98(5):629-639. Epub 2018 Feb 14.

Department of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, Aichi, 466-8560, Japan.

Hypothermia is a significant sign of sepsis, which is associated with poor prognosis, but few mechanisms underlying the regulation of hypothermia are known. Inducible nitric oxide synthase (iNOS) is a key inflammatory mediator of sepsis. However, the therapeutic benefit of iNOS inhibition in sepsis is still controversial, and requires elucidation in an accurate model system. In this study, wild-type (WT) mice showed temperature drops in a biphasic manner at the early and late phase of sepsis, and all mice died within 48 h of sepsis. In contrast, iNOS-knockout (KO) mice never showed the second temperature drop and exhibited improved mortality. Plasma nitric oxide (NO) levels of WT mice increased in the late phase of sepsis and correlated to hypothermia. The results indicate that iNOS-derived NO during the late phase of sepsis caused vasodilation-induced hypothermia and a lethal hypodynamic state. The expression of the iNOS mRNA was high in the lung of WT mice with sepsis, which reflects the pathology of acute respiratory distress syndrome (ARDS). We obtained the results in a modified keyhole-type cecal ligation and puncture model of septic shock induced by minimally invasive surgery. In this accurate and reproducible model system, we transplanted the bone marrow cells of GFP transgenic mice into WT and iNOS-KO mice, and evaluated the role of increased pulmonary iNOS expression in cell migration during the late phase of sepsis. We also investigated the quantity and type of bone marrow-derived cells (BMDCs) in the lung. The number of BMDCs in the lung of iNOS-KO mice was less than that in the lung of WT mice. The major BMDCs populations were CD11b-positive, iNOS-negative cells in WT mice, and Gr-1-positive cells in iNOS-KO mice that expressed iNOS. These results suggest that sustained hypothermia may be a beneficial guide for future iNOS-targeted therapy of sepsis, and that iNOS modulated the migratory efficiency and cell type of BMDCs in septic ARDS.
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http://dx.doi.org/10.1038/s41374-018-0021-zDOI Listing
May 2018

Visualization of Arc promoter-driven neuronal activity by magnetic resonance imaging.

Neurosci Lett 2018 02 21;666:92-97. Epub 2017 Dec 21.

Department of Brain Function, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan.

Visualization of direct neuronal activity to understand brain function is one of the most important challenges in neuroscience. We have previously demonstrated that in vivo and in vitro gene expression of the ferritin reporter system could be detected by magnetic resonance imaging (MRI). In addition, increased neuronal activity induces Arc, an immediate early gene, and insertion of a destabilized fluorescent reporter dVenus under Arc promoter control has been used for monitoring neuronal activities in the brain by optical imaging. In this study, to visualize Arc promoter-driven neuronal activities directly, we generated transgenic mice and cell lines that express a destabilized fusion reporter ferritin-mKate2 under Arc promoter control. When transgenic mice and cell lines were treated with pilocarpine, a non-selective muscarinic agonist, an increase in T2-weighted image signal was successfully found in neuronal cells. There was a difference in peak time between MRI and fluorescence imaging, which might result from the binding process of iron with ferritin. Visualization of Arc promoter-driven neuronal activity is essential to understand neural mechanisms underlying cognitive processes and complex behaviors, and could be a useful tool for therapeutic approaches in the brain by MRI.
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http://dx.doi.org/10.1016/j.neulet.2017.12.041DOI Listing
February 2018

Extracellular Lactate Dehydrogenase A Release From Damaged Neurons Drives Central Nervous System Angiogenesis.

EBioMedicine 2018 Jan 7;27:71-85. Epub 2017 Dec 7.

Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.

Angiogenesis, a prominent feature of pathology, is known to be guided by factors secreted by living cells around a lesion. Although many cells are disrupted in a response to injury, the relevance of degenerating cells in pathological angiogenesis is unclear. Here, we show that the release of lactate dehydrogenase A (LDHA) from degenerating neurons drives central nervous system (CNS) angiogenesis. Silencing neuronal LDHA expression suppressed angiogenesis around experimental autoimmune encephalomyelitis (EAE)- and controlled cortical impact-induced lesions. Extracellular LDHA-mediated angiogenesis was dependent on surface vimentin expression and vascular endothelial growth factor receptor (VEGFR) phosphorylation in vascular endothelial cells. Silencing vimentin expression in vascular endothelial cells prevented angiogenesis around EAE lesions and improved survival in a mouse model of glioblastoma. These results elucidate novel mechanisms that may mediate pathologic angiogenesis and identify a potential molecular target for the treatment of CNS diseases involving angiogenesis.
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http://dx.doi.org/10.1016/j.ebiom.2017.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828296PMC
January 2018

LC-MS/MS imaging with thermal film-based laser microdissection.

