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1.  Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes 
Nature medicine  2013;19(11):1496-1504.
The protective role of Sirt1 in renal damage was investigated. Sirt1 in proximal tubules (PT) was downregulated before albuminuria occurred in streptozotocin-induced or obese-type (db/db) diabetic mice. PT-specific Sirt1 transgenic (TG) and knockout (KO) mice showed prevention and aggravation of the glomerular changes occurring in diabetes, respectively, and non-diabetic KO mice exhibited albuminuria, suggesting that Sirt1 in PT affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by Sirt1-mediated epigenetic regulation in podocytes contributed to albuminuria. These phenomena were not observed in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PT to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the auto-fluorescence of photoactivatable NMN, and injection of fluorescence-labeled NMN. In human subjects with diabetes, Sirt1 and Claudin-1 levels were correlated with proteinuria level. Sirt1 in PT protects against albuminuria in diabetes through maintaining NMN concentrations around glomeruli and controlling podocyte function.
PMCID: PMC4041199  PMID: 24141423
2.  Effect of single tablet of fixed-dose amlodipine and atorvastatin on blood pressure/lipid control, oxidative stress, and medication adherence in type 2 diabetic patients 
Oxidized low-density lipoprotein (LDL) plays central roles in the formation and progression of atherosclerotic lesions. Malondialdehyde (MDA)-modified LDL (MDA-LDL) is speculated to be generated as a result of oxidative stress in the human body. Because both amlodipine and atorvastatin have been reported to reduce oxidative stress, it is expected that both drugs would have a favorable influence to reduce oxidative stress.
The objective of this study was to investigate the effects of a single pill of amlodipine (5 mg)/atorvastatin (10 mg) on oxidative stress, blood pressure/lipid control and adherence to medication in patients with type 2 diabetes.
This combination tablet was administered to 29 patients (16 male), and MDA-LDL, blood pressure, lipid profile, renal/liver function, CPK, hs-CRP, adiponectin, BNP, and HbA1c were measured at baseline, 6, and 12 months, and baPWV and mean IMT were measured at baseline and 12 months. Medication adherence was examined using a questionnaire at 6 months.
MDA-LDL was decreased significantly. LDL-C, TG, and Cr were significantly decreased at 6 and 12 months compared with baseline. eGFR was increased at 6 months, and urinary albumin/creatinine ratio was decreased at 12 months. BNP was decreased at 6 and 12 months, and adiponectin was increased at 12 months. Both mean IMT and baPWV were significantly decreased. The results of the questionnaire showed that 93% of patients were satisfied with this medication. No severe adverse event was observed.
This combination tablet controlled both hypertension and dyslipidemia well in type 2 diabetic patients. The deceases in mean IMT and baPWV might suggest the improvement of atherosclerosis by this medication, which could be caused by the reduction of oxidative stress measured by MDA-LDL. In addition, this medication is expected to improve medication adherence.
PMCID: PMC4032353  PMID: 24860622
Malondialdehyde-modified low-density lipoprotein; Oxidative stress; Amlodipine; Atorvastatin; Diabetes mellitus; Hypertension; Dyslipidemia; Atherosclerosis; Medication adherence; Combination tablet
3.  KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria 
The Journal of Clinical Investigation  2014;124(6):2523-2537.
The transcription factor Kruppel-like factor 4 (KLF4) has the ability, along with other factors, to reprogram somatic cells into induced pluripotent stem (iPS) cells. Here, we determined that KLF4 is expressed in kidney glomerular podocytes and is decreased in both animal models and humans exhibiting a proteinuric. Transient restoration of KLF4 expression in podocytes of diseased glomeruli in vivo, either by gene transfer or transgenic expression, resulted in a sustained increase in nephrin expression and a decrease in albuminuria. In mice harboring podocyte-specific deletion of Klf4, adriamycin-induced proteinuria was substantially exacerbated, although these animals displayed minimal phenotypical changes prior to adriamycin administration. KLF4 overexpression in cultured human podocytes increased expression of nephrin and other epithelial markers and reduced mesenchymal gene expression. DNA methylation profiling and bisulfite genomic sequencing revealed that KLF4 expression reduced methylation at the nephrin promoter and the promoters of other epithelial markers; however, methylation was increased at the promoters of genes encoding mesenchymal markers, suggesting selective epigenetic regulation of podocyte gene expression. Together, these results suggest that KLF4 epigenetically modulates podocyte phenotype and function and that the podocyte epigenome can be targeted for direct intervention and reduction of proteinuria.
