Publications by authors named "Naoki Tanaka"

308 Publications

Pemafibrate Protects against Fatty Acid-Induced Nephropathy by Maintaining Renal Fatty Acid Metabolism.

Metabolites 2021 Jun 9;11(6). Epub 2021 Jun 9.

Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.

As classical agonists for peroxisomal proliferator-activated receptor alpha (PPARα), fibrates activate renal fatty acid metabolism (FAM) and provide renoprotection. However, fibrate prescription is limited in patients with kidney disease, since impaired urinary excretion of the drug causes serious adverse effects. Pemafibrate (PEM), a novel selective PPARα modulator, is mainly excreted in bile, and, thus, may be safe and effective in kidney disease patients. It remains unclear, however, whether PEM actually exhibits renoprotective properties. We investigated this issue using mice with fatty acid overload nephropathy (FAON). PEM (0.5 mg/kg body weight/day) or a vehicle was administered for 20 days to 13-week-old wild-type male mice, which were simultaneously injected with free fatty acid (FFA)-binding bovine serum albumin from day 7 to day 20 to induce FAON. All mice were sacrificed on day 20 for assessment of the renoprotective effect of PEM against FAON. PEM significantly attenuated the histological findings of tubular injury caused by FAON, increased the renal expressions of mRNA and proteins related to FAM, and decreased renal FFA content and oxidative stress. Taken together, PEM exhibits renoprotective effects through the activation and maintenance of renal FAM and represents a promising drug for kidney disease.
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http://dx.doi.org/10.3390/metabo11060372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230306PMC
June 2021

Mucosal defect size predicts the adequacy of resection of ≤10 mm nonpedunculated colorectal polyps using a new cold snare polypectomy technique.

Eur J Gastroenterol Hepatol 2021 May 21. Epub 2021 May 21.

Digestive Disease Center, Showa Inan General Hospital, Komagane Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.

Objectives: There is still room for improvement in the methods used to achieve complete polyp resection. The aim of this study was to develop a cold snare polypectomy technique that will reliably result in resections containing the muscularis mucosae and the lateral polyp margins.

Materials And Methods: Nonpedunculated polyps ≤10 mm were resected using a dedicated cold snare with the goal of creating a mucosal defect approximately 1 cm in dia. The completeness of resection of the lateral and vertical polyp margins was examined histologically.

Results: The cases of 201 patients (mean age 67 ± 13 years; 115 men) with 500 eligible polyps were enrolled. The mean polyp size was 6.1 ± 1.8 mm (range 1-10 mm). The mean mucosal defect size immediately after resection was 7.7 ± 2.5 mm (range 3-15 mm). Overall, the complete resection rate in which the lateral and vertical margins were free from the neoplasia tissue was 92% (417/454, 95% CI, 89-94); in the remaining 8% of cases, the vertical margins showed complete resection but the lateral margins could not be evaluated due to the fragmentation of resected polyps. A mucosal defect ≥7 mm predicted complete resection of the mucosal layer containing the muscularis mucosae.

Conclusion: Complete mucosal layer resection of nonpedunculated colorectal polyps ≤10 mm was reliably achieved using a cold snare technique that produced a mucosal defect ≥7 mm in dia.
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http://dx.doi.org/10.1097/MEG.0000000000002156DOI Listing
May 2021

Electron doping of single-walled carbon nanotubes using pyridine-boryl radicals.

Chem Commun (Camb) 2021 Jun;57(49):6019-6022

Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan. and International Institute for Carbon-Neutral Energy Research (WPI-I2CNER), Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan and Center for Molecular Systems (CMS), Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.

Pyridine-boryl (py-boryl) radicals serve as efficient electron-doping reagents for single-walled carbon nanotubes (SWCNTs). The doping mechanism comprises electron transfer from the py-boryl radical to the SWCNT. The formation of a stable py-boryl cation is essential for efficient doping; the captodative effect of the py-boryl cation is important to this process.
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http://dx.doi.org/10.1039/d1cc01354hDOI Listing
June 2021

Single-Round DNA Aptamer Selection by Combined Use of Capillary Electrophoresis and Next Generation Sequencing: An Aptaomics Approach for Identifying Unique Functional Protein-Binding DNA Aptamers.

Chemistry 2021 Jul 10;27(39):10058-10067. Epub 2021 Jun 10.

Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama, 338-8570, Japan.

In DNA aptamer selection, existing methods do not discriminate aptamer sequences based on their binding affinity and function and the reproducibility of the selection is often poor, even for the selection of well-known aptamers like those that bind the commonly used model protein thrombin. In the present study, a novel single-round selection method (SR-CE selection) was developed by combining capillary electrophoresis (CE) with next generation sequencing. Using SR-CE selection, a successful semi-quantitative and semi-comprehensive aptamer selection for thrombin was demonstrated with high reproducibility for the first time. Selection rules based on dissociation equilibria and kinetics were devised to obtain families of analogous sequences. Selected sequences of the same family were shown to bind thrombin with high affinity. Furthermore, data acquired from SR-CE selection was mined by creating sub-libraries that were categorized by the functionality of the aptamers (e. g., pre-organized aptamers versus structure-induced aptamers). Using this approach, a novel fluorescent molecular recognition sensor for thrombin with nanomolar detection limits was discovered. Thus, in this proof-of-concept report, we have demonstrated the potential of a "DNA Aptaomics" approach to systematically design functional aptamers as well as to obtain high affinity aptamers.
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http://dx.doi.org/10.1002/chem.202100177DOI Listing
July 2021

Short-term intensive gastrointestinal endoscopy training program.

