Publications by authors named "Tatsuaki Matsubara"

127 Publications

Sustainable Effects of Human Dental Pulp Stem Cell Transplantation on Diabetic Polyneuropathy in Streptozotocine-Induced Type 1 Diabetes Model Mice.

Cells 2021 09 18;10(9). Epub 2021 Sep 18.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya 464-8651, Japan.

Dental pulp stem cells (DPSCs) are suitable for use in regenerative medicine. Cryopreserved human DPSCs (hDPSCs) ameliorate diabetic polyneuropathy, and the effects of hDPSC transplantation are related to VEGF and NGF secretion. This study evaluated the long-term effects of a single transplantation of hDPSCs on diabetic polyneuropathy. hDPSCs were obtained from human third molars extracted for orthodontic treatment, which were then transplanted into the unilateral hindlimb skeletal muscles 8 weeks after streptozotocin injection in nude mice. The effects of hDPSC transplantation were analyzed at 16 weeks post-transplantation. DPSC transplantation significantly improved delayed nerve conduction velocity, decreased blood flow, and increased sensory perception thresholds. Furthermore, the hDPSC-conditioned medium promoted the neurite outgrowth of dorsal root ganglion neurons. In conclusion, the therapeutic effects of hDPSC transplantation with a single injection last for prolonged periods and may be beneficial in treating long-term diabetic polyneuropathy.
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http://dx.doi.org/10.3390/cells10092473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466318PMC
September 2021

The Effects of Insulin on Immortalized Rat Schwann Cells, IFRS1.

Int J Mol Sci 2021 May 23;22(11). Epub 2021 May 23.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya 464-8651, Japan.

Schwann cells play an important role in peripheral nerve function, and their dysfunction has been implicated in the pathogenesis of diabetic neuropathy and other demyelinating diseases. The physiological functions of insulin in Schwann cells remain unclear and therefore define the aim of this study. By using immortalized adult Fischer rat Schwann cells (IFRS1), we investigated the mechanism of the stimulating effects of insulin on the cell proliferation and expression of myelin proteins (myelin protein zero (MPZ) and myelin basic protein (MBP). The application of insulin to IFRS1 cells increased the proliferative activity and induced phosphorylation of Akt and ERK, but not P38-MAPK. The proliferative potential of insulin-stimulated IFRS1 was significantly suppressed by the addition of LY294002, a PI3 kinase inhibitor. The insulin-stimulated increase in MPZ expression was significantly suppressed by the addition of PD98059, a MEK inhibitor. Furthermore, insulin-increased MBP expression was significantly suppressed by the addition of LY294002. These findings suggest that both PI3-K/Akt and ERK/MEK pathways are involved in insulin-induced cell growth and upregulation of MPZ and MBP in IFRS1 Schwann cells.
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http://dx.doi.org/10.3390/ijms22115505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197103PMC
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Case Report: Non-episodic Angioedema With Eosinophilia in a Young Lactating Woman.

Front Immunol 2021 26;12:627360. Epub 2021 Apr 26.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Angioedema with eosinophilia is classified into two types: episodic angioedema with eosinophilia (EAE), known as Gleich's syndrome, and non-episodic angioedema with eosinophilia (NEAE). We present the case of a young lactating woman with non-episodic angioedema. She had no history of parasitic or nonparasitic infections. Physical examination showed striking, non-pitting edema in both lower extremities. Her weight had not changed significantly throughout the course of the illness. She exhibited no other symptoms, and her vital signs were normal. There was no evidence of anemia, hypoalbuminemia, thyroid dysfunction, heart failure, renal failure, or postpartum cardiomyopathy. Based on these findings, we diagnosed her with angioedema with eosinophilia. Given the scarcity of information about this condition, we explored the dynamics between cytokines/chemokines and edema in this patient. We successfully quantified the edema by bioimpedance analysis. In addition, we revealed the involvement of interleukin-5 (IL-5), thymus- and activation-regulated chemokine/C-C motif chemokine ligand-17 (TARC/CCL-17), eotaxin-3/CCL-26, tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), monocyte chemotactic protein-4/CCL-13 (MCP-4/CCL-13), eotaxin-1/CCL-11, and regulated on activation, normal T expressed and secreted/CCL-5 (RANTES/CCL-5) in NEAE. Lastly, we elucidated the strong association between these parameters. To the best of our knowledge, this is the first such study of its kind.
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http://dx.doi.org/10.3389/fimmu.2021.627360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107285PMC
September 2021

Efficacy of extracellular vesicles from dental pulp stem cells for bone regeneration in rat calvarial bone defects.

Inflamm Regen 2021 Apr 14;41(1):12. Epub 2021 Apr 14.

Department of Removable Prosthodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, 464-8651, Japan.

Background: Extracellular vesicles (EVs) are known to be secreted by various cells. In particular, mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) have tissue repair capacity and anti-inflammatory properties. Dental pulp stem cells (DPSCs), which are MSCs isolated from pulp tissue, are less invasive to the body than other MSCs and can be collected from young individuals. In this study, we investigated the efficacy of EVs secreted by DPSCs (DPSC-EVs) for bone formation.

Methods: DPSC-EVs were isolated from the cell culture medium of DPSCs. DPSC-EVs were unilaterally injected along with collagen (COL), beta-tricalcium phosphate (β-TCP) or hydroxyapatite (HA) into rat calvarial bone defects. The effects of DPSC-EVs were analyzed by micro-computed tomography (micro-CT) and histological observation.

Results: Micro-CT showed that administration of DPSC-EVs with the abovementioned scaffolds resulted in bone formation in the periphery of the defects. DPSC-EVs/COL specifically resulted in bone formation in the center of the defects. Histological observation revealed that DPSC-EVs/COL promoted new bone formation. Administration of DPSC-EVs/COL had almost the same effect on the bone defect site as transplantation of DPSCs/COL.

