Publications by authors named "Takashi Tanaka"

470 Publications

Quality of life and lung function after pleurectomy/decortication for malignant pleural mesothelioma.

Interact Cardiovasc Thorac Surg 2021 May 8. Epub 2021 May 8.

Department of Thoracic Surgery, Hyogo College of Medicine, Hyogo, Japan.

Objectives: Impact of pleurectomy/decortication (P/D) on quality of life (QOL) is not widely reported. We investigated QOL and lung function after P/D.

Methods: A single-centre, retrospective cohort study was performed among patients who underwent P/D for malignant mesothelioma between June 2014 and June 2018 at Hyogo College of Medicine. Data at 4 points before and 3, 6 and 12 months on QOL and lung function were evaluated with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and pulmonary function tests.

Results: Forty-five out of 65 patients completed SF-36. Physical function and role physical decreased from 78 to 65 and 69 to 41 and did not recover. Body pain decreased from 74 to 52. It increased to 62 at 12 months but was lower than before. General health perceptions, vitality and social function decreased from 56 to 49, 50 to 47 and 63 to 50, respectively, but returned to baseline. Role emotional decreased from 75 to 54, then once increased to 63, but decreased again to 58. Mental health tended to improve from 58 to 70. Thirty-eight patients out of 45 completed pulmonary function tests. Forced vital capacity and forced expiratory volume in 1 s decreased from 98% to 61% and 93% to 67% and did not increase. Right-sided surgery or complications was the risk factors of poor lung function but no significant risk factors in QOL.

Conclusions: This study suggests that P/D had an impact on QOL. Despite the lack of recovery in lung function QOL in mental aspects tended to improve, suggesting that pulmonary function tests alone are limited in assessing QOL.
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http://dx.doi.org/10.1093/icvts/ivab139DOI Listing
May 2021

Formation of Dehydrohexahydroxydiphenoyl Esters by the Oxidative Coupling of Galloyl Esters in an Aqueous Medium Involved in Ellagitannin Biosynthesis.

Chem Asian J 2021 May 7. Epub 2021 May 7.

Nagasaki University: Nagasaki Daigaku, Graduate School of Biomedical Sciences, 1-14, Bunkyo-machi, 8528521, Nagasaki, JAPAN.

Hexahydroxydiphenoyl (HHDP) and dehydrohexahydroxydiphenoyl (DHHDP) groups are the major acyl components of ellagitannins, which are polyphenols whose biosynthesis have attracted considerable attention; however, the mechanisms of the production of HHDP and DHHDP in the ellagitannin biosynthesis have not been clarified. With the aim of elucidating such a mechanism, this study investigates the CuCl2-mediated oxidation of simple galloyl derivatives in an aqueous medium. It is shown that the oxidation of methyl gallate affords a DHHDP-type dimer, whose reduction with Na2S2O4 yields an HHDP-type dimer. However, the oxidation of the HHDP-type product over CuCl2 does not afford the parent DHHDP ester. The oxidation of 1,4-butanediol digallate under the same conditions produces a DHHDP-type product via the intramolecular coupling of galloyl groups. These results strongly suggest that the DHHDP group is the initial product of the oxidative coupling of two galloyl groups in the ellagitannin biosynthesis, and subsequent reductive metabolism affords HHDP esters.
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http://dx.doi.org/10.1002/asia.202100380DOI Listing
May 2021

Usefulness of hematopoietic progenitor cell monitoring to predict autologous peripheral blood stem cell harvest timing: A single-center retrospective study.

Transfus Apher Sci 2021 Apr 24:103150. Epub 2021 Apr 24.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Japan.

Introduction: In autologous peripheral blood stem cell harvest (APBSCH), CD34-positive cells have been measured to assess the numbers of hematopoietic stem cells, but measurement requires specialized equipment. Recently, there was a report that peripheral blood hematopoietic progenitor cells (HPCs) are useful indicators of the presence of hematopoietic stem cells. We examined the usefulness of HPC monitoring to predict APBSCH timing.

Methods: We retrospectively analyzed the relationship between HPC and collected CD34-positive cells in 84 consecutive patients who underwent APBSCH.

Results: According to the receiver operating characteristics curve for the collection of ≥2 × 106 CD34-positive cells/kg, the HPC cut-off value on the day before collection was 21/μL, while that on the day of collection was 41/μL. No significant factors were found in the univariate analysis except for the HPC count on the day before collection (p < 0.001) and the day of collection (p < 0.001). According to the multivariate analysis, the HPC count on the day before collection (p < 0.001) and the day of collection (p < 0.001) were also factors that strongly influenced the quantity of CD34-positive cells collected.

Conclusion: Our results suggest that the HPC count on not only the day of collection but also the day before collection is a good indicator for appropriate APBSCH timing.
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http://dx.doi.org/10.1016/j.transci.2021.103150DOI Listing
April 2021

Comparative study of agarose-gel microcapsules and Cryotop in cryopreservation of extremely small numbers of human spermatozoa.