Pediatr Int 2021 Apr 4. Epub 2021 Apr 4.

Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan.

Background: In Japan there are limited opportunities for pediatric gastrointestinal (GI) trainees to learn GI endoscopy. This study investigated whether a short-term intensive training for three months in adult GI unit enabled pediatric GI trainees to acquire the required number of cases and the technical competence to preform pediatric GI endoscopic procedures.

Methods: This was a retrospective case series of pediatric GI trainees who underwent three months of intensive endoscopy training that also included direct observation and a questionnaire. The numbers of esophagogastroduodenoscopy (EGD), ileocolonoscopy and snare polypectomies each trainee performed as well as cecal intubation rates were collected with the goal of meeting standards of overseas educational guidelines. The trainees were also asked about continuing experience with pediatric endoscopic procedures after the intensive training.

Results: There were 10 enrolled trainees, 9 men, average age, 34 (range, 29-41). The average number (range) of EGD and ileocolonoscopy which the 10 trainees had done before this training period was 52 (0-200) and 15 (0-20), respectively. The average number (range) of EGD, ileocolonoscopy and snare polypectomy per each trainee were 651.7 (485-814), 159.2 (130-195) and 25.8 (10-55), respectively over three months: all trainees thus fulfilled all criteria of minimal training requirements. All trainees also reached required threshold in cecal intubation rate (>90%). In addition, all trainees were able to perform pediatric endoscopic procedures alone after the intensive training period.

Conclusion: Short-term intensive training for three months in adult GI setting enabled pediatric GI trainees to acquire technical competence for pediatric endoscopic procedures.
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http://dx.doi.org/10.1111/ped.14721DOI Listing
April 2021

A rare case of penetration related to ischemic duodenitis after ventricular assist device implantation for dilated cardiomyopathy.

Clin J Gastroenterol 2021 Aug 24;14(4):1186-1190. Epub 2021 Mar 24.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Tohoku University Hospital, 1-1, Seiryo-Cho, Aoba-Ku, Sendai, Miyagi, 980-8574, Japan.

A 66-year-old man with a history of diabetes and dilated cardiomyopathy underwent the implantation of a ventricular assist device (VAD) at the age of 62. He suffered from epigastralgia for a month and then visited our hospital with complaints of severe epigastralgia and hematemesis. A physical examination revealed abdominal distension without rigidity. Laboratory data showed severe systemic inflammation, multiple organ failure, and disseminated intravascular coagulation. Computed tomography showed multifocal thickness of the gastroduodenal wall with surrounding panniculitis, gas in a portal vein and a perigastric vein. Emergency esophago-gastro duodenoscopy (EGD) demonstrated a large erosion in the antrum of the stomach, and penetration surrounded by circumferentially ischemic mucosa in the second and third portions of the duodenum. Based on informed consent, conservative therapy was performed, and his condition improved enabling the start of oral intake on the 37th hospital day. However, 7 days later, there was a relapse of epigastralgia after a meal. Gastrointestinal series and EGD revealed a 10-mm-long pinhole-like stricture at the site. After laparoscopic gastro-jejunal bypass surgery, he has remained in a good condition for 2 years. We demonstrated a rare case of penetration due to severe ischemic duodenitis 4 years after VAD implantation.
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http://dx.doi.org/10.1007/s12328-021-01346-1DOI Listing
August 2021

Pemafibrate, a novel selective PPARα modulator, attenuates tamoxifen-induced fatty liver disease.

Clin J Gastroenterol 2021 Jun 22;14(3):846-851. Epub 2021 Mar 22.

Digestive Disease Center, Showa Inan General Hospital, Komagane, Japan.

Estrogen receptor (ER) antagonists, such as tamoxifen and toremifene, are widely used as adjuvant therapies for ER-positive breast cancer. These agents sometimes cause hepatosteatosis and steatohepatitis and it is problematic whether these agents should be withdrawn due to fatty liver disease and liver dysfunction. We herein describe a patient with fatty liver disease and hypertriglyceridemia during tamoxifen treatment, which significantly improved by adding pemafibrate, a novel PPARα activator designated as a selective PPARα modulator. Serial analysis during pemafibrate treatment revealed significant increases in circulating ketone bodies, which are indicators of hepatic fatty acid (FA) β-oxidation. As far as we know, this is the first report demonstrating the beneficial effect of pemafibrate on tamoxifen-induced fatty liver disease, which is likely due to enhanced hepatic FA β-oxidation by PPARα stimulation. Future large-scale studies will be needed to verify the current observation.
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http://dx.doi.org/10.1007/s12328-021-01386-7DOI Listing
June 2021

Linked colour imaging versus white-light colonoscopy for the detection of flat colorectal lesions: A randomized controlled trial.

Colorectal Dis 2021 Jun 16;23(6):1414-1420. Epub 2021 Mar 16.

Digestive Disease Center, Showa Inan General Hospital, Komagane, Japan.

Aim: Linked colour imaging is an image-enhanced endoscopy system that emphasizes the red portion of the mucosa's colour. Our aim was to compare the effectiveness of linked colour imaging with white-light colonoscopy for the detection of flat-type colorectal polyps.

