Publications by authors named "Hideki Hayashi"

350 Publications

Carotid micromesh stent for the cervical carotid artery dissecting aneurysm in a patient with vascular Eagle syndrome.

J Stroke Cerebrovasc Dis 2022 May 13;31(8):106487. Epub 2022 May 13.

Department of Neurosurgery, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka 530-8480, Japan.

Objectives: An elongated styloid process may cause vascular Eagle syndrome that includes cervical carotid artery (CCA) dissection with stenosis and aneurysm formation. There are only four reported cases with vascular Eagle syndrome-related CCA dissecting aneurysm treated with carotid artery stenting (CAS). This is the first report of applying a dual-layer nitinol micromesh stent (CASPER) for vascular Eagle syndrome-related CCA dissecting aneurysm.

Case Presentation: A 38-year-old man presented with a sudden onset of aphasia and right hemiplegia. Cerebral angiography demonstrated the left CCA dissecting aneurysm. The superior trunk of the left middle cerebral artery (MCA) was also occluded, and emergent thrombectomy was performed. Computed tomography with angiography (CTA) revealed that a 33 mm-long styloid process compressed the CCA at the aneurysm formation. Three weeks later, a CASPER stent was applied for the CCA aneurysm under the flow reversal system. Immediately after stent placement, blood flow in the aneurysm became stagnant, and postoperative CTA demonstrated regression of the aneurysm. The aneurysm did not recur for 6 months with no styloid process resection.

Conclusions: The dual-layer nitinol micromesh stent (CASPER) was useful to treat vascular Eagle syndrome-related CCA dissecting aneurysm.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2022.106487DOI Listing
May 2022

Unique Mode of Antiviral Action of a Marine Alkaloid against Ebola Virus and SARS-CoV-2.

Viruses 2022 Apr 15;14(4). Epub 2022 Apr 15.

Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan.

Lamellarin α 20-sulfate is a cell-impenetrable marine alkaloid that can suppress infection that is mediated by the envelope glycoprotein of human immunodeficiency virus type 1. We explored the antiviral action and mechanisms of this alkaloid against emerging enveloped RNA viruses that use endocytosis for infection. The alkaloid inhibited the infection of retroviral vectors that had been pseudotyped with the envelope glycoprotein of Ebola virus and SARS-CoV-2. The antiviral effects of lamellarin were independent of the retrovirus Gag-Pol proteins. Interestingly, although heparin and dextran sulfate suppressed the cell attachment of vector particles, lamellarin did not. In silico structural analyses of the trimeric glycoprotein of the Ebola virus disclosed that the principal lamellarin-binding site is confined to a previously unappreciated cavity near the NPC1-binding site and fusion loop, whereas those for heparin and dextran sulfate were dispersed across the attachment and fusion subunits of the glycoproteins. Notably, lamellarin binding to this cavity was augmented under conditions where the pH was 5.0. These results suggest that the final action of the alkaloid against Ebola virus is specific to events following endocytosis, possibly during conformational glycoprotein changes in the acidic environment of endosomes. Our findings highlight the unique biological and physicochemical features of lamellarin α 20-sulfate and should lead to the further use of broadly reactive antivirals to explore the structural mechanisms of virus replication.
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http://dx.doi.org/10.3390/v14040816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028129PMC
April 2022

Pharmaceutical intervention for adverse events improves quality of life in patients with cancer undergoing outpatient chemotherapy.

J Pharm Health Care Sci 2022 Mar 2;8(1). Epub 2022 Mar 2.

Department of Pharmacy, Gifu University Hospital, Yanagido 1-1, Gifu, 501-1194, Japan.

Background: The effect of pharmaceutical intervention to treat adverse events on quality of life (QOL) in outpatients receiving cancer chemotherapy is unclear. We investigated whether pharmaceutical intervention provided by pharmacists in collaboration with physicians improves QOL with outpatient cancer chemotherapy.

Methods: We conducted a single-center retrospective descriptive study of pharmaceutical intervention for patients receiving outpatient cancer chemotherapy at Gifu University Hospital between September 2017 and July 2020. We assessed patient QOL using the Japanese version of the EuroQol 5 Dimension5 Level (EQ-5D-5L). Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. We compared the EQ-5D-5L utility value and incidence of grade 2 or higher adverse events before and after pharmaceutical intervention.

Results: Our analysis included 151 patients who underwent 210 chemotherapy cycles. Pharmaceutical intervention significantly improved patients' EQ-5D-5L utility values from 0.8197 to 0.8603 (P < 0.01). EQ-5D-5L utility values were significantly improved after pharmaceutical intervention for nausea and vomiting (pre-intervention 0.8145, post-intervention 0.8603, P = 0.016), peripheral neuropathy (pre-intervention 0.7798, post-intervention 0.7988, P = 0.032) and pain (pre-intervention 0.7625, post-intervention 0.8197, P = 0.035). Although not statistically significant, the incidence of grade 2 or higher adverse events, including nausea and vomiting, dermopathy, pain, oral mucositis, diarrhea and dysgeusia, tended to be lower post-intervention than pre-intervention.

Conclusions: Pharmaceutical intervention by pharmacists in collaboration with physicians may improve QOL in patients undergoing outpatient cancer chemotherapy.
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http://dx.doi.org/10.1186/s40780-022-00239-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889741PMC
March 2022

Effect of Progranulin on Proliferation and Differentiation of Neural Stem/Progenitor Cells after Oxygen/Glucose Deprivation.

Int J Mol Sci 2022 Feb 9;23(4). Epub 2022 Feb 9.

Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Hachioji 192-0392, Japan.