Syst Biol Reprod Med 2021 May 3:1-7. Epub 2021 May 3.

International Center for Reproductive Medicine.

We investigated the feasibility of agarose-gel microcapsules to cryopreserve extremely small numbers of sperm for assisted reproductive technology. Semen samples were collected from 16 patients attending the center for reproductive medicine male infertility clinic at a university hospital. We used agarose microcapsules to cryopreserve extremely small numbers of sperm from 16 patients with male infertility (10 with sperm concentration ≥1 million/mL; 6 with sperm concentration <1 million/mL). Six spermatozoa were injected into agarose-gel microcapsules and cryopreserved in a liquid nitrogen tank for 7 days. The Crytop method was used for cryopreservation as a control. After thawing, spermatozoa were recovered. Sperm recovery rates, motility and viability, and recovery time were compared.The post-thawing recovery rate, motility rate, and viability rate were higher whereas the recovery time was shorter in samples preserved using the agarose-gel microcapsule method compared to samples preserved using the Cryotop method in both the group with sperm concentrations of 1 million/mL or above and the group with sperm concentrations of less than 1 million/mL. This study demonstrated that using the agarose-gel microcapsule method increased post-thawing sperm recovery rate, sperm motility rate, and sperm viability rate, and reduced sperm recovery time compared with the conventional Cryotop method when cryopreserving samples with low sperm count. Although requiring further study, the agarose-gel microcapsule method shows much promise as a new option for freezing sperm.
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http://dx.doi.org/10.1080/19396368.2021.1873457DOI Listing
May 2021

Does mirabegron deteriorate spermatogenesis? A lesson from spinal cord injury cases.

Low Urin Tract Symptoms 2021 Apr 30. Epub 2021 Apr 30.

Department of Urology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan.

Objectives: To evaluate whether the long-term usage of mirabegron, which was reported to have potential side effects on male reproductive organs in animal studies, was harmful to spermatogenesis in human testis.

Methods: Thirty consecutive patients with spinal cord injury (20-48 years old) who performed clean intermittent catheterization were involved in this study. Ten patients were treated with mirabegron (50 mg/d) for more than 2 years and refrained from using an antimuscarinic agent due to the side effects of constipation and dry mouth. Twenty patients were treated with neither anticholinergic agents nor mirabegron. All underwent conventional testicular sperm extraction. The sperm recovery rate and histopathologic findings of the retrieved testicular tissue were compared between both groups.

Results: We found no difference in the sperm recovery rate (P = .083) between both groups. Spinal cord injury patients treated with mirabegron had better spermatogenesis than those not treated with mirabegron (P < .05).

Conclusions: From these data, we conclude that the therapeutic dose of mirabegron had no harmful effect on spermatogenesis in spinal cord injury patients of reproductive age.
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http://dx.doi.org/10.1111/luts.12383DOI Listing
April 2021

Screening of inhibitors targeting heat shock protein 47 involved in the development of idiopathic pulmonary fibrosis.

ChemMedChem 2021 Apr 22. Epub 2021 Apr 22.

Nagasaki University School of Medicine Graduate School of Biomedical Sciences: Nagasaki Daigaku Igakubu Daigakuin Ishiyakugaku Sogo Kenkyuka, Respiratory medicine, JAPAN.

Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is causally related to fibrotic diseases, including idiopathic pulmonary fibrosis. The identification of compounds that interfere with the HSP47-collagen interaction is essential for the development of relevant therapeutics. Herein, we prepared human HSP47 as a soluble fusion protein expressed in E. coli and established an assay system for HSP47 inhibitor screening. We screened a natural and synthetic compound library established at Nagasaki University. Among 1023 compounds, 13 exhibited inhibitory activity against human HSP47, of which three inhibited its function in a dose-dependent manner. Epigallocatechin-3-O-gallate, one of these three compounds, is a typical polyphenol compound derived from tea leaves. Structurally related compounds were synthesized and examined for their activity, revealing a hydroxyl group at A-ring position 5 as important for its activity. The present findings provide valuable insight for the development of natural product-derived therapeutics for fibrotic diseases, including idiopathic pulmonary fibrosis.
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http://dx.doi.org/10.1002/cmdc.202100064DOI Listing
April 2021

Gastroesophageal Varices and Hyperplastic Nodules of the Liver in a Patient with Anorexia Nervosa.

Intern Med 2021 Apr 19. Epub 2021 Apr 19.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan.