Method: This was a single-centre, randomized controlled trial. Enrolled patients were those aged ≥50 years undergoing cap-assisted colonoscopy for colorectal cancer screening. They were randomized in a 1:1 ratio for observation using linked colour imaging or white-light colonoscopy. All colorectal polyps detected were removed or biopsied. The primary outcome was the number of flat-type polyps per patient in patients in whom flat polyps were detected. Secondary outcomes included adenoma and polyp detection rates.

Results: There were 302 subjects randomized: 152 to linked colour imaging and 150 to white-light colonoscopy. There were no differences in the clinical features between the two arms. The number of flat polyps detected per patient using linked colour imaging was approximately twice that with white light (2.9 ± 3.0 vs 1.2 ± 1.6, p = 0.045). Linked colour imaging also proved superior to white-light colonoscopy in terms of adenoma and polyp detection rates [adenomas 66% (101/152) vs 49% (73/150), p = 0.0024; polyps 69% (105/152) vs 55% (82/150), p = 0.013]. The ratio of polyps detected in the right colon compared with those detected in the left colon was significantly greater using linked colour than white-light imaging (168/64 vs 93/84; p < 0.001).

Conclusion: Compared with white-light colonoscopy, linked colour imaging improved adenoma and polyp detection rates, including detection of flat-type colorectal polyps.
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http://dx.doi.org/10.1111/codi.15605DOI Listing
June 2021

[A Case of Metachronous Anal Metastasis from Rectal Cancer].

Gan To Kagaku Ryoho 2020 Dec;47(13):1918-1920

Dept. of Surgery, Tohoku University Graduate School of Medicine.

A 49-year-old man underwent low anterior resection for rectal cancer with liver and lung metastases. He refused additional systemic chemotherapy. After 10 months, he presented with a painful anal tumor and we performed trans-anal resection of the tumor. Histopathological examination revealed a metastasis of the rectal cancer. Chemotherapy was performed subsequently. He survived 7 months after the second surgery without local recurrence. We reported a rare case of anal metastasis from rectal cancer.
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December 2020

Efficacy of laparoscopic sleeve gastrectomy for patient with morbid obesity and type 1 diabetes mellitus: a case report.

Surg Case Rep 2021 Jan 6;7(1). Epub 2021 Jan 6.

Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Background: Bariatric surgery is effective for the treatment of patients with morbid obesity and type 2 diabetes mellitus (T2DM), for body weight loss and glycemic control. However, in Japan, there has been no previous report of the effectiveness bariatric surgery in a case of morbid obesity associated with acute onset type 1 diabetes mellitus (T1DM), in which pancreatic β-cells were destroyed and endogenous insulin was depleted.

Case Presentation: A 36-year-old woman with morbid obesity and T1DM, diagnosed when she was 6 years, was admitted for bariatric surgery. At her first consultation, she had a body weight of 106.7 kg and a body mass index of 42.2 kg/m. Her HbA1c level was 9.0%, with a required daily insulin dose of 75 units. She underwent laparoscopic sleeve gastrectomy. At 1 year after surgery, her body weight had decreased to 81.0 kg and her body mass index to 32.2 kg/m. In addition, her daily required dose of insulin had decreased to 24 units, with an improvement in her HbA1c level to 7.7%.

Conclusions: Although further evidence needs to be accumulated, including long-term outcomes, laparoscopic sleeve gastrectomy may provide an effective treatment for patients with morbid obesity and T1DM for body weight loss, improvement in HbA1c level, and insulin dose reduction.
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http://dx.doi.org/10.1186/s40792-020-00989-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788116PMC
January 2021

Serum thrombospondin 2 is a novel predictor for the severity in the patients with NAFLD.

Liver Int 2021 03 20;41(3):505-514. Epub 2021 Jan 20.

Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.

Aim: Thrombospondins are a family of multidomain and secretory glycoproteins. Among them, thrombospondin 2 (TSP2) encoded by TSP2 gene has been reported to be involved in various functions such as collagen/fibrin formation, maintenance of normal blood vessel density and cell adhesion properties. Microarray analyses ranked TSP2 as one of the most highly up-regulated genes in the fibrotic liver in patients with non-alcoholic fatty liver disease (NAFLD). Since TSP2 possesses unique properties as a secretory protein, we hypothesized that hepatic TSP2 gene expression levels would be reflected in serum TSP2 levels. In this study, we examined the relationship between serum TSP2 concentrations and clinicopathological findings in NAFLD patients.

Methods: One hundred and thirty NAFLD patients who had undergone liver biopsy between 2009 and 2015 were retrospectively enrolled. Serum samples were collected at the time of biopsy, and TSP2 was measured by enzyme immunoassays.

Results: Serum TSP2 levels moderately correlated with ballooning (r = 0.56, P < .001) and fibrosis stage (r = 0.53, P < .001). The AUC values of TSP2 for predicting mild fibrosis (≧F1), moderate fibrosis (≧F2) and severe fibrosis (≧F3) were 0.73, 0.76 and 0.82 respectively. Additionally, NAFLD activity score (NAS) correlated best with TSP2 (r = 0.52, P < .001) compared to conventional NAFLD-related biomarkers, such as cytokeratin 18 M30, hyaluronic acid, type IV collagen 7S, APRI and FIB-4 index.