Anal Bioanal Chem 2018 Jan 28;410(2):491-499. Epub 2017 Nov 28.

Department of Brain Function, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi, 464-8601, Japan.

Mass spectrometry (MS) imaging is a useful tool for direct and simultaneous visualization of specific molecules. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is used to evaluate the abundance of molecules in tissues using sample homogenates. To date, however, LC-MS/MS has not been utilized as an imaging tool because spatial information is lost during sample preparation. Here we report a new approach for LC-MS/MS imaging using a thermal film-based laser microdissection (LMD) technique. To isolate tissue spots, our LMD system uses a 808-nm near infrared laser, the diameter of which can be freely changed from 2.7 to 500 μm; for imaging purposes in this study, the diameter was fixed at 40 μm, allowing acquisition of LC-MS/MS images at a 40-μm resolution. The isolated spots are arranged on a thermal film at 4.5-mm intervals, corresponding to the well spacing on a 384-well plate. Each tissue spot is handled on the film in such a manner as to maintain its spatial information, allowing it to be extracted separately in its individual well. Using analytical LC-MS/MS in combination with the spatial information of each sample, we can reconstruct LC-MS/MS images. With this imaging technique, we successfully obtained the distributions of pilocarpine, glutamate, γ-aminobutyric acid, acetylcholine, and choline in a cross-section of mouse hippocampus. The protocol we established in this study is applicable to revealing the neurochemistry of pilocarpine model of epilepsy. Our system has a wide range of uses in fields such as biology, pharmacology, pathology, and neuroscience. Graphical abstract Schematic Indication of LMD-LC-MS/MS imaging.
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http://dx.doi.org/10.1007/s00216-017-0739-2DOI Listing
January 2018

Difference in Antibody Responses to Antigens in Japanese Tuberculosis Patients Infected with the Beijing/Non-Beijing Genotype.

J Immunol Res 2017 15;2017:4797856. Epub 2017 Jan 15.

Division of Emerging Infectious Diseases, Department of Internal Medicine, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan; Laboratory of Disaster-Related Infectious Disease, International Research Institute of Disaster Science, Tohoku University, Sendai, Miyagi 980-8574, Japan; Graduate School of Health Science Studies, Kibi International University, 8 Igamachi, Takahashi 716-8508, Japan.

The Beijing genotype (MTB), notorious for its virulence and predisposition to relapse, could be identified by spoligotyping based on genetic heterogeneity. The plasma samples from 20 cases of Beijing and 16 cases of non-Beijing MTB infected individuals and 24 healthy controls (HCs) were collected, and antibodies against 11 antigens (Rv0679c142Asn, Rv0679c142Lys, Ag85B, Ag85A, ARC, TDM-M, TDM-K, HBHA, MDP-1, LAM, and TBGL) were measured by ELISA. Compared to the HCs, the MTB infected subjects showed higher titers of anti-Ag85B IgG (positivity 58.2%) and anti-ACR IgG (positivity 48.2%). Of note, anti-ACR IgG showed higher titer in Beijing MTB infected tuberculosis (TB) patients than in HC (Kruskal-Wallis test, < 0.05), while the levels of anti-Ag85B, anti-TBGL, anti-TDM-K, and anti-TDM-M IgG were higher in non-Beijing TB patients than in HC. Moreover, anti-Ag85B IgG showed higher response in non-Beijing TB patients than in Beijing TB patients ( < 0.05; sensitivity, 76.9% versus 44.4%). The sensitivity and specificity analysis showed that 78.8% Beijing infected individuals were negative in anti-TBGL-IgG or/and anti-Ag85B-IgG, while 75.0% of those were positive in anti-TBGL-IgA or/and anti-ACR-IgG tests. These results indicate the possibility of developing antibody-based test to identify Beijing MTB.
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http://dx.doi.org/10.1155/2017/4797856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5274661PMC
March 2017

Optogenetic control of cell differentiation in channelrhodopsin-2-expressing OS3, a bipotential glial progenitor cell line.

