Polycystic kidney disease (PKD) is a common genetic disorder arising from developmental and postnatal processes. Defects in primary cilia and their signaling (eg, mTOR) underlie the pathogenesis. However, how mTOR regulates tubular integrity remains unclear. The paucity of faithful models has limited our understanding of pathogenesis and, therefore, the refinement of therapeutic targets. To understand the role of mTOR in early cystogenesis, we studied an in-house mouse model, Cd79a-Cre;Tsc1ff. (Cd79a-Tsc1 KO hereafter), recapitulating human autosomal-dominant PKD histology. Cre-mediated Tsc1 depletion driven by the promoter for Cd79a, a known B-cell receptor, activated mTORC1 exclusively along the distal nephron from embryonic day 16 onward. Cysts appeared in the distal nephron at 1 weeks of age and mice developed definite PKD by 4 weeks. Cd79a-Tsc1 KO tubule cells proliferated at a rate comparable to controls after birth but continued to divide even after postnatal day 14 when tubulogenesis is normally completed. Apoptosis occurred only after 9 weeks. During postnatal days 7–11, pre-cystic Cd79a-Tsc1 KO tubule cells showed cilia elongation, aberrant cell intercalation, and mitotic division, suggesting that defective cell planar polarity (PCP) may underlie cystogenesis. mTORC1 was activated in a portion of cyst-lining cells and occasionally even when Tsc1 was not depleted, implying a non-autonomous mechanism. Our results indicate that mTORC1 overactivation in developing distal tubules impairs their postnatal narrowing by disrupting morphogenesis, which orients an actively proliferating cell toward the elongating axis. The interplay between mTOR and cilium signaling, which coordinate cell proliferation with PCP, may be essential for cystogenesis.

Introduction Adipose insulin-resistant but normal weight phenotype has not been reported and hence was characterized in young Japanese women. Research design and methods Body composition, a broad range of cardiometabolic health and dietary intake were cross-sectionally measured in 166 normal weight young Japanese women. They were grouped into tertile of adipose tissue-insulin resistance (AT-IR) index (fasting insulin×free fatty acids) and analyzed by analysis of variance and then Bonferroni’s multiple comparison procedure. Results Body mass index averaged <21 kg/m 2 and waist <72 cm, and did not differ among three groups of women. Fasting glucose and triglycerides and homeostasis model assessment-insulin resistance were higher in the highest compared with the median and lowest AT-IR tertile. However, there was no difference in fat mass and distribution, high-density lipoprotein cholesterol and blood pressure. In addition, high-sensitivity C reactive protein (hsCRP) and resting pulse rate were higher as well. In multivariate logistic regression analyses, fasting glucose (OR: 1.10, 95% CI: 1.02 to 1.18, p=0.012), fasting triglycerides (OR: 1.04, 95% CI: 1.02 to 1.06, p<0.001), resting pulse rate (OR: 1.07, 95% CI: 1.03 to 1.11, p<0.001) and hsCRP (OR: 2.30, 95% CI: 1.01 to 5.2, p=0.04) were associated with the high AT-IR tertile. Conclusions Adipose insulin-resistant but normal weight phenotype may be associated with increased sympathetic nervous system and low-grade systemic inflammation in addition to glucose and lipid dysmetabolism through mechanisms unrelated to adiposity in young Japanese women.

α-Lipoic acid (ALA) is a vitamin-like substance that is an indispensable supporting factor for a large number of enzymes. Due to its optical activity, ALA has optical isomers RALA and SALA. The major role of RALA is in energy metabolism. However, RALA cannot be used as a pharmaceutical or nutraceutical because it is sensitive to heat and acid conditions. Previous studies have shown that RALA complexed with γ-cyclodextrin (CD) has a higher antioxidant capacity than that of free RALA. The antioxidant enzyme system protects against intense exercise-induced oxidative damage and is related to the physical status of athletes. The aim of this study was to examine the effect of CD/RALA complex supplementation on antioxidant activity and performance during high-intensity exercise. Twenty-four male C3H/HeSlc mice were divided into four groups (n = 6): swimming+distilled water administration (C), swimming+CD/RALA supplementation (CD/RALA), swimming+RALA suplementation (RALA), and swimming+CD supplementation (CD). Blood ammonia elevation due to exercise stress was repressed by CD/RALA supplementation. The oxidative stress in the kidney increased after exercise and was reduced by CD/RALA supplementation. Our findings suggest that CD/RALA supplementation may be useful for improving the exercise performance in athletes.

