Low dose red yeast rice with monacolin K lowers LDL cholesterol and blood pressure in Japanese with mild dyslipidemia: A multicenter, randomized trial.

BACKGROUND AND OBJECTIVES: Red yeast rice contains monacolin K, an inhibitor of cholesterol synthesis, and gamma-aminobutyric acid, a neurotransmitter. The daily dose of red yeast rice and monacolin K in previous studies was relatively high; therefore, there were safety concerns. We aimed to examine the effects of low daily dose red yeast rice on arteriosclerosis in patients with mild dyslipidemia. METHODS AND STUDY DESIGN: Eighteen patients without known cardiovascular disease and unsatisfactory low-density lipoprotein cholesterol (3.96±0.19 mmol/L) controlled only by diet therapy were randomly allocated to receive low dose red yeast rice (200 mg/day) containing 2 mg monacolin K or diet therapy alone for 8 weeks. The primary outcome was the absolute change in low-density lipoprotein cholesterol. Secondary outcomes included total cholesterol, apolipoprotein B, and blood pressure. RESULTS: Low-density lipoprotein cholesterol decreased significantly in the red yeast rice group than in the diet therapy group (median [interquartile range]: control -0.20 [-0.62, 1.19] mmol/L vs. red yeast rice -0.96 [-1.05, -0.34] mmol/L, p=0.030). The red yeast rice group also exhibited significant decreases in total cholesterol, apolipoprotein B, and blood pressure. No severe treatment-related adverse effects on muscles, liver, or renal function were observed. CONCLUSIONS: We found that patients in the red yeast rice group exhibited significant reductions in lowdensity lipoprotein cholesterol, total cholesterol, apolipoprotein B, and blood pressure without any recognised adverse effect. This suggests that low daily dose red yeast rice could reduce cardiovascular risk in patients with dyslipidemia.

A new enzyme-linked immunosorbent assay system for human serum hepatic triglyceride lipase.

There is no established method for measuring human hepatic triglyceride (TG) lipase (HTGL) concentration in serum. In this study, we developed new monoclonal Abs (MoAbs) (9A1 mouse MoAb and 141A1 rat MoAb) that react with HTGL both in serum and in postheparin plasma (PHP) and established a novel ELISA system for measuring serum HTGL and PHP-HTGL concentrations. To confirm the specificity of MoAbs, we performed immunoprecipitation-immunoblotting analysis. Both 9A1 mouse MoAb and 141A1 rat MoAb were able to immunoprecipitate not only recombinant HTGL and PHP-HTGL but also serum HTGL, demonstrating that HTGL exists in serum obtained without heparin injection. This method yielded intra- and interassay coefficients of variation of <6% and showed no cross-reactivity with LPL or endothelial lipase. In clinical analysis on 42 male subjects with coronary artery disease, there were strong positive correlations of serum HTGL concentration to PHP-HTGL concentration (r = 0.727, P < 0.01). Serum HTGL concentrations showed positive correlations to serum TGs (r = 0.314, P < 0.05) and alanine aminotransferase (r = 0.406, P < 0.01), and tendencies toward positive correlations to LDL cholesterol, small dense LDL, and γGTP. These results suggest that this new ELISA method for measuring serum HTGL is applicable in daily clinical practice.

Triphosphasumanene Trisulfide: High Out-of-Plane Anisotropy and Janus-Type π-Surfaces.

A triphosphasumanene trisulfide was designed and synthesized as an out-of-plane anisotropic π-conjugated molecule. Incorporating three anisotropic phosphine sulfide moieties into a sumanene skeleton induced a cumulative anisotropy with a large dipole moment (12.0 D), which is aligned in perpendicular direction with respect to the π-framework and more than twice as large as those of conventional out-of-plane anisotropic molecules. In the crystal, the molecules align to form columnar structures, in which electron-rich and electron-deficient sides of the π-framework face each other. The interactions between the electron-rich surfaces, which contain three sulfur atoms, and Au(111) were examined by X-ray photoelectron spectroscopy.