Conclusions: These results suggest that DPSC-EVs may be effective tools for bone tissue regeneration.
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http://dx.doi.org/10.1186/s41232-021-00163-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048358PMC
April 2021

A large-scale observational study to investigate the current status of diabetic complications and their prevention in Japan (JDCP study 6): baseline dental and oral findings.

Diabetol Int 2021 Jan 15;12(1):52-61. Epub 2020 Oct 15.

Institution for Advanced Dental Sciences, Tokushinkai Group, Tokyo, Japan.

Japan Diabetes Complication and Prevention prospective (JDCP) study was conducted to examine the association between glycemic control and oral conditions in a large database of Japanese patients with diabetes. It included a total of 6099 patients with diabetes (range, 40-75 years) who had been treated as outpatients between 2007 and 2009. The mean number of present teeth at baseline was 19.8 and women with type 2 diabetes had fewer teeth than men with type 2 diabetes. Within the previous year, 17% of all patients had lost teeth. At baseline, 32% had experienced gingival swelling, 69% had brushed more than twice a day, 37% had used interdental cleaning aids, and 43% had undergone regular dental checkups. Multiple logistic regression analysis indicated that type 1 patients with HbA1c ≥ 7.0% were at higher risk of having fewer than 20 teeth (odds ratio [OR] 2.38; 95% confidence interval [CI] 1.25-4.78), and type 2 patients with HbA1c ≥ 8.0% also were at high risk of having fewer than 20 teeth (OR 1.16; 95% CI 1.00-1.34), after adjustment for nine possible confounding factors. In conclusion, patients with diabetes were found to be at high risk of tooth loss, and the poorer the glycemic control, the higher the risk of tooth loss in these patients.
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http://dx.doi.org/10.1007/s13340-020-00465-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790965PMC
January 2021

Impact of the clinical frailty scale on clinical outcomes and bleeding events in patients with ST-segment elevation myocardial infarction.

Heart Vessels 2021 Jun 7;36(6):799-808. Epub 2021 Jan 7.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The Clinical Frailty Scale (CFS) is a simple tool to assess patients' frailty and may help to predict adverse outcomes in elderly patients. The aim of the present study was to examine the impact of CFS on clinical outcomes and bleeding events after successful percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI). We enrolled 266 consecutive patients with STEMI who underwent primary PCI in between January 2015 and June 2018. Patients were categorized into two groups based on the CFS stages: CFS 1-3 and CFS ≥ 4. We collected the data and evaluated the relationship between the CFS grade and the incidence of major adverse cardiovascular events (MACE) and Bleeding Academic Research Consortium 3 or 5 bleeding events. Of these patients, CFS ≥ 4 was present in 59 (22.2%). During the follow-up, 37.3% in the CFS ≥ 4 group and 8.2% in the CFS 1-3 group experienced MACE. In Kaplan-Meier analysis, the proportion of MACE-free survival for 4 years was significantly lower in the CFS ≥ 4 group (log-rank P < 0.001). Additionally, the proportion of bleeding event-free survival was significantly lower in the CFS ≥ 4 group (log-rank P < 0.001). The CFS (per 1-grade increase) remained an independent significant predictor of MACE on multivariate Cox proportional hazard analysis [hazard ratio 1.39 (95% confidence interval: 1.08 to 1.79, P = 0.01)]. In conclusion, CFS was an independent predictor of future adverse cardiac events in patients with STEMI. Therefore, the assessment of CFS is crucial in this population.
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http://dx.doi.org/10.1007/s00380-020-01764-0DOI Listing
June 2021

Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Ameliorates the Development of Periodontitis.

J Diabetes Res 2020 19;2020:8843310. Epub 2020 Nov 19.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Periodontitis is one of the diabetic complications due to its high morbidity and severity in patients with diabetes. The prevention of periodontitis is especially important in diabetic patients because the relationship between diabetes and periodontitis is bidirectional. Here, we evaluated the impacts of glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide on the amelioration of periodontitis. Five-wk-old Male Sprague-Dawley (SD) rats ( = 30) were divided into 3 groups: normal, periodontitis, and periodontitis with liraglutide treatment groups. Periodontitis was induced by ligature around the maxillary second molar in SD rats. Half of the rats were administered liraglutide for 2 weeks. Periodontitis was evaluated by histological staining, gene expressions of inflammatory cytokines in gingiva, and microcomputed tomography. Periodontitis increased inflammatory cell infiltration, macrophage accumulation, and gene expressions of tumor necrosis factor- and inducible nitric oxide synthase in the gingiva, all of which were ameliorated by liraglutide. Liraglutide decreased M1 macrophages but did not affect M2 macrophages in periodontitis. Moreover, ligature-induced alveolar bone resorption was ameliorated by liraglutide. Liraglutide treatment also reduced osteoclasts on the alveolar bone surface. These results highlight the beyond glucose-lowering effects of liraglutide on the treatment of periodontitis.
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http://dx.doi.org/10.1155/2020/8843310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695495PMC
October 2021

Impact of skeletal muscle mass on clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