We found an effective roasting method that enhances the effects on various radical scavenging activities of polysaccharide (alginic acid) derived from the marine brown alga Lessonia trabeculata. These enhancing effects were observed by a roasting treatment under relatively high temperature conditions (160ºC and 180ºC), which were measured by (i) a stable radical compound diphenylpicrylhydrazyl (DPPH), (ii) a hydroperoxide generating system of linoleic acid autooxidation, and (iii) an opsonized zymosan (Opz)-induced oxygen radical generating system in human blood neutrophils. Although a significant enhancing effect of the roasting treatment on the radical scavenging activity of the alginic acid itself was not detected under relatively low temperature conditions (100ºC and 130ºC), the roasting treatment of a mixture of alginic acid and several specific amino acids caused considerable radical scavenging activities under the same roasting conditions. When alginic acid was roasted at relatively high temperatures (160ºC or 180ºC), the mixture of the alginic acid and specific amino acids exhibited much higher radical scavenging activities than did the alginic acid alone. The significance of this finding is discussed from the viewpoint of healthy food science.

〈Background〉 We reported on the characteristics of green tea extract (GTE)-induced hepatotoxicity in rats. Using this model, we explored the inhibitory effects of n-9 PUFA, mead acid (MA), by dietary supplementation. 〈Methods〉 7-week-old male Sprague-Dawley rats received a single intraperitoneal injection of 200 mg/kg GTE, serum and liver were collected 24, 48 hrs, and 7 days after the GTE injection. The control or 4.8% MA diets was given from one week before GTE injection to sacrifice. Control diet + saline, 4.8% MA diet + saline, control diet + GTE, and 4.8% MA diet + GTE groups were set. Serum biomarkers of hepatotoxicity [aspartate aminotransferase (AST), alanine aminotransferase (ALT)], liver histopathology, and immunohistochemistry of apoptosis (γH2A.X), oxidative stress (8-nitroguanosine) and hypoxia [hypoxia inducible factor (HIF)-1α] were examined. Fatty acid in serum and liver tissue of the control diet + saline and 4.8% MA diet+ saline groups were analyzed. 〈Results〉 In the control diet + GTE group, AST and ALT levels increased. Centrilobular hepatocellular necrosis was seen 24 and 48 hrs after GTE exposure. Furthermore, the levels of these changes decreased in the MA diet group. In the control diet + GTE group, γH2A.X, 8-nitroguanosine, and HIF-1α-positive hepatocytes appeared and peaked at 48 hrs. The level of these changes reduced by MA diet feeding. MA composition in the serum and liver significantly increased in the MA diet group, compared to the control diet group. 〈Conclusion〉The levels of GTE-induced liver damage, such as serum biomarkers, histology, and immunohistochemistry for hepatotoxicity were inhibited by MA diet feeding. This effect may be related to suppression of cell death via the pathway of oxidative stress and hypoxia in the liver.

A mode of action of acetaminophen （APAP）-induced renal toxicity is supposedly via N-acetyl-p-benzoquinone imine. In this renal toxicity model we explored the inhibitory effects of mead acid （MA）, which is an n-9 PUFA of dietary supplementation. Seven week-old male SD rats received a single intraperitoneal injection of 500 mg/kg APAP and serum and kidney samples were collected at 24 and 48hrs after. Basal or 4.8% MA diets were given from one week before the APAP injection until sacrifice. Experimental groups were basal diet + vehicle, 4.8% MA diet + vehicle, basal diet + APAP, and 4.8% MA diet + APAP. Biomarkers of renal toxicity （blood urea nitrogen （BUN）, creatinine （CRE））, histopathology of kidney and immunohistochemistry for drug-metabolizing enzyme （cytochrome P4502E1（CYP2E1）） and oxidative stress （heme oxgenase （HO-1）, thymidine glycol （TG）） were performed. The diacron-reactive oxygen metabolites （d-ROMs） and bioantioxidant power （BAP） tests were conducted to detect oxidative stress and anti-oxidative activity in serum, respectively. In the basal diet+ APAP group, the BUN and CRE levels were significantly increased and acute necrosis and dilatation in the renal outer medullary area were present. Tubular necrosis was detected mainly in proximal tubules which was positive for CYP2E1. HO-1 and TG signals were also seen in these epithelia. In contrast, these tubular changes and expression of HO-1signal were reduced in the rats fed the MA diet. MA supplementation inhibited APAP induced renal toxicity via the decreased level of oxidative stress in kidney.