We report a case of anorexia nervosa (AN) with gastroesophageal varices (GEV) in a 36-year-old woman. The patient presented to our hospital with progressive bloating due to severe ascites. She had no history of alcohol intake. Esophagogastroduodenoscopy and enhanced computed tomography revealed GEV and multiple hepatic nodules, respectively. The histological examination of a liver biopsy specimen revealed similar features to nonalcoholic fatty liver disease and showed hyperplastic nodules that were suspected to be related to the uneven distribution of portal blood flow in the liver. In conclusion, patients with long-term AN should undergo abdominal imaging to detect signs of portal hypertension.
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http://dx.doi.org/10.2169/internalmedicine.6855-20DOI Listing
April 2021

Physical function predicts mortality in patients with cancer: a systematic review and meta-analysis of observational studies.

Support Care Cancer 2021 Mar 26. Epub 2021 Mar 26.

Institute for Human Movement and Medical Sciences, Niigata University of Health and Welfare, Niigata, Japan.

Purpose: This systematic review and meta-analysis aimed to determine whether physical function can predict mortality in patients with cancer.

Methods: Literature searches were conducted in Web of Science, CINAHL, the Cochrane Library, ProQuest, PEDro, and PubMed for articles published before September 2020. Four review authors retrieved studies using predetermined eligibility criteria and conducted quality assessment and data extraction.

Results: A total of 1356 titles and abstracts were screened; ultimately, 26 studies were determined to be suitable for meta-analysis. Grip strength was significantly associated with mortality risk in patients with cancer (hazard ratio [HR] = 1.15, P = 0.005). Gait speed was also associated with mortality risk (HR = 1.58, P = 0.0004). In grip strength and gait speed, the subgroup comprised of patients with cancer aged ≥ 80 years had a higher effect size than that of patients aged < 80 years. The short physical performance battery measurement was markedly associated with mortality risk, showing the largest effect size (HR = 2.37, P < 0.00001). The 6-min walking test distance was significantly associated with mortality risk (HR = 1.55, P = 0.001). The timed up and go test was significantly associated with mortality risk with a high effect size (HR = 2.66, P < 0.00001).

Conclusion: This systematic review and meta-analysis demonstrated that physical function predicted mortality in patients with cancer. Furthermore, physical function outcomes in patients aged 80 years and above reflected a higher mortality.
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http://dx.doi.org/10.1007/s00520-021-06171-3DOI Listing
March 2021

Imaging evaluation of hereditary renal tumors: a pictorial review.

Jpn J Radiol 2021 Mar 23. Epub 2021 Mar 23.

Department of Radiology, Okayama University Hospital, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan.

More than 10 hereditary renal tumor syndromes (HRTSs) and related germline mutations have been reported with HRTS-associated renal and extrarenal manifestations with benign and malignant tumors. Radiologists play an important role in detecting solitary or multiple renal masses with or without extrarenal findings on imaging and may raise the possibility of an inherited predisposition to renal cell carcinoma, providing direction for further screening, intervention and surveillance of the patients and their close family members before the development of potentially lethal renal and extrarenal tumors. Renal cell carcinomas (RCCs) associated with von Hippel-Lindau disease are typically slow growing while RCCs associated with HRTSs, such as hereditary leiomyomatosis and renal cell carcinoma syndrome, are highly aggressive. Therefore, radiologists need to be familiar with clinical and imaging findings of renal and extrarenal manifestations of HRTSs. This article reviews clinical and imaging findings for the evaluation of patients with well-established HRTSs from a radiologist's perspective to facilitate the clinical decision-making process for patient management.
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http://dx.doi.org/10.1007/s11604-021-01109-5DOI Listing
March 2021

Current status of oral anticoagulant adherence in Japanese patients with atrial fibrillation: A claims database analysis.

J Cardiol 2021 Mar 2. Epub 2021 Mar 2.

Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19 Nishiazabu, Minato-Ku, Tokyo 106-0031, Japan.

Background: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). We investigated the adherence of DOACs for years known to be associated with the effectiveness in Japanese NVAF patients, using a claim database.

Method: We performed a retrospective evaluation of NVAF patients in a claims database in Japan, who initiated dabigatran, rivaroxaban, and apixaban between April 2011 and June 2016. Drug persistence was assessed by Kaplan-Meier method for the initially-prescribed DOAC and all DOACs including switched ones. Proportion of days covered (PDC) was also evaluated in patients with persistent prescription and compared among DOACs.

Results: In the total of 671 patients, rivaroxaban (47%) was more prescribed than dabigatran (28%) and apixaban (25%). Drug persistence at 3 years was higher in rivaroxaban (69%) than dabigatran (57%) and apixaban (67%). Including switching to other DOACs, persistence of DOACs was 72% at 3 years without significant differences between index-DOACs. In multivariate Cox regression analysis, absence of hypertension, and prior history of cancer were significantly associated with the drug discontinuation of all DOACs. The mean PDC was ~ 95% and the frequency of high-adherent patients (PDC ≥0.80) was more than 90%, which similarly persisted at 3 years and showed no significant differences between index DOACs.