Cardiovasc Interv Ther 2021 Oct 31;36(4):514-522. Epub 2020 Oct 31.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Low skeletal muscle mass is one of the components of sarcopenia. However, the prognostic impact of skeletal muscle mass on clinical outcomes in patients after transcatheter aortic valve replacement (TAVR) remains unclear. Therefore, we assessed the impact of skeletal muscle mass on future cardiovascular events in patients undergoing TAVR. We enrolled 71 consecutive patients who underwent TAVR for symptomatic severe aortic stenosis. We applied bilateral psoas muscles as an indicator of skeletal muscle mass. Psoas muscle volumes were measured from the origin of psoas at the level of the lumbar vertebrae to its insertion in the lesser trochanter on three-dimensional computed tomography datasets. Psoas muscle mass index (PMI) was calculated as psoas muscle volume/height (cm/m). According to the median value of PMIs (79.8 and 60.0 cm/m for men and women), the enrolled patients were divided into two groups. During the follow-up, 11 (31.4%) patients in low PMI group and 4 (11.1%) in high PMI group experienced major adverse cardiovascular events (MACE) defined as a composite of death from any cause, myocardial infarction, heart failure hospitalization, and stroke. The proportion of MACE-free survival was significantly lower in low PMI group (log-rank P = 0.033), mainly due to the difference of hospital readmission for congestive heart failure. On multivariate Cox proportional hazard analysis, PMI remained an independent negative predictor of MACE [hazard ratio 0.95 (95% confidence interval 0.92-0.98, P = 0.002)]. In conclusion, low skeletal muscle mass independently predicted MACE in patients undergoing TAVR.
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http://dx.doi.org/10.1007/s12928-020-00725-8DOI Listing
October 2021

Direct Comparison of Therapeutic Effects on Diabetic Polyneuropathy between Transplantation of Dental Pulp Stem Cells and Administration of Dental Pulp Stem Cell-Secreted Factors.

Int J Mol Sci 2020 Aug 23;21(17). Epub 2020 Aug 23.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya 464-8651, Japan.

Stem cell transplantation is a potential novel therapy for diabetic polyneuropathy. Dental pulp stem cells (DPSCs) are attractive stem cell sources because DPSCs can be isolated from extracted teeth and cryopreserved while retaining viability. In this study, we directly compared the efficacy of the transplantation of DPSCs and the administration of the secreted factors from DPSCs (DPSC-SFs) on diabetic polyneuropathy. Eight weeks after streptozotocin injection, DPSCs (1.0 × 10 cells/rat) or DPSC-SFs (1.0 mL/rat) were administered into the unilateral hindlimb skeletal muscles of diabetic Sprague-Dawley rats. DPSC transplantation and DPSC-SF administration did not affect blood glucose levels and body weights in the diabetic rats. Both DPSC transplantation and DPSC-SF administration significantly ameliorated sciatic nerve conduction velocity and sciatic nerve blood flow, accompanied by increases in muscle bundle size, vascular density in the skeletal muscles and intraepidermal nerve fiber density in the diabetic rats, while there was no difference between the results for DPSCs and DPSC-SFs. These results suggest that the efficacy of both DPSC transplantation and DPSC-SF administration for diabetic polyneuropathy four weeks after transplantation/administration was mainly due to the multiple secretomes secreted from transplanted DPSCs or directly injected DPSC-SFs in the early phase of transplantation/administration.
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http://dx.doi.org/10.3390/ijms21176064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503871PMC
August 2020

Transplantation of human dental pulp stem cells ameliorates diabetic polyneuropathy in streptozotocin-induced diabetic nude mice: the role of angiogenic and neurotrophic factors.

Stem Cell Res Ther 2020 06 16;11(1):236. Epub 2020 Jun 16.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, 464-8651, Japan.

Background: Dental pulp stem cells (DPSCs) have high proliferation and multi-differentiation capabilities that maintain their functionality after cryopreservation. In our previous study, we demonstrated that cryopreserved rat DPSCs improved diabetic polyneuropathy and that the efficacy of cryopreserved rat DPSCs was equivalent to that of freshly isolated rat DPSCs. The present study was conducted to evaluate whether transplantation of cryopreserved human DPSCs (hDPSCs) is also effective for the treatment of diabetic polyneuropathy.

Methods: hDPSCs were isolated from human impacted third molars being extracted for orthodontic reasons. Eight weeks after the induction of diabetes in nude mice, hDPSCs (1 × 10/limb) were unilaterally transplanted into the hindlimb skeletal muscle, and vehicle (saline) was injected into the opposite side as a control. The effects of hDPSCs were analyzed at 4 weeks after transplantation.

Results: hDPSC transplantation significantly ameliorated reduced sensory perception thresholds, delayed nerve conduction velocity, and decreased the blood flow to the sciatic nerve in diabetic mice 4 weeks post-transplantation. Cultured hDPSCs secreted the vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) proteins. A subset of the transplanted hDPSCs was localized around the muscle bundles and expressed the human VEGF and NGF genes at the transplanted site. The capillary/muscle bundle ratio was significantly increased on the hDPSC-transplanted side of the gastrocnemius muscles in diabetic mice. Neutralizing antibodies against VEGF and NGF negated the effects of hDPSC transplantation on the nerve conduction velocity in diabetic mice, suggesting that VEGF and NGF may play roles in the effects of hDPSC transplantation on diabetic polyneuropathy.

Conclusions: These results suggest that stem cell transplantation with hDPSCs may be efficacious in treating diabetic polyneuropathy via the angiogenic and neurotrophic mechanisms of hDPSC-secreted factors.
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http://dx.doi.org/10.1186/s13287-020-01758-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298811PMC
June 2020

Therapeutic potential for insulin on type 1 diabetes-associated periodontitis: Analysis of experimental periodontitis in streptozotocin-induced diabetic rats.

J Diabetes Investig 2020 Nov 28;11(6):1482-1489. Epub 2020 May 28.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Aims/introduction: The association between diabetes and periodontal disease is considered to be bidirectional. However, there is still controversy surrounding the relationship between periodontal disease and type 1 diabetes. We investigated whether insulin improves periodontitis without any local treatments for periodontitis under type 1 diabetes conditions using the ligature-induced experimental periodontitis model.

Materials And Methods: Type 1 diabetic rats were induced by streptozotocin injection. Experimental periodontitis was induced by ligature in normal and diabetic rats. Half of the diabetic rats were treated with insulin. Two weeks after the ligature, periodontitis was evaluated.