We previously demonstrated that sivelestat, a selective neutrophil elastase inhibitor, attenuates the cleavage of progranulin (PGRN) and ischemia-induced cell injury in the brain. To obtain further insight into the role of PGRN, in the present study we evaluated the direct effects of sivelestat and recombinant PGRN (rPGRN) on the proliferation and differentiation of neural stem cells in cultures of neural stem/progenitor cells (NS/PC) under the ischemic condition in vitro. We demonstrated that oxygen/glucose deprivation (OGD)-induced cell proliferation of NS/PC was increased by rPGRN treatment. In addition, this increase was accompanied by increased phosphorylation of Akt and GSK-3β (Ser9) after OGD. But none of these responses occurred by treatment with sivelestat. Therefore, activation of the Akt/GSK-3β pathway could well be involved in this proliferative effect of rPGRN. Although OGD and reoxygenation-induced changes in the differentiation of NS/PC into neurons or astrocytes was not affected by treatment with rPGRN or sivelestat, it is noteworthy that rPGRN enhanced neurite outgrowth of β3-tubulin-positive neurons that had differentiated from the NS/PC. These findings suggest that enhancement of proliferation of endogenous NS/PC and neurite outgrowth of differentiated neurons from NS/PC by PGRN could be useful for a new therapeutic approach for cerebral ischemia.
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http://dx.doi.org/10.3390/ijms23041949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8879483PMC
February 2022

Comparison of estimated treatment effects between randomized controlled trials, case-matched, and cohort studies on laparoscopic versus open distal gastrectomy for advanced gastric cancer: a systematic review and meta-analysis.

Langenbecks Arch Surg 2022 Feb 3. Epub 2022 Feb 3.

Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan.

Purpose: In actual surgical research, case-matched studies are frequently conducted as an alternative to randomized controlled trials (RCTs). However, it is still unclear what differences there are between RCTs and case-matched studies in upper gastrointestinal surgery, and clarifying them is a very important clinical issue. Thus, the purpose of this study was to investigate estimated treatment effects between RCTs, case-matched studies, and cohort studies regarding laparoscopic distal gastrectomy (LDG) for advanced gastric cancer (AGC).

Methods: We searched the PubMed, Cochrane Central Register of Controlled Trials, and Web of Science databases for studies that compared LDG versus open distal gastrectomy for AGC published from the inception of the databases until July 2021. A meta-analysis was performed using the Review Manager version 5.3 software program from the Cochrane Collaboration, and six short-term outcomes and three long-term outcomes were assessed.

Results: Twenty-three studies with 13698 patients were included. There was no difference in estimated treatment effects between RCTs and case-matched studies for all outcomes except for the number of retrieved lymph nodes and postoperative complications. In terms of intraoperative blood loss, postoperative hospital stay, number of retrieved lymph nodes, and recurrence, observational studies tended to overestimate the treatment effects.

Conclusion: The estimated treatment effects of LDG for AGC in the case-matched study were almost the same as in the RCTs. However, to assess the true magnitude of the treatment effect, the design and actual implementation of the analysis must be critically evaluated.
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http://dx.doi.org/10.1007/s00423-022-02454-3DOI Listing
February 2022

Clinical Outcomes in Biopsy-Proven Nonalcoholic Fatty Liver Disease Patients: A Multicenter Registry-based Cohort Study.

Clin Gastroenterol Hepatol 2022 Jan 17. Epub 2022 Jan 17.

Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Background & Aims: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage.

Methods: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients.

Results: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality.

Conclusions: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.
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http://dx.doi.org/10.1016/j.cgh.2022.01.002DOI Listing
January 2022

[Successful Endoscopic Submucosal Dissection of Early Gastric Cancer after Ulcer Healing Associated with a Malignant Cycle-A Case Report].

Gan To Kagaku Ryoho 2021 Dec;48(13):2127-2129

Dept. of Frontier Surgery, Graduate School of Medicine, Chiba University.

A 79-year-old man was detected with anemia on medical examination and underwent gastroscopy at the previous hospital. Gastroscopy revealed a 15-mm ulcerative lesion(Type 0-Ⅱc plus Ⅲ)on the greater curvature of the upper gastric body. Tumor biopsy showed well-differentiated adenocarcinoma. The patient was suspected of deep submucosal invasion due to poor stretching of the gastric wall and the ulcer depth; hence, he was transferred to our hospital for surgery. When gastroscopy was repeated, the ulcer was found to be scarred(Type 0-Ⅱc), thereby indicating the occurrence of intramucosal carcinoma; hence, endoscopic submucosal dissection was performed. The pathological finding showed 10×6 mm, tub1, pT1a, ly0, v0, pUL1, pHM0, pVM0, suggesting a curative resection. Early gastric cancer of the depressed type is known to develop a malignant cycle with repeated improvements and exacerbations of the ulcer. Diagnosing the depth of tumor invasion is particularly difficult when there is an active ulcer. For small lesions with active ulcers, repeating gastroscopy might allow for correct diagnosis and appropriate treatment.
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December 2021

A case report of duodenal arteriovenous malformation: usefulness of intraoperative indocyanine green angiography for precise identification of the lesion.

Surg Case Rep 2022 Jan 4;8(1). Epub 2022 Jan 4.

Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, 260-8677, Japan.

Background: Arteriovenous malformation (AVM) of the gastrointestinal (GI) tract can cause bleeding. The treatment choice for GI tract AVM is surgical resection of the involved bowel segment with complete resection of the nidus. The AVM formed in the duodenum or pancreatic head could also cause gastrointestinal bleeding, and there are several reports of pancreaticoduodenectomy as its treatment. However, if the area of AVM can be accurately identified during surgery, it may be possible to completely resect the AVM while preserving the organ. We report a case of duodenal AVM in a patient successfully treated with a subtotal stomach-preserving duodenal bulb resection using intraoperative indocyanine green (ICG) angiography technique.

Case Presentation: An 18-year-old man was diagnosed with duodenal AVM after several examinations for anemia and was referred to our hospital for further treatment. Preoperative imaging studies showed that the inflow vessels of this duodenal AVM were the inferior pyloric artery and the superior duodenal artery, and the AVM was localized to the duodenal bulb. Thereafter, stomach-preserving duodenal bulb resection preceded by ligation of the inflow vessels was performed. During the surgery, ICG angiography clearly demonstrated the area, where the nidus was distributed, and a duodenal bulb resection with complete resection of the AVM was successfully performed. There was no recurrence at the 6-month follow-up.

Conclusions: Intraoperative ICG angiography was a useful procedure for precise identification of the AVM of the GI tract.
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http://dx.doi.org/10.1186/s40792-021-01356-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727664PMC
January 2022

Influence of liver stiffness heterogeneity on staging fibrosis in patients with nonalcoholic fatty liver disease.