In the present study, the therapeutic effects of dietary supplemental mead acid (MA), an n-9 polyunsaturated fatty acid, was tested in two different acute liver injury rat models. Six-week old Sprague Dawley rats were given basal diet with and without 4.8% MA. One-week later control rats remained on their basal and 4.8% MA diets while treated rats on basal and 4.8% MA diet received a single intraperitoneal injection of 2 mL/kg carbon tetrachloride (CCl4) or 500 mg/kg acetaminophen (APAP). Serum and liver samples were collected 48hrs after CCl4 or APAP injection. Serum biomarkers of hepatotoxicity (aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (T-BIL)), histopathology, and immunohistochemistry for oxidative stress were examined. Fatty acids in total lipids were also analyzed. Biomarker levels were decreased in the CCl4-or APAP- injected 4.8% MA diet groups compared to the CCl4-or APAP- injected basal diet groups. In serum and liver, the concentration of MA was significantly higher in the MA diet group as compared to controls. Our experimental results demonstrate that MA reduced the severity of liver injury in these models by its antioxidant activity.

BACKGROUND AND OBJECTIVES:Although roles of ABC (HbA1c, blood pressure [BP] and LDL-cholesterol) goal attainment on CVD risk outcomes have been well established, it is less studied whether ABC goal attainment associates with ABC variability, non-traditional risk factors.METHODS AND STUDY DESIGN:Intrapersonal mean levels and standard deviation (SD) of HbA1c, BP and LDL-cholesterol, fasting and post-breakfast plasma glucose (PG) and serum triglyceride (TG) during 12 months were calculated in 168 type 2 diabetes patients (aged 62.3 years, 53.6% men). Associations of ABC goal attainment with non-traditional glycemic, BP and lipid risk factors were analyzed.RESULTS:Among 168 patients, 92 (54.8%), 91 (54.2%) and 111 (66.1%) patients achieved HbA1C, BP and cholesterol goal, respectively, and 47 (28.0 %), 45 (26.8 %), 63 (37.5 %) and 13 (7.7 %) achieved triplegoal, dual-goal, single-goal and no-goal, respectively. Achieving more ABC goals was associated with stepwise decreases in mean levels and SD of fasting and post-breakfast PG, and HbA1c. It was also associated with stepwise decreases in mean levels and SD of fasting and post-breakfast TG, and LDL-cholesterol. Further, achieving more ABC goals was associated with stepwise decreases in brachial pulse pressure and mean levels and SD of systolic BP.CONCLUSIONS:ABC goal achievement was associated with a broad range of non-traditional glycemic, BP and lipid risk factors in type 2 diabetic patients. Reaching more ABC treatment targets may be important for reductions in long-term ABC variability and postprandial dysmetabolism.

In the present study, the dietary effects of mead acid (MA; 5,8,11‑eicosatrienoic acid) on 7,12‑dimethylbenz[a]anthracene (DMBA)‑induced breast cancer in female Sprague‑Dawley rats were examined. The 2.4 and 4.8% MA diets were commenced when the rats were 6 weeks of age. DMBA was administered by a single oral ingestion when the rats were 7 weeks of age, and the rats were maintained on the respective diets until 19 weeks of age. Tumor weight, histopathology, cell kinetics, and the fatty acid composition in breast tissue and serum were examined. In the control (CTR) group, the DMBA‑exposed rats were fed a basal diet (0% MA). The results revealed that there were no significant differences in tumor incidence, cell kinetics and in the N‑6/N‑3 ratio in breast tissue between the groups. Only the N‑6/N‑3 ratio of fatty acid composition in serum was significantly decreased in the 2.4% MA diet group. In previous studies, the 2.4% MA diet was shown to suppress N‑methyl‑N‑nitrosourea‑induced luminal A mammary cancer by decreasing cancer cell proliferation. The findings of the present study differ from those of previous studies with different breast cancer models. To further clarify the effects of MA against breast carcinogenesis, further investigations with different experimental breast cancer models are recommended.

