Publications by authors named "Mie Kurata"

57 Publications

Active aneurysm thrombosis after Kawasaki disease in an adult: Insight into anticoagulation therapy.

J Cardiol Cases 2021 May 21;23(5):206-209. Epub 2020 Nov 21.

Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

The management of systemic artery aneurysms secondary to Kawasaki disease (KD) in adults remains a therapeutic challenge. KD guidelines recommend the use of anticoagulation therapy with warfarin in addition to antiplatelet therapy when a giant coronary aneurysm or a history of thrombosis is documented. However, long-term use of warfarin presents several concerns. This case reports acute thrombotic occlusion due to the giant arterial aneurysm in an adult KD. A surgical resection of the aneurysm was performed because of recurrent thrombotic events, despite anticoagulant therapy with warfarin. Pathological examinations revealed a layered thrombus with inflammation in the aneurysm and Factor Xa expression mainly in newly formed thrombus. This study provides an insight into the anticoagulation therapy for cardiovascular sequelae after KD. < This study, along with pathological evidence, illustrates that Factor Xa might contribute to thrombotic events after Kawasaki disease.>.
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http://dx.doi.org/10.1016/j.jccase.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103331PMC
May 2021

The association between renal elasticity evaluated by Real-time tissue elastography and renal fibrosis.

Clin Exp Nephrol 2021 May 8. Epub 2021 May 8.

Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Background: The progression of chronic kidney disease (CKD) depends on the extent of fibrosis in the kidneys; however, a renal biopsy is necessary to evaluate the severity of renal fibrosis. Real-time tissue elastography (RTE), which measures heartbeat-induced tissue displacement, can assess the elasticity of organs. Here, we aimed to investigate the correlation between renal elasticity and the extent of fibrosis in renal biopsy samples.

Methods: We investigated 29 consecutive patients who underwent a renal biopsy at Ehime University Hospital from February 2018 to August 2019. Renal fibrosis was categorized into three grades, mild (< 25%), moderate (25-50%), and severe (> 50%), based on the total affected area within the biopsy sample. The association between renal elasticity assessed by RTE and the grade of renal fibrosis was evaluated, and a receiver operating characteristic curve was used to distinguish the severity of renal fibrosis.

Results: The mean age and estimated glomerular filtration rate (eGFR) were 58.8 years and 55.2 mL/min/1.73 m, respectively. The median urine protein-to-creatinine ratio was 1.24 g/gCr. The mean renal elasticity of mild, moderate, and severe renal fibrosis was 3.40, 3.98, and 4.77, respectively. Renal elasticity of native kidneys was significantly positively correlated with the grade of renal fibrosis (ρ = 0.529, P = 0.003). At the cutoff point of 3.81, the area under the curve, sensitivity, and specificity were 0.778, 68.4%, and 81.8%, respectively.

Conclusion: Real-time tissue elastography is a promising, non-invasive method for assessing renal fibrosis in patients with CKD.
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http://dx.doi.org/10.1007/s10157-021-02063-2DOI Listing
May 2021

A single-chain antibody generation system yielding CAR-T cells with superior antitumor function.

Commun Biol 2021 Mar 2;4(1):273. Epub 2021 Mar 2.

Division of Immune Regulation, Proteo-Science Center, Ehime University, Toon, Ehime, Japan.

Cancer immunotherapy using T cells redirected with chimeric antigen receptor (CAR) has shown a lot of promise. We have established a single-chain antibody (scFv) generation system in which scFv library-expressing CAR-T cells can be screened appropriately based on their antitumor functions. A variable region library containing the variable and J regions of the human immunoglobulin light or heavy chain was fused with the variable region of a heavy or light chain encoded by an existing tumor-specific antibody to generate a new scFv library. Then, scFv library-expressing CAR-T cells were generated and stimulated with target cells to concentrate the antigen-specific population. Using this system, target-specific recognition of CAR-T cells appeared to be finely tuned by selecting a new variable region. Importantly, we have demonstrated that the newly optimized scFv-expressing CAR-T cells had better proliferation capacity and durable phenotypes, enabling superior reactivity against advanced tumors in vivo in comparison with the original CAR-T cells. Therefore, the optimization of an scFv is needed to maximize the in vivo antitumor functions of CAR-T cells. This system may allow us to adjust an immunological synapse formed by an scFv expressed by CAR-T cells and a target antigen, representing an ideal form of CAR-T-cell immunotherapy.
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http://dx.doi.org/10.1038/s42003-021-01791-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925539PMC
March 2021

Pathological Evidence of Native Aortic Valve Injury After Impella Support.

Circ Heart Fail 2021 Feb 22;14(2):e007571. Epub 2021 Jan 22.

Department of Cardiology, Pulmonology, Hypertension, and Nephrology (H.H., J.A.., O.Y.), Ehime University Graduate School of Medicine, Toon, Japan.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007571DOI Listing
February 2021

Enhanced Masses on Contrast-Enhanced Breast: Differentiation Using a Combination of Dynamic Contrast-Enhanced MRI and Quantitative Evaluation with Synthetic MRI.

J Magn Reson Imaging 2021 02 11;53(2):381-391. Epub 2020 Sep 11.

Department of Radiology, Ehime University Graduate School of Medicine, Toon, Japan.

Background: The addition of synthetic MRI might improve the diagnostic performance of dynamic contrast-enhanced MRI (DCE-MRI) in patients with breast cancer.

Purpose: To evaluate the diagnostic value of a combination of DCE-MRI and quantitative evaluation using synthetic MRI for differentiation between benign and malignant breast masses.

Study Type: Retrospective, observational.

Population: In all, 121 patients with 131 breast masses who underwent DCE-MRI with additional synthetic MRI were enrolled.

Field Strength/sequence: 3.0 Tesla, T -weighted DCE-MRI and synthetic MRI acquired by a multiple-dynamic, multiple-echo sequence.

Assessment: All lesions were differentiated as benign or malignant using the following three diagnostic methods: DCE-MRI type based on the Breast Imaging-Reporting and Data System; synthetic MRI type using quantitative evaluation values calculated by synthetic MRI; and a combination of the DCE-MRI + Synthetic MRI types. The diagnostic performance of the three methods were compared.

Statistical Tests: Univariate (Mann-Whitney U-test) and multivariate (binomial logistic regression) analyses were performed, followed by receiver-operating characteristic curve (AUC) analysis.

