Publications by authors named "Takeshi Ohta"

105 Publications

Phase II study of stereotactic body radiotherapy with hydrogel spacer for prostate cancer: acute toxicity and propensity score-matched comparison.

Radiat Oncol 2021 Jun 12;16(1):107. Epub 2021 Jun 12.

Department of Radiology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyoku, Tokyo, 113-8655, Japan.

Background: The efficacy of a hydrogel spacer in stereotactic body radiotherapy (SBRT) has not been clarified. We evaluated the safety and efficacy of SBRT in combination with a hydrogel spacer for prostate cancer.

Methods: This is a prospective single-center, single-arm phase II study. Prostate cancer patients without lymph node or distant metastasis were eligible. All patients received a hydrogel spacer insertion, followed by SBRT of 36.25 Gy in 5 fractions with volumetric modulated arc therapy. The primary endpoint was physician-assessed acute gastrointestinal (GI) toxicity within 3 months. The secondary endpoints were physician-assessed acute genitourinary (GU) toxicity, patient-reported outcomes evaluated by the EPIC and FACT-P questionnaires, and dosimetric comparison. We used propensity score-matched analyses to compare patients with the hydrogel spacer with those without the spacer. The historical data of the control without a hydrogel spacer was obtained from our hospital's electronic records.

Results: Forty patients were enrolled between February 2017 and July 2018. A hydrogel spacer significantly reduced the dose to the rectum. Grade 2 acute GI and GU toxicity occurred in seven (18%) and 17 (44%) patients. The EPIC bowel and urinary summary score declined from the baseline to the first month (P < 0.01, < 0.01), yet it was still significantly lower in the third month (P < 0.01, P = 0.04). For propensity score-matched analyses, no significant differences in acute GI and GU toxicity were observed between the two groups. The EPIC bowel summary score was significantly better in the spacer group at 1 month (82.2 in the spacer group and 68.5 in the control group).

Conclusions: SBRT with a hydrogel spacer had the dosimetric benefits of reducing the rectal doses. The use of the hydrogel spacer did not reduce physician-assessed acute toxicity, but it improved patient-reported acute bowel toxicity.

Trial Registration: Trial registration: UMIN-CTR, UMIN000026213. Registered 19 February 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000029385 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13014-021-01834-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199395PMC
June 2021

The amelioration of T2DM rat femoral bone achieved by anti-osteoporosis of caprine CSN1S2 protein through bone morphogenetic protein signaling pathway.

Acta Biochim Pol 2021 May;68(2):265-275

Graduate School of Agriculture, Kyoto University, Kyoto, Japan.

We investigated the potential anti-glycation and anti-osteoporosis properties of Caprine milk CSN1S2 protein on the serum AGEs and sRAGE level, osteogenic factors expressions, femoral bone mesostructure, histomorphometry, and hydroxyapatite crystals changes in T2DM rats. Varying doses of Caprine milk CSN1S2 protein (0, 375, 750, and 1500 mg/kg BW) were used to treat the control and T2DM rats. We measured AGEs and sRAGE level; RUNX2, OSX, BMP2, and Caspase-3 expressions in rats using ELISA and immunohistochemistry, respectively. The mesostructure and histomorphometry of femoral bone was analyzed using SEM Microscope and BoneJ software, then hydroxyapatite crystal size was determined using SEM-XRD. T2DM rats showed a high level of AGEs and a low level of sRAGE, the RUNX2, OSX, and BMP2 expression was down regulated, BV, BV.TV, Tb.Th, Tb.Sp, increased and SMI levels declined, respectively. Vice versa, after administration of the CSN1S2 protein to T2DM rats, improvement in all levels of molecular and cellular markers was achieved. In the CSN1S2 highest dose, AGEs level declined and sRAGE level elevated in T2DM rats. The 375 and 750 mg/kgBW of CSN1S2 protein was able to upregulate the RUNX2, OSX, and BMP2 expression in T2DM rats, thus improving the normalization of osteoclasts and osteoblasts number. The whole dose of CSN1S2 triggered the thickening of trabecular bone wall, granule formation, and normalized the trabecular thickness (Tb.Th) parameter of T2DM rats. The hydroxyapatite crystal size was increased in the highest dose of CSN1S2-treated T2DM rats. This study indicated that CSN1S2 protein had a protective effect against osteoporosis in the T2DM rat bones by means of glycation pathway inhibition, bone histomorphometry and mesostructure improvement via bone morphometric protein signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18388/abp.2020_5553DOI Listing
May 2021

GPR52 accelerates fatty acid biosynthesis in a ligand-dependent manner in hepatocytes and in response to excessive fat intake in mice.

iScience 2021 Apr 2;24(4):102260. Epub 2021 Mar 2.

Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan.

Gpr52 is an orphan G-protein-coupled receptor of unknown physiological function. We found that Gpr52-deficient ( ) mice exhibit leanness associated with reduced liver weight, decreased hepatic lipogenesis, and enhanced insulin sensitivity. Treatment of the hepatoma cell line HepG2 cells with c11, the synthetic GPR52 agonist, increased fatty acid biosynthesis, and GPR52 knockdown (KD) abolished the lipogenic action of c11. In addition, c11 induced the expressions of lipogenic enzymes ( and ), whereas these inductions were attenuated by GPR52-KD. In contrast, cholesterol biosynthesis was not increased by c11, but its basal level was significantly suppressed by GPR52-KD. High-fat diet (HFD)-induced increase in hepatic expression of and its targets ( and ) was absent in mice with alleviated hepatosteatosis. Our present study showed that hepatic GPR52 promotes the biosynthesis of fatty acid and cholesterol in a ligand-dependent and a constitutive manner, respectively, and Gpr52 participates in HFD-induced fatty acid synthesis in liver.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995607PMC
April 2021

JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits significant anti-inflammatory effect while maintaining bone mineral density in mice.

Eur J Pharmacol 2021 Mar 18;895:173880. Epub 2021 Jan 18.

Faculty of Agriculture, Department of Agrobiology, Niigata University, Niigata, Japan.