Conclusion: In a real-world Japanese claim data analysis, about 70% of patients under DOAC showed persistence with anticoagulation therapy at 3 years. High adherence to DOACs assessed by PDC (over 90%) persisted to 3 years regardless of the types of DOACs.
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http://dx.doi.org/10.1016/j.jjcc.2021.02.007DOI Listing
March 2021

Development of an undulator with a variable magnetic field profile.

J Synchrotron Radiat 2021 Mar 10;28(Pt 2):404-409. Epub 2021 Feb 10.

Department of Material Science, University of Hyogo, Koto 3-2-1, Kamigori, Hyogo 678-1297, Japan.

An undulator generating a magnetic field whose longitudinal profile is arbitrarily varied has been developed, which is one of the key components in a number of proposed new concepts in free-electron lasers. The undulator is composed of magnet modules, each of which corresponds to a single undulator period, and is driven by a linear actuator to change the magnetic gap independently. To relax the requirement on the actuator, the mechanical load on each module due to magnetic force acting from opponent and adjacent modules is reduced by means of two kinds of spring systems. The performance of the constructed undulator has been successfully demonstrated by magnetic measurement and characterization of synchrotron radiation.
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http://dx.doi.org/10.1107/S1600577521000989DOI Listing
March 2021

Novel Endoscopic Therapy for Gastric Varices Using Direct Forward-Viewing Endoscopic Ultrasonography.

Case Rep Gastroenterol 2021 Jan-Apr;15(1):28-34. Epub 2021 Jan 21.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan.

Gastric varices (GV) carry a high risk of massive hemorrhage because of potential rupture. To reduce the risk associated with GV, patients need to undergo hemostatic and preventive treatment. The objective of this retrospective study was to evaluate the usefulness of a new method, direct forward-viewing endoscopic ultrasonography (DFV-EUS) for the treatment of GV. We performed endoscopic injection sclerotherapy with histoacryl (EIS-HA) using DFV-EUS for GV in four patients. The paracentesis success rate was 75% (3/4). DFV-EUS has a significant advantage for the treatment of GV in that it can show physicians endoscopic and ultrasound views in real time during the delivery of the sclerosant into the GV. However, the proper use of the ultrasound view must be elucidated through further research for safer and more effective therapy. In the presence of distance between the mucosal surface and vascular lumen or when the blood flow site requires puncture as an additional treatment, DFV-EUS might be a good candidate for the treatment of GV. Altogether, EIS-HA with DFV-EUS might be a new therapeutic option for patients with GV.
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http://dx.doi.org/10.1159/000510132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879242PMC
January 2021

Development of Small-Diameter Elastin-Silk Fibroin Vascular Grafts.

Front Bioeng Biotechnol 2020 14;8:622220. Epub 2021 Jan 14.

Department of Biotechnology, Tokyo University of Agriculture & Technology, Koganei, Japan.

Globally, increasing mortality from cardiovascular disease has become a problem in recent years. Vascular replacement has been used as a treatment for these diseases, but with blood vessels <6 mm in diameter, existing vascular grafts made of synthetic polymers can be occluded by thrombus formation or intimal hyperplasia. Therefore, the development of new artificial vascular grafts is desirable. In this study, we developed an elastin (EL)-silk fibroin (SF) double-raschel knitted vascular graft 1.5 mm in diameter. Water-soluble EL was prepared from insoluble EL by hydrolysis with oxalic acid. Compared to SF, EL was less likely to adhere to platelets, while vascular endothelial cells were three times more likely to adhere. SF artificial blood vessels densely packed with porous EL were fabricated, and these prevented the leakage of blood from the graft during implantation, while the migration of cells after implantation was promoted. Several kinds of C solid-state NMR spectra were observed with the EL-SF grafts in dry and hydrated states. It was noted that the EL molecules in the graft had very high mobility in the hydrated state. The EL-SF grafts were implanted into the abdominal aorta of rats to evaluate their patency and remodeling ability. No adverse reactions, such as bleeding at the time of implantation or disconnection of the sutured ends, were observed in the implanted grafts, and all were patent at the time of extraction. In addition, vascular endothelial cells were present on the graft's luminal surface 2 weeks after implantation. Therefore, we conclude that EL-SF artificial vascular grafts may be useful where small-diameter grafts are required.
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http://dx.doi.org/10.3389/fbioe.2020.622220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874157PMC
January 2021

An interplay of NOX1-derived ROS and oxygen determines the spermatogonial stem cell self-renewal efficiency under hypoxia.

Genes Dev 2021 Feb 14;35(3-4):250-260. Epub 2021 Jan 14.

Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.