Neurochem Int 2017 Mar 6;104:49-63. Epub 2017 Jan 6.

Department of Brain Function, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan.

Alterations in the intracellular ion environment have been identified as one of the signals playing a critical role in the control of cellular proliferation and differentiation; however, the mechanisms responsible for signal transduction remain unclear. Recent studies have reported that channelrhodopsin-2 (ChR2) is a rapidly gated blue light (BL)-sensitive cation channel suitable for the non-invasive control of ion influx. We herein examined the expression of differentiation-associated markers by photo-activation and its signal transduction in ChR2-expressing OS3 (OS3ChR2) cells, which are clonal bipotential glial progenitor cells. Increases were observed in intracellular Na and Ca concentrations in OS3ChR2 cells with BL exposure. Alterations in the intracellular ion environment, particularly in Ca, led to increases in the expression of oligodendrocyte markers including galactocerebrosides (GalC) and decreases in that of astrocyte markers such as glial fibrillary acidic protein (GFAP). These alterations also triggered activation of the ERK1/2 signaling pathway, which is involved in cell survival, and PI3K/Akt/mTOR signaling pathway, which is involved in oligodendrocyte differentiation, characterized by GalC expression. Moreover, when photo-activated OS3ChR2 cells were injected into mice with lysophosphatidyl choline (LPC)-induced demyelination, deficits in motor function were reduced. Our results demonstrated that signal transduction by ChR2-expressing glial progenitor cells may be controlled through alterations induced in the intracellular ion environment by photo-activation and results in oligodendrocyte differentiation from glial progenitor cells. Our results also suggest that ChR2-expressing glial progenitor cells have potential as a useful tool for therapeutic approaches to brain and spinal cord disorders associated with oligodendrocyte dysfunctions.
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http://dx.doi.org/10.1016/j.neuint.2016.12.022DOI Listing
March 2017

Soluble Siglec-9 suppresses arthritis in a collagen-induced arthritis mouse model and inhibits M1 activation of RAW264.7 macrophages.

Arthritis Res Ther 2016 06 7;18(1):133. Epub 2016 Jun 7.

Department of Oral and Maxillofacial Surgery/Protective Care for Masticatory Disorders, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.

Background: The aim of this study was to assess the effects of soluble sialic acid-binding immunoglobulin-type lectin (sSiglec)-9 on joint inflammation and destruction in a murine collagen-induced arthritis (CIA) model and in monolayer cultures of murine macrophages (RAW264.7 cells and peritoneal macrophages) and fibroblast-like synoviocytes (FLS) derived from patients with rheumatoid arthritis.

Methods: DBA/1J mice were immunized with type II collagen. Effects of sSiglec-9 were evaluated using a physiologic arthritis score, histological analysis, serum tumor necrosis factor (TNF)-α concentration, and the proportion of forkhead box P3 (Foxp3)-positive regulatory T (Treg) cells. In vivo biofluorescence imaging was used to assess the distribution of sSiglec-9. Levels of M1 (TNF-α, interleukin [IL]-6, and inducible nitric oxide synthase) and M2 (CD206, Arginase-1, and IL-10) macrophage markers and phosphorylation of intracellular signaling molecules were examined in macrophages, and levels of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 were examined in FLS.

Results: sSiglec-9 significantly suppressed the clinical and histological incidence and severity of arthritis. The proportion of Foxp3-positive Treg cells significantly improved and serum TNF-α concentration decreased in vivo. Although sSiglec-9 reduced the expression of M1 markers in macrophages, it did not affect the expression of M2 markers and MMPs in FLS. Nuclear factor (NF)-kB p65 phosphorylation was attenuated by sSiglec-9, and chemical blockade of the NF-kB pathway reduced M1 marker expression in RAW264.7 cells.

Conclusions: In this study, we have demonstrated the therapeutic effects of sSiglec-9 in a murine CIA model. The mechanism underlying these effects involves the suppression of M1 proinflammatory macrophages by inhibiting the NF-kB pathway. sSiglec-9 may provide a novel therapeutic option for patients with rheumatoid arthritis refractory to currently available drugs.
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http://dx.doi.org/10.1186/s13075-016-1035-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897938PMC
June 2016

Diagnostic value of antibody responses to multiple antigens from Mycobacterium tuberculosis in active and latent tuberculosis.