Conclusion: Serum TSP2 levels reflected hepatocyte ballooning, fibrosis and NAS in NAFLD patients. For clinical application of serum TSP2 as a predictor of NAFLD histological activity, additional validation and mechanistic investigations are required.
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http://dx.doi.org/10.1111/liv.14776DOI Listing
March 2021

Investigation on the Interactions between Self-Assembled β-Sheet Peptide Nanofibers and Model Cell Membranes.

Int J Mol Sci 2020 Dec 14;21(24). Epub 2020 Dec 14.

Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Gosyokaido-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.

Self-assembled peptide nanofibers (NFs) obtained from β-sheet peptides conjugated with drugs, including antigenic peptides, have recently attracted significant attention. However, extensive studies on the interactions of β-sheet peptide NFs with model cell membranes have not been reported. In this study, we investigated the interactions between three types of NFs, composed of PEG-peptide conjugates with different ethylene glycol (EG) lengths (6-, 12- and 24-mer), and dipalmitoylphosphatidylcholine (DPPC) Langmuir membranes. When increasing the EG chain length, those interactions significantly decreased considering measurements in the presence of the NFs of: (i) changes in surface pressure of the DPPC Langmuir monolayers and (ii) surface pressure-area (π-) compression isotherms of DPPC. Because the observed trend was similar to the EG length dependency with regard to cellular association and cytotoxicity of the NFs that was reported previously, the interaction of NFs with phospholipid membranes represented a crucial factor to determine the cellular association and toxicity of the NFs. In contrast to NFs, no changes were observed with varying EG chain length on the interaction of the building block peptide with the DPPC membrane. The results obtained herein can provide a design guideline on the formulation of β-sheet peptide NFs, which may broaden its potential.
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http://dx.doi.org/10.3390/ijms21249518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765088PMC
December 2020

Dietary Restriction Suppresses Steatosis-Associated Hepatic Tumorigenesis in Hepatitis C Virus Core Gene Transgenic Mice.

Liver Cancer 2020 Sep 10;9(5):529-548. Epub 2020 Jul 10.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.

Background And Aims: Dietary restriction (DR) is a preventive strategy for obesity, metabolic syndrome, cardiovascular disease, and diabetes. Although an interconnection between obesity, metabolic syndrome, fatty liver, and hepatocellular carcinoma has been documented, the mechanism and impact of DR on steatosis-derived hepatocarcinogenesis are not fully understood. This study aimed to evaluate whether DR can prevent hepatic tumorigenesis.

Methods: Male hepatitis C virus core gene transgenic (HCVcpTg) mice that develop spontaneous age-dependent insulin resistance, hepatic steatosis, and ensuing liver tumor development without apparent hepatic fibrosis, were fed with either a control diet ad libitum (control group) or 70% of the same control diet (DR group) for 15 months, and liver phenotypes were investigated.

Results: DR significantly reduced the number and volume of liver tumors. DR attenuated hepatic oxidative and endoplasmic reticulum stress and markedly suppressed nuclear factor-κB, signal transducer and activator of transcription 3 (STAT3) and STAT5, and phosphorylation of extracellular signal-regulated kinase, leading to downregulation of several pro-oncogenic mediators, such as cyclin D1. Serum insulin and insulin-like growth factor 1 levels, as well as hepatic expression of insulin receptor substrate 1/2, phosphatidylinositol-3 kinase, and serine/threonine-protein kinase AKT, were downregulated by DR. A transcriptome analysis revealed that STAT3 signaling and lipogenesis were the most suppressed hepatocarcinogenic pathways affected by DR. Additionally, DR stimulated autophagy and p62/sequestosome 1 degradation, enhanced phosphorylation of AMP-activated protein kinase α, increased fibroblast growth factor 21 expression, and attenuated expression of senescence-associated secretory phenotypes.

Conclusion: DR suppressed steatosis-associated hepatic tumorigenesis in HCVcpTg mice, mainly due to attenuation of pathways involved in inflammation, cellular stress, cell proliferation, insulin signaling, and senescence. These findings support the notion that persistent 30% reduction of daily food intake is beneficial for preventing steatosis-associated hepatocarcinogenesis caused by HCV core protein.
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http://dx.doi.org/10.1159/000508308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548900PMC
September 2020

Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes-Potential Applications for Diabetes and NAFLD.

Biomolecules 2020 10 15;10(10). Epub 2020 Oct 15.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.

G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of extracellular ligands. Understanding how GPCRs work at the molecular level has important therapeutic implications, as 30-40% of the drugs currently in clinical use mediate therapeutic effects by acting on GPCRs. Like many other cell types, liver function is regulated by GPCRs. More than 50 different GPCRs are predicted to be expressed in the mouse liver. However, knowledge of how GPCRs regulate liver metabolism is limited. A better understanding of the metabolic role of GPCRs in hepatocytes, the dominant constituent cells of the liver, could lead to the development of novel drugs that are clinically useful for the treatment of various metabolic diseases, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In this review, we describe the functions of multiple GPCRs expressed in hepatocytes and their role in metabolic processes.
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http://dx.doi.org/10.3390/biom10101445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602561PMC
October 2020

Non-alcoholic fatty liver disease later diagnosed as myotonic dystrophy.