The Chemistry of Heterasumanenes.

Our studies on the synthesis of heterasumanenes, where benzylic carbon atoms of the sumanene are replaced by heteroatom functionalities, are summarized. Starting from triphenylene, repetitive lithiation at a bay position followed by introduction of silylene or germylene units provided the first trisila- and trigermasumanenes with no substituents on the skeletal carbon atoms. The synthesis of a trisilasumanene bearing six butoxy groups on the skeletal carbon atoms was also accomplished by our original sila-Friedel-Crafts reaction. A heterasumanene bearing three different heteroatom functionalities was also prepared from triphenylenothiophene by a sequential lithiation method, even though protecting groups were necessary to prevent lithiation at the α-carbon atoms of the dibenzothiophene unit. Structural analysis and optical properties of the novel heterasumanenes are also described.

Sex Differences in Associations Among Obesity, Metabolic Abnormalities, and Chronic Kidney Disease in Japanese Men and Women.

AIMS: The present study aimed to investigate relationships among abdominal obesity, metabolic abnormalities, and the prevalence of chronic kidney disease (CKD) in relatively lean Japanese men and women. PARTICIPANTS AND METHODS: The participants included 8133 men and 15 934 women between 40 and 75 years of age recruited from the government health check-up center in Kanazawa City, Japan. The prevalence of abdominal obesity, high blood pressure, dyslipidemia, and high fasting plasma glucose levels were assessed according to the Japanese criteria for metabolic syndrome. The estimated glomerular filtration rate (eGFR) was calculated using the modified Modification of Diet in Renal Disease equation for the Japanese population, and participants with an eGFR <60 mL/min/1.73 m(2) and/or proteinuria were diagnosed with CKD. RESULTS: Overall, 23% of males and 14% of females met criteria for CKD. Having more numerous complicated metabolic abnormalities was significantly associated with a higher odds ratio (OR) of CKD for men and women, irrespective of abdominal obesity. However, there was a sex difference in the OR of CKD for obese participants without metabolic abnormalities, such that abdominal obesity without metabolic abnormalities was significantly associated with a higher OR for men (multivariate-adjusted OR 1.63; 95% confidence interval [CI], 1.16-2.28) but not for women (OR 1.01; 95% CI, 0.71-1.44). CONCLUSIONS: The present findings demonstrated that obesity without metabolic abnormalities was associated with a higher risk of CKD in men but not women in a relatively lean Japanese population.

Changes in lipoprotein lipase and endothelial lipase mass in familial hypercholesterolemia during three-drug lipid-lowering combination therapy.

BACKGROUND: This study was performed to compare the effects of three different lipid-lowering therapies (statins, ezetimibe, and colestimide) on lipoprotein lipase and endothelial lipase masses in pre-heparin plasma (pre-heparin LPL and EL mass, respectively) from patients with familial hypercholesterolemia (FH). FH is usually treated by coadministration of these three drugs. METHODS: The pre-heparin LPL and EL masses were measured in fresh frozen plasma drawn and stored at various time points during coadministration of the three drugs from patients with heterozygous FH harboring a single mutation in the LDL receptor (n = 16, mean age 63 years). The patients were randomly divided into two groups based on the timing when ezetimibe was added. RESULTS: Plasma LPL mass concentration was significantly reduced by rosuvastatin at 20 mg/day (median = 87.4 [IQR: 71.4-124.7] to 67.5 [IQR: 62.1-114.3] ng/ml, P < 0.05). In contrast, ezetimibe at 10 mg/day as well as colestimide at 3.62 g/day did not alter its level substantially (median = 67.5 [IQR: 62.1-114.3] to 70.2 [IQR: 58.3-106.2], and to 74.9 [IQR: 55.6-101.3] ng/ml, respectively) in the group starting with rosuvastatin followed by the addition of ezetimibe and colestimide. On the other hand, the magnitude in LPL mass reduction was lower in the group starting with ezetimibe at 10 mg/day before reaching the maximum dose of 20 mg/day of rosuvastatin. Plasma EL mass concentration was significantly increased by rosuvastatin at 20 mg/day (median = 278.8 [IQR: 186.7-288.7] to 297.0 [IQR: 266.2-300.2] ng/ml, P < 0.05), whereas other drugs did not significantly alter its level. CONCLUSION: The effects on changes of LPL and EL mass differed depending on the lipid-lowering therapy, which may impact the prevention of atherosclerosis differently.