Results: Univariate and multivariate analyses showed that the mean T relaxation time in a breast mass obtained by synthetic MRI prior to injection of contrast agent (pre-T ) was the only significant quantitative value acquired by synthetic MRI that could independently differentiate between malignant and benign breast masses. The AUC for all enrolled breast masses assessed by DCE-MRI + Synthetic MRI type (0.83) was significantly greater than that for the DCE-MRI type (0.70, P < 0.05) or synthetic MRI type (0.73, P < 0.05). The AUC for category 4 masses assessed by the DCE-MRI + Synthetic MRI type was significantly greater than that for those assessed by the DCE-MRI type (0.74 vs. 0.50, P < 0.05).

Data Conclusion: A combination of synthetic MRI and DCE-MRI improves the accuracy of diagnosis of benign and malignant breast masses, especially category 4 masses. Level of Evidence 4 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:381-391.
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http://dx.doi.org/10.1002/jmri.27362DOI Listing
February 2021

KN3014, a piperidine-containing small compound, inhibits auto-secretion of IL-1β from PBMCs in a patient with Muckle-Wells syndrome.

Sci Rep 2020 08 11;10(1):13562. Epub 2020 Aug 11.

Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Shitsukawa 454, Toon, Ehime, 791-0295, Japan.

NLRP3, an intracellular pattern recognition receptor, recognizes numerous pathogens and/or its own damage-associated molecules, and forms complexes with the adaptor protein ASC. These complexes constitute the NLRP3 inflammasome, a platform for processing interleukin (IL)-1β and/or IL-18. Several NLRP3 mutations result in constitutive activation of the NLRP3 inflammasome, causing cryopyrin-associated periodic syndrome (CAPS). To the best of our knowledge, small compounds that specifically inhibit inflammasome activation through the pyrin domain (PYD) have not yet been developed. This study describes an attempt to develop small compounds targeting the NLRP3 inflammasome. A core chemical library of 9,600 chemicals was screened against reconstituted NLRP3 inflammasome in a cell-free system with an amplified luminescence proximity homogeneous assay and a cell-based assay by human peripheral blood mononuclear cells (PBMCs). Inflammasome activation was evaluated by ASC-speck formation in human PBMCs, accompanied by IL-1β secretion and processing, and by using IL-1β-based dual operating luciferase (IDOL) mice. The activity of these compounds was evaluated clinically using PBMCs from a patient with Muckle-Wells syndrome (MWS), a type of CAPS, with an R260W mutation in NLRP3. Screening identified KN3014, a piperidine-containing compound targeting the interaction between NLRP3 and ASC through the PYD. KN3014 reduced ASC-speck formation in human PBMCs, luminescence from IDOL mice, and auto-secretion of IL-1β by PBMCs from the patient with MWS. These findings suggest that KN3014 may be an attractive candidate for treatment of MWS, as well as other NLRP3 inflammasomopathies.
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http://dx.doi.org/10.1038/s41598-020-70513-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419506PMC
August 2020

Malignant Ovarian Steroid Cell Tumor, Not Otherwise Specified, Causes Virilization in a 4-Year-Old Girl: A Case Report and Literature Review.

Case Rep Oncol 2020 Jan-Apr;13(1):358-364. Epub 2020 Apr 2.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan.

We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing's syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection.
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http://dx.doi.org/10.1159/000506044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184839PMC
April 2020

Met-PET uptake index for total tumor resection: identification of C-methionine uptake index as a goal for total tumor resection including infiltrating tumor cells in glioblastoma.

Neurosurg Rev 2021 Feb 15;44(1):587-597. Epub 2020 Feb 15.

Department of Neurosurgery, Ehime University School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.

Glioblastoma multiforme (GBM) is largely due to glioma stem cells (GSCs) that escape from total resection of gadolinium (Gd)-enhanced tumor on MRI. The aim of this study is to identify the imaging requirements for maximum resection of GBM with infiltrating GSCs. We investigated the relationship of tumor imaging volume between MRI and C-methionine (Met)-PET and also the relationship between Met uptake index and tumor activity. In ten patients, tumor-to-contralateral normal brain tissue ratio (TNR) was calculated to evaluate metabolic activity of Met uptake areas which were divided into five subareas by the degrees of TNR. In each GBM, tumor tissue was obtained from subareas showing the positive Met uptake. Immunohistochemistry was performed to examine the tumor proliferative activity and existence of GSCs. In all patients, the volume of Met uptake area at TNR ≦ 1.4 was larger than that of the Gd-enhanced area. The Met uptake area at TNR 1.4 beyond the Gd-enhanced tumor was much wider in high invasiveness-type GBMs than in those of low invasiveness type, and survival was much shorter in the former than the latter types. Immunohistochemistry revealed the existence of GSCs in the area showing Met uptake at TNR 1.4 and no Gd enhancement. Areas at TNR > 1.4 included active tumor cells with relatively high Ki-67 labeling index. In addition, it was demonstrated that GSCs could exist beyond the border of Gd-enhanced tumor. Therefore, to obtain maximum resection of GBMs, including infiltrating GSCs, aggressive surgical excision that includes the Met-positive area at TNR 1.4 should be considered.
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http://dx.doi.org/10.1007/s10143-020-01258-7DOI Listing
February 2021

Prognostic significance of immunohistochemical subtypes based on the stage of B-cell differentiation in primary CNS lymphoma.

Int J Clin Exp Pathol 2019 1;12(4):1457-1467. Epub 2019 Apr 1.

Department of Neurosurgery, Ehime University School of Medicine 454 Shitsukawa, Toon, Ehime 791-0295, Japan.