World J Hepatol 2020 Sep;12(9):685-692

Digestive Disease Center, Showa Inan General Hospital, Komagane 399-4117, Japan.

Background: Myotonic dystrophy (MD) is sometimes accompanied by metabolic/endocrine disorders, including dyslipidemia, central obesity, and hypogonadism. Due to considerable individual differences in the severity and progression of myopathy, MD patients with minimal-to-mild muscle symptoms might be followed as having other diseases, such as non-alcoholic fatty liver disease (NAFLD).

Case Summary: A 40-year-old non-obese man without a history of regular ethanol consumption was referred to our hospital due to persistent liver dysfunction and hyperlipidemia. His body mass index was 23.4 kg/m. Liver histology demonstrated macrovesicular steatosis, ballooned hepatocytes with eosinophilic inclusion bodies, and perisinusoidal fibrosis, leading to the diagnosis of non-alcoholic steatohepatitis (NASH). Although he had no discernable muscle pain or weakness, persistently high serum creatine kinase (CK) and myoglobin levels as well as the presence of frontal baldness, a hatched face, history of cataract surgery, and grip myotonia indicated the possibility of MD. Southern blotting of the patient's DNA revealed the presence of CTG repeats, confirming the diagnosis.

Conclusion: When gastroenterologists encounter NAFLD/NASH patients, serum CK should be verified. If hyperCKemia, frontal baldness, a hatched face, history of cataract surgery, and grip myotonia are noted, the possibility of MD may be considered.
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http://dx.doi.org/10.4254/wjh.v12.i9.685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522559PMC
September 2020

An Organic Borate Salt with Superior -Doping Capability for Organic Semiconductors.

Adv Sci (Weinh) 2020 Sep 6;7(17):2001322. Epub 2020 Jul 6.

Institut für Physik and IRIS Adlershof Humboldt-Universität zu Berlin Berlin D-12489 Germany.

Molecular doping allows enhancement and precise control of electrical properties of organic semiconductors, and is thus of central technological relevance for organic (opto-) electronics. Beyond single-component molecular electron acceptors and donors, organic salts have recently emerged as a promising class of dopants. However, the pertinent fundamental understanding of doping mechanisms and doping capabilities is limited. Here, the unique capabilities of the salt consisting of a borinium cation (MesB; Mes: mesitylene) and the tetrakis(penta-fluorophenyl)borate anion [B(CF)] is demonstrated as p-type dopant for polymer semiconductors. With a range of experimental methods, the doping mechanism is identified to comprise electron transfer from the polymer to MesB, and the positive charge on the polymer is stabilized by [B(CF)]. Notably, the former salt cation leaves during processing and is not present in films. The anion [B(CF)] even enables the stabilization of polarons and bipolarons in poly(3-hexylthiophene), not yet achieved with other molecular dopants. From doping studies with high ionization energy polymer semiconductors, the effective electron affinity of MesB[B(CF)] is estimated to be an impressive 5.9 eV. This significantly extends the parameter space for doping of polymer semiconductors.
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http://dx.doi.org/10.1002/advs.202001322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507313PMC
September 2020

A saturated fatty acid-rich diet enhances hepatic lipogenesis and tumorigenesis in HCV core gene transgenic mice.

J Nutr Biochem 2020 11 3;85:108460. Epub 2020 Jul 3.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan; Research Center for Social Systems, Shinshu University, Matsumoto, Japan. Electronic address:

Previous studies suggested that high consumption of saturated fatty acid (SFA) is a risk factor for liver cancer. However, it remains unclear how dietary SFA affects liver tumorigenesis. This study aimed to investigate the impact of a SFA-rich diet on hepatic tumorigenesis using hepatitis C virus core gene transgenic (HCVcpTg) mice that spontaneously developed hepatic steatosis and tumors with aging. Male HCVcpTg mice were treated for 15 months with a purified control diet or SFA-rich diet prepared by replacing soybean oil in the control diet with hydrogenated coconut oil, and phenotypic changes were assessed. In this special diet, almost all dietary fatty acids were SFA. Long-term feeding of SFA-rich diet to HCVcpTg mice increased hepatic steatosis, liver dysfunction, and the prevalence of liver tumors, likely due to stimulation of de novo lipogenesis, activation of the pro-inflammatory and pro-oncogenic transcription factor nuclear factor-kappa B (NF-κB), enhanced c-Jun N-terminal kinase/activator protein 1 (JNK/AP-1) signaling and induction of the oncogenes cyclin D1 and p62/sequestosome 1. The SFA-rich diet did not affect liver fibrosis or autophagy. Collectively, long-term SFA-rich diet consumption promoted hepatic tumorigenesis mainly through activation of lipogenesis, NF-κB, and JNK/AP-1 signaling. We therefore propose that HCV-infected patients should avoid excessive intake of SFA-rich foods to prevent liver cancer.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756930PMC
November 2020

Continuous glucose monitoring in patients with remission of type 2 diabetes after laparoscopic sleeve gastrectomy without or with duodenojejunal bypass.

Clin Obes 2020 Dec 6;10(6):e12409. Epub 2020 Sep 6.

Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.