Results: Insulin treatment significantly improved inflammatory cell infiltration and inflammatory cytokine gene expression, leading to suppression of alveolar bone loss, in the periodontitis of diabetic rats. Insulin also suppressed the periodontitis-increased nitric oxide synthase-positive cells in periodontal tissue of the diabetic rats. Even without induction of periodontitis, diabetic rats showed decreased gingival blood flow and an increased number of nitric oxide synthase-positive cells in the gingiva and alveolar bone loss compared with normal rats, all of which were ameliorated by insulin treatment. We further confirmed that insulin directly suppressed lipopolysaccharide-induced inflammatory cytokine expressions in THP-1 cells.

Conclusions: There were abnormalities of periodontal tissue even without the induction of periodontitis in streptozotocin-induced diabetic rats. Insulin treatment significantly ameliorated periodontitis without local periodontitis treatment in diabetic rats. These data suggest the therapeutic impacts of insulin on periodontitis in type 1 diabetes.
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http://dx.doi.org/10.1111/jdi.13276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610127PMC
November 2020

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals.

Commun Biol 2019 8;2:115. Epub 2019 Apr 8.

23Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503 Japan.

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (<5 × 10) including eight novel loci. Of these, missense variants of and were predicted to be damaging to the function of these proteins; another five loci-, , , , and -are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, , is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.
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http://dx.doi.org/10.1038/s42003-019-0339-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453927PMC
April 2020

Conditioned media from dental pulp stem cells improved diabetic polyneuropathy through anti-inflammatory, neuroprotective and angiogenic actions: Cell-free regenerative medicine for diabetic polyneuropathy.

J Diabetes Investig 2019 Sep 23;10(5):1199-1208. Epub 2019 Apr 23.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Aims/introduction: Dental pulp stem cells (DPSCs) can be easily obtained from teeth for general orthodontic reasons. We have previously reported the therapeutic effects of DPSC transplantation for diabetic polyneuropathy. As abundant secretomes from DPSCs are considered to play a central role in the improvement of diabetic polyneuropathy, we investigated whether direct injection of DPSC-conditioned media (DPSC-CM) into hindlimb skeletal muscles ameliorates diabetic polyneuropathy in diabetic rats.

Materials And Methods: DPSCs were isolated from the dental pulp of Sprague-Dawley rats. Eight weeks after the induction of diabetes, DPSC-CM was injected into the unilateral hindlimb skeletal muscles in both normal and diabetic rats. The effects of DPSC-CM on diabetic polyneuropathy were assessed 4 weeks after DPSC-CM injection. To confirm the angiogenic effect of DPSC-CM, the effect of DPSC-CM on cultured human umbilical vascular endothelial cell proliferation was investigated.

Results: The administration of DPSC-CM into the hindlimb skeletal muscles significantly ameliorated sciatic motor/sensory nerve conduction velocity, sciatic nerve blood flow and intraepidermal nerve fiber density in the footpads of diabetic rats. We also showed that DPSC-CM injection significantly increased the capillary density of the skeletal muscles, and suppressed pro-inflammatory reactions in the sciatic nerves of diabetic rats. Furthermore, an in vitro study showed that DPSC-CM significantly increased the proliferation of umbilical vascular endothelial cells.

Conclusions: We showed that DPSC-CM injection into hindlimb skeletal muscles has a therapeutic effect on diabetic polyneuropathy through neuroprotective, angiogenic and anti-inflammatory actions. DPSC-CM could be a novel cell-free regenerative medicine treatment for diabetic polyneuropathy.
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http://dx.doi.org/10.1111/jdi.13045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717901PMC
September 2019

Chemerin promotes angiogenesis in vivo.

Physiol Rep 2018 Dec;6(24):e13962

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Chemerin acts as a chemotactic factor for leukocyte populations expressing the G protein-coupled receptor CMKLR1 (ChemR23). It is also an adipocytokine involved in obesity and metabolic syndromes. Previous studies have demonstrated that chemerin promotes angiogenesis in vitro, although the precise mechanism has not been elucidated. In this study, we have investigated whether chemerin regulates angiogenic processes and validated the associated mechanisms. In this study, chemerin stimulated angiogenesis in mice, which was demonstrated using Matrigel plug implantation assay, mouse corneal models of angiogenesis, and ex vivo rat aortic ring assay. To explore the mechanisms by which chemerin induced angiogenesis, we examined the effects of chemerin in human umbilical vein endothelium cells (HUVECs). Chemerin stimulated the differentiation of HUVECs into capillary-like structures, promoted the proliferation of HUVECs, and functioned as a chemoattractant in migration assays. Chemerin induced the phosphorylation of Akt and p42/44 extracellular signal-regulated kinase (ERK) in HUVECs and chemerin promotes angiogenesis via Akt and ERK. SiRNA against the chemerin receptor CMKLR1 but not that against another chemerin receptor, CCRL2, completely inhibited the chemerin-induced migration and angiogenesis of HUVECs, which indicates that chemerin promotes the migration and angiogenic activities of HUVECs mainly through CMKLR1.
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http://dx.doi.org/10.14814/phy2.13962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306368PMC
December 2018

Interethnic analyses of blood pressure loci in populations of East Asian and European descent.

Nat Commun 2018 11 28;9(1):5052. Epub 2018 Nov 28.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
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http://dx.doi.org/10.1038/s41467-018-07345-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261994PMC
November 2018

Clinical Characteristics of Nonobese Patients with Acute Coronary Syndrome and Increased Epicardial Fat Volume.

J Atheroscler Thromb 2018 Oct 1;25(10):1044-1052. Epub 2018 Feb 1.

Department of Cardiology, Nagoya University Graduate School of Medicine.