Primary central nervous system lymphoma (PCNSL) has been immunohistochemically classified into two subtypes, germinal center (GC) B-cell and non-GC B-cell, but the prognostic impact of these subtypes remains debated. We investigated clinical features and prognostic significance of immunohistochemical subtypes that were identified by expression patterns of three B-cell differentiation markers in PCNSL. We also analyzed a factor related to responsiveness to high-dose methotrexate (HD-MTX) chemotherapy. Tumors from 32 PCNSL patients were immunohistochemically evaluated for expression of cluster of differentiation (CD) 10, B-cell lymphoma-6 (BCL-6), and multiple myeloma oncogene-1 (MUM-1) and classified into subtypes according to the expression patterns of these markers. Clinical features and prognostic outcome of these subtypes were investigated. Twenty-three patients were treated with HD-MTX-based chemotherapy followed by whole-brain radiation therapy (WBRT), and nine were treated with WBRT alone. Three immunohistochemical subtypes were identified, including A-type expressing CD10, BCL-6, and MUM-1 (12 patients), B-type expressing BCL-6 and MUM-1 (12 patients) and C-type expressing MUM-1 only (8 patients). Response rate in the HD-MTX therapy group was 57.1% (4/7) in A-type, 87.5% (7/8) in B-type, and 75% (6/8) in C-type. C-type with the lowest metabolic activity showed significantly longer overall survival than A-type with the higher uptake of methionine (71.6 versus 39.6 months) (P<0.05). Immunohistochemical identification of PCNSL based on the B-cell differentiation stage revealed three types of tumors, showing different metabolic activity and survival time. Refined immunohistochemical classification of PCNSL subtypes may become a useful tool for predicting more accurate prognosis and accessing sensitivity to HD-MTX therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947071PMC
April 2019

Valve Interstitial Cell-Specific Cyclooxygenase-1 Associated With Calcification of Aortic Valves.

Ann Thorac Surg 2020 07 22;110(1):40-49. Epub 2019 Nov 22.

Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan.

Background: The molecular mechanisms underlying aortic valve calcification are poorly understood. Here, we aimed to identify the master regulators of calcification by comparison of genes in valve interstitial cells (VICs) with calcified and noncalcified aortic valves.

Methods: Calcified aortic valves were surgically excised from patients with aortic valve stenosis who required aortic valve replacements. Noncalcified and calcified sections were obtained from aortic valve leaflets. Collagenase-digested tissues were seeded into dishes, and VICs adhering to the dishes were cultured for 3 weeks, followed by comprehensive gene expression analysis. Functional analyses of identified proteins were performed by in vitro calcification assays. Tissue localization was determined by immunohistochemical staining for normal (n = 11) and stenotic valves (n = 30).

Results: We found 87 genes showing greater than a twofold change in calcified tissues. Among these genes, 68 were downregulated and 19 were upregulated. Cyclooxygenase-1 (COX1) messenger RNA and protein levels were upregulated in VICs from calcified tissues. The COX1 messenger RNA and protein levels in VICs were also strongly increased by stimulation with osteoblast differentiation medium. These were VIC-specific phenotypes and were not observed in other cell types. Immunohistochemical staining revealed that COX1-positive VICs were specifically localized in the calcified area of aortic valve tissues.

Conclusions: The VIC-specific COX1 overexpression played a crucial role in calcification by promoting osteoblast differentiation in aortic valve tissues.
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http://dx.doi.org/10.1016/j.athoracsur.2019.09.085DOI Listing
July 2020

Dual-energy computed tomography for evaluation of breast cancer: value of virtual monoenergetic images reconstructed with a noise-reduced monoenergetic reconstruction algorithm.

Jpn J Radiol 2020 Feb 4;38(2):154-164. Epub 2019 Nov 4.

Department of Radiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.

Purpose: To evaluate the image quality and lesion visibility of virtual monoenergetic images (VMIs) reconstructed using a new monoenergetic reconstruction algorithm (nMERA) for evaluation of breast cancer.

Materials And Methods: Forty-two patients with 46 breast cancers who underwent 4-phasic breast contrast-enhanced computed tomography (CT) using dual-energy CT (DECT) were enrolled. We selected the peak enhancement phase of the lesion in each patient. The selected phase images were generated by 120-kVp-equivalent linear blended (M120) and monoenergetic reconstructions from 40 to 80 keV using the standard reconstruction algorithm (sMERA: 40, 50, 60, 70, 80) and nMERA (40 +, 50 +, 60 +, 70 +, 80 +). The contrast-to-noise ratio (CNR) was calculated and objectively analyzed. Two independent readers subjectively scored tumor visibility and image quality each on a 5-point scale.

Results: The CNR at 40 + and tumor visibility scores at 40 + and 50 + were significantly higher than those on M120. The CNR at 50 + was not significantly different from that on M120. However, the overall image quality score at 40 + was significantly lower than that at 50 + and on M120 (40 + vs M120, P < 0.0001 and 40 + vs 50 +, P = 0.0001).

Conclusions: VMI reconstructed with nMERA at 50 keV is preferable for evaluation of patients with breast cancer.
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http://dx.doi.org/10.1007/s11604-019-00897-1DOI Listing
February 2020

A simple mouse model of pericardial adhesions.

J Cardiothorac Surg 2019 Jun 28;14(1):124. Epub 2019 Jun 28.

Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.

Background: Postoperative pericardial adhesions are considered a risk factor for redo cardiac surgery. Several large- and medium-size animal models of pericardial adhesions have been reported, but small animal models for investigating the development of anti-adhesion materials and molecular mechanisms of this condition are lacking. In this study, we aimed to establish a simple mouse model of pericardial adhesions to address this gap.

Methods: We administered blood, minocycline, picibanil, and talc into the murine pericardial cavity via one-shot injection. Micro-computed tomography analyses of contrast agent-injected mice were carried out for methodological evaluation. We investigated various dosages and treatment durations for molecules identified to be inducers of pericardial adhesion. The adhesive grade was quantified by scoring the strength and volume of adhesion tissues at sacrificed time points. Histological staining with hematoxylin and eosin and Masson's trichrome, and immunostaining for F4/80 or αSMA was performed to investigate the structural features of pericardial adhesions, and pathological features of the pericardial adhesion tissue were compared with human clinical specimens.

Results: Administration of talc resulted in the most extensive pericardial adhesions. Micro-computed tomography imaging data confirmed that accurate injection into the pericardial cavity was achieved. We found the optimal condition for the formation of strong pericardial adhesions to be injection of 2.5 mg/g talc for 2 weeks. Furthermore, histological analysis showed that talc administration led to an invasion of myofibroblasts and macrophages in the pericardial cavity and epicardium, consistent with pathological findings in patients with left ventricular assistive devices.

Conclusions: We successfully established a simple mouse model of talc-induced pericardial adhesions, which mimics human pathology and could contribute to solving the clinical issues related to pericardial adhesions.
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http://dx.doi.org/10.1186/s13019-019-0940-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599257PMC
June 2019

The role of interleukin-1 in general pathology.