Classic glucocorticoids have been prescribed for various inflammatory diseases, such as rheumatoid arthritis, due to their outstanding anti-inflammatory effects. However, glucocorticoids cause numerous unwanted side effects, including osteoporosis and diabetes. Hence, selective glucocorticoid receptor modulators (SGRMs), which retain anti-inflammatory effects with minimized side effects, are among the most anticipated drugs in the clinical field. The assumption is that there are two major mechanisms of action via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, anti-inflammatory effects of glucocorticoids are largely due to TR, while the side effects associated with glucocorticoids are mostly mediated through TA. We previously reported that JTP-117968, a novel SGRM, maintained partial TR activity while remarkably reducing the TA activity. In this study, we investigated the anti-inflammatory effect of JTP-117968 on a lipopolysaccharide (LPS) challenge model and collagen-induced arthritis (CIA) model in mice. Meanwhile, we tested the effect of JTP-117968 on the bone mineral density (BMD) in mouse femur to evaluate the side effect. Based on the evaluation, JTP-117968 reduced the plasma levels of tumor necrosis factor α induced by LPS challenge in mice significantly. Remarkably, CIA development was suppressed by JTP-117968 comparably with prednisolone and PF-802, an active form of fosdagrocorat that has been developed clinically as an orally available SGRM. Strikingly, the side effect of JTP-117968 on mouse femoral BMD was much lower than those of PF-802 and prednisolone. Therefore, JTP-117968 has attractive potential as a new therapeutic option against inflammatory diseases with minimized side effects compared to classic glucocorticoids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2021.173880DOI Listing
March 2021

JTP-109192, a novel G protein-coupled receptor 119 agonist, prevents atherosclerosis by improving hypercholesterolaemia in congenic spontaneously hyperlipidaemic mice.

Clin Exp Pharmacol Physiol 2021 03 4;48(3):381-388. Epub 2020 Nov 4.

Graduate School of Science and Technology, Niigata University, Niigata, Japan.

G protein-coupled receptor 119 (GPR119) expression in pancreatic β-cells and intestinal L-cells is a potential therapeutic target for the treatment of type 2 diabetes. Previously, we have reported that the GPR119 agonist JTP-109192 improves glucose metabolism with single and repeated administration. Conversely, overexpression of the Gpr119 gene reportedly regulates cholesterol transporter expression in animal models, and a natural GPR119 agonist, oleoylethanolamide (OEA), improves atherosclerosis. Therefore, improving dyslipidaemia is considered a possible feature of GPR119 agonists. In the present study, the lipid-lowering effect of JTP-109192 was examined in BALB/c background spontaneously hyperlipidaemic (SHL) mice with repeated administration, once daily for 12 weeks. On repeated administration, JTP-109192 revealed a cholesterol-lowering effect and improved atherosclerosis following histopathological examination. With further investigation, the cholesterol-lowering effect and subsequent antiatherosclerotic effect of JTP-109192 was attributed to changes in intestinal cholesterol metabolism gene expression. Based on these results, JTP-109192 represents a new potential antihypercholesterolaemic agent for the treatment of dyslipidaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1440-1681.13423DOI Listing
March 2021

The Caprine casein-alpha-S2 protein modulates the molecular mechanism of insulin signal transduction in type 2 diabetes rat.

Acta Biochim Pol 2020 Sep;67(3):401-408

1)Research Center of Smart Molecule of Natural Genetics Resource, Brawijaya University, Malang, East Java, Indonesia, 2)DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science and Technology (AIST), and Tsukuba Life Science Innovation, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.

This study purpose was to investigate the association of casein-alpha-S2 protein of Caprine milk and molecular mechanismofinsulin signaltransduction in type2 diabetes mellitus (T2DM). The Caprine milk CSN1S2 protein treatment of 0, 375, 750, and 1500mg/kg BW were conducted to the control and T2DM rats. We observed several physiological parameters of all rats. The levels of insulin and TNF-α in the plasma were measured using ELISA.The expressions of proteins and mRNA levels of diabetes-related genes in the pancreas tissues were analyzed using Western Blotting and Real-Time PCR, respectively. Our study found that diabetic rats had lower body weight, food intake, and fecal weight compared with control rats. The Caprine milk CSN1S2 protein consumption affected the body weight of diabetic rats to increase, especially at the dose of 750mg/kg BW.Interestingly, the genes associated with insulin signaling were improved by the CSN1S2 protein treatment in diabetic rats, although their blood glucose and cholesterol level were not affected. The diabetic rats showed an elevated insulin level and GLUT4 protein expression after treatment. We also reported that the CSN1S2-treated diabetic rats had a gradually reduced expression of TNF-α and VCAM-1 in dose-dependent. Moreover, the 750mg/kg BW of CSN1S2 treatment enhanced the mRNA expressions of INS-receptor, GLUT4, IGF-1, CAMKK, and CAMKIV in diabetic rats. The ability of Caprine milk CSN1S2 protein to regulate the molecular mechanisms in the diabetes-signaling pathway indicated its potential therapeutic effects on diabetes management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18388/abp.2020_5357DOI Listing
September 2020

The sphingosine-1-phosphate receptor modulator, FTY720, prevents the incidence of diabetes in Spontaneously Diabetic Torii rats.

Clin Exp Pharmacol Physiol 2021 Jun 12;48(6):869-876. Epub 2020 Oct 12.

Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.

The sphingosine-1-phosphate (S1P) receptor modulator regulates lymphocyte trafficking, resulting in its depletion from circulation, which ultimately causes immunosuppression. In this study, we investigated the preventive effect of fingolimod (FTY720) in the non-obese type 2 diabetic model, Spontaneously Diabetic Torii (SDT) rats. The S1P receptor modulator, FTY720 (0.3 mg/kg p.o.), was administered for 12 weeks to SDT rats from 5 to 17 weeks of age. Based on our findings, FTY720 could suppress the incidence of diabetes in SDT rats. Further, glucose intolerance was improved in FTY720-treated SDT rats at 14 weeks of age. Based on the haematological and histological analyses performed at 17 to 18 weeks of age, a decrease in lymphocytes and monocytes in the peripheral blood and a decrease in lymphocyte and atrophy in spleen occurred in the FTY720-treated SDT rats. Furthermore, the pancreatic changes, such as inflammation, atrophy, and fibrosis in islets observed in SDT rats were improved by FTY720 treatment. These findings suggest that the immunomodulatory effects of FTY720 reduced the pancreatic lesion in SDT rats, thereby demonstrating its preventive effect against diabetes. The development of diabetes in SDT rats is related to disorders of the immune system. However, the S1P receptor modulator may be useful for treating type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1440-1681.13405DOI Listing
June 2021

Embryonic MTHFR contributes to blastocyst development.