Analysis of pancreatic endocrine function in patients with IgG4-related diseases, in whom autoimmune pancreatitis was ruled out by diagnostic imaging.

IgG4-related disease (IgG4RD) is a newly recognized systemic disease characterized by the elevation of serum IgG4 levels and abundant IgG4-positive plasma cell infiltration into the involved organs. Few data exist regarding the relationship between diabetes or glucose intolerance and IgG4RD in the absence of obvious type 1 autoimmune pancreatitis (AIP). Therefore, we are characterizing pancreatic endocrine function in IgG4RD patients with no signs of type 1 AIP. 28 patients (12 men, mean age 62.1 years old) were diagnosed as having IgG4RD from serum IgG4 levels, histopathology and images. Diagnostic imaging ruled out obvious type 1AIP. We used 75g oral glucose tolerance tests (OGTT) and arginine tolerance tests (ATT) to evaluate pancreatic endocrine function. Patients' serum IgG4 and HbA1c levels were 603±437 mg/dL and 6.6±1.0%, respectively. The results of OGTT on 23 patients showed that 12 patients had diabetes, 4 had impaired glucose tolerance, and 7 had normal glucose tolerance. Interestingly, insulin secretion was preserved in most of the patients, even in diabetic patients, on OGTT and ATT. Glucagon hyperreactivity was observed in 10 of the 19 patients who underwent ATT. Twenty-three patients were treated for IgG4RD with glucocorticoids. Their HbA1c levels were significantly elevated during the first six months of treatment, but improved after twelve months in parallel with glucocorticoid therapy. These results demonstrate the high frequency of pancreatic endocrine dysfunction in IgG4RD even when there is no indication of AIP, thus revealing that pancreatic endocrine dysfunction frequently occurs in IgG4RD without obvious type 1 AIP.

Familial hypercholesterolemia with special focus on Japan.

Familial hypercholesterolemia (FH) is an inherited disorder characterized by increased low-density lipoprotein LDL) cholesterol and atherosclerotic cardiovascular disease. Although initial genetic analysis linked FH to LDL receptor mutations, subsequent work demonstrated that a gain-of-function mutation in the proprotein convertase subtilisin/kexin type 9 (PCSK9), which causes LDL-R degradation, was shown to be the cause of FH. In this review, we describe the history of research on FH, its clinical phenotyping and genotyping and advances in treatment with special focus on Japan.

Post-prandial remnant lipoprotein metabolism in autosomal recessive hypercholesterolaemia.

BACKGROUND: Phenotype of autosomal recessive hypercholesterolaemia (ARH), a rare lipid disorder, is known to be milder than that of homozygous familial hypercholesterolaemia (FH) with LDL receptor gene mutation. However, few data exist regarding the functional differences in ARH and FH particularly in terms of remnant-like particles' (RLP) metabolism. MATERIALS AND METHODS: Blood sampling was performed up to 6h after OFTT cream loading (50 g/body surface area) with 2-h intervals in a single ARH proband, four heterozygous FH patients with LDL receptor gene mutation and four normal controls. Plasma lipoprotein and RLP fraction were determined by HPLC system. The area under curve (AUC) of each lipoprotein including RLP fractions was evaluated. RESULTS: The AUC of TG, RLP cholesterol (RLP-C) and RLP triglyceride (RLP-TG) levels of heterozygous FH subjects was significantly higher than those of controls (466±71 mg/dL×h vs. 303±111 mg/dL×h, P<0·05; 35±7 mg/dL×h vs. 21±8 mg/dL×h, P<0·05; 124±57 mg/dL×h vs. 51±13 mg/dL×h, P<0·05, respectively). Under these conditions, those values of ARH were close to those of controls (310 mg/dL×h, 22 mg/dL×h, 23 mg/dL×h, respectively). CONCLUSION: These data demonstrate that unlike in FH, RLP clearance is preserved in ARH. The preservation of post-prandial RLP clearance may contribute to the mild phenotype of ARH compared with FH.