Diagn Microbiol Infect Dis 2015 Nov 29;83(3):278-85. Epub 2015 Jul 29.

Division of Emerging Infectious Diseases, Graduate School of Medicine, Tohoku University, 21 Seiryo-machi, Aoba-ku, Sendai, 980-8574 Miyagi, Japan; Division of Disaster-related Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Miyagi, Japan. Electronic address:

We investigated the antibody responses to 10 prospective Mycobacterium tuberculosis (MTB) antigens and evaluated their ability to discriminate between latent (LTBI) and active pulmonary tuberculosis (TB). Our results indicate that plasma levels of anti-α-crystallin (ACR), antilipoarabinomannan, anti-trehalose 6,6'-dimycolate, and anti-tubercular-glycolipid antigen antibodies were higher in patients with active TB, compared to those in the LTBI and control subjects. No differences in the antibodies were observed between the control and LTBI subjects. Antibodies against the glycolipid antigens could not distinguish between Mycobacterium avium complex (MAC)-negative TB patients and MAC-infected LTBI individuals. The most useful serological marker was antibodies to ACR, with MAC-negative TB patients having higher titers than those observed in MAC-positive LTBI and control subjects. Our data indicate that antibody to ACR is a promising target for the serological diagnosis of patients with active TB patients. When dealing with antiglycolipid antibodies, MAC coinfection should always be considered in serological studies.
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http://dx.doi.org/10.1016/j.diagmicrobio.2015.07.021DOI Listing
November 2015

Nanoparticles speckled by ready-to-conjugate lanthanide complexes for multimodal imaging.

Nanoscale 2015 Sep 24;7(36):14829-37. Epub 2015 Jul 24.

Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2217-14 Hayashi-Cho, Takamatsu, Kagawa 761-0395, Japan.

Multimodal and multifunctional contrast agents receive enormous attention in the biomedical imaging field. Such contrast agents are routinely prepared by the incorporation of organic molecules and inorganic nanoparticles (NPs) into host materials such as gold NPs, silica NPs, polymer NPs, and liposomes. Despite their non-cytotoxic nature, the large size of these NPs limits the in vivo distribution and clearance and inflames complex pharmacokinetics, which hinder the regulatory approval for clinical applications. Herein, we report a unique method that combines magnetic resonance imaging (MRI) and fluorescence imaging modalities together in nanoscale entities by the simple, direct and stable conjugation of novel biotinylated coordination complexes of gadolinium(III) to CdSe/ZnS quantum dots (QD) and terbium(III) to super paramagnetic iron oxide NPs (SPION) but without any host material. Subsequently, we evaluate the potentials of such lanthanide-speckled fluorescent-magnetic NPs for bioimaging at single-molecule, cell and in vivo levels. The simple preparation and small size make such fluorescent-magnetic NPs promising contrast agents for biomedical imaging.
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http://dx.doi.org/10.1039/c5nr00959fDOI Listing
September 2015

Novel positively charged nanoparticle labeling for in vivo imaging of adipose tissue-derived stem cells.

PLoS One 2014 3;9(11):e110142. Epub 2014 Nov 3.

Research Center for Innovative Nanobiodevices, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan; Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan; Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Hayashi-cho 2217-14, Takamatsu 761-0395, Japan.

Stem cell transplantation has been expected to have various applications for regenerative medicine. However, in order to detect and trace the transplanted stem cells in the body, non-invasive and widely clinically available cell imaging technologies are required. In this paper, we focused on magnetic resonance (MR) imaging technology, and investigated whether the trimethylamino dextran-coated magnetic iron oxide nanoparticle -03 (TMADM-03), which was newly developed by our group, could be used for labeling adipose tissue-derived stem cells (ASCs) as a contrast agent. No cytotoxicity was observed in ASCs transduced with less than 100 µg-Fe/mL of TMADM-03 after a one hour transduction time. The transduction efficiency of TMADM-03 into ASCs was about four-fold more efficient than that of the alkali-treated dextran-coated magnetic iron oxide nanoparticle (ATDM), which is a major component of commercially available contrast agents such as ferucarbotran (Resovist), and the level of labeling was maintained for at least two weeks. In addition, the differentiation ability of ASCs labeled with TMADM-03 and their ability to produce cytokines such as hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2), were confirmed to be maintained. The ASCs labeled with TMADM-03 were transplanted into the left kidney capsule of a mouse. The labeled ASCs could be imaged with good contrast using a 1T MR imaging system. These data suggest that TMADM-03 can therefore be utilized as a contrast agent for the MR imaging of stem cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110142PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217721PMC
August 2015

Protective effect of INI-0602, a gap junction inhibitor, on dopaminergic neurodegeneration of mice with unilateral 6-hydroxydopamine injection.