J Assist Reprod Genet 2020 Aug 7;37(8):1807-1814. Epub 2020 Aug 7.

Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan.

Purpose: Reduction in methylenetetrahydrofolate reductase (MTHFR) activity due to genetic variations in the MTHFR gene has been controversially implicated in subfertility in human in vitro fertilization. However, there is no direct gene-knockdown study of embryonic MTHFR to assess its involvement in mammalian preimplantation development. The purpose of this study is to investigate expression profiles and functional roles of MTHFR in bovine preimplantation development.

Methods: Reverse transcription-quantitative PCR (RT-qPCR) and analysis of publicly available RNA-seq data were performed to reveal expression levels of MTHFR during bovine preimplantation development. We knocked down MTHFR by siRNA-mediated RNA interference from the 8- to 16-cell stage and assessed the effects on preimplantation development.

Results: The RT-qPCR analysis showed relatively high MTHFR expression at the GV oocyte stage, which was decreased toward the 8- to 16-cell stage and then slightly restored at the blastocyst stage. Public data-based analysis also showed the similar pattern of expression with substantial embryonic expression at the blastocyst stage. MTHFR knockdown reduced the blastocyst rate (P < 0.01) and the numbers of total (P < 0.0001), trophectoderm (P < 0.0001), and inner cell mass (P < 0.001) cells.

Conclusion: The results indicate that embryonic MTHFR is indispensable for normal blastocyst development. The findings provide insight into the debatable roles of MTHFR in fertility and may be applicable for the improvement of care for early embryos via modulation of surrounding folate-related nutritional conditions in vitro and/or in utero, depending on the parental and embryonic MTHFR genotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10815-020-01898-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468012PMC
August 2020

Hyperglycemia contributes to the development of Leydig cell hyperplasia in male Spontaneously Diabetic Torii rats.

J Toxicol Pathol 2020 Apr 20;33(2):121-129. Epub 2020 Mar 20.

Laboratory of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.

Spontaneously Diabetic Torii (SDT) rats are a well-known animal model of non-obese type 2 diabetes mellitus. Although this animal model has been studied extensively over the last decade, the incidence rates of Leydig cell hyperplasia and tumors in this model have not been reported. In this study, pathophysiological analyses of the testes were performed on male SDT rats, to understand the effect of insulin treatment on the development of Leydig cell hyperplasia and tumors and the expression of integrins and extracellular matrix proteins. Testicular Leydig cell hyperplasia and tumors were observed in SDT rats at 64 weeks of age but were rarely identified in Sprague-Dawley (SD) rats of the same age. Insulin treatment decreased plasma glucose and HbA1c levels, and interestingly, decreased the number of hyperplastic Leydig cell foci and Leydig cell tumors in treated animals. A similar reduction in the expression of Ki67 in these Leydig cell foci was also observed. In addition, insulin treatment decreased the expression of integrin α5, integrin β1, integrin αvβ3, fibronectin, and vitronectin in hyperplastic Leydig cell foci. These results suggest that insulin might decrease the incidence of Leydig cell hyperplasia by reducing Leydig cell proliferation and the expression of integrins and extracellular matrix proteins through the reduction of serum glucose concentrations in these animals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1293/tox.2019-0088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218238PMC
April 2020

Fast Statistical Iterative Reconstruction for Mega-voltage Computed Tomography.

J Med Invest 2020 ;67(1.2):30-39

Department of Radiology, The University of Tokyo Hospital, Japan.

Statistical iterative reconstruction is expected to improve the image quality of computed tomography (CT). However, one of the challenges of iterative reconstruction is its large computational cost. The purpose of this review is to summarize a fast iterative reconstruction algorithm by optimizing reconstruction parameters. Megavolt projection data was acquired from a TomoTherapy system and reconstructed using in-house statistical iterative reconstruction algorithm. Total variation was used as the regularization term and the weight of the regularization term was determined by evaluating signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and visual assessment of spatial resolution using Gammex and Cheese phantoms. Gradient decent with an adaptive convergence parameter, ordered subset expectation maximization (OSEM), and CPU/GPU parallelization were applied in order to accelerate the present reconstruction algorithm. The SNR and CNR of the iterative reconstruction were several times better than that of filtered back projection (FBP). The GPU parallelization code combined with the OSEM algorithm reconstructed an image several hundred times faster than a CPU calculation. With 500 iterations, which provided good convergence, our method produced a 512 × 512 pixel image within a few seconds. The image quality of the present algorithm was much better than that of FBP for patient data. J. Med. Invest. 67 : 30-39, February, 2020.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2152/jmi.67.30DOI Listing
June 2021

Sodium-glucose cotransporters: Functional properties and pharmaceutical potential.

J Diabetes Investig 2020 Jul 16;11(4):770-782. Epub 2020 Apr 16.

Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.

Glucose is the most abundant monosaccharide, and an essential source of energy for most living cells. Glucose transport across the cell membrane is mediated by two types of transporters: facilitative glucose transporters (gene name: solute carrier 2A) and sodium-glucose cotransporters (SGLTs; gene name: solute carrier 5A). Each transporter has its own substrate specificity, distribution, and regulatory mechanisms. Recently, SGLT1 and SGLT2 have attracted much attention as therapeutic targets for various diseases. This review addresses the basal and functional properties of glucose transporters and SGLTs, and describes the pharmaceutical potential of SGLT1 and SGLT2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378437PMC
July 2020

Publisher Correction: Prediction of malignant glioma grades using contrast-enhanced T1-weighted and T2-weighted magnetic resonance images based on a radiomic analysis.

Sci Rep 2020 Feb 17;10(1):3073. Epub 2020 Feb 17.

Department of Radiology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-60086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026034PMC
February 2020

Conventional and novel impacts of ferric citrate on iron deficiency anemia and phosphorus metabolism in rats.