Bariatric surgery is associated with a high remission rate of type 2 diabetes mellitus. However, it is unclear whether patients showing remission of diabetes actually have normal blood glucose levels throughout the day. We therefore performed continuous glucose monitoring (CGM) in 15 ambulatory patients showing remission of diabetes after laparoscopic sleeve gastrectomy (LSG) without or with duodenojejunal bypass (DJB) at the time of diabetic remission (12.9 ± 1.8 months after bariatric surgery). The definition of remission of diabetes was based on the American Diabetes Association criteria. The mean, SD, and coefficient of variation (CV) of glucose calculated from CGM were 6.2 ± 0.6 mmol/L, 1.5 ± 0.4 mmol/L, and 23.7 ± 6.2%, respectively. These values were higher than those of healthy participants without diabetes previously reported. The percentages of time spent above 10.0 mmol/L and below 3.9 mmol/L were 2.6 (IQR 0-5.0)% and 0 (IQR 0-8.0)%, respectively. Thus, patients with remission of diabetes after LSG or LSG/DJB still had substantial periods of hyperglycemia and hypoglycemia throughout the day. Therefore, we must manage patients with diabetes carefully, even after apparent remission of type 2 diabetes in response to bariatric surgery.
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http://dx.doi.org/10.1111/cob.12409DOI Listing
December 2020

Long-Lived Charge-Transfer State from B-N Frustrated Lewis Pairs Enchained in Supramolecular Copolymers.

J Am Chem Soc 2020 Sep 17;142(39):16681-16689. Epub 2020 Sep 17.

Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo, Chikusa, Nagoya 464-8602, Japan.

The field of supramolecular polymers is rapidly expanding; however, the exploitation of these systems as functional materials is still elusive. To become competitive, supramolecular polymers must display microstructural order and the emergence of new properties upon copolymerization. To tackle this, a greater understanding of the relationship between monomers' design and polymer microstructure is required as well as a set of functional monomers that efficiently interact with one another to synergistically generate new properties upon copolymerization. Here, we present the first implementation of frustrated Lewis pairs into supramolecular copolymers. Two supramolecular copolymers based on π-conjugated -bridged triphenylborane and two different triphenylamines display the formation of B-N pairs within the supramolecular chain. The remarkably long lifetime and the circularly polarized nature of the resulting photoluminescence emission highlight the possibility to obtain an intermolecular B-N charge transfer. These results are proposed to be the consequences of the enchainment of B-N frustrated Lewis pairs within 1D supramolecular aggregates. Although it is challenging to obtain a precise molecular picture of the copolymer microstructure, the formation of random blocklike copolymers could be deduced from a combination of optical spectroscopic techniques and theoretical simulation.
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http://dx.doi.org/10.1021/jacs.0c06921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530894PMC
September 2020

Tips for operation of inguinal hernia after implantation of artificial urinary sphincter following radical prostatectomy: report of two cases.

J Surg Case Rep 2020 Aug 24;2020(8):rjaa150. Epub 2020 Aug 24.

Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Urinary incontinence is one of the common complications after radical prostatectomy along with inguinal hernia. Artificial urethral sphincter implantation is widely accepted as a treatment option. We report two surgical cases of inguinal hernia after artificial urethral sphincter implantation for urinary incontinence following radical prostatectomy. In Case 1, since the device went through the inguinal canal, adhesion around the pubis was extremely hard. In Case 2, the device was placed on the ventral side of the rectus abdominis muscle, so it was operable almost as normal. In each case, the surgical procedure was considered carefully after confirming the location of the device by preoperative computed tomography and ultrasonography. Hernia repair was successfully performed using the Lichtenstein method. There are few reports regarding surgical repair of inguinal hernia following artificial urinary sphincter implantation. Preoperative image and appropriate choice of approach could facilitate safe and secure surgery.
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http://dx.doi.org/10.1093/jscr/rjaa150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444616PMC
August 2020

Efficacy and Safety of Low-Molecular-Weight Heparin on Prevention of Venous Thromboembolism after Laparoscopic Operation for Gastrointestinal Malignancy in Japanese Patients: A Multicenter, Open-Label, Prospective, Randomized Controlled Trial.

J Am Coll Surg 2020 11 19;231(5):501-509.e2. Epub 2020 Aug 19.

Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan. Electronic address:

Background: The risk of venous thromboembolism (VTE) after surgery for malignancy in Japanese patients is unclear; therefore, standard prevention protocols have not been established, especially for minimally invasive procedures. We aimed to investigate the additional effect of low molecular weight heparin (LMWH) on prevention of VTE after laparoscopic surgery for gastrointestinal malignancy.

Study Design: From February 2013 to January 2017, 400 patients scheduled for laparoscopic surgery were included. Cases were randomly allocated to the physical therapy group (Control group; 201 patients) or to the combination-therapy group (LMWH group; 199 patients), in which enoxaparin sodium (20 mg [= 2000 IU] twice a day) was administered for 1 week postoperatively in addition to the physical therapy. A diagnosis of VTE was made by contrast-enhanced CT or ultrasonography when symptomatic or D-dimer was ≥10 μg/mL.

Results: VTE was observed in 1.2% and 4.0% of patients in the LMWH and Control groups, respectively (odds ratio [OR] 0.3, 95% confidence interval [CI] 0.03-1.53). Pulmonary embolism was confirmed only in the Control group (1.7%). No major bleeding occurred in either group. Logistic multiple regression analysis revealed that surgical time extension (OR 1.02, 95% CI 1.00-1.04) was a risk factor of VTE, while administration of LMWH (OR 0.21, 95% CI 0.03-0.99), male sex (OR 0.12, 95% CI 0.01-0.60), and early cancer (OR 0.17, 95% CI 0.02-0.82) reduced the risk of VTE.