PMCID: PMC4089466  PMID: 24812666
5.  Ghrelin Protects against Renal Damages Induced by Angiotensin-II via an Antioxidative Stress Mechanism in Mice 
PLoS ONE  2014;9(4):e94373.
We explored the renal protective effects by a gut peptide, Ghrelin. Daily peritoneal injection with Ghrelin ameliorated renal damages in continuously angiotensin II (AngII)-infused C57BL/6 mice as assessed by urinary excretion of protein and renal tubular markers. AngII-induced increase in reactive oxygen species (ROS) levels and senescent changes were attenuated by Ghrelin. Ghrelin also inhibited AngII-induced upregulations of transforming growth factor-β (TGF-β) and plasminogen activator inhibitor-1 (PAI-1), ameliorating renal fibrotic changes. These effects were accompanied by concomitant increase in mitochondria uncoupling protein, UCP2 as well as in a key regulator of mitochondria biosynthesis, PGC1α. In renal proximal cell line, HK-2 cells, Ghrelin reduced mitochondria membrane potential and mitochondria-derived ROS. The transfection of UCP2 siRNA abolished the decrease in mitochondria-derived ROS by Ghrelin. Ghrelin ameliorated AngII-induced renal tubular cell senescent changes and AngII-induced TGF-β and PAI-1 expressions. Finally, Ghrelin receptor, growth hormone secretagogue receptor (GHSR)-null mice exhibited an increase in tubular damages, renal ROS levels, renal senescent changes and fibrosis complicated with renal dysfunction. GHSR-null mice harbored elongated mitochondria in the proximal tubules. In conclusion, Ghrelin suppressed AngII-induced renal damages through its UCP2 dependent anti-oxidative stress effect and mitochondria maintenance. Ghrelin/GHSR pathway played an important role in the maintenance of ROS levels in the kidney.
PMCID: PMC3991592  PMID: 24747517
7.  miR-34c attenuates epithelial-mesenchymal transition and kidney fibrosis with ureteral obstruction 
Scientific Reports  2014;4:4578.
micro RNAs (miRNAs) are small non-coding RNAs that act as posttranscriptional repressors by binding to the 3′-UTR of target mRNAs. On the other hand, mesenchymal-epithelial transition (EMT) and kidney fibrosis is a pathological process of chronic kidney disease (CKD), and its relationship to miRNAs is becoming recognized as a potential target for CKD therapies. To find new miRNAs involved in EMT, we examined miRNA expression in experimental models of EMT and renal epithelialization using microarray, and found that miR-34c attenuates EMT induced by TGF-β in a mouse tubular cell line. To confirm the effects of miR-34c in vivo, we administered the precursor of miR-34c to mice with unilateral ureteral obstruction, and miR-34c decreased kidney fibrosis area and the expression of connective tissue growth factor, α-SMA, collagen type 1, collagen type 3 and fibronectin. In conclusion, our study showed miR-34c attenuates EMT and kidney fibrosis of mice with ureteral obstruction.