Various edible algae have been traditionally consumed as healthy food stuffs in Asian countries such as China, Korea and Japan, and roasting treatments have been carried out on some of these edible algae for the improvement of their taste and flavor. In the present paper, we analyzed the effect of roasting treatments on the radical scavenging activity of a typical Japanese edible brown alga, Laminaria japonica (L. japonica, Ma-konbu). The effect was estimated by a stable radical compound, diphenylpicrylhydrazyl (DPPH) and a chemiluminescence assay of superoxide anion generation using hypoxanthine (HPX) and xanthine oxidase (XOD) system. Weak but significant radical scavenging activities against the DPPH radical and superoxide anion were observed in the water extract of L. japonica when it was roasted at 130-150ºC. Very strong radical-scavenging activities were detected under much higher temperature conditions (180-200ºC). The enhancing effect of the roasting treatment on the radical scavenging activity was highly associated with the roasting-induced increase of polyphenol and tannin in the L. japonica extract. The sugar concentrations in the L. japonica extracts under different roasting conditions were significantly, but not strongly associated with their radical scavenging activities. The protein concentrations in the L. japonica extracts, however, were not associated with their radical scavenging activities under different roasting conditions. Furthermore, the extracts of L. japonica roasted under higher temperature conditions (180-200ºC) caused strong radical scavenging effects on the generation of opsonized zymosan (Opz)-induced reactive oxygen species (ROS) generation in human blood neutrophils, which was measured by chemiluminescence assay. These experimental results suggest that the roasting treatment of L. japonica causes an enhancing effect on the radical scavenging activity in the extract of this alga, and is associated with the increase in various radical scavenging substances in the extract. The significance of this finding is discussed from the viewpoint of healthy food science.

BACKGROUND:We investigated cross-sectional and prospective associations of ABC (hemoglobin A1c (HbA1c), blood pressure and low-density lipoprotein cholesterol) goal attainment with chronic kidney disease. Cross-sectional association with carotid intima-media thickness (IMT) was evaluated as well. METHODS:Prevalence of low estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2) and albuminuria (urinary albumin-to-creatinine ratio (ACR) ≥ 30 mg/g) were assessed at baseline and after a median follow-up of 6.0 years in 168 patients with type 2 diabetes with preserved kidney function (aged 62.3 years, 53.6% men). Carotid IMT was measured at baseline only. RESULTS:At baseline, 47 (28.0%), 45 (26.8%), 63 (37.5%) and 13 (7.7%) patients achieved triple-goal, dual-goal, single-goal and no-goal, respectively. Achieving more ABC targets was associated with lower log ACR (P < 0.01), lower percentage of albuminuria (P = 0.02), and lower carotid IMT (P < 0.01) at baseline. Over 6.0 years, eGFR decreased from 76 ± 16 to 67 ± 18 mL/min/1.73 m2 (P < 0.01) whereas ACR levels did not change. There were 32 patients with incident reduced eGFR, eight with GFR stage progression, 15 with progression of albuminuric stages and five with doubling of ACR within the microalbuminuric range. Achieving more ABC targets decreased the percentage of deterioration of GFR stages (30.8%, 28.6%, 24.4% and 14.9%, respectively, P = 0.01). Achieving two or more (8.9% and 8.5%, respectively) compared with one or less ABC targets (15.4% and 15.9%, respectively) was associated with less deterioration of albuminuria (P < 0.001). Although achieving more ABC targets was associated with lower annual decline in eGFR, the difference was not significant. CONCLUSIONS:ABC goal achievement has shown cross-sectional and prospective associations with deterioration of chronic kidney disease in type 2 diabetic patients with preserved kidney function. Cross-sectional association with carotid IMT has been demonstrated as well. Reaching more ABC treatment targets may be important for preventing adverse renal outcomes.