Hepatology 2021 Dec 24. Epub 2021 Dec 24.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Background And Aims: Despite that hepatic fibrosis often affects the liver globally, spatial distribution can be heterogeneous. This study aimed to investigate the effect of liver stiffness (LS) heterogeneity on concordance between MR elastography (MRE)-based fibrosis staging and biopsy staging in patients with NAFLD.

Approach And Results: We retrospectively evaluated data from 155 NAFLD patients who underwent liver biopsy and 3 Tesla MRE and undertook a retrospective validation study of 169 NAFLD patients at three hepatology centers. Heterogeneity of stiffness was assessed by measuring the range between minimum and maximum MRE-based LS measurement (LSM). Variability of LSM was defined as the stiffness range divided by the maximum stiffness value. The cohort was divided into two groups (homogenous or heterogeneous), according to whether variability was below or above the average for the training cohort. Based on histopathology and receiver operating characteristic (ROC) analysis, optimum LSM thresholds were determined for MRE-based fibrosis staging of stage 4 (4.43, kPa; AUROC, 0.89) and stage ≥3 (3.93, kPa; AUROC, 0.89). In total, 53 had LSM above the threshold for stage 4. Within this group, 30 had a biopsy stage of <4. In 86.7% of these discordant cases, variability of LSM was classified as heterogeneous. In MRE-based LSM stage ≥3, 88.9% of discordant cases were classified as heterogeneous. Results of the validation cohort were similar to those of the training cohort.

Conclusions: Discordance between biopsy- and MRE-based fibrosis staging is associated with heterogeneity in LSM, as depicted with MRE.
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http://dx.doi.org/10.1002/hep.32302DOI Listing
December 2021

Antivirus activity, but not thiolreductase activity, is conserved in interferon-gamma-inducible GILT protein in arthropod.

Mol Immunol 2021 12 10;140:240-249. Epub 2021 Nov 10.

Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan; Program for Nurturing Global Leaders in Tropical Medicine and Emerging Communicable Diseases, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. Electronic address:

We have previously reported that gamma-interferon inducible lysosomal thiolreductase (GILT) functions as a host defense factor against retroviruses by digesting disulfide bonds on viral envelope proteins. GILT is widely conserved even in plants and fungi as well as animals. The thiolreductase active site of mammalian GILT is composed of a CXXC amino acid motif, whereas the C-terminal cysteine residue is changed to serine in arthropods including shrimps, crabs, and flies. GILT from Penaeus monodon (PmGILT) also has the CXXS motif instead of the CXXC active site. We demonstrate here that a human GILT mutant (GILT C75S) with the CXXS motif and PmGILT significantly inhibit amphotropic murine leukemia virus vector infection in human cells without alterning its expression level and lysosomal localization, showing that the C-terminal cysteine residue of the active site is not required for the antiviral activity. We have reported that human GILT suppresses HIV-1 particle production by digestion of disulfide bonds on CD63. However, GILT C75S mutant and PmGILT did not digest CD63 disulfide bonds, and had no effect on HIV-1 virion production, suggesting that they do not have thiolreductase activity. Taken together, this study found that antiviral activity, but not thiolreductase activity, is conserved in arthropod GILT proteins. This finding provides a new insight that the common function of GILT is antiviral activity in many animals.
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http://dx.doi.org/10.1016/j.molimm.2021.10.018DOI Listing
December 2021

Apolipoprotein E-Containing Lipoproteins and LRP1 Protect From NMDA-Induced Excitotoxicity Associated With Reducing α2-Macroglobulin in Müller Glia.

Invest Ophthalmol Vis Sci 2021 10;62(13):23

Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.

Purpose: Optic nerve damage leads to impairment of visual functions. We previously demonstrated that apolipoprotein E-containing lipoproteins (E-LPs) protect retinal ganglion cells (RGCs) from degeneration in a glaucoma model of glutamate/aspartate transporter-deficient mice. This study aimed to determine whether E-LPs protect RGCs from N-methyl-D-aspartate (NMDA)-induced excitotoxicity, and to investigate the details of an indirect neuroprotective mechanism of E-LPs by reducing α2-macroglobulin, which interferes with the neuroprotective effect of E-LPs, in Müller glia.

Methods: Excitotoxicity was caused by intravitreal injection of NMDA, and then retinae were subjected to immunoblotting or quantitative reverse transcription-PCR. Primary cultures of mouse mixed retinal cells and mouse Müller glia were used for evaluating the effects of E-LPs on the expression of α2-macroglobulin.

Results: Intravitreal injection of E-LPs protected the optic nerve from degeneration and attenuated the increase in α2-macroglobulin in aqueous humor and retina of rats. E-LPs directly decreased the expression and secretion of α2-macroglobulin in primary cultures of Müller glia; this decrease in production of α2-macroglobulin was blocked by knockdown of the low-density lipoprotein receptor-related protein 1 (LRP1) with small interfering RNA. E-LPs promoted the phosphorylation of STAT3, whereas Stattic, an inhibitor of STAT3, restored the expression of α2-macroglobulin decreased by E-LPs.

Conclusions: In addition to our previous findings of the protection of RGCs by E-LPs, the new observations in Müller glia indicate that a reduction of the intraocular α2-macroglobulin, regulated by the E-LP-LRP1-STAT3 pathway, might be an additional protective mechanism against excitotoxicity in the retina.
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http://dx.doi.org/10.1167/iovs.62.13.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556555PMC
October 2021

Corrigendum: Cytotoxic Effects of Arsenite in Combination With Gamabufotalin Against Human Glioblastoma Cell Lines.

Front Oncol 2021 8;11:778834. Epub 2021 Oct 8.

Department of Applied Biochemistry, Tokyo University of Pharmacy & Life Sciences, Hachioji, Japan.

[This corrects the article DOI: 10.3389/fonc.2021.628914.].
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http://dx.doi.org/10.3389/fonc.2021.778834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532021PMC
October 2021

A prospective, phase II trial of monotherapy with low-dose afatinib for patients with EGFR, mutation-positive, non-small cell lung cancer: Thoracic oncology research group 1632.