Conclusions: Postoperative LMWH administration is safe. The additional effect of LMWH administration on the physical therapy was not statistically proven in this study. However, it could be useful for the patients with risk factors such as female sex, long operation time, and higher cancer stage.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.08.734DOI Listing
November 2020

Development of a brain-permeable peptide nanofiber that prevents aggregation of Alzheimer pathogenic proteins.

PLoS One 2020 24;15(7):e0235979. Epub 2020 Jul 24.

Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Kyoto, Japan.

Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidβ in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid βby trapping amyloid β onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235979PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380640PMC
September 2020

Acute liver failure with severe steatosis induced by mushroom.

Liver Int 2020 09 16;40(9):2291-2292. Epub 2020 Jul 16.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.

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http://dx.doi.org/10.1111/liv.14588DOI Listing
September 2020

Invasive liver abscess syndrome accompanied by spondylodiscitis: a case report and review of the literature.

Clin J Gastroenterol 2020 Oct 7;13(5):927-934. Epub 2020 Jul 7.

Department of Internal Medicine, Nagano Prefectural Kiso Hospital, Kiso, Japan.

A 65-year-old man who had diabetes mellitus was referred to our hospital due to fever and back pain. Laboratory findings showed liver dysfunction and C-reactive protein (CRP) elevation. Enhanced computed tomography (CT) showed multiple liver abscesses, hepatic vein and inferior vena cava thrombosis, and spondylodiscitis in the fourth lumbar vertebrae. Based on several detections of Klebsiella pneumoniae (K. pneumoniae) in blood culture, he was diagnosed as having invasive liver abscess syndrome (ILAS), which is characterized by liver abscess and metastatic infection caused by K. pneumoniae. Despite the prompt improvement of liver abscess and thrombosis, after administering antibiotics and anticoagulant, spondylodiscitis worsened. Additionally, iliopsoas abscess emerged on repeated CT imaging. Lumbar laminectomy was needed as a radical treatment. We reviewed 12 cases of ILAS representing spondylodiscitis, and surgical treatments for spondylodiscitis were required in 7 of these cases (58%). When encountering patients with liver abscess and spondylodiscitis, we should consider the possibility of invasive disseminated K. pneumoniae infection, which is hard to treat with antibiotics alone and sometimes requires surgical treatments for spondylodiscitis.
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http://dx.doi.org/10.1007/s12328-020-01161-0DOI Listing
October 2020

Risk of Gastrointestinal Endoscopic Procedure-Related Bleeding in Patients With or Without Continued Antithrombotic Therapy.

Dig Dis Sci 2021 May 16;66(5):1548-1555. Epub 2020 Jun 16.

Digestive Disease Center, Showa Inan General Hospital, 3230 Akaho, Komagane, 399-4117, Japan.

Background: Prospective studies on bleeding risk during/after gastrointestinal endoscopic procedures are rare.

Aim: We investigated the risk of endoscopic procedure-related bleeding in patients with biopsy and/or cold snare polypectomy (CSP) in relation to antithrombotic therapy.

Methods: This prospective, observational single-center cohort study (NCT02594813) enrolled consecutive patients who underwent diagnostic esophagogastroduodenoscopy (EGD) or colonoscopy. The primary outcome measure was delayed bleeding in patients with biopsy and/or CSP who required endoscopic treatment within 2 weeks post-procedure. The secondary outcomes were immediate bleeding and the number of hemostatic clips used during the procedure.

Results: From November 2015 to October 2018 at our institution, 3069 (mean age, 66 years) and 37,887 (57 years) patients underwent EGD with and without antithrombotic therapy, respectively. In addition, 1116 (72 years) and 11,901 (65 years) patients had colonoscopy with and without antithrombotic therapy, respectively. In the 3069 EGD patients receiving antithrombotic therapy, no delayed bleeding occurred, whereas immediate bleeding occurred in 9 of 141 patients (6.4%) with biopsy. Of the 1116 colonoscopy patients receiving antithrombotic therapy, delayed bleeding occurred in three of 228 (1.3%) following CSP. Immediate bleeding occurred in nine of 225 (4%) following biopsy and in 32 of 228 (14%) following CSP. Multivariate analysis following univariate analysis identified chronic kidney disease and CSP as factors significantly associated with procedure-related bleeding in patients taking antithrombotic agents.

Conclusion: The risk of delayed bleeding in diagnostic EGD with biopsy or in colonoscopy with biopsy and/or CSP was low despite continuation of antithrombotic therapy.
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http://dx.doi.org/10.1007/s10620-020-06393-1DOI Listing
May 2021

Polyunsaturated fatty acid deficiency affects sulfatides and other sulfated glycans in lysosomes through autophagy-mediated degradation.

FASEB J 2020 07 5;34(7):9594-9614. Epub 2020 Jun 5.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.