J Neural Transm (Vienna) 2014 Nov 18;121(11):1349-55. Epub 2014 Apr 18.

Department of Brain Function, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan.

INI-0602, a novel gap junction hemichannel inhibitor, was administered to hemi-Parkinsonism mice generated by striatal 6-hydroxydopamine injection. INI-0602 prevented the toxic activation of microglia, such as the increased number of the activated form, enlargement of cell bodies and induction of proinflammatory cytokines, such as IL-1β and TNFα, in the ipsilateral striatum. On the other hand, INI-0602 induced the expression of neurotrophic factors, such as brain-derived neurotrophic factor and NT-4/5, in the 6-hydroxydopamine-treated striatum. INI-0602 treatment blocked not only dopaminergic loss in both the striatum and substantia nigra, but also apomorphine-induced rotational behavior.
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http://dx.doi.org/10.1007/s00702-014-1209-zDOI Listing
November 2014

Glutamate release from astrocyte cell-line GL261 via alterations in the intracellular ion environment.

J Neural Transm (Vienna) 2014 8;121(3):245-57. Epub 2013 Oct 8.

Department of Brain Function, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan.

Astrocytes modify and maintain neural activity and functions via gliotransmitter release such as, glutamate. They also change their properties and functions in response to alterations of ion environment resulting from neurotransmission; however, the direct evidence for whether intracellular ion alteration in astrocytes triggers gliotransmitter release is not indicated. Recent studies have reported that channelrhodopsin-2 (ChR2) is useful for alteration of intracellular ion environment in several types of cells with blue light exposure. Here, we show that ChR2-expressing GL261 (GLChR2) cells, clonal astrocytes, change their properties by photo-activation. Increased intracellular sodium and calcium ion concentrations and an altered membrane potential were observed in GLChR2 cells with blue light exposure. Alterations in the intracellular ion environment caused intracellular acidification and the inhibition of proliferation. In addition, it triggered glutamate release from GLChR2 cells. Glutamate from GLChR2 cells acted on N18 cells, clonal neuronal cells, as both a transmitter and neurotoxin depending on photo-activation. Our results show that the properties of ChR2-expressing astrocytes can be controlled by blue light exposure, and cation influx through photo-activated ChR2 might trigger functional cation influx via endogenous channels and result in the increase of glutamate release. Further, our results suggest that ChR2-expressing glial cells could become a useful tool in understanding the roles of glial cell activation and neural communication in the regulation of brain functions.
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http://dx.doi.org/10.1007/s00702-013-1096-8DOI Listing
October 2014

Photouncaging nanoparticles for MRI and fluorescence imaging in vitro and in vivo.

ACS Nano 2013 Nov 7;7(11):9851-9. Epub 2013 Oct 7.

Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) , Takamatsu, Kagawa 761-0395, Japan.