Lung Cancer 2021 11 31;161:49-54. Epub 2021 Aug 31.

Department of Pulmonary Medicine and Oncology, Nippon Medical School Hospital, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, Japan. Electronic address:

Objectives: Afatinib is an effective treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, the toxicity associated with this agent often leads to dose modifications. The aim of this study was to assess the efficacy, safety and plasma concentrations of low dose afatinib monotherapy in patients with EGFR mutation-positive NSCLC.

Patients And Methods: This was a multicenter, single-arm, open-label, phase II trial involving treatment-naïve patients with advanced EGFR mutation-positive NSCLC. From March 2017 to September 2018, 53 patients were enrolled from 21 institutions in Japan. Patients initially received afatinib 20 mg/day orally. For patients in whom the tumor progressed within stable disease, the investigators were able to increase the afatinib dose (10 mg increments). The primary endpoint was progression-free survival (PFS). The threshold and expected median PFS was 9.2 and 13.8 months, respectively. Additionally, the correlation of the plasma concentration of low-dose afatinib with clinical outcome and adverse events were evaluated.

Results: The median age of patients was 70 years (range: 37-85 years); 28 patients (52.8%) were females. The median duration of the follow-up was 20.8 months. The median PFS, and overall survival were 12.6 months (90% confidence interval [CI]: 9.7-14.3 months), and not reached, respectively. The primary endpoint was met. The objective response rate and disease control rate were 66.0% (95% CI: 51.7-78.5) and 92.5% (95% CI: 81.8-97.9), respectively. Grade ≥ 3 adverse events occurred in 12 patients (22.6%), including diarrhea in four patients (7.5%). The rate of adverse events was lower than that observed in previous phase III studies of 40 mg afatinib.

Conclusion: Based on its promising clinical efficacy and tolerability profile, monotherapy with low-dose afatinib should become one of the standard therapies for EGFR mutation-positive NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.08.007DOI Listing
November 2021

Cytotoxic Effects of Hellebrigenin and Arenobufagin Against Human Breast Cancer Cells.

Front Oncol 2021 26;11:711220. Epub 2021 Aug 26.

Department of Applied Biochemistry, Tokyo University of Pharmacy & Life Sciences, Hachioji, Japan.

Development of new therapeutic strategies for breast cancer is urgently needed due to the sustained emergence of drug resistance, tumor recurrence and metastasis. To gain a novel insight into therapeutic approaches to fight against breast cancer, the cytocidal effects of hellebrigenin (Helle) and arenobufagin (Areno) were investigated in human estrogen receptor (ER)-positive breast cancer cell line MCF-7 and triple-negative breast cancer cell line MDA-MB-231. Helle exhibited more potent cytotoxicity than Areno in both cancer cells, and MCF-7 cells were more susceptible to both drugs in comparison with MDA-MB-231 cells. Apoptotic-like morphological characteristics, along with the downregulation of the expression level of Bcl-2 and Bcl-xL and the upregulation of the expression level of Bad, were observed in Helle-treated MCF-7 cells. Helle also caused the activation of caspase-8, caspase-9, along with the cleavage of poly(ADP-ribose) polymerase in MCF-7 cells. Helle-mediated necrosis-like phenotype, as evidenced by the increased propidium iodide (PI)-positive cells was further observed. G/M cell cycle arrest was also induced by Helle in the cells. Upregulation of the expression level of p21 and downregulation of the expression level of cyclin D1, cyclin E1, cdc25C and survivin were observed in MCF-7 cells treated with Helle and occurred in parallel with G/M arrest. Autophagy was triggered in MCF-7 cells and the addition of wortmannin or 3-MA, two well-known autophagy inhibitors, slightly but significantly rescued the cells. Furthermore, similar alterations of some key molecules associated with the aforementioned biological phenomena were observed in MDA-MB-231 cells. Intriguingly, the numbers of PI-positive cells in Helle-treated MCF-7 cells were significantly reduced by wortmannin and 3-MA, respectively. In addition, Helle-triggered G/M arrest was significantly corrected by wortmannin, suggesting autophagy induction contributed to Helle-induced cytotoxicity of breast cancer cells by modulating necrosis and cell cycle arrest. Collectively, our results suggested potential usefulness of both Helle and Areno in developing therapeutic strategies to treat patients with different types of breast cancer, especially ER-positive breast cancer.
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http://dx.doi.org/10.3389/fonc.2021.711220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427765PMC
August 2021

Clinical impact of monitoring frequency per day as a prospective audit and feedback strategy for patients receiving antimicrobial agents by injection.

Int J Clin Pract 2021 Nov 14;75(11):e14785. Epub 2021 Sep 14.

Center for Nutrition Support & Infection Control, Gifu University Hospital, Gifu, Japan.

Background: Implementation of antimicrobial stewardship programmes improve antimicrobial therapies and thus result in better patient outcomes and safety. The impact of prospective audit and feedback (PAF) is likely dependent on how frequently it is conducted, and how quickly after antibiotic prescription it is initiated. To our knowledge, however, no report has yet investigated the impact of an increase in monitoring frequency per day on PAF strategy. Here, we evaluated the clinical impact of an increase in monitoring frequency per day as a PAF strategy in patients receiving antimicrobial injections.

Methods: We conducted a single-centre, retrospective observational pre-post study to evaluate the impact of increasing the frequency of monitoring from once daily (once daily review group) to twice daily (twice daily review group). Time to intervention and clinical outcomes were compared before and after implementation of twice daily review.

Results: Time to intervention for inappropriate antimicrobial therapy was significantly shorter in the twice daily review group than the once daily review group (5.1 ± 6.1 hours vs 29.9 ± 21.5 hours, HR: 4.53, 95% CI: 2.90-7.07, P < .001). The twice daily review group had a significantly lower rate of clinical failure (16.2% vs 38.3%, P = .004) and hepatotoxicity (4.1% vs 15.0%, P = .035) than the once daily review group.

Conclusions: An increase in monitoring frequency from once daily to twice daily significantly shortened the time to intervention for inappropriate antimicrobial therapy, with a concomitant reduction in clinical failure and hepatotoxicity.
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http://dx.doi.org/10.1111/ijcp.14785DOI Listing
November 2021

[Rethinking Lacunar Stroke: Beyond Fisher's Curse].