Aim: Increased epicardial fat volume (EFV) is an independent risk factor for acute coronary syndrome (ACS). Although EFV increases with body mass index (BMI), some ACS patients have an increased EFV but normal BMI. We here investigated the clinical characteristics of nonobese ACS patients with an increased EFV.

Methods: A total of 197 Japanese patients hospitalized for ACS was evaluated for EFV, abdominal visceral fat area (VFA), and lipid and glucose profiles. Control subjects comprised 141 individuals who were suspected of having ACS but whose coronary computed tomography findings were normal.

Results: EFV was increased in ACS patients compared with control subjects (120±47 versus 95±45 mL, P<0.01). ACS patients were divided into four groups based on average EFV (120 mL) and a BMI obesity cutoff of 25 kg/m. For the 30 nonobese ACS patients with an above-average EFV, EFV was positively correlated with VFA (r=0.23, P=0.031). These individuals were significantly older (74±10 years) and tended to have a higher homeostasis model assessment-insulin resistance value (5.5±3.8) compared with other ACS patients. Among nonobese study subjects, EFV was independently associated with ACS (odds ratio=2.01, P=0.021) and correlated with abdominal circumference (r=0.26, P=0.017).

Conclusion: Nonobese ACS patients with an increased EFV were elderly and tended to manifest insulin resistance. Measurement of EFV may prove informative for evaluation of ACS risk among elderly nonobese individuals with an increased abdominal girth.
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http://dx.doi.org/10.5551/jat.42663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193182PMC
October 2018

Transplantation of dental pulp stem cells improves long-term diabetic polyneuropathy together with improvement of nerve morphometrical evaluation.

Stem Cell Res Ther 2017 Dec 13;8(1):279. Epub 2017 Dec 13.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.

Background: Although previous reports have revealed the therapeutic potential of stem cell transplantation in diabetic polyneuropathy, the effects of cell transplantation on long-term diabetic polyneuropathy have not been investigated. In this study, we investigated whether the transplantation of dental pulp stem cells (DPSCs) ameliorated long-term diabetic polyneuropathy in streptozotocin (STZ)-induced diabetic rats.

Methods: Forty-eight weeks after STZ injection, we transplanted DPSCs into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation (i.e., 52 weeks after STZ injection) the effects of DPSC transplantation on diabetic polyneuropathy were assessed.

Results: STZ-induced diabetic rats showed significant reductions in the sciatic motor/sensory nerve conduction velocity, increases in the current perception threshold, and decreases in capillary density in skeletal muscles and intra-epidermal nerve fiber density compared with normal rats, all of which were ameliorated by DPSC transplantation. Furthermore, sural nerve morphometrical analysis revealed that the transplantation of DPSCs significantly increased the myelin thickness and area. DPSC-conditioned media promoted the neurite outgrowth of dorsal root ganglion neurons and increased the viability and myelin-related protein expression of Schwann cells.

Conclusions: These results indicated that the transplantation of DPSCs contributed to the neurophysiological and neuropathological recovery from a long duration of diabetic polyneuropathy.
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http://dx.doi.org/10.1186/s13287-017-0729-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729514PMC
December 2017

Impact of Coronary Stent Fracture on Restenotic Neointimal Tissue Characterization After Drug-Eluting Stent Implantation.

Int Heart J 2017 Dec 17;58(6):861-867. Epub 2017 Nov 17.

Department of Cardiology, Nagoya University Graduate School of Medicine.

Although drug-eluting stents (DESs) reduce the rates of in-stent restenosis (ISR) and subsequent target lesion revascularization, stent fracture (SF) after DES implantation has become an important concern because of its potential association with restenosis and stent thrombosis. We aimed to assess the pathogenic impact of SF on in-stent restenotic neointimal tissue components after DES implantation. We analyzed 43 consecutive patients (14 with SF and 29 without SF) with ISR requiring revascularization after DES implantation between January 2008 and March 2014. For evaluation of in-stent tissue components, integrated backscatter intravascular ultrasound (IB-IVUS) was performed. SF was defined as complete or partial separation of stent segments observed using plain fluoroscopy or intravascular ultrasound. On volumetric IB-IVUS analyses, patients with SF had a significantly higher percentage of lipid tissue volume within the neointima and a significantly lower percentage of fibrous tissue volume than those without (37.3 ± 18.9% versus 24.9 ± 12.4%, P = 0.02, and 61.2 ± 18.3 versus 72.6 ± 12.1%, P = 0.04, respectively). Moreover, SF was positively correlated with the percentage of lipid volume on multiple linear regression analysis after adjustment for confounding factors (β = 0.36, P = 0.03). The interval from stent implantation was similar in both groups (47.0 ± 28.7 versus 37.7 ± 33.3 months; P = 0.39). In conclusion, SF is associated with larger lipid tissue volume within the neointima after DES placement, suggesting a contribution to the development of neoatherosclerosis and vulnerable neointima. Thus SF might lead to future adverse coronary events.
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http://dx.doi.org/10.1536/ihj.16-571DOI Listing
December 2017

Role of poly(ADP-ribose) polymerase activation in the pathogenesis of periodontitis in diabetes.

J Clin Periodontol 2017 Oct 30;44(10):971-980. Epub 2017 Aug 30.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Aim: The aetiology of progressive periodontitis in diabetes has not yet been elucidated. We previously demonstrated that nitrosative stress is increased in diabetic rats with periodontitis. Nitrosative stress induces poly(ADP-ribose) polymerase (PARP) activation. Here, we demonstrated the involvement of PARP activation in diabetic periodontitis and detailed the therapeutic effects of PARP inhibitor.