J Vet Med Sci 2020 Mar 29;82(3):379-386. Epub 2020 Jan 29.

Department of Agrobiology, Faculty of Agriculture, Niigata University, 2-8050 Igarashi, Nishiku, Niigata 950-2181, Japan.

Ferric citrate is an oral iron-based phosphate binder, being known to affect iron status and improve iron deficiency anemia (IDA) in chronic kidney disease (CKD) patients. We examined whether oral administration of ferric citrate could change iron status and improve anemia without affecting phosphorus metabolism in iron deficiency anemia rats. In Normal rat study, normal rats were fed a diet containing 0.3 or 3% ferric citrate for 11 days for setting the dose and administration period of ferric citrate. The effects of ferric citrate on iron status- and phosphorus metabolism-related parameters were evaluated using blood and urine samples. Next, an iron deficiency anemia was induced by feeding iron-depleted diet in rats. After 7 days of starting the iron-depleted diet, 0.3% ferric citrate was administered for 7 days by dietary admixture. Iron status- and phosphorus metabolism-related parameters were evaluated with blood and urine samples. In Normal rat study, 3% ferric citrate treatment increased serum iron level and transferrin saturation (TSAT), and decreased serum phosphorus level, intact fibroblast growth factor 23 (iFGF23) level, and urinary phosphorus excretion, but 0.3% ferric citrate treatment showed no effects. On the other hand, in Iron deficiency anemia rat study, 0.3% ferric citrate treatment increased iron status-related parameters and improved anemia, but did not show any apparent changes in phosphorus metabolism-related parameters. In conclusion, ferric citrate could have hematopoietic effects without affecting phosphorus metabolism, and could be a potential option for the treatment of IDA in patients without CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1292/jvms.19-0641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118491PMC
March 2020

Analysis of haemodynamics and angiogenic response to ischaemia in the obese type 2 diabetic model Spontaneously Diabetic Torii Lepr (SDT fatty) rats.

Clin Exp Pharmacol Physiol 2020 04 16;47(4):583-590. Epub 2020 Jan 16.

Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University, Kitashirakawa, Kyoto, Japan.

Peripheral artery disease (PAD) is defined as peripheral blood flow impairment, especially in the legs, caused by atherosclerotic stenosis. The disease decreases quality of life because of intermittent claudication or necrosis of the leg. The hindlimb ischaemia model, in which ischaemia is induced by femoral artery ligation, is often utilized as a PAD model. In the hindlimb ischaemia model, nonmetabolic syndrome animals are mainly used. In this study, we investigated the usefulness of Spontaneously Diabetic Torii Lepr (SDT fatty) rats, a new model for obese type 2 diabetes, as a new PAD animal model. We found that hindlimb blood flow in SDT fatty rats was significantly lower than that in Sprague-Dawley (SD) rats under nonischaemic conditions. Furthermore, SDT fatty rats showed a significantly higher plasma nitrogen oxide level, shorter prothrombin time, and shorter activated partial thromboplastin time than SD rats. In addition, we found that the change in blood flow 7 days after induction of hindlimb ischaemia and the number of Von Willebrand factor-positive vessels in gastrocnemius muscles were significantly lower in SDT fatty rats than in SD rats. These results suggest that excess production of reactive oxygen species and coagulation activation could be involved in lower blood flow in non-ischaemic rats and that decreased angiogenesis could be involved in the poor recovery of blood flow in SDT fatty rats with hindlimb ischaemia. Taken together, our results suggest that SDT fatty rats might be useful as a new model for PAD with metabolic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1440-1681.13239DOI Listing
April 2020

Prediction of malignant glioma grades using contrast-enhanced T1-weighted and T2-weighted magnetic resonance images based on a radiomic analysis.

Sci Rep 2019 12 19;9(1):19411. Epub 2019 Dec 19.

Department of Radiology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

We conducted a feasibility study to predict malignant glioma grades via radiomic analysis using contrast-enhanced T1-weighted magnetic resonance images (CE-T1WIs) and T2-weighted magnetic resonance images (T2WIs). We proposed a framework and applied it to CE-T1WIs and T2WIs (with tumor region data) acquired preoperatively from 157 patients with malignant glioma (grade III: 55, grade IV: 102) as the primary dataset and 67 patients with malignant glioma (grade III: 22, grade IV: 45) as the validation dataset. Radiomic features such as size/shape, intensity, histogram, and texture features were extracted from the tumor regions on the CE-T1WIs and T2WIs. The Wilcoxon-Mann-Whitney (WMW) test and least absolute shrinkage and selection operator logistic regression (LASSO-LR) were employed to select the radiomic features. Various machine learning (ML) algorithms were used to construct prediction models for the malignant glioma grades using the selected radiomic features. Leave-one-out cross-validation (LOOCV) was implemented to evaluate the performance of the prediction models in the primary dataset. The selected radiomic features for all folds in the LOOCV of the primary dataset were used to perform an independent validation. As evaluation indices, accuracies, sensitivities, specificities, and values for the area under receiver operating characteristic curve (or simply the area under the curve (AUC)) for all prediction models were calculated. The mean AUC value for all prediction models constructed by the ML algorithms in the LOOCV of the primary dataset was 0.902 ± 0.024 (95% CI (confidence interval), 0.873-0.932). In the independent validation, the mean AUC value for all prediction models was 0.747 ± 0.034 (95% CI, 0.705-0.790). The results of this study suggest that the malignant glioma grades could be sufficiently and easily predicted by preparing the CE-T1WIs, T2WIs, and tumor delineations for each patient. Our proposed framework may be an effective tool for preoperatively grading malignant gliomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-55922-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923390PMC
December 2019

Visual enhancement of Cone-beam CT by use of CycleGAN.

Med Phys 2020 Mar 3;47(3):998-1010. Epub 2020 Jan 3.

Department of Radiology, University of Tokyo Hospital, Tokyo, 113-8655, Japan.

Purpose: Cone-beam computed tomography (CBCT) offers advantages over conventional fan-beam CT in that it requires a shorter time and less exposure to obtain images. However, CBCT images suffer from low soft-tissue contrast, noise, and artifacts compared to conventional fan-beam CT images. Therefore, it is essential to improve the image quality of CBCT.