Brain Nerve 2021 Sep;73(9):991-998

Department of Neurology, Brain Research Institute, Niigata University.

Lipohyalinosis is an important concept in the independence of lacunar stroke; however, its role has been overemphasized and has led to much confusion in the understanding of lacunar stroke. Classical lipohyalinosis has declined following the widespread availability of antihypertensive therapy, and lacunar stroke secondary to age-related hyaline atherosclerosis is more commonly observed in clinical practice. Clinically diagnosed lacunar stroke is associated with several etiopathogenetic contributors. Excluding cardiogenic embolism, lacunar stroke can be categorized based on the detection of an atheroma. Atheroma imaging is possible in recent years, and strokes that are not associated with an atheroma are shown to present with deep white matter hyperintensity on MRI. Additionally, risk gene analysis has confirmed a group of risk genes associated with the extracellular matrix in lacunar stroke with white matter hyperintensity on MRI. These findings suggest the role of a variety of etiopathogenetic mechanisms underlying lacunar stroke and that lacunar stroke with deep white matter hyperintensity on MRI may be attributable to unique pathogenetic contributors. This group is known to be strongly associated with genetic contributors. Hopefully, lacunar stroke will be diagnosed from this perspective with the development of interventional strategies tailored to the pathogenesis of this condition.
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http://dx.doi.org/10.11477/mf.1416201876DOI Listing
September 2021

TMPRSS2 Activates Hemagglutinin-Esterase Glycoprotein of Influenza C Virus.

J Virol 2021 10 18;95(21):e0129621. Epub 2021 Aug 18.

Virus Research Center, Clinical Research Division, Sendai Medical Center, Sendai, Miyagi, Japan.

Influenza C virus (ICV) has only one kind of spike protein, the hemagglutinin-esterase (HE) glycoprotein. HE functions similarly to hemagglutinin (HA) and neuraminidase of the influenza A and B viruses (IAV and IBV, respectively). It has a monobasic site, which is cleaved by some host enzymes. The cleavage is essential to activating the virus, but the enzyme or enzymes in the respiratory tract have not been identified. This study investigated whether the host serine proteases, transmembrane protease serine S1 member 2 (TMPRSS2) and human airway trypsin-like protease (HAT), which reportedly cleave HA of IAV/IBV, are involved in HE cleavage. We established TMPRSS2- and HAT-expressing MDCK cells (MDCK-TMPRSS2 and MDCK-HAT). ICV showed multicycle replication with HE cleavage without trypsin in MDCK-TMPRSS2 cells as well as IAV did. The HE cleavage and multicycle replication did not appear in MDCK-HAT cells infected with ICV without trypsin, while HA cleavage and multistep growth of IAV appeared in the cells. Amino acid sequences of the HE cleavage site in 352 ICV strains were completely preserved. Camostat and nafamostat suppressed the growth of ICV and IAV in human nasal surface epithelial (HNE) cells. Therefore, this study revealed that, at least, TMPRSS2 is involved in HE cleavage and suggested that nafamostat could be a candidate for therapeutic drugs for ICV infection. Influenza C virus (ICV) is a pathogen that causes acute respiratory illness, mostly in children, but there are no anti-ICV drugs. ICV has only one kind of spike protein, the hemagglutinin-esterase (HE) glycoprotein on the virion surface, which possesses receptor-binding, receptor-destroying, and membrane fusion activities. The HE cleavage is essential for the virus to be activated, but the enzyme or enzymes in the respiratory tract have not been identified. This study revealed that transmembrane protease serine S1 member 2 (TMPRSS2), and not human airway trypsin-like protease (HAT), is involved in HE cleavage. This is a novel study on the host enzymes involved in HE cleavage, and the result suggests that the host enzymes, such as TMPRSS2, may be a target for therapeutic drugs of ICV infection.
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http://dx.doi.org/10.1128/JVI.01296-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513465PMC
October 2021

Anorexia, pain and peripheral neuropathy are associated with a decrease in quality of life in patients with advanced pancreatic cancer receiving outpatient chemotherapy - a retrospective observational study.

J Pharm Health Care Sci 2021 Aug 2;7(1):27. Epub 2021 Aug 2.

Department of Pharmacy, Gifu University Hospital, Yanagido 1-1, Gifu, 501-1194, Japan.

Background: Cancer chemotherapy usually improves clinical outcomes in patients with advanced pancreatic cancer (APC), but can also cause moderate-to-severe adverse events (AEs). We investigated the relationship between moderate-to-severe AEs and quality of life (QOL) in patients with APC who received outpatient chemotherapy.

Methods: We recruited APC patients who received outpatient chemotherapy in Gifu University Hospital between September 2017 and December 2018. Adverse events related to chemotherapy were assessed by a pharmacist collaborating with a physician using common terminology criteria for AEs (CTCAE) ver 4.0, and QOL of patients was self-assessed by patients using the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L Japanese edition 2). Associations between the EQ-5D-5L utility value and serious AEs were assessed using proportional odds logistic regression.

Results: A total of 59 patients who received 475 chemotherapy cycles were included. The proportional odds logistic regression indicated that grade ≥ 2 anorexia, pain and peripheral neuropathy were significantly correlated with a decreased EQ-5D-5L utility value. Pharmaceutical intervention for these AEs significantly improved the patients' EQ-5D-5L utility value.

Conclusions: Anorexia, pain and peripheral neuropathy were significantly associated with a decrease in QOL. It is assumed that appropriate pharmaceutical intervention with particular emphasis on these AEs can improve the QOL of pancreatic cancer patients receiving outpatient chemotherapy.
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http://dx.doi.org/10.1186/s40780-021-00210-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327438PMC
August 2021

[Development of Photocatalysts-Coated Polyethylene Terephthalate Film for Degradation and Elimination of Chemotherapy Drugs].

Gan To Kagaku Ryoho 2021 Jul;48(7):933-937

Dept. of Pharmacy, Gifu University Hospital.