Inflamm Regen 2019 6;39:12. Epub 2019 Jun 6.

Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan.

Interleukin-1, an inflammatory cytokine, is considered to have diverse physiological functions and pathological significances and play an important role in health and disease. In this decade, interleukin-1 family members have been expanding and evidence is accumulating that highlights the importance of interleukin-1 in linking innate immunity with a broad spectrum of diseases beyond inflammatory diseases. In this review, we look back on the definition of "inflammation" in traditional general pathology and discuss new insights into interleukin-1 in view of its history and the molecular bases of diseases, as well as current progress in therapeutics.
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http://dx.doi.org/10.1186/s41232-019-0101-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551897PMC
June 2019

Amyloid β directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system.

Inflamm Regen 2018 12;38:27. Epub 2018 Nov 12.

1Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Centre, Shitsukawa 454, Toon, Ehime 791-0295 Japan.

Background: Alzheimer's disease is a neurodegenerative disease characterized by the interstitial deposition of amyloid β (Aβ) plaque, which is thought to be related to chronic neuroinflammation. Aβ is known to make fibrils via oligomers from monomers. Aβ has been reported to activate the NLRP3 inflammasome in infiltrated macrophages. NLRP3, an intracellular pattern recognition receptor, has been reported to recognize numerous pathogens and/or metabolites and form complexes with adopter protein ASC to make the inflammasome, an interleukin (IL)-1β-processing platform. Although reactive oxygen species from mitochondria have been reported to be involved in the activation of the NLRP3 inflammasome in microglial cells upon the deposition of Aβ, whether Aβ directly or indirectly activates the NLRP3 inflammasome remains unclear.

Methods: We prepared monomers, oligomers, and fibrils of Aβ, which promoted the interaction between NLRP3 and each form of Aβ and analyzed the interaction between NLRP3 and ASC induced by each form of Aβ in a cell-free system with the amplified luminescent proximity homogeneous assay. We also confirmed the physiological relevance in a cell-based assay using human embryonic kidney 293T cells and human peripheral mononuclear cells.

Results: Monomers, oligomers, and fibrils of Aβ were successfully prepared. Aβ oligomers and fibrils interacted with NLRP3. Aβ oligomers and fibrils induced the interaction between NLRP3 and ASC. However, Aβ monomers did not interact with NLRP3 or induce interaction between NLRP3 and ASC in the cell-free system, and IL-1β was not secreted according to the cell-based assay.

Conclusion: Oligomerized Aβ originating from non-toxic Aβ monomers directly interacted with NLRP3, leading to the activation of the NLRP3 inflammasome. This may be an attractive target for the treatment of Alzheimer's disease.
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http://dx.doi.org/10.1186/s41232-018-0085-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231249PMC
November 2018

Positron emission tomography/computed tomography detection of increased F-fluorodeoxyglucose uptake in the cardiac atria of patients with atrial fibrillation.

Int J Cardiol 2019 05 31;283:171-177. Epub 2018 Oct 31.

Department of Radiology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Background: Direct evidence of inflammatory activity in the atria of patients with atrial fibrillation (AF) is scarce. We assessed the capability of positron-emission tomography/computed tomography (PET/CT) to diagnose AF based on fluorodeoxyglucose (FDG) uptake in the atrial wall.

Methods And Results: Among 8233 patients who underwent FDG-PET/CT as work-up for malignancies, we identified 180 consecutive patients with AF (2.2%). Of those, we selected 137 patients who had fasted >12 h before FDG injection for inclusion in the experimental group (88 men and 49 women; age: 72.7 ± 8.9 years). Controls were 62 age- and sex-matched patients without AF. For visual analysis, we used a 4-point grading system. For quantitative analysis, we used the maximum standard uptake value (SUVmax) in the left (LA) and right atrial (RA) myocardium and the target-to-background ratio (TBR) of SUVmax to blood pool activity. The sensitivity, specificity, and positive-predictive value for detecting AF visually were 54.0%, 95.2%, and 96.1%, respectively; for quantitative analysis, the respective values were 65.7%, 75.8%, and 85.7%. Multivariable analysis of 11 clinical and imaging variables showed significant associations with RA SUVmax (odds ratio [OR]: 14.353, P = 0.026) and LA volume (OR: 1.371, P = 0.0001). The RA TBR was greater in cases with persistent AF than in those with paroxysmal AF (P < 0.0001). Pathological investigation of 4 autopsy hearts confirmed infiltration of extravascular macrophages and lymphocytes in the regions with FDG uptake.

Conclusions: Higher atrial FDG uptake was associated with AF. PET/CT could be a useful tool for detecting local inflammation in the atria with AF.
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http://dx.doi.org/10.1016/j.ijcard.2018.10.106DOI Listing
May 2019

Biochemical and histological evidence of deteriorated bioprosthetic valve leaflets: the accumulation of fibrinogen and plasminogen.

Biol Open 2018 Aug 8;7(8). Epub 2018 Aug 8.

Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan

Calcification of bioprosthetic valves (BVs) implanted in aortic position can result in gradual deterioration and necessitate aortic valve replacement. The molecular mechanism of calcium deposition on BV leaflets has been investigated, but remains to be fully elucidated. The present study aimed to identify explanted bioprosthetic valve (eBV)-specific proteins using a proteomics approach and to unveil their biochemical and histological involvements in calcium deposition on BV leaflets. Calcification, fibrosis, and glycosylation of the valves were histologically assessed using Von Kossa, Masson's Trichrome and Alcian Blue staining, as well as immunostaining. Protein expression in the explanted biological valves was analysed using proteomics and western blotting. In a histological evaluation, αSMA-positive myofibroblasts were not observed in eBV, whereas severe fibrosis occurred around calcified areas. SDS-PAGE revealed three major bands with considerably increased intensity in BV leaflets that were identified as plasminogen and fibrinogen gamma chain (100 kDa), and fibrinogen beta chain (50 and 37 kDa) by mass analysis. Immunohistochemistry showed that fibrinogen β-chain was distributed throughout the valve tissue. On the contrary, plasminogen was strongly stained in CD68-positive macrophages, as evidenced by immunofluorescence. The results suggest that two important blood coagulation-related proteins, plasminogen and fibrinogen, might affect the progression of BV degeneration.
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http://dx.doi.org/10.1242/bio.034009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124578PMC
August 2018

IAPP/amylin deposition, which is correlated with expressions of ASC and IL-1β in β-cells of Langerhans' islets, directly initiates NLRP3 inflammasome activation.