Methods: In this paper, we propose a synthetic approach to translate CBCT images with deep neural networks. Our method requires only unpaired and unaligned CBCT images and planning fan-beam CT (PlanCT) images for training. The CBCT images and PlanCT images may be obtained from other patients as long as they are acquired with the same scanner settings. Once trained, three-dimensionally reconstructed CBCT images can be directly translated into high-quality PlanCT-like images.

Results: We demonstrate the effectiveness of our method with images obtained from 20 prostate patients, and provide a statistical and visual comparison. The image quality of the translated images shows substantial improvement in voxel values, spatial uniformity, and artifact suppression compared to those of the original CBCT. The anatomical structures of the original CBCT images were also well preserved in the translated images.

Conclusions: Our method produces visually PlanCT-like images from CBCT images while preserving anatomical structures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mp.13963DOI Listing
March 2020

A Novel TNF-α Converting Enzyme (TACE) Selective Inhibitor JTP-96193 Prevents Insulin Resistance in KK-A Type 2 Diabetic Mice and Diabetic Peripheral Neuropathy in Type 1 Diabetic Mice.

Biol Pharm Bull 2019 ;42(11):1906-1912

Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc.

Tumor necrosis factor-α (TNF-α) converting enzyme/a disintegrin and metalloproteinase domain-containing protein 17 (TACE/ADAM17) is a key sheddase that releases TNF-α from its inactive precursor and is thought as a new drug target to inhibit TNF-α production. In the present study, pharmacological effects of a novel TACE selective inhibitor, JTP-96193, on type 2 diabetes and diabetic peripheral neuropathy (DPN) as its major complication was examined. Enzyme inhibitory activity of JTP-96193 on TACE and other ADAMs was measured in in vitro. High fat-induced obese mice and type 2 diabetic KK-A mice were used to evaluate the effect of JTP-96193 on insulin resistance. Finally, streptozotocin (STZ)-induced diabetic mice were treated with JTP-96193 to evaluate the sciatic motor nerve conduction velocities (MNCV). JTP-96193 selectively inhibited human TACE activity with IC value of 5.4 nM and showed more than 1800-fold selectivity against other matrix metalloproteinases. In mouse models of obesity and diabetes, JTP-96193 reduced the TNF-α release from the fat tissue and prevented development of diabetes and improved insulin resistance, respectively. Furthermore, JTP-96193 prevented delay of sciatic MNCV without any effects on blood glucose or insulin levels in STZ-induced diabetic mice. TACE inhibitor is effective on insulin resistance and DPN independent from glucose-lowering effect. These pharmacological properties of JTP-96193 may be helpful to treat type 2 diabetes accompanied by its microvascular complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.b19-00526DOI Listing
May 2020

Pathological Features of Diabetic Retinopathy in Spontaneously Diabetic Torii Fatty Rats.

J Diabetes Res 2019 15;2019:8724818. Epub 2019 Sep 15.

Department of Ophthalmology, Jichi Medical University, Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama, Saitama 330-8503, Japan.

Objective: The Spontaneously Diabetic Torii (SDT) fatty rat, established by introducing the allele (obesity gene) of the Zucker fatty rat into the SDT rat genome, is a new model of obese type 2 diabetes. We studied the pathologic features of diabetic retinopathy (DR) in this animal.

Methods: The eyes of SDT fatty, SDT (controls), and Sprague Dawley (SD) rats (normal controls) were enucleated at 8, 16, 24, 32, and 40 weeks of age ( = 5-6 for each rat type at each age). The retinal thicknesses, numbers of retinal folds, and choroidal thicknesses were evaluated. Immunostaining for glial fibrillary acidic protein (GFAP) and vascular endothelial growth factor (VEGF) was performed. Quantitative analyses of the immunopositive regions were performed using a cell-counting algorithm.

Results: The retinas tended to be thicker in the SDT fatty rats and SDT rats than in the SD rats; the choroids tended to be thicker in the SDT fatty rats than in the SD rats. The retinal folds in the SDT fatty rats developed earlier and were more severe than in the SDT rats. Quantitative analyses showed that the GFAP- and VEGF-positive regions in the retinas of the SDT fatty rats were significantly larger than those of the SDT rats.

Conclusions: SDT fatty rats developed more severe DR earlier than the SDT rats. The SDT fatty rats might be useful as a type 2 diabetes animal model to study DR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/8724818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766157PMC
April 2020

Chronic treatment of JTP-109192, a novel G-protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker Fatty rats.

Clin Exp Pharmacol Physiol 2019 10 30;46(10):910-919. Epub 2019 Aug 30.

Graduate School of Science and Technology, Niigata University, Niigata, Japan.

G-protein coupled receptor 119 (GPR119) expression in pancreatic β-cells and intestinal L cells is a potential therapeutic target for treating type 2 diabetes. A natural GPR119 agonist oleoylethanolamide is well known to enhance a glucose-stimulated insulin secretion (GSIS) and glucagon-like peptide-1 (GLP-1) secretion by elevating intracellular cAMP levels. In the present study, a glucose lowering effect of the GPR119 agonist, JTP-109192 leading to improvement of insulin sensitivity was examined in Zucker Fatty (ZF) rats. We investigated the in vitro effects of JTP-109192 on GSIS in the rat pancreatic β-cell line (INS1E) cells and on GLP-1 secretion in the murine enteroendocrine cell line (GLUTag) cells. We also investigated the effect of JTP-109192 on GSIS in Sprague-Dawley (SD) rats with single administration and its effect on glucose metabolism in ZF rats with repeated administration once daily for about 6 weeks. After repeated administration, the hyperinsulinaemic euglycaemic glucose clamp test was performed to evaluate insulin sensitivity. JTP-109192 increased intracellular cAMP levels (EC value: 3.6 nmol/L) and enhanced GSIS in the INS1E cells and GLP-1 secretion in GLUTag cells. In SD rats, a single administration of JTP-109192 enhanced GSIS at high blood glucose levels. The repeated administrations in ZF rats improved glucose metabolism without lack of drug efficacy (tachyphylaxis) and increased glucose infusion rates due to improvement of insulin sensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1440-1681.13152DOI Listing
October 2019

Cloning, expression, and characterization of novel GH5 endoglucanases from Thermobifida alba AHK119.