Reactive oxygen species (ROS) produced by NADPH1 oxidase 1 (NOX1) are thought to drive spermatogonial stem cell (SSC) self-renewal through feed-forward production of ROS by the ROS-BCL6B-NOX1 pathway. Here we report the critical role of oxygen on ROS-induced self-renewal. Cultured SSCs proliferated poorly and lacked BCL6B expression under hypoxia despite increase in mitochondria-derived ROS. Due to lack of ROS amplification under hypoxia, NOX1-derived ROS were significantly reduced, and -deficient SSCs proliferated poorly under hypoxia but normally under normoxia. NOX1-derived ROS also influenced hypoxic response in vivo because -deficient undifferentiated spermatogonia showed significantly reduced expression of HIF1A, a master transcription factor for hypoxic response. Hypoxia-induced poor proliferation occurred despite activation of MYC and suppression of CDKN1A by HIF1A, whose deficiency exacerbated self-renewal efficiency. Impaired proliferation of - or -deficient SSCs under hypoxia was rescued by depletion. Consistent with these observations, -deficient SSCs proliferated actively only under hypoxia but not under normoxia. On the other hand, chemical suppression of mitochondria-derived ROS or mitochondria-specific topoisomerase deficiency did not influence SSC fate, suggesting that NOX1-derived ROS play a more important role in SSCs than mitochondria-derived ROS. These results underscore the importance of ROS origin and oxygen tension on SSC self-renewal.
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http://dx.doi.org/10.1101/gad.339903.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849365PMC
February 2021

Seven-Step Stereodivergent Total Syntheses of Punicafolin and Macaranganin.

J Am Chem Soc 2021 01 14;143(3):1428-1434. Epub 2021 Jan 14.

Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.

The first total syntheses of punicafolin () and macaranganin () were achieved in seven steps, respectively, from commercial α-d-glucose. The characteristic features of the synthesis are (1) sequential site-selective introduction of the adequate galloyl groups into unprotected d-glucose by a catalyst-controlled manner and (2) stereodivergent construction of the 3,6-HHDP bridge by oxidative phenol coupling of a common intermediate via a ring-flipping process of the glucose core. Because no protective groups were used for glucose throughout the process, extremely short-step total syntheses of natural glycosides and (MW 938) were performed.
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http://dx.doi.org/10.1021/jacs.0c10714DOI Listing
January 2021

Ellagitannins and Oligomeric Proanthocyanidins of Three Polygonaceous Plants.

Molecules 2021 Jan 11;26(2). Epub 2021 Jan 11.

Department of Natural Product Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.

The aim of this study was to characterize hydrolyzable tannins in Polygonaceous plants, as only a few plants have previously been reported to contain ellagitannins. From , a new hydrolyzable tannin called persicarianin was isolated and characterized to be 3--galloyl-4,6-()-dehydrohexahydroxydiphenoyl-d-glucose. Interestingly, acid hydrolysis of this compound afforded ellagic acid, despite the absence of a hexahydroxydiphenoyl group. From the rhizome of var. , a large amount of granatin A, along with minor ellagitannins, helioscpoinin A, davicratinic acids B and C, and a new ellagitannin called polygonanin A, were isolated. Based on 2D nuclear magnetic resonance (NMR) spectroscopic examination, the structure of polygonanin A was determined to be 1,6-()-hexahydroxydiphenoyl-2,4-hydroxychebuloyl-β-d-glucopyranose. These are the second and third hydrolyzable tannins isolated from Polygonaceous plants. In addition, oligomeric proanthocyanidins of and were characterized by thiol degradation. These results suggested that some Polygonaceous plants are the source of hydrolyzable tannins not only proanthocyanidins.
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http://dx.doi.org/10.3390/molecules26020337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828057PMC
January 2021

Modulation of TNFR 1-triggered two opposing signals for inflammation and apoptosis via RIPK 1 disruption by geldanamycin in rheumatoid arthritis.

Clin Rheumatol 2021 Jan 7. Epub 2021 Jan 7.

Rheumatology & Allergology, NHO Osaka Minami Medical Center, Kidohigashi-machi, Kawachinagano, Osaka, 586-8521, Japan.

Objectives: To evaluate the ability of geldanamycin to modulate two opposing TNFα/TNFR1-triggered signals for inflammation and cell death.

Methods: The effects of geldanamycin on TNFα-induced proinflammatory cytokine production, apoptosis, NF-κB activation, caspase activation, and necroptosis in a human rheumatoid synovial cell line (MH7A) were evaluated via ELISA/qPCR, flow cytometry, dual-luciferase reporter assay, and western blotting assay, respectively. In addition, therapeutic effects on murine collagen-induced arthritis (CIA) were also evaluated.

Results: Geldanamycin disrupted RIPK1 in MH7A, thereby inhibiting TNFα-induced proinflammatory cytokine production and enhancing apoptosis. TNFα-induced NF-κB and MLKL activation was inhibited, whereas caspase 8 activation was enhanced. Recombinant RIPK1 restored the geldanamycin-mediated inhibition of TNFα-induced NF-κB activation. In addition, GM showed more clinical effectiveness than a conventional biologic TNF inhibitor, etanercept, in murine CIA and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA.