PMCID: PMC3974136  PMID: 24694752
8.  Plasma Antimicrobial Peptide LL-37 Level Is Inversely Associated with HDL Cholesterol Level in Patients with Type 2 Diabetes Mellitus 
Introduction. Relation between atherosclerosis and innate immunity has attracted attention. As the antimicrobial peptide, LL-37, could have an important role in atherosclerosis, we supposed that there could be a meaningful association of plasma LL-37 level with risk factors for cardiovascular disease in subjects with type 2 diabetes mellitus. Materials and Methods. We evaluated plasma LL-37 level and other clinical markers in Japanese subjects with type 2 diabetes mellitus (n = 133, 115 men and 18 women; age 64.7 ± 11.5 years; HbA1c 8.1 ± 1.6%). Plasma level of LL-37 was measured by ELISA. Results. Mean plasma LL-37 level was 71.2 ± 22.3 ng/mL. Plasma LL-37 level showed significant correlations with HDL cholesterol (r = −0.450, P < 0.01), triglyceride (r = 0.445, P < 0.01), and high sensitive C-reactive protein (r = 0.316, P < 0.01) but no significant correlation with age, body mass index, HbA1c, estimated glomerular filtration rate, 25-hydroxyvitamin D, or vitamin D binding protein. Multiple linear regression analysis showed significant correlations of plasma LL-37 level with HDL cholesterol (β = −0.411, P < 0.01) and high sensitive C-reactive protein (β = 0.193, P < 0.05). Conclusion. Plasma LL-37 level was positively correlated with inflammatory markers and negatively correlated with HDL cholesterol in patients with type 2 diabetes mellitus.
PMCID: PMC3984791  PMID: 24790601
9.  Basal-Supported Oral Therapy with Sitagliptin Counteracts Rebound Hyperglycemia Caused by GLP-1 Tachyphylaxis 
Introduction. Treatment with a glucagon-like peptide 1 (GLP-1) analog fails in some patients due to rebound hyperglycemia caused by tachyphylaxis (GLP-1 tachyphylaxis). We investigated the efficacy of basal-supported oral therapy (BOT) with insulin glargine and sitagliptin for counteracting GLP-1 tachyphylaxis. Materials and Methods. The subjects were 12 men and 3 women aged 59.9 ± 10.0 years who had been treated with GLP-1 analogs. All of them had developed rebound hyperglycemia caused by GLP-1 tachyphylaxis. Their GLP-1 analog-based therapy was switched to BOT with insulin glargine plus sitagliptin and other medications. The primary outcomes were whether switching of therapy was associated with a change of hemoglobin A1c (HbA1c) and whether weight gain occurred. Results. Baseline HbA1c was 8.0 ± 0.9%. It decreased to 7.3 ± 0.9% at 3 months after switching (P < 0.01) and to 7.2 ± 0.9% at 4 months (P < 0.05). Weight gain was 1.1 kg after 1 month (P < 0.01) and 2.3 kg after 5 months (P < 0.01). Conclusion. Switching to BOT with insulin glargine and sitagliptin improved glycemic control. The significant decrease of HbA1c demonstrated that this combination can counteract deterioration of glycemic control due to rebound hyperglycemia secondary to GLP-1 tachyphylaxis. However, weight gain remains a problem.
PMCID: PMC3967600  PMID: 24738001
10.  Pancreatic body adenocarcinoma with neuroendocrine tumor characteristics: A case report 
Oncology Letters  2014;7(4):1049-1052.
A 61-year-old female with pancreatic body cancer underwent a distal pancreatectomy. The tumor was a moderately- to poorly-differentiated adenocarcinoma. Tumor growth filled the dilated main pancreatic duct (MPD) and infiltrated the surrounding area. Six months later, metastases to the left diaphragm and MPD of the remnant pancreatic head were detected. Chemoradiotherapy was administered, but the patient succumbed 22 months after surgery. An autopsy demonstrated that a moderately- to poorly-differentiated adenocarcinoma had arisen from the pancreatic head and infiltrated the duodenum and bile duct. Huge liver metastases and multiple peritoneal disseminations were also present. Microscopically, a portion of the tumor had a pseudo-rosette appearance in the adenocarcinoma component, while another section showed characteristics of a neuroendocrine tumor (NET) immunohistochemically. The original surgically-resected tumor also showed NET characteristics immunohistochemically. It is therefore necessary to search for NET components in pancreatic cancer with atypical growth and metastases, even when adenocarcinoma has been diagnosed histologically.
PMCID: PMC3961464  PMID: 24944667
pancreatic adenocarcinoma; neuroendocrine tumor; immunohistochemistry
11.  The Role of Individual Domains and the Significance of Shedding of ATP6AP2/(pro)renin Receptor in Vacuolar H+-ATPase Biogenesis 
PLoS ONE  2013;8(11):e78603.