Int J Immunopathol Pharmacol 2018 Jan-Dec;32:2058738418788749

1 Department of Pathology, Proteo-Science Center and Graduate School of Medicine, Ehime University, Toon, Japan.

Recent findings revealed that type 2 diabetes mellitus (T2D) is a chronic inflammatory disease and an islet amyloid polypeptide (IAPP)/amylin, is deposited within pancreatic islets. IAPP/amylin has been reported to activate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in infiltrated macrophages. NLRP3, an intracellular pattern recognition receptor, has been shown to recognize pathogens and/or metabolites and complexes with the adopter protein apoptosis-associated speck-like protein containing a caspase-recruitment domain ASC to form a huge complex, called an inflammasome, an interleukin (IL)-1β-processing platform. Although reactive oxygen species (ROS) were reported to be involved in activation of NLRP3 inflammasome, we were hypothesized that IAPP could directly activate NLRP3 inflammasome, leading to islets β-cell death. We analyzed expression of the inflammasome components ASC, NLRP3, caspase-1, IL-1β, IAPP/amylin, and insulin immunohistochemically in Langerhans' islets of autopsy cases. The initial event of NLRP3 inflammasome activation was assessed using a cell-free system consisting of NLRP3 and ASC with the amplified luminescent proximity homogeneous assay. IAPP/amylin deposition in Langerhans' islets was detected and significantly correlated with expressions of IL-1β and ASC. IAPP/amylin directly interacted with NLRP3 and initiated an interaction between NLRP3 and ASC in a cell-free system. The deposition of IAPP/amylin in β-cells of Langerhans' islets may act together with the expression level of an inflammasome component, ASC, to regulate IL-1β processing, and directly lead to the dysfunction of β-cells. The interaction between IAPP/amylin and NLRP3 could be an attractive drug target to avoid both inflammation and β-cell death for T2D therapy.
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http://dx.doi.org/10.1177/2058738418788749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050799PMC
December 2018

Cerebral amyloid angiopathy-related inflammation with epilepsy mimicking a presentation of brain tumor: A case report and review of the literature.

Int J Surg Case Rep 2018 29;48:95-100. Epub 2018 May 29.

Department of Neurosurgery, Ehime University School of Medicine, 454 Shitsukawa, Toon, Ehime 791-0295, Japan.

Introduction: Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare and treatable variant of cerebral amyloid angiopathy, lacks specific imaging and clinical features, and requires invasive brain biopsy to confirm the diagnosis. We report the case of a patient with nonconvulsive status epilepticus (NCSE) caused by CAA-ri in the right occipital lobe.

Presentation Of Case: A 78-year-old man with a history of hypertension and rheumatoid arthritis was admitted to our hospital following an episode of seizures. CT scan showed a low-attenuating subcortical lesion in the right occipital lobe. MRI revealed the lesion as hypointense on T1-weighted imaging (WI) and hyperintense on T2-WI, showing no enhancement on T1-WI contrast-enhanced with gadolinium. In addition, T2*-weighted gradient-recalled echo (T2*-GRE) and susceptibility-weighted imaging (SWI) revealed extensive cortical microbleeds. Biopsy to determine the exact diagnosis revealed histological findings of reactive changes and perivascular inflammatory infiltration associated with amyloid deposition in vessel walls. These findings were consistent with CAA-ri. Corticosteroid therapy with dexamethasone was initiated for a short period as a diagnostic and therapeutic maneuver, resulting in marked reductions in the lesion.

Discussion: CAA is generally associated with intracerebral hemorrhage, dementia, and small cerebral infarctions in the elderly population, but in a small proportion of cases is related to inflammatory responses to vascular deposits of Aβ, as so-called CAA-ri.

Conclusion: CAA-ri should be considered among the differential diagnoses for causes of unprovoked seizure onset in elderly individuals, when associated with petechial hemorrhages on T2*-GRE and SWI sequences on MRI.
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http://dx.doi.org/10.1016/j.ijscr.2018.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041117PMC
May 2018

Applications of reconstituted inflammasomes in a cell-free system to drug discovery and elucidation of the pathogenesis of autoinflammatory diseases.

Inflamm Regen 2017 3;37. Epub 2017 May 3.

Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, 791-0295 Ehime Japan.

The inflammasome, typically consisting of a Nod-like receptor, apoptosis-associated speck-like protein, and pro-caspase-1, has recently been identified as a huge intracellular complex, which plays a crucial role in interleukin-1 maturation or specific physiological functions. Two Nod-like receptors, such as nucleotide-binding oligomerization domains-containing protein (Nod)1 and Nod2, interact with the receptor-interacting protein serine-threonine kinase (RIPK)2 accompanied by Iκ-B kinase (IKK) complexes to construct the nodosome, leading to nuclear factor (NF)-κB activation. The aberrant activation of inflammasomes or nodosomes causes autoinflammatory diseases. Therefore, inflammasomes may be attractive targets to treat autoinflammatory diseases. Our aim is to develop reconstituted inflammasomes in a cell-free system to discover specific molecular-target drugs and elucidate the molecular pathogenesis of autoinflammatory diseases. In this review, we describe reconstituted inflammasomes in a cell-free system.
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http://dx.doi.org/10.1186/s41232-017-0040-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725934PMC
May 2017

Combined morphological, immunohistochemical and genetic analyses of medulloepithelioma in the posterior cranial fossa.

Neuropathology 2018 Apr 3;38(2):179-184. Epub 2017 Oct 3.

Department of Neurosurgery, Ehime University School of Medicine, Toon, Japan.