Conclusions: GM disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway, while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line. Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF inhibitor. Key Points • Geldanamycin (GM) disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line, MH7A. • GM showed more clinical effectiveness than a conventional biologic TNF-inhibitor, etanercept, in murine collagen-induced arthritis (CIA), and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA. • Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF-inhibitor.
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http://dx.doi.org/10.1007/s10067-021-05579-wDOI Listing
January 2021

Characterization of readmission after allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Jan 7. Epub 2021 Jan 7.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.

To elucidate the incidence, causes, and risk factors associated with readmission due to transplant-related complications, we studied 213 consecutive patients who were discharged without progression of primary disease after their first allogeneic hematopoietic cell transplantation at our center between 2013 and 2016. The median patient age was 50 years (range, 18-71 years). Eighty-three patients had AML or MDS, 66 had lymphoma, 28 had ALL, 23 had ATL, and 13 had other diseases. The median duration of hospitalization for transplantation was 56 days (range 27-325 days). The cumulative incidences of readmission due to transplant-related complications were 8% at 30 days, 16% at 100 days, and 25% at 1 year after discharge. The most frequent cause of readmission was infection, followed by graft-versus-host disease throughout the first year. In multivariate analysis, steroid use at discharge was the only risk factor associated with readmission within 30 days, and steroid use at discharge, absolute lymphocyte count < 500/µl at discharge, and documented bacterial infection during admission were risk factors associated with readmission within 1 year. Our results indicated that factors during hospitalization or discharge, but not at transplantation, were associated with readmission. Patients with these risk factors should be monitored carefully after discharge.
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http://dx.doi.org/10.1038/s41409-020-01190-wDOI Listing
January 2021

Elobixibat, an ileal bile acid transporter inhibitor, ameliorates non-alcoholic steatohepatitis in mice.

Hepatol Int 2021 Jan 4. Epub 2021 Jan 4.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, Fukuoka, 814-0180, Japan.

Background: Recent studies have suggested that several types of toxic bile acids (BAs) are involved in the pathogenesis of non-alcoholic steatohepatitis (NASH). In the present study, we aimed to determine whether elobixibat, an ileal bile acid transporter (IBAT) inhibitor, would ameliorate NASH in mice.

Methods: C57BL/6N mice were fed a methionine and choline-deficient (MCD) to induce NASH or standard diet as control for 8 weeks (n = 5 per group). The MCD diet-fed mice were administered elobixibat 5 days a week for 4 weeks by gavage (n = 5). The effects of the treatments on liver histopathology, proinflammatory cytokine concentrations, intestinal epithelial tight junctions, and the intestinal microbial composition were then assessed.

Results: In MCD-fed mice, hepatic fibrosis and inflammatory cell infiltration developed, and the serum aspartate transaminase activity and BA concentration were higher than the control. In addition, the proinflammatory cytokine concentrations were high in the liver and mesenteric lymph nodes (MLN), and the expression of intestinal epithelium tight junction proteins, claudin1, was increased. In the intestinal microbial composition, the abundance of the Lachnospiraceae and Ruminococcaeae were decreased, whereas that of the Enterobacteriaceae was increased. Treatment with elobixibat reduced the serum BA and increased the fecal BA concentration, and ameliorated the liver inflammation and fibrosis. It also reduced the expression of proinflammatory cytokines in the liver and MLNs, and transforming growth factor-β expression in the liver. Finally, elobixibat normalized intestinal tight junction protein level and the composition of the intestinal microbiota.

Conclusion: Elobixibat ameliorates NASH-related histopathology, reduces cytokine expression, and normalizes the intestinal microbial composition in MCD-fed mice, which suggests that it may represent a promising candidate for the therapy of NASH.
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http://dx.doi.org/10.1007/s12072-020-10107-0DOI Listing
January 2021

Effect of donor type on volume of blood transfusions required after allogeneic hematopoietic cell transplantation.

Int J Hematol 2021 Apr 3;113(4):518-529. Epub 2021 Jan 3.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.

We reviewed blood product use in 729 consecutive allogeneic hematopoietic cell transplantation (allo-HCT) recipients at our center to assess the volume of red blood cells (RBCs) and platelets required after allo-HCT. The median number of bags required by day 30 was 4 for RBCs (range 0-22) and 9.5 for platelets (0-53). Multivariate analysis showed that related peripheral blood stem cell transplantation (PBSCT) required a significantly lower RBC transfusion volume by day 30 compared to unrelated bone marrow transplantation (UBMT). PBSCT from haplo-identical related donors and cord blood transplantation (CBT) required a significantly greater RBC transfusion volume. For platelet transfusion, related and unrelated PBSCT required a significantly lower volume than UBMT, and CBT a greater volume. Other factors independently associated with greater RBC transfusion volume were male sex, disease status other than complete remission, and major ABO mismatch. For platelet transfusion, these were male sex, disease status, and HCT-specific comorbidity index of 1. Although the burden of blood transfusions may not be the most important factor when choosing a donor type, our findings may provide a foundation for nationwide strategies to prepare blood products and inform aspects of national healthcare expenditures.
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http://dx.doi.org/10.1007/s12185-020-03041-2DOI Listing
April 2021

Hepatitis B virus core-related antigen is useful for surveillance of hepatocellular carcinoma recurrence in a patient with occult hepatitis B virus infection: Case report.