The ATPase 6 accessory protein 2 (ATP6AP2)/(pro)renin receptor (PRR) is essential for the biogenesis of active vacuolar H+-ATPase (V-ATPase). Genetic deletion of ATP6AP2/PRR causes V-ATPase dysfunction and compromises vesicular acidification. Here, we characterized the domains of ATP6AP2/PRR involved in active V-ATPase biogenesis. Three forms of ATP6AP2/PRR were found intracellularly: full-length protein and the N- and C-terminal fragments of furin cleavage products, with the N-terminal fragment secreted extracellularly. Genetic deletion of ATP6AP2/PRR did not affect the protein stability of V-ATPase subunits. The extracellular domain (ECD) and transmembrane domain (TM) of ATP6AP2/PRR were indispensable for the biogenesis of active V-ATPase. A deletion mutant of ATP6AP2/PRR, which lacks exon 4-encoded amino acids inside the ECD (Δ4M) and causes X-linked mental retardation Hedera type (MRXSH) and X-linked parkinsonism with spasticity (XPDS) in humans, was defective as a V-ATPase-associated protein. Prorenin had no effect on the biogenesis of active V-ATPase. The cleavage of ATP6AP2/PRR by furin seemed also dispensable for the biogenesis of active V-ATPase. We conclude that the N-terminal ECD of ATP6AP2/PRR, which is also involved in binding to prorenin or renin, is required for the biogenesis of active V-ATPase. The V-ATPase assembly occurs prior to its delivery to the trans-Golgi network and hence shedding of ATP6AP2/PRR would not affect the biogenesis of active V-ATPase.
PMCID: PMC3817224  PMID: 24223829
12.  C-Reactive Protein, High-Molecular-Weight Adiponectin and Development of Metabolic Syndrome in the Japanese General Population: A Longitudinal Cohort Study 
PLoS ONE  2013;8(9):e73430.
To clarify predictive values of C-reactive protein (CRP) and high-molecular-weight (HMW) adiponectin for development of metabolic syndrome.
Research Design and Methods
We conducted a prospective cohort study of Japanese workers who had participated in an annual health checkup in 2007 and 2011. A total of 750 subjects (558 men and 192 women, age 46±8 years) who had not met the criteria of metabolic syndrome and whose CRP and HMW-adiponectin levels had been measured in 2007 were enrolled in this study. Associations between CRP, HMW-adiponectin and development of metabolic syndrome after 4 years were assessed by logistic regression analysis and their predictive values were compared by receiver operating characteristic analysis.
Among 750 subjects, 61 (8.1%) developed metabolic syndrome defined by modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria and 53 (7.1%) developed metabolic syndrome defined by Japan Society for the Study of Obesity (JASSO) in 2011. Although CRP and HMW-adiponectin were both significantly correlated with development of metabolic syndrome, multivariate logistic regression analysis revealed that HMW-adiponectin but not CRP was associated with metabolic syndrome independently of BMI or waist circumference. Adding these biomarkers to BMI or waist circumference did not improve the predictive value for metabolic syndrome.
Our findings indicate that the traditional markers of adiposity such as BMI or waist circumference remain superior markers for predicting metabolic syndrome compared to CRP, HMW-adiponectin, or the combination of both among the Japanese population.
PMCID: PMC3772031  PMID: 24069195
13.  Past Obesity as well as Present Body Weight Status Is a Risk Factor for Diabetic Nephropathy 
Aims. We analyzed the prevalence of nephropathy according to past body weight status in Japanese subjects with type 2 diabetes because the influence of past obesity on diabetic complications is not certain. Methods. We examined the prevalence of nephropathy in 2927 subjects with type 2 diabetes mellitus according to current BMI and maximum BMI in the past. We defined “current obesity” as BMI on hospitalization of 25 or more, “previous obesity” as BMI on hospitalization of less than 25 and self-reported maximum BMI in the past of 25 or more, and “continuously lean” as maximum BMI of less than 25. Results. The prevalence of nephropathy was significantly higher in subjects with current obesity (40.6%) or previous obesity (35.6%) than in those who were continuously lean (24.3%) (P < 0.017). In logistic regression analysis, previous obesity, as well as current obesity, was a significant risk factor for nephropathy, independent of sex, age, disease duration, hypertension, dyslipidemia, HbA1c, and diabetic retinopathy. Conclusions. Obesity in the past, as well as the present body weight status, was a risk factor for diabetic nephropathy.