Prolonged exposure to anticancer drugs can lead to health damage in medical professionals as well as in patients and their families, and can be a serious issue. The risk of occupational acute exposure to anticancer drugs in medical professionals has largely been reduced following the establishment of guidelines for safe handling of hazardous drugs. However, the problem of pollution associated with residual anticancer drugs attached to the surface of floors and walls in the prescription laboratory, treatment room and the lavatory remains unsolved. We have recently developed a polyethylene terephthalate(PET) film coated with photocatalysts such as titanium dioxide and tungsten oxide. In the present study, the ability of the PET film to degrade anticancer drugs was tested by dripping anticancer drug solution on to the surface of the film followed by irradiation with LED light. The contents of several anticancer drugs, including 5-fluorouracil, cyclophosphamide, and cisplatin, were greatly reduced after 24 hr irradiation. Therefore, the present photocatalysts-coated PET film may become a useful tool to reduce the risk for exposure to hazardous agents including anticancer drugs.
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July 2021

Rab3a, a small GTP-binding protein, is required for the stabilization of the murine leukaemia virus gag protein.

Small GTPases 2021 Jun 27:1-21. Epub 2021 Jun 27.

Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.

We recently identified a CD63-interacting protein to understand the role of CD63 in virion production of the human immunodeficiency virus type 1, and we have found that Rab3a forms a complex with CD63. In this study, we analysed the effect of Rab3a on virion production of the murine leukaemia virus (MLV), which is another member of the retrovirus family. We found that Rab3a silencing induced lysosomal degradation of the MLV Gag protein, and recovery of the Rab3a expression restored the level of the Gag protein through a complex formation of MLV Gag and Rab3a, indicating that Rab3a is required for MLV Gag protein expression. In contrast, CD63 silencing decreased the infectivity of released virions but had no effect on virion production, indicating that CD63 facilitates the infectivity of released MLV particles. Although Rab3a induced CD63 degradation in uninfected cells, the complex of MLV Gag and Rab3a suppressed the Rab3a-mediated CD63 degradation in MLV-infected cells. Finally, we found that the MLV Gag protein interacts with Rab3a to stabilize its own protein and CD63 that facilitates the infectivity of released MLV particles. Considering the involvement of Rab3a in lysosome trafficking to the plasma membrane, it may also induce cell surface transport of the MLV Gag protein.
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http://dx.doi.org/10.1080/21541248.2021.1939631DOI Listing
June 2021

Neuroprotective effects of Senkyunolide I against glutamate-induced cells death by attenuating JNK/caspase-3 activation and apoptosis.

Biomed Pharmacother 2021 Aug 25;140:111696. Epub 2021 May 25.

Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan. Electronic address:

Glutamate-induced neurotoxicity is one of the most important pathogenic mechanisms in neurological diseases and is widely used as an in vitro model for ischemic stroke. Senkyunolide I (SEI), an active constituent derived from traditional Chinese medicine Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, has been shown to have beneficial effects against focal cerebral ischemia-reperfusion in rats. However, the mechanisms underlying SEI-mediated neuroprotection remain not well understood. Thus, we explored the influence of SEI in glutamate-mediated injury to mouse neuroblastoma (Neuro2a) cells and determined the mechanisms involved. Neuro2a cells were treated with SEI under exposure to glutamate for 24 h. Cell viability was assessed by using WST-1 reagents, and apoptosis was evaluated using Annexin V-FITC and a PI double staining kit. The protein expression levels of p-AKT, AKT, p-GSK3β, GSK3β, p-p38, p38, p-ERK, ERK, p-JNK, JNK, Bcl-2, Bax, Bcl-xl, p-Bad, Bad, p53, and cleaved caspase-3 were determined by Western blot analysis. Glutamate significantly decreased cell viability and elevated the level of apoptosis. Treatment with SEI reversed those effects. Furthermore, the expression of p-JNK/JNK and cleaved caspase-3 were also reduced after treatment with SEI. Our findings demonstrate that SEI protected Neuro2a cells against glutamate toxicity by regulating JNK/caspase-3 pathway and apoptosis. Thus, SEI maybe a promising candidate for neuroprotection.
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http://dx.doi.org/10.1016/j.biopha.2021.111696DOI Listing
August 2021

Possible involvement of progranulin in the protective effect of elastase inhibitor on cerebral ischemic injuries of neuronal and glial cells.

Mol Cell Neurosci 2021 06 29;113:103625. Epub 2021 Apr 29.

Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Electronic address:

In a previous study, we demonstrated that neutrophil elastase is activated in the brain parenchyma after cerebral ischemia, which enzyme cleaves progranulin (PGRN), an anti-inflammatory factor. In that study, we also found that sivelestat, a selective neutrophil elastase inhibitor, attenuates ischemia-induced inflammatory responses. However, it was not clear whether this anti-inflammatory effect was due to the direct effect of sivelestat. In this study, we evaluated the effects of sivelestat or recombinant PGRN (rPGRN) on cell injuries in cultured neurons, astrocytes, and microglia under oxygen/glucose deprivation (OGD) conditions. We demonstrated that OGD-induced neuronal cell injury, astrocyte activation, and increased proinflammatory cytokines caused by microglial activation, were suppressed by rPGRN treatment, whereas sivelestat had no effect on any of these events. These results indicate that the anti-inflammatory responses after in vivo cerebral ischemia were not due to the direct action of sivelestat but due to the suppression of PGRN cleavage by inhibition of elastase activity. It was also suggested that the pleiotropic effect of rPGRN could be attributed to the differentiation of M1 microglia into anti-inflammatory type M2 microglia. Therefore, the inhibition of PGRN cleavage by sivelestat could contribute to the establishment of a new therapeutic approach for cerebral ischemia.
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http://dx.doi.org/10.1016/j.mcn.2021.103625DOI Listing
June 2021

Cytotoxic Effects of Arsenite in Combination With Gamabufotalin Against Human Glioblastoma Cell Lines.

Front Oncol 2021 16;11:628914. Epub 2021 Mar 16.

Department of Applied Biochemistry, Tokyo University of Pharmacy & Life Sciences, Hachioji, Japan.