Background Studies demonstrated that visit-to-visit variability in low-density lipoprotein cholesterol (LDLC) is an independent predictor of cardiovascular events in subjects with coronary artery disease. Whether visit-to-visit variability in LDLC levels affects subclinical atherosclerosis is unknown. This study sought to evaluate the role of visit-to-visit variability in LDLC levels on subclinical atherosclerosis. Methods We evaluated 162 type 2 diabetic patients with measurement of carotid intima-media thickness (IMT). Intrapersonal mean and standard deviation (SD) of six measurements of LDLC during 12 months were calculated. Multivariate linear regressions assessed the independent correlates of carotid IMT. Results The mean and SD of LDLC were 112 ± 22 and 15 ± 10 mg/dL, respectively, and 43.2% of patients were on hypolipidemic drugs. Age (standardized β = 0.355, P < 0.001), male sex (standardized β = 0.234, P = 0.002) and SD-LDLC (standardized β = 0.201, P = 0.009) emerged as independent determinants of carotid maximum IMT independently of mean LDLC levels, body mass index (BMI), waist circumference, duration and treatment of diabetes, means and SDs of glycemic and other lipid variables, and uses of hypolipidemic and anti-hypertensive medications (R2 = 0.15). Results did not change when mean IMT was used instead of maximum IMT. After controlling for age and sex, maximum IMT was thicker in patients with the highest compared to those with other three quartiles of SD-LDLC combined (1.14 ± 0.04 (SE) vs. 1.01 ± 0.02 mm, P = 0.01). Independent determinants of SD-LDLC were mean LDLC, use of hypolipidemic drugs, fasting triglyceride and visit-to-visit variability in HbA1c. Conclusions Consistency of LDLC levels may be important to subclinical atherosclerosis in real-world patients with type 2 diabetes. It may be important for patients on lipid-lowering drugs to prevent non-compliance.

Background/Aim: Metabolic syndrome-induced lifestyle-related diseases include diabetes mellitus (DM) and hypertension, and Zn-based compounds have effects on DM. We aimed to investigate the ameliorating effects of bis(hinokitiolato) Zn, [Zn(hkt)(2)] on lipid metabolism in the liver and kidney, histopathologically. Materials and Methods: We used a high-fat diet (HFD)-fed C57BL/6J mouse model and administered a diet containing 10-20 mg Zn/kg body weight (BW) or 20 mg pioglitazone/kg BW as the positive control. After the treatments, we collected blood, liver, and kidney samples and morphologically evaluated the mouse organs for fat accumulation. Results: After a 4-month HFD administration, ectopic fat deposition was detected in the liver and kidney. Furthermore, Zn accumulation in the liver and kidney increased following [Zn(hkt)(2)] treatment, that reduced lipid accumulations and lipid toxicity in these tissues. Conclusion: The results of this study suggest that [Zn(hkt)(2)] could be a novel anti-dyslipidaemia compound for treating diet-induced obesity.

BACKGROUND:Associations of whole blood viscosity (WBV) with metabolic syndrome (MS) have not been extensively studied in patients with type 2 diabetes.METHODS:Intrapersonal means of 12 measurements of waist circumference, blood pressure (BP) and high-density lipoprotein cholesterol and those of six measurements of fasting and post-breakfast triglycerides (TG) during 12 months were calculated in a cohort of 168 patients with type 2 diabetes. Based on these means, MS was diagnosed according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of abdominal obesity. WBV was calculated from hematocrit and total serum protein concentrations by a validated formula.RESULTS:Diabetes patients with MS (n = 77) had higher WBV as compared to those without MS (6.38 ± 0.06 vs. 6.10 ± 0.07 cP, P = 0.004). As the number of MS components increased, WBV increased (component number 1: 6.12 ± 0.10, 2: 6.09 ± 0.10, 3: 6.37 ± 0.08, 4: 6.42 ± 0.10, 5: 6.30 ± 0.15 cP, P for trends = 0.001). Multiple regression analysis revealed that male gender, diastolic BP and post-breakfast TG were determinants of WBV independent of fasting TG, body mass index (BMI) and waist circumference (R2 = 0.258).CONCLUSIONS:Both the presence of MS and the number of MS components were associated with higher WBV in patients with type 2 diabetes. Physicians need to perform a close follow-up of type 2 diabetes patients with MS on inhibitors of sodium-glucose co-transporters 2, which may increase stroke risk associated with an increase in hematocrit and therefore blood viscosity. Post-breakfast TG was an independent determinant of WBV. Elevated WBV may represent an important confounder of the relationship between MS, postprandial hyperlipidemia and elevated cardiovascular risk in this population.