PMCID: PMC3770043  PMID: 24065991
14.  Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY) 
Aim. This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD) and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus. Methods. This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 20 mg once a day (n = 12) or losartan at a dose of 50 mg once a day (n = 7) for 12 months. Body fat area as determined by CT scanning and hepatic fat content based on the liver-to-spleen (L/S) ratio, as well as several parameters of glycemic and lipid metabolism, were compared before and after 12 months. Results. The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from 0.87 ± 0.26 to 0.59 ± 0.22 mEq/L (mean ± SD), P = 0.005) and a significant increase in L/S ratio (P = 0.049) evaluated by CT scan, while these parameters were not changed in the losartan group. Conclusion. Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver.
PMCID: PMC3755443  PMID: 23997767
15.  Loss of Pdk1-Foxo1 Signaling in Myeloid Cells Predisposes to Adipose Tissue Inflammation and Insulin Resistance 
Diabetes  2012;61(8):1935-1948.
Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage/granulocyte-specific mutations, including a Pdk1 knockout (LysMPdk1−/−), a Pdk1 knockout with transactivation-defective Foxo1 (Δ256LysMPdk1−/−), a constitutively active nuclear (CN) Foxo1 (CNFoxo1LysM), or a transactivation-defective Foxo1 (Δ256Foxo1LysM). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The LysMPdk1−/− mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CNFoxo1LysM promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CNFoxo1LysM mice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow–derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1/Foxo1 pathway is important in regulating insulin sensitivity in vivo.
PMCID: PMC3402298  PMID: 22586579
16.  Hepatic arterial infusion chemotherapy with gemcitabine and 5-fluorouracil or oral S-1 improves the prognosis of patients with postoperative liver metastases from pancreatic cancer 
Molecular and Clinical Oncology  2013;1(5):869-874.
Hepatic metastasis is a common cause of treatment failure following resection of pancreatic cancer. In this study, we report our results of hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) plus 5-fluorouracil (5-FU) or oral S-1 treatment for postoperative liver metastases from pancreatic cancer. Seven patients with postoperative liver metastases from pancreatic cancer received HAI with GEM plus 5-FU or oral S-1 between October, 2008 and September, 2010 at Kanazawa University Hospital (Kanazawa, Japan). Three out of the 7 cases exhibited a partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) and stable disease (SD) was achieved in 3 out of the 7 cases (response rate, 85.7%). A decrease in serum tumor marker CA 19-9 levels was observed after 10 HAI treatment cycles in 5 out of the 7 cases. The median time to treatment failure was 8 months (range, 0–17 months). Adverse events included grade 3 leukocytopenia in 1 case and anemia in all 7 cases, although 5 out of the 7 patients were anemic prior to HAI therapy. Grade 2 thrombocytopenia was also observed in 2 cases. Non-hematological events, such as nausea, diarrhea, liver injury or neuropathy and life-threatening toxicities were not reported; however, 6 patients (85.7%) developed catheter-related complications and the HAI catheter and subcutaneous implantable port system had to be removed. These findings demonstrated that HAI may deliver high doses of chemotherapeutic agents directly into the tumor vessels, producing increased regional levels with greater efficacy and a lower incidence/severity of systemic side effects. In conclusion, HAI chemotherapy is a safe and effective treatment for liver metastases from pancreatic cancer.