Glioblastoma is a fatal primary malignant brain tumor, and the 5-year survival rate of treated glioblastoma patients still remains <5%. Considering the sustained development of metastasis, tumor recurrence, and drug resistance, there is an urgent need for the novel therapeutic approaches to combat glioblastoma. Trivalent arsenic derivative (arsenite, As) with remarkable clinical efficacy in leukemia has been shown to exert cytocidal effect against glioblastoma cells. Gamabufotalin, an active bufadienolide compound, also shows selective cytocidal effect against glioblastoma cells, and has been suggested to serve as a promising adjuvant therapeutic agent to potentiate therapeutic effect of conventional anticancer drugs. In order to gain novel insight into therapeutic approaches against glioblastoma, the cytotoxicity of As and gamabufotalin was explored in the human glioblastoma cell lines U-87 and U-251. In comparison with U-251 cells, U-87 cells were highly susceptible to the two drugs, alone or in combination. More importantly, clinically achieved concentrations of As combined with gamabufotalin exhibited synergistic cytotoxicity against U-87 cells, whereas showed much less cytotoxicity to human normal peripheral blood mononuclear cells. G/M cell cycle arrest was induced by each single drug, and further augmented by their combination in U-87 cells. Downregulation of the expression levels of cdc25C, Cyclin B1, cdc2, and survivin was observed in U-87 cells treated with the combined regimen and occurred in parallel with G/M arrest. Concomitantly, lactate dehydrogenase leakage was also observed. Intriguingly, SB203580, a specific inhibitor of p38 MAPK, intensified the cytotoxicity of the combined regimen in U-87 cells, whereas wortmannin, a potent autophagy inhibitor, significantly rescued the cells. Collectively, G/M arrest, necrosis and autophagy appeared to cooperatively contribute to the synergistic cytotoxicity of As and gamabufotalin. Given that p38 MAPK serves an essential role in promoting glioblastoma cell survival, developing a possible strategy composed of As, gamabufotalin, and a p38 MAPK inhibitor may provide novel insight into approaches designed to combat glioblastoma.
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http://dx.doi.org/10.3389/fonc.2021.628914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009626PMC
March 2021

Comprehensive stratum corneum ceramide profiling reveals reduced acylceramides in ichthyosis patient with CERS3 mutations.

J Dermatol 2021 Apr 25;48(4):447-456. Epub 2021 Jan 25.

Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.

The stratum corneum (SC) of the epidermis acts as a skin permeability barrier, and abnormalities in SC formation lead to several skin disorders. Lipids, especially the epidermis-specific ceramide classes ω-O-acylceramides (acylceramides) and protein-bound ceramides, are essential for skin barrier formation. Ceramide synthase 3 (CERS3) is involved in the synthesis of acylceramides and protein-bound ceramides, and CERS3 mutations cause autosomal recessive congenital ichthyosis. In the present study, we measured ceramide synthase activity and performed comprehensive SC ceramide profiling in an ichthyosis patient with compound heterozygous CERS3 mutations: nonsense mutation p.Arg75* and missense mutation p.Arg229His. The activity of p.Arg75* and p.Arg229His mutant CERS3 proteins was reduced to 4% and 56%, respectively, of the wild-type protein. In the patient's SC, acylceramide levels were greatly reduced, but the levels of protein-bound ceramides remained almost unchanged. Non-acylated ceramide levels were also affected in the patient; in particular, the levels of ceramides composed of sphingosine and non-hydroxy or α-hydroxy fatty acid were substantially higher than in healthy controls. These results suggest that a reduction in acylceramide levels alone leads to ichthyosis. Although protein-bound ceramides are synthesized from acylceramides, levels of acylceramides and protein-bound ceramides are not necessarily correlated.
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http://dx.doi.org/10.1111/1346-8138.15725DOI Listing
April 2021

Albumin-bilirubin score for predicting neuropsychiatric symptoms in patients receiving ifosfamide-based chemotherapy.

J Clin Pharm Ther 2021 Jun 4;46(3):794-799. Epub 2021 Jan 4.

Department of Pharmacy, Gifu University Hospital, Gifu, Japan.

What Is Known And Objective: Ifosfamide, an alkylating agent, is widely used in the treatment of malignant diseases. However, these treatments are often limited due to the incidence of neuropsychiatric symptoms such as delirium, seizures, hallucinations and agitation. In this study, we examined risk factors for neuropsychiatric symptoms in patients receiving ifosfamide-based chemotherapy.

Methods: The study cases were patients with cancer receiving ifosfamide-based chemotherapy between April 2007 and March 2018. Risk analysis for ifosfamide-related neuropsychiatric symptoms was determined by time-dependent Cox proportional hazard regression analysis.

Results And Discussion: Of 183 eligible patients, 32 patients (17.5%) experienced ifosfamide-related neuropsychiatric symptoms. Time-dependent Cox proportional hazard model showed that the albumin-bilirubin (ALBI) score was significantly correlated with the incidence of ifosfamide-related neuropsychiatric symptoms (hazard ratio [HR] =1.45, 95% confidence interval [CI] = 1.05-2.01, p = 0.025). Additionally, there were correlations between the predicted risk of neuropsychiatric symptoms and ifosfamide-dose per cycle (HR =0.51, 95% CI = 0.27-0.94, p = 0.030) and creatinine clearance (Ccr) (HR = 0.53, 95% CI = 0.28-1.00, p = 0.050). In contrast, neither serum albumin nor total bilirubin was a significant risk factor for neuropsychiatric symptoms.

What Is New And Conclusion: These findings indicate that ALBI score may be a useful biomarker for predicting neuropsychiatric symptoms in patients receiving ifosfamide-based chemotherapy.
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http://dx.doi.org/10.1111/jcpt.13355DOI Listing
June 2021

Effects of laminin-111 peptide coatings on rat neural stem/progenitor cell culture.

Exp Cell Res 2021 03 22;400(1):112440. Epub 2020 Dec 22.

Department of Clinical Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Hachioji, 192-0392, Japan.