Medulloepithelioma is a rare and highly malignant primitive neuroectodermal tumor that usually occurs in childhood. The diagnosis of this entity required only morphological analysis until the World Health Organization classification of central nervous system (CNS) tumors was revised, and now genetic analysis is necessary. We report a case of medulloepithelioma in the posterior cranial fossa that was diagnosed by both morphological and genetic analyses based on this classification. A 10-month-old girl was admitted to our hospital with consciousness disturbance and vomiting. Neuroimaging revealed a partially calcified mass and cyst formation in the posterior cranial fossa. Partial resection of the tumor was performed and histological findings revealed multilayered rosettes with LIN28A staining, but genetic analysis showed no amplification of the C19MC microRNA cluster at 19q14.32. Therefore, we diagnosed the tumor as medulloepithelioma belonging to other CNS embryonal tumors. The patient was immediately treated with systemic high-dose chemotherapy. Follow-up neuroimaging 10 months later showed no signs of recurrence. Medulloepitheliomas are difficult to diagnose by routine HE staining and require combined morphological, immunohistochemical and genetic analyses to provide an accurate diagnosis.
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http://dx.doi.org/10.1111/neup.12431DOI Listing
April 2018

Neoatherosclerosis development following bioresorbable vascular scaffold implantation in diabetic and non-diabetic swine.

PLoS One 2017 12;12(9):e0183419. Epub 2017 Sep 12.

Department of Cardiology, Thoraxcenter, Cardiovascular Research school COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.

Background: DM remains a risk factor for poor outcome after stent-implantation, but little is known if and how DM affects the vascular response to BVS.

Aim: The aim of our study was to examine coronary responses to bioresorbable vascular scaffolds (BVS) in swine with and without diabetes mellitus fed a 'fast-food' diet (FF-DM and FF-NDM, respectively) by sequential optical coherence tomography (OCT)-imaging and histology.

Methods: Fifteen male swine were evaluated. Eight received streptozotocin-injection to induce DM. After 9 months (M), 32 single BVS were implanted in epicardial arteries with a stent to artery (S/A)-ratio of 1.1:1 under quantitative coronary angiography (QCA) and OCT guidance. Lumen, scaffold, neointimal coverage and composition were assessed by QCA, OCT and near-infrared spectroscopy (NIRS) pre- and/or post-procedure, at 3M and 6M. Additionally, polarization-sensitive (PS)-OCT was performed in 7 swine at 6M. After sacrifice at 3M and 6M, histology and polymer degradation analysis were performed.

Results: Late lumen loss was high (~60%) within the first 3M after BVS-implantation (P<0.01 FF-DM vs. FF-NDM) and stabilized between 3M and 6M (<5% change in FF-DM, ~10% in FF-NDM; P>0.20). Neointimal coverage was highly heterogeneous in all swine (DM vs. NDM P>0.05), with focal lipid accumulation, irregular collagen distribution and neointimal calcification. Likewise, polymer mass loss was low (~2% at 3M, ~5% at 6M;P>0.20) and not associated with DM or inflammation.

Conclusion: Scaffold coverage showed signs of neo-atherosclerosis in all FF-DM and FF-NDM swine, scaffold polymer was preserved and the vascular response to BVS was not influenced by diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183419PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595285PMC
October 2017

Perivascular Adipose Tissue Angiotensin II Type 1 Receptor Promotes Vascular Inflammation and Aneurysm Formation.

Hypertension 2017 10 31;70(4):780-789. Epub 2017 Jul 31.

From the Department of Cardiology, Pulmonology, Hypertension and Nephrology (Tomoki Sakaue, J.S., M.H., C.S., A.T., T.N., T.U., J.A., T.O., J.H., S.I.), Department of Cardiovascular and Thoracic Surgery (H.N., Tomohisa Sakaue, T.Y., H.I.), and Department of Analytical Pathology (M.K.), Ehime University Graduate School of Medicine, Toon, Japan; and Division of Pathology, Proteo-Science Center (M.K.), Ehime University, Toon, Japan.

Perivascular adipose tissue exhibits characteristics of active local inflammation, which contributes to the development of atherosclerotic disease as a complication of obesity/metabolic syndrome. However, the precise role of perivascular adipose tissue in the progression of abdominal aortic aneurysm remains unclear. To test the hypothesis that genetic deletion of angiotensin II type 1a (AT) receptor in perivascular visceral adipose tissue (VAT) can attenuate aortic aneurysm formation in apolipoprotein E-deficient (ApoE) mice, we performed adipose tissue transplantation experiments by using an angiotensin II-induced aneurysm murine model, in which we transplanted VAT from ApoE or ApoE AT donor mice onto the abdominal aorta of ApoE recipient mice. Compared with ApoE VAT transplantation, ApoE AT VAT transplantation markedly attenuated aortic aneurysm formation, macrophage infiltration, and gelatinolytic activity in the abdominal aorta. AT receptor activation led to the polarization of macrophages in perivascular VAT toward the proinflammatory phenotype. Moreover, osteopontin expression and gelatinolytic activity were considerably lower in ApoE AT perivascular VAT than in ApoE perivascular VAT, and angiotensin II-induced osteopontin secretion from adipocytes was eliminated after deletion of AT receptor in adipocytes. Notably, induction of macrophage migration by conditioned medium from angiotensin II-stimulated wild-type adipocytes was suppressed by treatment with an osteopontin-neutralizing antibody, and ApoE OPN VAT transplantation more potently attenuated aortic aneurysm formation than ApoE VAT transplantation. Our findings indicate a previously unrecognized effect of AT receptor in perivascular VAT on the pathogenesis of abdominal aortic aneurysm.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09512DOI Listing
October 2017

Histological assessment of the efficacy of drug-eluting beads in portal tumor thrombosis of hepatocellular carcinoma.

Radiol Case Rep 2017 Mar 27;12(1):179-184. Epub 2016 Dec 27.

Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.

A 58-year-old man was diagnosed with advanced hepatocellular carcinoma with portal vein tumor thrombosis (PVTT). The tumors were multiple and existed in both lobes. Drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) was performed for the tumors in the left lobe. Embosphere and Hepasphere were selected for embolization of the arterioportal shunt, followed by loaded epirubicin infusion into the left hepatic artery. Computed tomography showed reduction of PVTT. However, liver failure progressed, and the patient died 67 days after DEB-TACE. Autopsy showed that the beads reached the tumor thrombosis in the portal vein. The prognosis of hepatocellular carcinoma with PVTT is poor. Although there are no established treatments for unresectable PVTT, DEB-TACE might be a useful option for such cases.
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http://dx.doi.org/10.1016/j.radcr.2016.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310373PMC
March 2017

Proteomics-based analysis of lung injury-induced proteins in a mouse model of common bile duct ligation.

Surgery 2017 06 28;161(6):1525-1535. Epub 2017 Jan 28.

Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan. Electronic address:

Background: Lung injury is a life-threatening complication in patients with liver dysfunction. We recently provided an experimental lung injury model in mouse with common bile duct ligation. In this study, we aimed to characterize the pathologic and biochemical features of lung tissues in common bile duct ligation mice using a proteomic approach.

Methods: Common bile ducts of BALB/c mice, 8 weeks of age, were ligated operatively. CD31-expressing pulmonary cells were sorted with immunomagnetic microbeads, and protein profiles were examined by 2-dimensional gel electrophoresis. Based on the results of protein identification, immunohistochemistry and quantitative reverse transcription polymerase chain reaction were carried out in pulmonary and hepatic tissues.

Results: Two-dimensional gel electrophoresis revealed 3 major inflammation-associated proteins exhibiting considerable increases in the number of CD31-positive pulmonary cells after common bile duct ligation. Mass spectrometry analysis identified these proteins as SerpinB1a (48 kDa), ANXA1 (46 kDa), and S100A9 (16 kDa). Furthermore, the 3 proteins were more highly expressed in dilated pulmonary blood vessels of common bile duct ligation mice, in which neutrophils and monocytes were prominent, as shown by immunohistochemistry. More importantly, SerpinB1a mRNA and protein were significantly upregulated in the liver, whereas S100A9 and ANXA1 mRNA and protein were upregulated in the lungs, as shown by quantitative reverse transcription polymerase chain reaction and Western blotting.

Conclusion: We identified 3 proteins that were highly expressed in the lung after common bile duct ligation using a proteomics-based approach.
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http://dx.doi.org/10.1016/j.surg.2016.12.017DOI Listing
June 2017

Plasma thrombin-cleaved osteopontin as a potential biomarker of acute atherothrombotic ischemic stroke.

Hypertens Res 2017 Jan 25;40(1):61-66. Epub 2016 Aug 25.

Department of Neurosurgery, Washokai Sadamoto Hospital, Ehime, Japan.

We investigated whether thrombin-cleaved osteopontin N-terminal is useful as a blood biomarker of acute atherothrombotic ischemic stroke. Acute ischemic stroke patients were prospectively evaluated with brain magnetic resonance imaging and cardiac evaluations for etiological diagnosis according to the Trial of Org 10172 in Acute Stroke Treatment classification. They were divided into the atherothrombotic and non-atherothrombotic groups. Thrombin-cleaved osteopontin N-terminal, osteopontin, matrix metalloproteinase-9, S100B, C-reactive protein and D-dimer levels were measured from blood samples collected at admission. After excluding patients who met the exclusion criteria or had stroke of other/undetermined etiology, 60 of the 100 patients initially enrolled were included in the final analysis. The ischemic stroke subtypes were atherothrombotic (n=28, 46.7%), cardioembolic (n=19, 31.7%) and lacunar (n=13, 21.7%). Thrombin-cleaved osteopontin N-terminal and matrix metalloproteinase-9 levels were significantly higher in the atherothrombotic than in the non-atherothrombotic group (median (interquartile range): 5.83  (0.0-8.6 ) vs. 0.0  (0.0-3.3) pmol l, P=0.03 and 544   (322-749 ) vs. 343   (254-485) ng ml, P=0.01, respectively). After adjustment for the prevalence of hypertension, diabetes and dyslipidemia, thrombin-cleaved osteopontin N-terminal levels of >5.47 pmol l (odds ratio, 16.81; 95% confidence interval, 3.53-80.10) and matrix metalloproteinase-9 levels of >605.5 ng ml (6.59; 1.77-24.60) were identified as independent predictors of atherothrombosis. Within 3 h from stroke onset, only thrombin-cleaved osteopontin N-terminal independently predicted atherothrombosis and thus may add valuable, time-sensitive diagnostic information in the early evaluation of ischemic stroke, especially the atherothrombotic subtype.
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http://dx.doi.org/10.1038/hr.2016.110DOI Listing
January 2017

Nod2-Nodosome in a Cell-Free System: Implications in Pathogenesis and Drug Discovery for Blau Syndrome and Early-Onset Sarcoidosis.

ScientificWorldJournal 2016 15;2016:2597376. Epub 2016 Jun 15.

Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Shitsukawa 454, Toon, Ehime 791-0295, Japan.

Nucleotide-binding oligomerization domain-containing protein (Nod) 2 is an intracellular pattern recognition receptor, which recognizes muramyl dipeptide (N-Acetylmuramyl-L-Alanyl-D-Isoglutamine: MDP), a bacterial peptidoglycan component, and makes a NF-κB-activating complex called nodosome with adaptor protein RICK (RIP2/RIPK2). Nod2 mutants are associated with the autoinflammatory diseases, Blau syndrome (BS)/early-onset sarcoidosis (EOS). For drug discovery of BS/EOS, we tried to develop Nod2-nodosome in a cell-free system. FLAG-tagged RICK, biotinylated-Nod2, and BS/EOS-associated Nod2 mutants were synthesized, and proximity signals between FLAG-tagged and biotinylated proteins were detected by amplified luminescent proximity homogeneous assay (ALPHA). Upon incubation with MDP, the ALPHA signal of interaction between Nod2-WT and RICK was increased in a dose-dependent manner. The ALPHA signal of interaction between RICK and the BS/EOS-associated Nod2 mutants was more significantly increased than Nod2-WT. Notably, the ALPHA signal between Nod2-WT and RICK was increased upon incubation with MDP, but not when incubated with the same concentrations, L-alanine, D-isoglutamic acid, or the MDP-D-isoform. Thus, we successfully developed Nod2-nodosome in a cell-free system reflecting its function in vivo, and it can be useful for screening Nod2-nodosome-targeted therapeutic molecules for BS/EOS and granulomatous inflammatory diseases.
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http://dx.doi.org/10.1155/2016/2597376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926014PMC
November 2017

Osteopontin deficiency reduces kidney damage from hypercholesterolemia in Apolipoprotein E-deficient mice.

Sci Rep 2016 06 29;6:28882. Epub 2016 Jun 29.

Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.

Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Osteopontin (OPN) has been implicated in the pathology of several renal conditions. This study was to evaluate the effects of OPN on hypercholesterolemia induced renal dysfunction. Eight-week-old male mice were divided into 4 groups: apolipoprotein E knockout (ApoE(-/-)) and ApoE/OPN knockout (ApoE(-/-)/OPN(-/-)) mice fed a normal diet (ND) or high cholesterol diet (HD). After 4 weeks, Periodic acid-Schiff (PAS) and oil red O staining revealed excessive lipid deposition in the glomeruli of ApoE(-/-)HD mice, however, significantly suppressed in ApoE(-/-)/OPN(-/-)HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression was lower in the glomeruli of ApoE(-/-)/OPN(-/-)HD mice than ApoE(-/-)HD mice. In vitro study, primary mesangial cells were incubated with recombinant mouse OPN (rmOPN). RmOPN induced LOX-1 mRNA and protein expression in primary mesangial cells. Pre-treatment with an ERK inhibitor suppressed the LOX-1 gene expression induced by rmOPN. These results indicate that OPN contributes to kidney damage in hypercholesterolemia and suggest that inhibition of OPN may provide a potential therapeutic target for the prevention of hypercholesterolemia.
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http://dx.doi.org/10.1038/srep28882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926090PMC
June 2016

Reconstituted AIM2 inflammasome in cell-free system.

J Immunol Methods 2015 Nov 8;426:76-81. Epub 2015 Aug 8.

Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Shitsukawa 454, Toon, Ehime 791-0295, Japan. Electronic address:

Absent in melanoma 2 (AIM2) is an intracellular pattern-recognition receptor, which is a member of the PYHIN protein family, consisting of a PYD domain and an IFN-inducible nuclear localization (HIN) domain. AIM2 is reported to oligomerize with adaptor protein ASC upon sensing bacterial and viral cytosolic DNA in order to form the AIM2 inflammasome, which activates caspase-1 leading to IL-1β secretion. Dysregulation of AIM2 inflammasome is supposed to result in autoinflammatory and autoimmune diseases. Thus, the development of new targeted drugs against AIM2 inflammasome would be important for the treatment of these diseases. However, since AIM2 inflammasome is an intracellular receptor, enforced internalization of both ligands and candidate molecules is necessary for the screening of AIM2-inflammasome-targeted molecules. We developed a reconstituted AIM2 inflammasome in a cell-free system with amplified luminescent proximity homogeneous assay (Alpha). Strong Alpha signal was detected upon incubation with poly-deoxyadenylic-deoxythymidylic acid, poly(dA:dT), whereas no Alpha signal was detected upon incubation with muramyl dipeptide, one of the NLR ligands of Nod2 ligand. The interaction between AIM2 and ASC was disrupted by an anti-human ASC monoclonal antibody, CRID3, a class of diarylsulfonylurea-containing compounds, and glycyrrhizin, a substance found in liquorice root. Thus, the reconstituted AIM2 inflammasome in a cell-free system is useful for screening AIM2-inflammasome-targeted therapeutic molecules.
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http://dx.doi.org/10.1016/j.jim.2015.08.004DOI Listing
November 2015

Angiographic and optical coherence tomography insights into bioresorbable scaffold thrombosis: single-center experience.

Circ Cardiovasc Interv 2015 May;8(5)

From the Departments of Interventional Cardiology (A.K., N.V.M., N.v.D., C.F., J.D., Y.O., R.D., M.V., F.K., P.d.J., F.Z., R.-J.v.G., E.R.) and Experimental Cardiology (A.A., M.K., H.v.B.), Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands.

Background: As bioresorbable vascular scaffolds (BVSs) are being increasingly used in complex real-world lesions and populations, BVS thrombosis cases have been reported. We present angiographic and optical coherence tomography (OCT) findings in a series of patients treated in our center for definite bioresorbable scaffold thrombosis.

Methods And Results: Up to June 2014, 14 patients presented with definite BVS thrombosis in our center. OCT was performed in 9 patients at the operator's discretion. Angiographic and OCT findings were compared with a control group comprising 15 patients with definite metallic stent thrombosis. In the BVS group, time interval from index procedure to scaffold thrombosis ranged from 0 to 675 days. Incomplete lesion coverage by angiography was identified in 4 of 14 cases, malapposition by OCT in 5 of 9 cases, strut discontinuity in 2 of 9 cases, and underexpansion in 2 of 9 cases. Five patients had discontinued dual antiplatelet therapy, and in 3 of them discontinued dual antiplatelet therapy discontinuation had occurred the week preceding the event. There were no significant differences in angiographic or OCT findings between BVS and metallic stent thrombosis.

Conclusions: Suboptimal implantation with incomplete lesion coverage, underexpansion, and malapposition comprises the main pathomechanism for both early and late BVS thrombosis, similar to metallic stent thrombosis. Dual antiplatelet therapy discontinuation seems to also be a secondary contributor in several late events. Our observations suggest that several potential triggers for BVS thrombosis could be avoided.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.114.002369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482452PMC
May 2015

Pathophysiology of lung injury induced by common bile duct ligation in mice.

PLoS One 2014 14;9(4):e94550. Epub 2014 Apr 14.

Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan.

Background: Liver dysfunction and cirrhosis affect vasculature in several organ systems and cause impairment of organ functions, thereby increasing morbidity and mortality. Establishment of a mouse model of hepatopulmonary syndrome (HPS) would provide greater insights into the genetic basis of the disease. Our objectives were to establish a mouse model of lung injury after common bile duct ligation (CBDL) and to investigate pulmonary pathogenesis for application in future therapeutic approaches.

Methods: Eight-week-old Balb/c mice were subjected to CBDL. Immunohistochemical analyses and real-time quantitative reverse transcriptional polymerase chain reaction were performed on pulmonary tissues. The presence of HPS markers was detected by western blot and microarray analyses.

Results: We observed extensive proliferation of CD31-positive pulmonary vascular endothelial cells at 2 weeks after CBDL and identified 10 upregulated and 9 down-regulated proteins that were associated with angiogenesis. TNF-α and MMP-9 were highly expressed at 3 weeks after CBDL and were less expressed in the lungs of the control group.

Conclusions: We constructed a mouse lung injury model by using CBDL. Contrary to our expectation, lung pathology in our mouse model exhibited differences from that of rat models, and the mechanisms responsible for these differences are unknown. This phenomenon may be explained by contrasting processes related to TNF induction of angiogenic signaling pathways in the inflammatory phase. Thus, we suggest that our mouse model can be applied to pulmonary pathological analyses in the inflammatory phase, i.e., to systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094550PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986091PMC
January 2015