PMCID: PMC3916203  PMID: 24649263
pancreatic cancer; liver metastasis; hepatic arterial infusion; gemcitabine; 5-fluorouracil; S-1
17.  Chondroblastoma of the distal femur resected through a small fenestra via computed tomography navigation and endoscopy: a case report 
Chondroblastoma is a benign bone tumor with a relatively high incidence in older children and adolescents during the period of active epiphyseal growth. It is generally regarded as a benign neoplasm, but sometimes it grows aggressively or recurs. To prevent recurrence, complete curettage is important; however, such an approach can be extremely difficult to perform precisely when the chondroblastoma arises deep in the epiphysis. In our patient’s case, we used a computed tomography-based navigation system with registration technique involving skin marker fiduciaries and endoscopic curettage of the lesion.
Case presentation
A 16-year-old Japanese girl presented to our facility with left knee joint pain, which started nine months before her initial examination. Computed tomography and magnetic resonance imaging studies of the left knee showed a radiolucent lesion with marginal sclerosis and lobular homogeneous hypo-intensity and hyper-intensity signals in the distal epiphysis of the left femoral epiphysis, carried through to the growth plate. To prevent recurrence of chondroblastoma and growth disturbance, we used a computed tomography-based navigation system with registration technique involving skin marker fiduciaries and endoscopic curettage of the lesion. Wide excision with total removal of the chondroblastoma in the distal femur often requires large exposure with associated drawbacks, where a wide excision near the growth plate can potentially lead to growth disturbance. Therefore, in an accessible location in the distal femur, endoscopic excision of chondroblastoma under navigation system guidance can be performed with minimal operative damage.
In the setting of a benign intra-osseous lesion infiltrating the growth plate, arthroscopic retrieval or excision under a computed tomography-based navigation system should be considered before proceeding with open surgery.
PMCID: PMC3700752  PMID: 23805921
18.  Kidney Specific Protein-Positive Cells Derived from Embryonic Stem Cells Reproduce Tubular Structures In Vitro and Differentiate into Renal Tubular Cells 
PLoS ONE  2013;8(6):e64843.
Embryonic stem cells and induced pluripotent stem cells have the ability to differentiate into various organs and tissues, and are regarded as new tools for the elucidation of disease mechanisms as well as sources for regenerative therapies. However, a method of inducing organ-specific cells from pluripotent stem cells is urgently needed. Although many scientists have been developing methods to induce various organ-specific cells from pluripotent stem cells, renal lineage cells have yet to be induced in vitro because of the complexity of kidney structures and the diversity of kidney-component cells. Here, we describe a method of inducing renal tubular cells from mouse embryonic stem cells via the cell purification of kidney specific protein (KSP)-positive cells using an anti-KSP antibody. The global gene expression profiles of KSP-positive cells derived from ES cells exhibited characteristics similar to those of cells in the developing kidney, and KSP-positive cells had the capacity to form tubular structures resembling renal tubular cells when grown in a 3D culture in Matrigel. Moreover, our results indicated that KSP-positive cells acquired the characteristics of each segment of renal tubular cells through tubular formation when stimulated with Wnt4. This method is an important step toward kidney disease research using pluripotent stem cells, and the development of kidney regeneration therapies.
PMCID: PMC3670839  PMID: 23755150
19.  A phase I study of neoadjuvant chemotherapy with gemcitabine plus oral S-1 for resectable pancreatic cancer 
Molecular and Clinical Oncology  2013;1(4):768-772.
The aim of this study was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose (RD) of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) plus oral S-1 in patients with resectable pancreatic cancer. Thirteen patients with radiologically proven resectable pancreatic cancer were included in this study. S-1 was administered orally for 14 consecutive days, and GEM was administered on days 8 and 15 for two pre-operative cycles. The dose of S-1 in this study was planned with fixed doses of GEM (1,000 mg/m2): 20, 30 and 40 mg/day for levels 0, 1 and 2, respectively. Treatment was initiated at level 1 in 3 patients, while adverse events occurred in 2 patients during the second course, leading to a dose reduction to level 0 for the 8 remaining patients. Two of the 10 patients enrolled at level 0 were excluded. Of the remaining 8 patients, GEM administration was terminated due to DLT on day 15, during the first course in 3 patients, while level 0 dosage reached MTD. Surgery was performed for the remaining 11 patients included in the study. Post-operative complications included pancreatic fistulas in 5 patients and Pseudomonas aeruginosa sepsis in 1 patient. Two of the 11 patients exhibited a partial response and 9 patients stable disease. Eight of the 11 tumor specimens showed histopathological evidence of tumor cell injury. In conclusion, NAC with GEM and S-1 was not well-tolerated in this study. However, pre-operative chemotherapy may be effective against pancreatic cancer. Therefore, it is necessary to reconsider NAC regimens for pancreatic cancer.