Neurons require adhesive scaffolds for their growth and differentiation. Laminins are a major cell adhesive component of basement membranes and have various biological activities in the peripheral and central nervous systems. Here, we evaluated the biological activities of 5 peptides derived from laminin-111 as a scaffold for mouse neuroblastoma Neuro2a cells and rat neural stem/progenitor cells (NPCs). The 5 peptides showed Neuro2a cell attachment activity similar to that of poly-d-lysine. However, when NPCs were cultured on the peptides, 2 syndecan-binding peptides, AG73 (RKRLQVQLSIRT, mouse laminin α1 chain 2719-2730) and C16 (KAFDITYVRLKF, laminin γ1 chain 139-150), demonstrated significantly higher cell attachment and neurite extension activities than other peptides including integrin-binding ones. Long-term cell culture experiments showed that both AG73 and C16 supported the growth of neurons and astrocytes that had differentiated from NPCs. Furthermore, C16 markedly promoted the expression of neuronal markers such as synaptosomal-associated protein-25 and syntaxin 1A. These results indicate that AG73 and C16 are useful for NPC cultures and that C16 can be applied to specialized research on synapses in differentiated neurons. These peptides have the potential for use as valuable biomaterials for NPC research.
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http://dx.doi.org/10.1016/j.yexcr.2020.112440DOI Listing
March 2021

Fluorescent Behavior of Dibenzazepine-containing Polymers in Epoxy Resin.

Anal Sci 2021 Jul 11;37(7):997-1001. Epub 2020 Dec 11.

Nagoya Municipal Industrial Research Institute.

Dibenzazepine derivatives were added to epoxy resin (bisphenol A diglycidyl ether, DGEBA). DSC analyses showed that DGEBA could be cured by the addition of secondary and tertiary alkylamine-type compounds, but not by the addition of an N-butoxycarbonyl substituted compound. Curing of the cast film and the adhesion of glass substrates by a dibenzazepine-containing polymers/DGEBA mixture was also observed. Therefore, the fluorescence spectra of dibenzazepine-containing polymers in DGEBA were compared. When the polymer was blended with DGEBA and the mixture was heated, the fluorescent λ changed. This spectral change depended on the substituent of the polymer. This fluorescent behavior suggests that the polymers are likely to be monitoring agents for curing and adhesion.
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http://dx.doi.org/10.2116/analsci.20P289DOI Listing
July 2021

Efficient viral delivery of Cas9 into human safe harbor.

Sci Rep 2020 12 8;10(1):21474. Epub 2020 Dec 8.

Department of Pathology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Gene editing using CRISPR/Cas9 is a promising method to cure many human genetic diseases. We have developed an efficient system to deliver Cas9 into the adeno-associated virus integration site 1 (AAVS1) locus, known as a safe harbor, using lentivirus and AAV viral vectors, as a step toward future in vivo transduction. First, we introduced Cas9v1 (derived from Streptococcus pyogenes) at random into the genome using a lentiviral vector. Cas9v1 activity was used when the N-terminal 1.9 kb, and C-terminal 2.3 kb fragments of another Cas9v2 (human codon-optimized) were employed sequentially with specific single-guide RNAs (sgRNAs) and homology donors carried by AAV vectors into the AAVS1 locus. Then, Cas9v1 was removed from the genome by another AAV vector containing sgRNA targeting the long terminal repeat of the lentivirus vector. The reconstituted Cas9v2 in the AAVS1 locus was functional and gene editing was efficient.
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http://dx.doi.org/10.1038/s41598-020-78450-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722726PMC
December 2020

Monoradicals and Diradicals of Dibenzofluoreno[3,2-]fluorene Isomers: Mechanisms of Electronic Delocalization.

J Am Chem Soc 2020 Nov 18. Epub 2020 Nov 18.

Department of Physical Chemistry, University of Malaga, Campus de Teatinos s/n, Malaga 29071, Spain.

The preparation of a series of dibenzo- and tetrabenzo-fused fluoreno[3,2-]fluorenes is disclosed, and the diradicaloid properties of these molecules are compared with those of a similar, previously reported series of anthracene-based diradicaloids. Insights on the diradical mode of delocalization tuning by constitutional isomerism of the external naphthalenes has been explored by means of the physical approach (dissection of the electronic properties in terms of electronic repulsion and transfer integral) of diradicals. This study has also been extended to the redox species of the two series of compounds and found that the radical cations have the same stabilization mode by delocalization that the neutral diradicals while the radical anions, contrarily, are stabilized by aromatization of the central core. The synthesis of the fluorenofluorene series and their characterization by electronic absorption and vibrational Raman spectroscopies, X-ray diffraction, SQUID measurements, electrochemistry, in situ UV-vis-NIR absorption spectroelectrochemistry, and theoretical calculations are presented. This work attempts to unify the properties of different series of diradicaloids in a common argument as well as the properties of the carbocations and carbanions derived from them.
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http://dx.doi.org/10.1021/jacs.0c09588DOI Listing
November 2020

Investigating the Relationship Between Neuronal Cell Death and Early DNA Methylation After Ischemic Injury.

Front Neurosci 2020 14;14:581915. Epub 2020 Oct 14.

Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan.

Cerebral ischemia induces neuronal cell death and causes various kinds of brain dysfunction. Therefore, prevention of neuronal cell death is most essential for protection of the brain. On the other hand, it has been reported that epigenetics including DNA methylation plays a pivotal role in pathogenesis of some diseases such as cancer. Accumulating evidences indicate that aberrant DNA methylation is related to cell death. However, DNA methylation after cerebral ischemia has not been fully understood yet. The aim of this present study was to investigate the relationships between DNA methylation and neuronal cell death after cerebral ischemia. We examined DNA methylation under the ischemic condition by using transient middle cerebral artery occlusion and reperfusion (MCAO/R) model rats and -methyl-D-aspartate (NMDA)-treated cortical neurons in primary culture. In this study, we demonstrated that DNA methylation increased in these neurons 24 h after MCAO/R and that DNA methylation, possibly through activation of DNA methyltransferases (DNMT) 3a, increased in such neurons immediately after NMDA treatment. Furthermore, NMDA-treated neurons were protected by treatment with a DNMT inhibitor that were accompanied by inhibition of DNA methylation. Our results showed that DNA methylation would be an initiation factor of neuronal cell death and that inhibition of such methylation could become an effective therapeutic strategy for stroke.
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http://dx.doi.org/10.3389/fnins.2020.581915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591788PMC
October 2020
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