Materials And Methods: Experimental periodontitis was induced by placing a nylon thread ligature. Half of the normal and diabetic rats received the PARP inhibitor, 1,5-isoquinolinediol, for 2 weeks. Gingival PARP activation was detected by immunostaining for poly(ADP-ribose). Periodontitis was evaluated by gingival inflammatory cell infiltration, inflammatory gene expressions and micro-CT analyses.

Results: Although both periodontitis and the presence of diabetes increased PARP activation in the gingiva, diabetic rats with periodontitis had the highest activation of PARP. Diabetic rats with periodontitis also showed significant increases in monocyte/macrophage invasion into the gingiva, inflammatory gene expressions, nitrotyrosine-positive cells in the gingiva and alveolar bone loss, all of which were suppressed by treatment with the PARP inhibitor.

Conclusions: These results indicate the involvement of PARP activation in the pathogenesis and aggravation of periodontal disease in diabetes and suggest the therapeutic potential of PARP inhibition for treating periodontal disease, especially in patients with diabetes.
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http://dx.doi.org/10.1111/jcpe.12758DOI Listing
October 2017

Efficacy of a Self-Assembling Peptide Hydrogel, SPG-178-Gel, for Bone Regeneration and Three-Dimensional Osteogenic Induction of Dental Pulp Stem Cells.

Tissue Eng Part A 2017 12 24;23(23-24):1394-1402. Epub 2017 Jul 24.

1 Division of Medical-Dental Regenerative Medicine, Center for Advanced Oral Science, Graduate of Dentistry, Aichi Gakuin University , Nagoya, Japan .

The aim of this study was to assess the efficacy of a self-assembling peptide hydrogel as a scaffold for bone regeneration. We used a neutral and injectable self-assembling peptide hydrogel, SPG-178-Gel. Bone defects (5 mm in diameter) in rat calvarial bones were filled with a mixture of alpha-modified Eagle's medium and peptide hydrogel. Three weeks after surgery, soft X-ray and microcomputed tomography (micro-CT) images of the gel-treated bones showed new bone formations in the periphery and in central areas of the defects. Next, we evaluated the three-dimensional osteogenic induction of dental pulp stem cells (DPSCs), a type of mesenchymal stem cell, in SPG-178-Gel. We first confirmed that the osteogenic differentiation of DPSCs was significantly promoted by osteogenic induction medium containing recombinant human bone morphogenetic protein-4 (rhBMP-4) in a two-dimensional cell culture. Then, we verified DPSC proliferation and osteogenic differentiation in a three-dimensional cell culture using SPG-178-Gel. The gene expression levels of osteopontin, osteocalcin, and collagen type I were significantly increased when DPSCs were cultured in SPG-178-Gel with the osteogenic induction medium. Micro-CT observations showed the formation of widespread calcium deposition. In conclusion, SPG-178-Gel was adequately effective as a scaffold and can be a suitable tool for bone formation in vivo and in vitro. These findings suggest that the self-assembling peptide hydrogel, SPG-178-Gel, could be a promising tool for bone tissue engineering.
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http://dx.doi.org/10.1089/ten.TEA.2017.0025DOI Listing
December 2017

Epigenome-wide association of myocardial infarction with DNA methylation sites at loci related to cardiovascular disease.

Clin Epigenetics 2017 15;9:54. Epub 2017 May 15.

Department of Genome Science, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, 464-8651 Japan.

Background: Development of cardiovascular disease (CVD), including coronary artery disease, arrhythmia, and ischemic stroke, depends on environmental and genetic factors. To investigate the epigenetic basis of myocardial infarction (MI), we performed an epigenome-wide association study for this condition in elderly Japanese subjects. A total of 192 case subjects with MI and 192 control subjects were recruited from hospital attendees and the general population, respectively. Genome-wide DNA methylation (DNAm) profiles for DNA isolated from whole blood were obtained by analysis with an Infinium HumanMethylation450 BeadChip. The relation of DNAm sites found to be significantly associated with MI to nearby single nucleotide polymorphisms (SNPs) previously shown to be associated with CVD was assessed in the control group.

Findings: Three DNAm sites (cg06642177, cg07786668, cg17218495) showed genome-wide significant associations with MI ( = 4.33 × 10, 3.96 × 10, and 3.77 × 10, respectively). Two of these sites (cg07786668, cg17218495) still showed such associations after adjustment for classical risk factors of MI ( = 1.04 × 10 and 6.60 × 10, respectively). The DNAm sites cg07786668 and cg17218495 are located in (zinc finger homeobox 3) and (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4) genes, respectively. SNPs in or that were previously found to be associated with CVD were not significantly associated with these DNAm sites in our control subjects.

Conclusions: We identified two DNAm sites-cg07786668 in and cg17218495 in - that are independently and significantly associated with MI. Our results suggest that the development of MI might be influenced by changes in DNAm at these sites via a pathway that differs from that affected by CVD-associated SNPs in these genes. The Kita-Nagoya Genomic Epidemiology (KING) study, which was the source of control samples in the present study, was registered in ClinicalTrials.gov (NCT00262691) on 6 December 2005.
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http://dx.doi.org/10.1186/s13148-017-0353-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432989PMC
March 2018

Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease.

PLoS One 2017 17;12(4):e0175649. Epub 2017 Apr 17.

Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: The genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested.

Methods And Results: We genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37-6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16-21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87-16.77; p = 0.076).

Conclusions: The RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175649PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393571PMC
May 2017

Association between plaque characteristics and the amount of debris captured by a filter-type distal protection device in patients with acute coronary syndrome.

Atherosclerosis 2017 03 8;258:72-78. Epub 2017 Feb 8.

Department of Cardiology, Nagoya Graduate School of Medicine, Nagoya, Japan.

Background And Aims: Disruption of atherosclerotic plaque and distal embolism often cause peri-procedural myocardial injury during percutaneous coronary intervention (PCI). In the present study, we evaluate the association between the characteristics of the target lesion and the amount of debris captured by the filter-type distal protection device.