Clin Case Rep 2020 Dec 16;8(12):3032-3037. Epub 2020 Sep 16.

Department of Gastroenterology and Medicine Faculty of Medicine Fukuoka University Fukuoka Japan.

Serum HBV core-related antigen (HBcrAg) is useful for detecting HCC in patients with occult HBV infection. Surveillance for HCC is needed in patients who are positive for HBcrAg, even if they are negative for HBsAg and HBV DNA.
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http://dx.doi.org/10.1002/ccr3.3360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752430PMC
December 2020

Data resource profile: JMDC claims databases sourced from Medical Institutions.

J Gen Fam Med 2020 Nov 30;21(6):211-218. Epub 2020 Aug 30.

Department of Health Informatics Kyoto University School of Public Health Kyoto Japan.

JMDC, Inc. (JMDC) has created a database, using data collected from medical institutions in Japan, consisting of claims (for hospitalization and outpatient treatment), diagnosis procedure combination (DPC) assessment forms, and clinical laboratory test values. The oldest data in this database that can be accessed relate to treatment in April 2014. Currently (the end of October 2019), the number of medical institutions is 218, consisting of 131 DPC-eligible hospitals and 87 DPC-ineligible hospitals. Using this database, it is possible to carry out an analysis that makes up for certain limitations of JMDC's another database of data from health insurance societies (eg, the disease status and test results cannot be ascertained, and there is insufficient access to data for elderly people). In addition, it is noteworthy that this database includes not only data from DPC-eligible hospitals but also data from some DPC-ineligible hospitals.
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http://dx.doi.org/10.1002/jgf2.367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689231PMC
November 2020

Silk fibroin vascular graft: a promising tissue-engineered scaffold material for abdominal venous system replacement.

Sci Rep 2020 12 3;10(1):21041. Epub 2020 Dec 3.

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

No alternative tissue-engineered vascular grafts for the abdominal venous system are reported. The present study focused on the development of new tissue-engineered vascular graft using a silk-based scaffold material for abdominal venous system replacement. A rat vein, the inferior vena cava, was replaced by a silk fibroin (SF, a biocompatible natural insoluble protein present in silk thread), tissue-engineered vascular graft (10 mm long, 3 mm diameter, n = 19, SF group). The 1 and 4 -week patency rates and histologic reactions were compared with those of expanded polytetrafluoroethylene vascular grafts (n = 10, ePTFE group). The patency rate at 1 and 4 weeks after replacement in the SF group was 100.0% and 94.7%, and that in the ePTFE group was 100.0% and 80.0%, respectively. There was no significant difference between groups (p = 0.36). Unlike the ePTFE graft, CD31-positive endothelial cells covered the whole luminal surface of the SF vascular graft at 4 weeks, indicating better endothelialization. SF vascular grafts may be a promising tissue-engineered scaffold material for abdominal venous system replacement.
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http://dx.doi.org/10.1038/s41598-020-78020-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713399PMC
December 2020

Production Mechanisms of Black Tea Polyphenols.

Chem Pharm Bull (Tokyo) 2020 ;68(12):1131-1142

Graduate School of Biomedical Sciences, Nagasaki University.

Black tea accounts for 70-80% of world tea production, and the polyphenols therein are produced by enzymatic oxidation of four tea catechins during tea fermentation. However, only limited groups of dimeric oxidation products, such as theaflavins, theasinensins, and theacitrins, have been isolated from black tea and chemically characterized. This is largely because of the complexity and heterogeneity of the oxidation products. To determine structures and production mechanisms of uncharacterized black tea polyphenols, in vitro model fermentation experiments using pure catechins and polyphenol oxidase have been applied, and basic oxidation mechanisms have been established. Contemporary methods, such as LC-MS, are also effective to identify catechin oxidation products in black tea. Despite ongoing efforts, almost 60% of the solids in black tea infusion remain uncharacterized. These compounds include the so-called thearubigins, which are a heterogeneous mixture of uncharacterized catechin oxidation products with oligomeric structures. This review summarizes the current knowledge of the production mechanisms of representative black tea polyphenols and presents recent progress in characterization of thearubigins.
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http://dx.doi.org/10.1248/cpb.c20-00295DOI Listing
January 2020

Highly Oxidized Ellagitannins of and Their Oxidation-Reduction Disproportionation.

J Nat Prod 2020 11 17;83(11):3424-3434. Epub 2020 Nov 17.

Usaien Pharmaceutical Company, Ltd., 1-4-6 Zaimoku, Saga 840-0055, Japan.