Metabolic changes in sulfatides and other sulfated glycans have been related to various diseases, including Alzheimer's disease (AD). However, the importance of polyunsaturated fatty acids (PUFA) in sulfated lysosomal substrate metabolism and its related disorders is currently unknown. We investigated the effects of deficiency or supplementation of PUFA on the metabolism of sulfatides and sulfated glycosaminoglycans (sGAGs) in sulfatide-rich organs (brain and kidney) of mice. A PUFA-deficient diet for over 5 weeks significantly reduced the sulfatide expression by increasing the sulfatide degradative enzymes arylsulfatase A and galactosylceramidase in brain and kidney. This sulfatide degradation was clearly associated with the activation of autophagy and lysosomal hyperfunction, the former of which was induced by suppression of the Erk/mTOR pathway. A PUFA-deficient diet also activated the degradation of sGAGs in the brain and kidney and that of amyloid precursor proteins in the brain, indicating an involvement in general lysosomal function and the early developmental process of AD. PUFA supplementation prevented all of the above abnormalities. Taken together, a PUFA deficiency might lead to sulfatide and sGAG degradation associated with autophagy activation and general lysosomal hyperfunction and play a role in many types of disease development, suggesting a possible benefit of prophylactic PUFA supplementation.
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http://dx.doi.org/10.1096/fj.202000030RRDOI Listing
July 2020

The N-terminal and C-terminal halves of histone H2A.Z independently function in nucleosome positioning and stability.

Genes Cells 2020 Aug 22;25(8):538-546. Epub 2020 Jul 22.

Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.

Nucleosome positioning and stability affect gene regulation in eukaryotic chromatin. Histone H2A.Z is an evolutionally conserved histone variant that forms mobile and unstable nucleosomes in vivo and in vitro. In the present study, we reconstituted nucleosomes containing human H2A.Z.1 mutants, in which the N-terminal or C-terminal half of H2A.Z.1 was replaced by the corresponding canonical H2A region. We found that the N-terminal portion of H2A.Z.1 is involved in flexible nucleosome positioning, whereas the C-terminal portion leads to weak H2A.Z.1-H2B association in the nucleosome. These results indicate that the N-terminal and C-terminal portions are independently responsible for the H2A.Z.1 nucleosome characteristics.
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http://dx.doi.org/10.1111/gtc.12791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496805PMC
August 2020

Gastric Duplication Cyst With Occult GIST Component.

ACG Case Rep J 2020 Feb 7;7(2):e00260. Epub 2020 Feb 7.

Division of Gastroenterology, Tohoku University Hospital, Sendai, Miyagi, Japan.

A 37-year-old man underwent screening examinations, and a pale-colored submucosal tumor was detected on gastric cardia. Endosonography showed a 15-mm cyst with hypoechoic nodules in the muscularis propria, and endoscopic ultrasound-guided fine-needle aspiration obtained mucinous fluid with atypical spindle cells positive for , indicating a gastrointestinal stromal tumor. Surgical resection was recommended, but he initially agreed to surveillance. After becoming larger for 8 years, partial gastrectomy was performed for the 22 × 22 × 15-mm capsulized lesion. Surprisingly, its histology was gastric duplication cyst without gastrointestinal stromal tumor. Gastric duplication cyst is a rare entity with the possibility of malignant complications, but careful assessment of endoscopic ultrasound-guided fine-needle aspiration might also be required.
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http://dx.doi.org/10.14309/crj.0000000000000260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145172PMC
February 2020

Mechanism of Bile Acid Reabsorption in the Biliopancreatic Limb After Duodenal-Jejunal Bypass in Rats.

Obes Surg 2020 07;30(7):2528-2537

Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Background: Bile acids (BAs) are important in the metabolic effects of bariatric surgery. Most BAs are reabsorbed in the ileum and recycled back to the liver. We have reported that this enterohepatic circulation was shortened by duodenal-jejunal bypass (DJB), and the biliopancreatic (BP)-limb plays an important role in reabsorption of BAs. However, the mechanism of BA reabsorption in BP-limb remains uncertain. We aimed to investigate the mechanisms of BA reabsorption after DJB, especially focusing on carrier-mediated transport of BAs and the impact of the presence or absence of lipids on BA reabsorption.

Methods: Otsuka-Long-Evans-Tokushima fatty rats or Sprague-Dawley rats were assigned to a control group and DJB group. BA levels in the divided small intestine were quantified with liquid chromatography-mass spectrometry. Labeled BA was injected and perfused with BA transporter inhibitors or mixture of lipids in the isolated BP-limb, and bile was sampled and analyzed.

Results: Conjugated BA levels in the BP-limb were significantly higher than that of the control group. BA absorption tended to decrease by the apical sodium-dependent BA transporter inhibitor and was significantly decreased by the organic anion-transporting peptide (OATP) inhibitor. BA absorption tended to increase in the absence of lipid solutions compared with that in the presence of lipid solutions.

Conclusion: We attributed the increased BA reabsorption in the BP-limb to lack of food in the BP-limb, which contains concentrated BAs and no lipids. OATP played an important role in BA reabsorption in the BP-limb. Therefore, BAs would be reabsorbed in different manners after DJB.
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http://dx.doi.org/10.1007/s11695-020-04506-3DOI Listing
July 2020

PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice.

Int J Mol Sci 2020 Mar 17;21(6). Epub 2020 Mar 17.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.

Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver.
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http://dx.doi.org/10.3390/ijms21062061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139552PMC
March 2020
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