PMCID: PMC3915328  PMID: 24649244
pancreatic cancer; gemcitabine; S-1; neoadjuvant chemotherapy; phase I
21.  Relationship between Stage of Diabetic Retinopathy and Pulse Wave Velocity in Japanese Patients with Type 2 Diabetes 
Journal of Diabetes Research  2013;2013:193514.
Objectives. We investigated the relationship between the stage of diabetic retinopathy and pulse wave velocity (PWV). Methods. This was a cross-sectional study of 689 patients (406 men and 283 women) with type 2 diabetes who were admitted to our hospital from 2004 to 2007. Brachial-ankle pulse wave velocity (baPWV) was measured by an arterial pressure measurement device as PWV/ABI. Diagnosis of diabetic retinopathy was made by ophthalmologists based on the Davis classification: no diabetic retinopathy (NDR), simple retinopathy (SDR), pre-proliferative retinopathy (pre-PDR), and proliferative retinopathy (PDR). Results. There was a significant difference in PWV between patients without diabetic retinopathy (1657.0 ± 417.9 m/s (mean ± SD)) and with diabetic retinopathy (1847.1 ± 423.9 m/s) (P < 0.001). In addition, the stage of diabetic retinopathy was associated with aortic PWV (1657.0 ± 417.9 m/s in NDR (n = 420), 1819.4 ± 430.3 m/s in SDR (n = 152), 1862.1 ± 394.0 m/s in pre-PDR (n = 54), and 1901.1 ± 433.5 m/s in PDR (n = 63) (P < 0.001)). Conclusions. In patients with diabetic retinopathy, even in those with SDR, PWV was higher than that in patients without diabetic retinopathy. Physicians should therefore pay attention to the value of PWV and macroangiopathy regardless of the stage of diabetic retinopathy.
PMCID: PMC3647565  PMID: 23671858
22.  Factors Associated with the Decline of Kidney Function Differ among eGFR Strata in Subjects with Type 2 Diabetes Mellitus 
Introduction. There is no report about risk factors for renal deterioration according to the clinical stage, divided by the estimated glomerular filtration rate (eGFR) in type 2 diabetes. Materials and Methods. We evaluated the factors correlated with the annual eGFR decline in 1303 subjects with type 2 diabetes whose eGFR was ≥30 mL/min/1.73 m2. eGFR strata were defined by baseline eGFR value as follows: stratum 1: ≥90, stratum 2: ≥60, <90, and stratum 3: ≥30, <60. Results. The annual eGFR decline was 2.3 ± 5.4 mL/min/1.73 m2 in overall subjects. Multiple linear regression analysis demonstrated that age, male sex, systolic blood pressure, logarithmically transformed albumin excretion rate (AER), eGFR strata, and hemoglobin concentration were significantly correlated with the annual eGFR decline. When stratified by eGFR, the factors that showed a significant correlation were different among eGFR strata. AER was significantly correlated with annual eGFR decline in all eGFR strata. Hemoglobin concentration showed a significant correlation only in the advanced eGFR stratum. Conclusion. The factors correlated with the annual eGFR decline were different among eGFR strata in type 2 diabetes mellitus, and hemoglobin concentration and AER were important factors for renal deterioration, especially in the advanced eGFR stratum.
PMCID: PMC3536318  PMID: 23316229
23.  A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT competent cells that express the ZEB transcription factors 
Cancer research  2011;71(21):6836-6847.