This study examined associations of annual glycemic variability and postprandial dysmetabolism with annual decline in estimated glomerular filtration rate (eGFR) in type 2 diabetic patients with different stages of nephropathy.

BACKGROUND:As association of metabolic syndrome (MS) with chronic kidney disease (CKD) has not been extensively studied in patients with type 2 diabetes, we addressed these issues.METHODS:Intrapersonal means of 12 measurements of waist circumference, blood pressure and high-density lipoprotein (HDL) cholesterol and those of six measurements of fasting triglycerides during 12 months were calculated in a cohort of 168 previously reported Japanese patients with type 2 diabetes. Based on these means, MS was diagnosed according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of abdominal obesity. CKD was defined as the presence of low estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2), albuminuria (urinary albumin/creatinine ratio (ACR) ≥ 30 mg/g) or both.RESULTS:Of 168 patients, 77 patients (46 %) had MS and 67 (40 %) had CKD. As the number of MS components increased from 1 through 5, the prevalence of albuminuria (9%, 38%, 30%, 41%, and 50%, P < 0.001), low eGFR (0%, 10%, 24%, 22%, and 50%, P < 0.001) and consequently, CKD increased (9%, 41%, 48%, 52%, and 75%, P < 0.001). Urinary ACR increased and eGFR decreased as a function of the number of MS components. As compared to patients without MS, prevalence of low eGFR (26% vs. 7%, P = 0.001) and CKD (52% vs. 30%, P = 0.005) was higher in patients with MS but prevalence of albuminuria did not differ (36% vs. 27%, P = 0.2).CONCLUSION:In Japanese patients with type 2 diabetes, the cluster of abnormalities related to MS was associated not only with higher prevalence of albuminuria, reduced kidney function and hence the increase in CKD but also with corresponding changes in urinary ACR and eGFR.

Background/Aims. Subclinical atherosclerosis and long-term glycemic variability have been reported to predict incident chronic kidney disease (CKD) in the general population. However, these associations have not been investigated in patients with type 2 diabetes with preserved kidney function. Methods. We prospectively followed up 162 patients with type 2 diabetes (mean age, 62.3 years; 53.6% men) and assessed whether carotid intima-media thickness (IMT) measured by B-mode ultrasound and visit-to-visit HbA1c variability are associated with deterioration of CKD (incident CKD defined as estimated GFR [eGFR] < 60 mL/min/1.73 m2 and progression of CKD stages) over a median follow-up of 6.0 years. At baseline, 25 patients (15.4%) had CKD. Cox proportional hazards regression models were used for identifying associated factors of CKD deterioration. Results. Estimated GFR decreased from 75.8±16.3 to 67.4±18.2 mL/min/1.73 m2 (p<0.01). Of 162 patients, 32 developed CKD and 8 made a progression of CKD stages. Multivariate Cox regression analysis revealed that carotid IMT (HR: 4.0, 95% CI: 1.1–14.226.7, and p=0.03) and coefficient of variation of HbA1c (HR: 1.12, 95%: 1.04–1.21, and p=0.003) were predictors of deterioration of CKD independently of age, mean HbA1c, urinary albumin/creatinine ratio, baseline eGFR, uric acid, and leucocyte count. Conclusions. Subclinical atherosclerosis and long-term glycemic variability predict deterioration of chronic kidney disease (as defined by incident or worsening CKD) in type 2 diabetic patients with preserved kidney function.