Methods: We enrolled 120 consecutive patients with acute coronary syndrome, who underwent coronary stent implantation with a filter-type distal protection device after integrated backscatter intravascular ultrasound (IB-IVUS) analysis. The amount of debris captured by the protection filter was measured through microscopic evaluation.

Results: The lipid and fibrous volume evaluated with IB-IVUS was significantly correlated with the amount of the captured debris (r = 0.657, p < 0.01), (r = 0.322, p < 0.01). The lipid plaque fraction showed a positive correlation (r = 0.335, p < 0.01), while the fibrous plaque fraction was found to be inversely correlated (r = -0.375, p < 0.01) with the amount of captured debris. Multivariate regression analysis showed that lipid volume correlated independently with the amount of captured debris.

Conclusion: The volume of the lipid-rich plaque was associated with the amount of procedure-related debris released and captured by the filter-type distal protection device.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.02.001DOI Listing
March 2017

Clinical characteristics of patients hospitalized for acute heart failure according to hospital arrival timing.

J Cardiol 2016 11 20;68(5):379-383. Epub 2016 Mar 20.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Whether clinical characteristics and outcomes in patients suffering acute heart failure (AHF) vary according to the timing of hospital arrival is unclear. We aimed to evaluate differences between subjects presenting in the daytime and nighttime.

Methods: A total of 679 patients with AHF were examined, classified into the two groups from the viewpoint of hospital arrival period into daytime (n=370; 8am-6pm) and nighttime (n=309; 6pm-8am).

Results: The prevalence of malnutrition and longer pre-hospital delay (≥48h) were greater, whereas a previous history of myocardial infarction, proportion of arrival by ambulance, and the frequency of New York Heart Association class IV symptoms, as well as systolic and diastolic blood pressure, and heart rate were lower in subjects presenting in the daytime. Patients with malnutrition defined as 5≥of the Controlling Nutrition Status scores demonstrate a longer pre-hospital delay compared to those without (34.2% vs. 19.9%, p<0.05). There was no significant difference in the 30-day outcomes but length of stay was significantly longer in subjects presenting in the daytime than in the nighttime. Multivariable logistic regression analysis revealed that systolic blood pressure, malnutrition, and chronic kidney disease were significantly related to prolonged length of stay.

Conclusions: Our present results suggest that patients with AHF who present in the daytime may have higher rate of malnutrition status and lower systolic blood pressure compared to those presenting in the nighttime.
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http://dx.doi.org/10.1016/j.jjcc.2016.02.018DOI Listing
November 2016

Increased expression of the adipocytokine omentin in the epicardial adipose tissue of coronary artery disease patients.

Atherosclerosis 2016 08 6;251:299-304. Epub 2016 Jul 6.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background And Aims: Omentin, an adipocytokine secreted by visceral adipose tissue, protects against obesity-linked cardiovascular complications. However, little is known about its role in epicardial adipose tissue (EAT) and coronary artery disease (CAD). We investigated the expression of omentin in EAT from CAD subjects.

Methods: EAT, subcutaneous adipose tissue (SCAT), and plasma samples were collected from CAD (n = 15; 23.3 ± 3.1 kg/m(2)) and non-CAD patients (n = 10; 20.8 ± 3.9 kg/m(2)). Omentin mRNA expression was measured using real-time PCR, while plasma concentrations were measured using an ELISA. EAT volume was determined with 64-slice computed tomography.

Results: Omentin expression in EAT and EAT volume were higher in CAD patients compared with controls (2.49 ± 2.6 vs. 0.85 ± 0.3, p = 0.002 and 113 ± 58 ml vs. 92.4 ± 30 ml, p = 0.045, respectively). Omentin expression in SCAT was similar between CAD and control patients (1.37 ± 0.84 vs. 1.07 ± 0.55, p = 0.267). Plasma omentin levels were lower in CAD patients compared with controls (343 ± 158 ng/ml vs. 751 ± 579 ng/ml, p = 0.025), and were negatively associated with the expression of omentin in EAT, in patients with CAD (β = -0.78, p = 0.049). On the other hand, there was no association between omentin in EAT and clinical variables in patients with non-CAD.

Conclusions: Omentin expression increases in the EAT of non-obese CAD patients, despite a decrease in plasma levels, suggesting that omentin may play a role in the pathogenesis of CAD.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.07.003DOI Listing
August 2016

Transplantation of dental pulp stem cells suppressed inflammation in sciatic nerves by promoting macrophage polarization towards anti-inflammation phenotypes and ameliorated diabetic polyneuropathy.

J Diabetes Investig 2016 Jul 31;7(4):485-96. Epub 2015 Dec 31.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Aims/introduction: Dental pulp stem cells (DPSCs) are thought to be an attractive candidate for cell therapy. We recently reported that the transplantation of DPSCs increased nerve conduction velocity and nerve blood flow in diabetic rats. In the present study, we investigated the immunomodulatory effects of DPSC transplantation on diabetic peripheral nerves.

Materials And Methods: DPSCs were isolated from the dental pulp of Sprague-Dawley rats and expanded in culture. Eight weeks after the streptozotocin injection, DPSCs were transplanted into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation, neurophysiological measurements, inflammatory gene expressions and the number of CD68-positive cells in sciatic nerves were assessed. To confirm the immunomodulatory effects of DPSCs, the effects of DPSC-conditioned media on lipopolysaccharide-stimulated murine macrophage RAW264.7 cells were investigated.