J Biosci Bioeng 2019 May 2;127(5):554-562. Epub 2018 Dec 2.

Center for Fiber and Textile Science, Kyoto Institute of Technology, Kyoto 606-8181, Japan.

Thermobifida alba AHK119 exhibits sufficient filter paper-degradation activity in its culture supernatant. AHK119-bMs (1365 bp) and AHK119-E5 (1425 bp), which encode novel GH5 family endoglucanases, were cloned from the genomic DNA of T. alba AHK119. AHK119-bMs and AHK119-E5 consisted of 454 and 474 amino acid residues, respectively, in which the catalytic domain (CD) and carbohydrate-binding module (CBM) were connected by an accessary module (linker region). The amino acid sequences of CD and CBM of AHK119-bMs were most identical to those of endo-β-mannanases (Man5As) from Thermobifidafusca TM51, T. halotolerans YIM90462, and T.cellulosilytica TB100. In contrast, the amino acid sequences of CD and CBM of AHK119-E5 were most identical to those of endo-1,4-β-glucanases (cellulases; Cel5As) from T. fusca and T. halotolerans YIM90462. However, the linker region of both the genes shared low identities with those of Man5As and Cel5As. AHK119-bMs showed broader specificities toward cellulosic substrates than Man5As, whereas AHK119-E5 showed higher activity toward insoluble cellulosic substrates than toward soluble ones, which was conflicting when compared with other Cel5As. In addition, AHK119-bMs and AHK119-E5 showed different requirements for metal ions from those of Man5As and Cel5As, respectively. Therefore, both the enzymes were identified as novel GH5 endoglucanases, and the accessary modules seemed to play important roles in their enzymatic properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbiosc.2018.10.015DOI Listing
May 2019

Hepatic lesions induced by feeding Western diets to Zucker fatty rats, an insulin-resistant model.

J Toxicol Pathol 2018 Oct 2;31(4):283-291. Epub 2018 Sep 2.

Japan Tobacco Inc., Central Pharmaceutical Research Institute, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.

Metabolic diseases including nonalcoholic steatohepatitis develop due to various environmental factors. In particular, the westernization of food is closely related to the development of these diseases. In this study, we investigated pathophysiological changes in the livers of Zucker fatty (ZF) rats induced by feeding Western diets. Male ZF rats were fed a sucrose/fat/cholesterol-enriched diet (Western diet, WD) or standard diet (SD) for 18 weeks, from 7 to 25 weeks of age. Body weight, food intake, and biochemical parameters were periodically measured, histopathological analyses were performed at 25 weeks, and mRNA expression in the liver was determined. ZF rats fed the WD (ZF-WD rats) developed obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and their alanine aminotransferase and aspartate aminotransferase levels increased compared with those of ZF rats fed the SD (ZF-SD rats). Hepatic lesions including fibrosis and necrosis were observed in the ZF-WD rats at 25 weeks; however, fibrosis and necrosis were not observed in the ZF-SD rats. Oxidative stress markers also increased in the livers of ZF-WD rats. Hepatic mRNA expression related to inflammation and fibrosis increased in the ZF-WD rats; however, mRNA expression related to lipid synthesis decreased. Microsomal triglyceride transfer protein mRNA levels in the ZF-WD rats also decreased. In Zucker lean rats fed the WD, similar changes were observed in the liver; however, the hepatic changes were not serious compared with ZF-WD rats. In conclusion, hepatic lesions, such as inflammation, fibrosis, and necrosis, were observed in the ZF-WD rats. The sucrose/fat/cholesterol-enriched diet induced significant lipotoxicity in the livers of animals in this insulin-resistant model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1293/tox.2018-0016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206288PMC
October 2018

Spontaneously Diabetic Torii (SDT) Fatty Rat, a Novel Animal Model of Type 2 Diabetes Mellitus, Shows Blunted Circadian Rhythms and Melatonin Secretion.

Int J Endocrinol 2018 23;2018:9065690. Epub 2018 Sep 23.

Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, Japan.

In patients with diabetes mellitus (DM), impairments of circadian rhythms, including the sleep-wake cycle, blood pressure, and plasma melatonin concentrations, are frequently observed. Animal models of DM are also reported to show aberrant circadian rhythms. However, the changes in the circadian rhythms of plasma soluble substances, including melatonin, in diabetic animals are controversial. In the present study, we investigated the circadian rhythms of spontaneous locomotor activity, metabolic parameters (plasma glucose, triglyceride, and total cholesterol), and plasma melatonin concentrations in Spontaneously Diabetic Torii (SDT) fatty rats, a novel animal model of type 2 DM. Although SDT fatty rats exhibited low locomotor activity in the dark phase, no phase shifts were observed. The circadian variations of plasma metabolic parameters were more apparent in the SDT fatty rats compared with control Sprague-Dawley (SD) rats. The circadian rhythms of plasma melatonin concentrations were significantly impaired in SDT fatty rats. To get an insight into the mechanism underlying the impaired melatonin secretion in SDT fatty rats, the expression of arylalkylamine N-acetyltransferase () and acetylserotonin O-methyltransferase () mRNA, which encode the rate-limiting enzymes for melatonin synthesis, was investigated in the pineal gland. There were no significant differences in and expression between the control SD and SDT fatty rats. These results suggest that SDT fatty rats show impaired circadian rhythms and dysregulated melatonin secretion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/9065690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174757PMC
September 2018

Pathophysiological abnormalities in the brains of Spontaneously Diabetic Torii-Lepr (SDT fatty) rats, a novel type 2 diabetic model.

J Vet Med Sci 2018 09 17;80(9):1385-1391. Epub 2018 Jul 17.

Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.