In the research on ellagitannin metabolism, two unique dehydroellagitannins, carpinins E () and F (), bearing dehydrohexahydroxydiphenoyl (DHHDP) and hydrated biscyclohexenetrione dicarboxyl ester (HBCHT) groups, were isolated from young leaves of . Upon heating in HO or treatment with pH 6 buffer at room temperature, and afforded the reduction product , isocarpinin A, with an ()-hexahydroxydiphenoyl (HHDP) group, suggesting the occurrence of redox disproportionation of the ()-DHHDP group. This was supported by the increase in production of in the pH 6 buffer solution by coexistence of epigallocatechin-3--gallate (), accompanied by oxidation of . In contrast, treatment of and with ascorbic acid yielded , carpinin A, with an ()-HHDP group. Upon heating with ascorbic acid, the HBCHT group was also reduced to an ()-HHDP group, and was converted to 2,3;4,6-bis()-HHDP glucose. In leaves of , the tannins and are dominant in young spring leaves, but compounds and become the major components of tannins in mature leaves. These results suggest that, in ellagitannin biosynthesis, oxidative coupling of the two galloyl groups first generates a DHHDP group, and subsequent reduction of DHHDP esters produces HHDP esters.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00893DOI Listing
November 2020

A pH-Adjustable Tissue Clearing Solution That Preserves Lipid Ultrastructures: Suitable Tissue Clearing Method for DDS Evaluation.

Pharmaceutics 2020 Nov 9;12(11). Epub 2020 Nov 9.

Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan.

Visualizing biological events and states to resolve biological questions is challenging. Tissue clearing permits three-dimensional multicolor imaging. Here, we describe a pH-adjustable tissue clearing solution, Seebest (SEE Biological Events and States in Tissues), which preserves lipid ultrastructures at an electron microscopy level. Adoption of polyethylenimine was required for a wide pH range adjustment of the tissue clearing solution. The combination of polyethylenimine and urea had a good tissue clearing ability for multiple tissues within several hours. Blood vessels stained with lipophilic carbocyanine dyes were deeply visible using the solution. Adjusting the pH of the solution was important to maximize the fluorescent intensity and suppress dye leakage during tissue clearing. The spatial distribution of doxorubicin and oxidative stress were observable using the solution. Moreover, spatial distribution of liposomes in the liver was visualized. Hence, the Seebest solution provides pH-adjustable, rapid, sufficient tissue clearing, while preserving lipid ultrastructures, which is suitable for drug delivery system evaluations.
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http://dx.doi.org/10.3390/pharmaceutics12111070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698078PMC
November 2020

Computationally Assisted Structural Revision of Flavoalkaloids with a Seven-Membered Ring: Aquiledine, Isoaquiledine, and Cheliensisine.

J Nat Prod 2020 11 21;83(11):3347-3353. Epub 2020 Oct 21.

Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.

Aquiledine and cheliensisine are flavoalkaloids isolated from and , respectively. Different structures have been proposed for these flavoalkaloids; however, their H and C NMR spectroscopic data were virtually identical. In this study, the structures of aquiledine and cheliensisine were revised on the basis of the DFT calculation of NMR data including DP4+ and -DP4 analysis, as well as specific rotations. Similarly, the structure of isoaquiledine, a regioisomer of aquiledine, was also revised. A biosynthetic pathway of these flavoalkaloids is proposed.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00691DOI Listing
November 2020

Melatonin stimulates transcription of the rat phosphoenolpyruvate carboxykinase gene in hepatic cells.

FEBS Open Bio 2020 Dec 2;10(12):2712-2721. Epub 2020 Nov 2.

Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Japan.

Melatonin plays physiological roles in various critical processes, including circadian rhythms, oxidative stress defenses, anti-inflammation responses, and immunity; however, the current understanding of the role of melatonin in hepatic glucose metabolism is limited. In this study, we examined whether melatonin affects gene expression of the key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK). We found that melatonin treatment increased PEPCK mRNA levels in rat highly differentiated hepatoma (H4IIE) cells and primary cultured hepatocytes. In addition, we found that melatonin induction was synergistically enhanced by dexamethasone, whereas it was dominantly inhibited by insulin. We also report that the effect of melatonin was blocked by inhibitors of mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK), RNA polymerase II, and protein synthesis. Furthermore, the phosphorylated (active) forms of ERK1 and ERK2 (ERK1/2) increased 15 min after melatonin treatment. We performed luciferase reporter assays to show that melatonin specifically stimulated promoter activity of the PEPCK gene. Additional reporter analysis using 5'-deleted constructs revealed that the regulatory regions responsive to melatonin mapped to two nucleotide regions, one between -467 and -398 nucleotides and the other between -128 and +69 nucleotides, of the rat PEPCK gene. Thus, we conclude that melatonin induces PEPCK gene expression via the ERK1/2 pathway at the transcriptional level, and that induction requires de novo protein synthesis.
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http://dx.doi.org/10.1002/2211-5463.13007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714082PMC
December 2020