Multimodal and multifunctional nanomaterials are promising candidates for bioimaging and therapeutic applications in the nanomedicine settings. Here we report the preparation of photouncaging nanoparticles with fluorescence and magnetic modalities and evaluation of their potentials for in vitro and in vivo bioimaging. Photoactivation of such bimodal nanoparticles prepared using photouncaging ligands, CdSe/ZnS quantum dots, and super paramagnetic iron oxide nanoparticles results in the systematic uncaging of the particles, which is correlated with continuous changes in the absorption, mass and NMR spectra of the ligands. Fluorescence and magnetic components of the bimodal nanoparticles are characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and elemental analyses using energy dispersive X-ray (EDX) spectroscopy and X-ray photoelectron spectroscopy (XPS). Bioconjugation of the nanoparticles with peptide hormones renders them with biocompatibility and efficient intracellular transport as seen in the fluorescence and MRI images of mouse melanoma cells (B16) or human lung epithelial adenocarcinoma cells (H1650). Biocompatibility of the nanoparticles is evaluated using MTT cytotoxicity assays, which show cell viability over 90%. Further, we combine MRI and NIR fluorescence imaging in C57BL/6 (B6) mice subcutaneously or intravenously injected with the photouncaging nanoparticles and follow the in vivo fate of the nanoparticles. Interestingly, the intravenously injected nanoparticles initially accumulate in the liver within 30 min post injection and subsequently clear by the renal excretion within 48 h as seen in the time-dependent MRI and fluorescence images of the liver, urinary bladder, and urine samples. Photouncaging ligands such as the ones reported in this article are promising candidates for not only the site-specific delivery of nanomaterials-based contrast agents and drugs but also the systematic uncaging and renal clearance of nanomaterials after the desired in vivo application.
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http://dx.doi.org/10.1021/nn4043699DOI Listing
November 2013

The utility of diffusion tensor imaging tractography for post-operative evaluation of a patient with hemispherotomy performed for intractable epilepsy.

Brain Dev 2014 Aug 24;36(7):641-4. Epub 2013 Aug 24.

Department of Neurosurgery, Nagasaki Medical Center, National Hospital Organization, Japan.

Hemispherotomy is an effective treatment for patients with severe epilepsy caused by hemispheric abnormalities such as hemimegalencephaly or other dysplastic malformations. Here, we report a 5-year-old boy who experienced right-side hemiconvulsion due to left hemispheric cortical dysplasia. He presented with mild right hemiparesis that had been present since seizure onset. Ictal electroencephalogram obtained during the hemiconvulsion showed localized epileptic discharges in the left hemisphere. He underwent a left peri-insular hemispherotomy. Three months after surgery, clonic convulsions returned in the left leg and EEG-video monitoring showed localized epileptic discharges in the frontal region. Magnetic resonance images showed that the genu of corpus callosum was unsectioned and diffusion tensor imaging tractography confirmed the presence of callosal fibers in the genu of the corpus callosum. Clonic convulsion disappeared after additional section of the corpus callosum. Further studies are warranted to determine the utility of diffusion tensor imaging tractography on the assessment of subcortical fibers following disconnective epilepsy surgery.
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http://dx.doi.org/10.1016/j.braindev.2013.08.001DOI Listing
August 2014

Singlet-oxygen-sensitizing near-infrared-fluorescent multimodal nanoparticles.

Angew Chem Int Ed Engl 2013 Sep 13;52(40):10559-63. Epub 2013 Aug 13.

Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Takamatsu, Kagawa 761-0395 (Japan); PRESTO (Japan) Science and Technology Agency (JST) (Japan).

Nanoprobes based on quantum clusters (QC) with near-infrared fluorescence, magnetic-resonance-imaging contrast, and singlet-oxygen-sensitized intracellular fluorescence are studied. The generation of singlet oxygen and singlet-oxygen-sensitized fluorescence uncaging by magnetic and NIR-emitting nanoparticles are exploited for multimodal bioimaging in vitro.
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http://dx.doi.org/10.1002/anie.201304264DOI Listing
September 2013

In vivo imaging of transplanted islets labeled with a novel cationic nanoparticle.

PLoS One 2013 22;8(2):e57046. Epub 2013 Feb 22.

Department of Advanced Medicine in Biotechnology and Robotics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.

To monitor pancreatic islet transplantation efficiency, reliable noninvasive imaging methods, such as magnetic resonance imaging (MRI) are needed. Although an efficient uptake of MRI contrast agent is required for islet cell labeling, commercially-available magnetic nanoparticles are not efficiently transduced into cells. We herein report the in vivo detection of transplanted islets labeled with a novel cationic nanoparticle that allowed for noninvasive monitoring of islet grafts in diabetic mice in real time. The positively-charged nanoparticles were transduced into a β-cell line, MIN6 cells, and into isolated islets for 1 hr. MRI showed a marked decrease in the signal intensity on T1- and T2-weighted images at the implantation site of the labeled MIN 6 cells or islets in the left kidneys of mice. These data suggest that the novel positively-charged nanoparticle could be useful to detect and monitor islet engraftment, which would greatly aid in the clinical management of islet transplant patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057046PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579774PMC
September 2013
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