In recent years, a relationship between diabetes and neurodegenerative diseases, such as Parkinson's disease, Alzheimer disease or depression, has been proposed. In this study, pathophysiological changes in the brain, especially in the hippocampus, of male SDT fatty rats with obesity and hyperglycemia were investigated. Brains of SD rats and SDT fatty rats were collected at 32 and 58 weeks of age, and parietal cortical thickness and number of pyramidal cells in the hippocampal cornu ammonis 1 and 3 (CA1 and CA3) regions were measured. At 58 weeks of age, the parietal cortical thickness and number of pyramidal cells in the hippocampal CA1 and CA3 regions were lower in SDT fatty rats than in age-matched SD rats. Measurements of mRNA in rat brains at 58 weeks of age showed that the expression of genes related to inflammatory responses (S100a9, TNFα, NF-κB) was elevated in SDT fatty rats. From the aforementioned results, changes suggestive of brain atrophy and impairment in cognitive function were observed in male SDT fatty rat brains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1292/jvms.18-0296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160888PMC
September 2018

Depression-related behavioural and neuroendocrine changes in the Spontaneously Diabetic Torii (SDT) fatty rat, an animal model of type 2 diabetes mellitus.

Clin Exp Pharmacol Physiol 2018 May 14. Epub 2018 May 14.

Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki, Osaka, Japan.

Depression is one of the most common psychiatric diseases and is commonly comorbid with type 1 or 2 diabetes mellitus (DM). However, the pathophysiology underlying the depressive state in DM remains poorly understood. Animal models are useful tools to investigate the association between depression and DM. In the present study we investigated whether the Spontaneously Diabetic Torii (SDT) fatty rat, a novel animal model of type 2 DM, shows depression-related features. We assessed depression-like behaviour, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and neurotransmitter levels in the brain. Behaviour was evaluated using a forced swimming test, and the HPA axis was evaluated with changes in plasma corticosterone levels after a swimming stress exposure or dexamethasone challenge. In addition, serotonin (5-hydroxytryptamine; 5-HT), noradrenaline, glutamate and γ-aminobutyric acid (GABA) concentrations in the frontal cortex, hippocampus and brain stem were measured. In the forced swimming test, SDT fatty rats exhibited increased duration of immobility compared with control Sprague-Dawley (SD) rats. Moreover, basal corticosterone levels were significantly elevated in SDT fatty compared with control SD rats. However, there were no stress-induced increases or changes in dexamethasone-induced suppression of corticosterone in SDT fatty compared with control SD rats. Furthermore, there were significant changes in 5-HT concentrations in the prefrontal cortex, and in GABA and glutamate concentrations in the hippocampus in SDT fatty compared with controls. The results of the present study suggest that the SDT fatty rat may be an appropriate model for diabetes with comorbid depression associated with neurotransmitter impairments and aberrant basal HPA hyperactivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1440-1681.12965DOI Listing
May 2018

Pathophysiological analyses of skeletal muscle in obese type 2 diabetes SDT fatty rats.

J Toxicol Pathol 2018 Apr 14;31(2):113-123. Epub 2018 Feb 14.

Department of Agrobiology, Faculty of Agriculture, Niigata University, 2-8050 Igarashi, Nishiku, Niigata, Niigata 950-2181, Japan.

Sarcopenia is the age-related decrease of muscle mass and function. Diabetes and obesity are known to be risk factors that exacerbate sarcopenia, but the underlying mechanism of diabetes-related sarcopenia is still unknown. Obese type 2 diabetes SDT fatty rats show early onset of severe diabetes and there have been no reports on the characteristics of their skeletal muscle. Therefore, pathophysiological analyses were performed for the skeletal muscle in these rats. Diabetic male SDT fatty rats were sacrificed at 8, 16, 24, 32 and 40 weeks of age. Age-matched Sprague Dawley (SD) rats were used as the normal control. In addition to biological blood parameters, the soleus and the extensor digitorum longus muscles were examined for muscle weight, histopathology, and protein synthesis and degradation. Muscle grip strength was also examined. These results revealed that the muscle weights of the SDT fatty rats were significantly decreased from 16 weeks of age. The mean cross-sectional area of muscle fibers in the SDT fatty rats decreased from 24 weeks of age. Increased intramyocellular lipid accumulation, identified by immunohistochemistry for adipophilin and TEM, was observed in the SDT fatty rats from 8 weeks of age. Plasma insulin-like growth factor (IGF)-1 levels and muscle strength in the SDT fatty rats decreased at 24 weeks of age and thereafter. These pathophysiological findings have been reported both in sarcopenia in aged humans and in patients with diabetes. In conclusion, the SDT fatty rat was considered to be a useful model for analysis of diabetes-related sarcopenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1293/tox.2017-0064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938212PMC
April 2018

Is the Occlusion Site of the Lenticulostriate Artery Identified on Admission Related to Clinical Prognosis in Patients with Lacunar Stroke?

J Stroke Cerebrovasc Dis 2018 Jul 17;27(7):2035-2042. Epub 2018 Apr 17.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Background: The mechanism of lacunar stroke (LS) is rather speculative due to the lack of neuropathological evidence in clinical practice. To explore the significance of the occlusion site of the lenticulostriate artery (LSA) to this mechanism, we investigated the characteristics and prognosis of patients with LS with proximal occlusions.

Materials And Methods: We studied 202 patients with acute LS in the region of the LSA. The presumed occlusion site of the LSA was assessed on coronal, diffusion-weighted magnetic resonance images. Based on the distance from the basal surface of the hemisphere to the proximal site of the lacunar infarct, patients were divided into 3 groups: proximal, middle, and distal site occlusions, and their characteristics and outcomes were compared.

Results: White blood cell counts, blood glucose, hemoglobin A1c, low-density lipoprotein cholesterol, triglyceride, and admission National Institutes of Health Stroke Scale score were statistically different among the 3 groups. In multivariate analysis, both high levels of white blood cells (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.01-1.33) and triglyceride (OR, 1.31; 95% CI, 1.09-1.61) were positively related to the proximal occlusion site. Proximal occlusion (OR, 3.98; 95% CI, 1.06-16.11) was related to poor outcome at discharge.

Conclusions: Proximal occlusion of the LSA was independently related to elevated triglyceride and white blood cell counts. Patients with LS with proximal LSA occlusion had severe neurological deficits both on admission and at discharge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.02.058DOI Listing
July 2018

Investigation of pharmacological responses to anti-diabetic drugs in female Spontaneously Diabetic Torii (SDT) fatty rats, a new nonalcoholic steatohepatitis (NASH) model.

J Vet Med Sci 2018 Jun 10;80(6):878-885. Epub 2018 Apr 10.

Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease, and some patients develop hepatic cirrhosis/carcinoma. Animal models play key roles in the development of new therapies for NASH. In this study, the pharmacological effects of metformin and pioglitazone were investigated in female Spontaneously Diabetic Torii (SDT) fatty rats to verify the utility of this model. The anti-diabetic drugs were administered to SDT fatty rats fed a cholesterol-enriched diet from 4 to 25 weeks, and changes in food intake, body weight, and blood chemistry parameters were evaluated every 4 weeks. The hepatic lipid content, mRNA expression in relation to lipid synthesis, inflammation, and fibrosis, and histopathological analyses were performed at 25 weeks. Pioglitazone improved hyperglycemia, hyperlipidemia, and abnormalities in hepatic parameters. The insulin levels were lower than those in the control rats before 16 weeks. Plasma glucose levels in the metformin-treated rats were lower than those in the control rats, and plasma alanine aminotransferase levels temporarily decreased. The lipid content and some mRNA expression in relation to fibrosis in the liver decreased with pioglitazone treatment, and the mRNA expression of microsomal triglyceride transfer protein increased. Hepatic fibrosis observed in the SDT fatty rats improved with pioglitazone treatment; however, the effect with metformin treatment was partial. These results in both drugs are in line with results in the human study, suggesting that the SDT fatty rat is useful for developing new anti-NASH drugs that show potential to regulate glucose/lipid metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1292/jvms.18-0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021872PMC
June 2018

Effects on Glycemic Control in Impaired Wound Healing in Spontaneously Diabetic Torii (SDT) Fatty Rats.

Med Arch 2018 Feb;72(1):4-8

Laboratory of Animal Genetics, Graduate School of Science and Technology, Niigata University, Niigata, Japan.

Introduction: Impaired diabetic wound healing is an important issue in diabetic complications. The present study aims to evaluate the protective effect on glycemic control against impaired diabetic wound healing using a diabetic rat model. We investigated the wound healing process and effect on the impaired wound repair by glycemic control in the Spontaneously Diabetic Torii (SDT) fatty rat, which is a new animal model of obese type 2 diabetes and may be a good model for study impaired wound healing.

Material And Methods: Male SDT fatty rats at 15 weeks of age were administered orally with sodium glucose co-transporter (SGLT) 2 inhibitor for 3 weeks. Wounds were induced at 2 weeks after SGLT 2 inhibitor treatment, and the wound areas were periodically examined in morphological and histological analyses.

Results: The SDT fatty rats showed a delayed wound healing as compared with the normal rats, but a glycemic control improved the impaired wound healing. In histological analysis in the skin of SDT fatty rats showed severe infiltration of inflammatory cell, hemorrhage and many . Thought that this results skin performance to be a delay of crust formation and regeneration of epithelium; however, these findings were ameliorated in the SGLT 2 inhibitor treated group.

Conclusion: Glycemic control is effective for treatment in diabetic wounds and the SDT fatty rat may be useful to investigate pathophysiological changes in impaired diabetic wound healing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5455/medarh.2018.72.4-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789560PMC
February 2018

Assessment of Pharmacological Responses to an Anti-diabetic Drug in a New Obese Type 2 Diabetic Rat Model.

Med Arch 2017 Dec;71(6):380-384

Laboratory of Animal Genetics, Division of Life and Food Sciences, Graduate School of Science and Technology, Niigata University, Niigata, Japan.

Introduction: The number of diabetic patients has recently been increasing worldwide, and numerous anti-diabetic drugs have been developed to induce good glycemic control. In particular, metformin, which exhibits glucose-lowering effects by suppressing gluconeogenesis in the liver, is widely used as a first line oral anti-diabetic drug for type 2 diabetes mellitus.

Material And Methods: In this study, the pharmacological effects of metformin were investigated using female and male Spontaneously Diabetic Torii (SDT) fatty rats, a new obese type 2 diabetic model.

Results: Two experiments were performed: an assessment of repeated treatment with metformin in female SDT fatty rats 5 to 13 weeks of age (experiment 1), and an assessment of repeated treatment with metformin in male SDT fatty rats 6 to 10 weeks of age (experiment 2). In female SDT fatty rats, metformin treatment led to good glycemic control, increases in sensory nerve conduction velocity, and improvements in pancreatic abnormalities such as irregular boundaries and vacuole form of islets. In male SDT fatty rats, metformin decreased blood glucose levels 4 weeks after treatment.

Conclusion: Metformin treatment led to maintained good glycemic control and improved neuropathy and pancreatic lesions in female SDT fatty rats. The SDT fatty rat is useful for the development of novel anti-diabetic agents that show potential to improve glucose metabolic disorders in the liver.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5455/medarh.2017.71.380-384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764610PMC
December 2017

JTE-852, a novel spleen tyrosine kinase inhibitor, blocks antigen-induced allergic reactions in rats.

J Vet Med Sci 2018 Mar 26;80(3):465-472. Epub 2018 Jan 26.

Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.

Conventional clinical treatments for allergy management remain suboptimal; new, orally available medications that improve a wide range of allergic signs have been desired. We previously demonstrated that JTE-852, a novel spleen tyrosine kinase inhibitor, potently and simultaneously suppresses secretion of granule contents, arachidonate metabolites, and cytokines from mast cells stimulated by immunoglobulin E-crosslinking. In the present study, we investigated the effects of JTE-852 in four rat models (sneezing, rhinorrhea, airway constriction, and airway inflammation) as representatives of allergy models. Rats were sensitized and challenged with antigen. Allergic reactions developed after challenge were detected. JTE-852 and current anti-allergic drugs (ketotifen, pranlukast, and prednisolone) were administered orally before challenge. JTE-852 showed significant blocking effects on antigen-induced allergic reactions in all models, indicating that JTE-852 in oral dosage form would improve a wide range of allergic signs. The current anti-allergic drugs, on the other hand, failed to display significant suppression in several models. Because JTE-852 suppresses the secretion of all three groups of allergic mediators from mast cells, it would be capable of targeting signs that current drugs cannot sufficiently relieve. We anticipate JTE-852 to be a promising new anti-allergic drug that is potentially more effective than conventional drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1292/jvms.17-0659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880827PMC
March 2018