Zinc finger E-box binding (ZEB) proteins ZEB1 and ZEB2 are transcription factors essential in transforming growth factor (TGF)-β-mediated senescence, epithelial to mesenchymal transition (EMT) and cancer stem cell function. ZEBs are negatively regulated by members of the miR-200 microRNA family, but precisely how tumor cells expressing ZEBs emerge during invasive growth remains unknown. Here we report that NOTCH3-mediated signaling prevents expansion of a unique subset of ZEB-expressing cells. ZEB expression was associated with the lack of cellular capability of undergoing NOTCH3-mediated squamous differentiation in human esophageal cells. Genetic inhibition of the Notch-mediated transcriptional activity by dominant-negative Mastermind-like1 (DNMAML1) prevented squamous differentiation and induction of Notch target genes including NOTCH3. Moreover, DNMAML1 enriched EMT competent cells exhibited robust upregulation of ZEBs, downregulation of the miR-200 family, and enhanced anchorage independent growth and tumor formation in nude mice. RNA interference (RNAi) experiments suggested the involvement of ZEBs in anchorage independent colony formation, invasion and TGF-β-mediated EMT. Invasive growth and impaired squamous differentiation was recapitulated upon Notch inhibition by DNMAML1 in organotypic 3D culture, a form of human tissue engineering. Together, our findings indicate that NOTCH3 is a key factor limiting the expansion of ZEB-expressing cells, providing novel mechanistic insights into the role of Notch signaling in the cell fate regulation and disease progression of squamous esophageal cancers.
PMCID: PMC3206139  PMID: 21890822
Notch; EMT; squamous cell differentiation; ZEB1; miR-200
24.  Cutaneous squamous cell carcinoma (SCC) arising in stump of amputated finger in a patient with resected glossal SCC 
BMC Research Notes  2012;5:595.
Cutaneous squamous cell carcinoma (SCC) of the hands and fingers are sometimes locally aggressive; with higher rates of regional metastasis than other cutaneous SCC, although distant metastasis is rare.
Case presentation
We present the case of a 62–year-old Japanese man with double cancers: a tongue SCC and a cutaneous SCC. Swelling of the finger lesion developed gradually around the entire remaining middle finger after accidental amputation at the proximal interphalangeal joint. Histopathological examination of the tumor on the stump of the amputated finger indicated a well-differentiated SCC. The past history indicated surgery for SCC of the tongue 3 years earlier; with histopathology of moderately-differentiated SCC.
Since dedifferentiation is unlikely in metastatic tumors, the cutaneous SCC of the finger is unlikely to have originated from the tongue SCC. Alternatively, the double cancer may be two unrelated lesions or the tongue tumor could have originated from the cutaneous SCC.
PMCID: PMC3607937  PMID: 23111060
Squamous cell carcinoma; Finger amputation stump; Glossal tumor; Double cancer
25.  Bile Acid Binding Resin Improves Metabolic Control through the Induction of Energy Expenditure 
PLoS ONE  2012;7(8):e38286.
Besides well-established roles of bile acids (BA) in dietary lipid absorption and cholesterol homeostasis, it has recently become clear that BA is also a biological signaling molecule. We have shown that strategies aimed at activating TGR5 by increasing the BA pool size with BA administration may constitute a significant therapeutic advance to combat the metabolic syndrome and suggest that such strategies are worth testing in a clinical setting. Bile acid binding resin (BABR) is known not only to reduce serum cholesterol levels but also to improve glucose tolerance and insulin resistance in animal models and humans. However, the mechanisms by which BABR affects glucose homeostasis have not been established. We investigated how BABR affects glycemic control in diet-induced obesity models.
Methods and Findings
We evaluated the metabolic effect of BABR by administrating colestimide to animal models for the metabolic syndrome. Administration of BABR increased energy expenditure, translating into significant weight reduction and insulin sensitization. The metabolic effects of BABR coincide with activation of cholesterol and BA synthesis in liver and thermogenesis in brown adipose tissue. Interestingly, these effects of BABR occur despite normal food intake and triglyceride absorption. Administration of BABR and BA had similar effects on BA composition and thermogenesis, suggesting that they both are mediated via TGR5 activation.
Our data hence suggest that BABR could be useful for the management of the impaired glucose tolerance of the metabolic syndrome, since they not only lower cholesterol levels, but also reduce obesity and improve insulin resistance.
PMCID: PMC3430641  PMID: 22952571

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