Results: Diabetic rats showed significant delays in sciatic nerve conduction velocities and decreased sciatic nerve blood flow, all of which were ameliorated by DPSC transplantation. The number of CD68-positive monocytes/macrophages and the gene expressions of M1 macrophage-expressed cytokines, tumor necrosis factor-α and interleukin-1β, were increased in the sciatic nerves of the diabetic rats. DPSC transplantation significantly decreased monocytes/macrophages and tumor necrosis factor-α messenger ribonucleic acid expression, and increased the gene expression of the M2 macrophage marker, CD206, in the sciatic nerves of the diabetic rats. The in vitro study showed that DPSC-conditioned media significantly increased the gene expressions of interleukin-10 and CD206 in lipopolysaccharide-stimulated RAW264.7 cells.

Conclusions: These results suggest that DPSC transplantation promoted macrophages polarization towards anti-inflammatory M2 phenotypes, which might be one of the therapeutic mechanisms for diabetic polyneuropathy.
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http://dx.doi.org/10.1111/jdi.12452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931198PMC
July 2016

Anti-inflammatory role of glucose-dependent insulinotropic polypeptide in periodontitis.

J Diabetes Investig 2016 Jul 7;7(4):497-505. Epub 2016 Jan 7.

Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.

Aims/introduction: The involvement of glucose-dependent insulinotropic polypeptide (GIP) on inflammation was explored in atherosclerosis and adipose tissue. Periodontal disease is a chronic inflammatory disease, and is considered one of the diabetic complications. In the present study, to examine the effect of GIP on periodontitis, we induced experimental periodontitis in glucose-dependent insulinotropic polypeptide receptor-knockout mice (GIPRKO). We also investigated the anti-inflammatory effect of GIP in a culture system.

Materials And Methods: Experimental periodontitis was induced by ligature wire in GIPRKO and C57BL/C mice. Two weeks after the ligature, immunohistological evaluation and inflammatory messenger ribonucleic acid expression in the gingiva was examined. To elucidate the role of GIP in inflammation, the effects of GIP on lipopolysaccharide-induced gene expressions in THP-1 cells were evaluated.

Results: Periodontitis increased inflammatory cell infiltration, macrophage accumulation and tumor necrosis factor-α and nitric oxide synthase gene expressions in the gingiva. Periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue. Mac-1-positive macrophages and the inflammatory gene expressions were significantly increased in periodontitis in GIPRKO compared with C57BL/C mice periodontitis. Immunohistochemical staining confirmed that GIP receptors were expressed in residual and infiltrated Mac-1-positive macrophages. The in vitro study showed that GIP suppressed lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide synthase gene expression in a dose-dependent manner. Furthermore, the inhibitory effect of GIP on lipopolysaccharide-induced inflammatory gene expressions was at least partially through cyclic adenosine monophosphate/protein kinase A pathway.

Conclusions: These results suggest the beneficial effects of GIP on periodontal disease. In diabetic patients, GIP is expected to have a direct anti-inflammatory effect on periodontitis in addition to its glucose-lowering effect.
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http://dx.doi.org/10.1111/jdi.12450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931199PMC
July 2016

Reverse association of omega-3/omega-6 polyunsaturated fatty acids ratios with carotid atherosclerosis in patients on hemodialysis.

Atherosclerosis 2016 06 1;249:65-9. Epub 2016 Apr 1.

Cardiolovascular Center, Nagoya Kyoritsu Hospital, Nagoya, Japan.

Background And Aims: Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are widely recognized to have beneficial effects against cardiovascular disease. We investigated the association of n-3 PUFAs levels with carotid atherosclerosis in patients on hemodialysis (HD), who are at high risk for cardiovascular events.

Methods: Carotid ultra-sound was performed in a total of 461 patients on HD (male 67%, age 67 ± 12years, diabetes rate 46%). Intima-media thickness (IMT) and the plaque score (PS) in carotid arteries were measured. Carotid atherosclerosis was defined as IMT >1.2 mm and/or PS > 5.0. The levels of n-6 PUFAs [dihomo-gamma-linolenic acid (DHLA) and arachidonic acid (AA)] and n-3 PUFAs [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] were also measured prior to carotid ultra-sound.

Results: Carotid atherosclerosis was observed in 94 patients (20.4%). Individual PUFAs levels were comparable between patients with and without carotid atherosclerosis. However, the ratio of EPA/AA and that of n-3/n-6 PUFAs were significantly lower in patients with carotid atherosclerosis compared to those without (median 0.36 vs. 0.41, p = 0.031 and 0.85 vs. 0.93, p = 0.041, respectively]. After adjustment for other confounders, the ratio of EPA/AA (OR 0.30, 95% CI 0.12-0.70, p = 0.0055) and the ratio of n-3/n-6 PUFAs (OR 0.45, 95% CI 0.25-0.80, p = 0.0066) showed an independent reverse association with carotid atherosclerosis. In addition, the area under receiver-operating characteristic curves for carotid atherosclerosis was significantly greater in an established risk model with EPA/AA and n-3/n-6 ratios than in the established risk model alone.

Conclusions: These data suggest that low ratios of both EPA/AA ratio and n-3/n-6 PUFAs were closely associated with carotid atherosclerosis in patients on HD.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.03.037DOI Listing
June 2016

Oxidative C-H Activation Approach to Pyridone and Isoquinolone through an Iron-Catalyzed Coupling of Amides with Alkynes.

Chem Asian J 2016 Feb 4;11(3):380-4. Epub 2015 Nov 4.

Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

An iron catalyst combined with a mild organic oxidant promotes both C-H bond cleavage and C-N bond formation, and forms 2-pyridones and isoquinolones from an alkene- or arylamide and an internal alkyne, respectively. An unsymmetrical alkyne gives the pyridone derivative with high regioselectivity, this could be due to the sensitivity of the reaction to steric effects because of the compact size of iron.
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http://dx.doi.org/10.1002/asia.201501095DOI Listing
February 2016
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