Homozygous familial lipoprotein lipase deficiency without obvious coronary artery stenosis.

The prevalence of familial lipoprotein lipase deficiency (LPLD) is approximately one in 1,000,000 in the general population. There are conflicting reports on whether or not LPLD is atherogenic. We conducted coronary computed tomographic (CT) angiography on two patients in their 70 s who had genetically confirmed LPLD. Patient 1 was a 73 year old woman with a body mass index (BMI) of 27.5 kg/m2, no history of diabetes mellitus and no history of drinking alcohol or smoking. At the time of her first visit, her serum total cholesterol, triglycerides and high-density lipoprotein cholesterol levels were 4.8 mmol/L, 17.3 mmol/L, and 0.5 mmol/L, respectively. She was treated with a lipid-restricted diet and fibrate but her serum TG levels remained extremely high. Next-generation sequencing analysis revealed a missense mutation (homo) in the LPL gene, c.662T>C (p. Ile221Thr), leading to the diagnosis of homozygous familial LPL deficiency (LPLD). Patient 2 was another 73- year- old woman. She also had marked hypertriglyceridemia with no history of diabetes mellitus, drinking alcohol, or smoking. Previous genetic studies showed she had a nonsense mutation (homozygous) in the LPL gene, c.1277G>A (p.Trp409Ter). To clarify the degree of coronary artery stenosis in these two cases, we conducted coronary CT angiography and found that no coronary artery stenosis in either the right or left coronary arteries. Based on the findings in these two elderly women along with previous reports on patients in their 60 s with LPLD and hypertriglyceridemia, we suggest that LPLD may not be associated with the development or progression of coronary artery disease.

Serum HDL-C values: An extremely useful marker for differentiating homozygous lipoprotein lipase deficiency from severe hypertriglyceridemia with other causes in Japan: A meta-analysis based on literatures on Japanese homozygous lipoprotein lipase deficiency.

BACKGROUNDS AND AIM: Lipoprotein lipase (LPL) deficiency is a genetic disorder with a defective gene for lipoprotein lipase, leading to very high triglycerides. In the daily practice it is much more common to come across severely hypertriglyceridemia without homozygous or compound heterozygous LPL deficiency (SHTG). METHODS: We investigated on how to screen homozygous or compound heterozygous LPL deficiency using lipid parameters by meta-analyzing past 20 subjects on this genetic disease reported by Japanese investigators. As a comparison with LPL deficiency, 21 subjects with SHTG from recent two studies were included in this study. RESULTS: Serum HDL-C levels were significantly lower in LPL deficiency than in SHTG (0.38 ± 0.13 vs 0.94 ± 0.28 mmol/L (mean ± SD), p < 0.001), whereas other serum lipids did not differ between the two groups. The ROC curve ± standard error for serum HDL-C for discriminating the two groups was 0.97 ± 0.019. Sensitivity and specificity for distinguishing the two groups were 90% and 95%, respectively when serum HDL-C 0.62 mmol/L was adopted as cut point. CONCLUSION: We found for the first time that serum HDL-C is an extremely useful marker for discriminating LPL deficiency from SHTG in Japanese population.

The Association between Anthropometric Indices of Obesity and Chronic Kidney Disease in Middle-aged Japanese Men and Women: A Cohort Study.

Objective This study investigated associations between three indices of obesity-the body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR)-and the incidence of chronic kidney disease (CKD). Methods The employees of a company in Japan (1,725 men, 1,186 women; aged 35-55 years) had BMI, WC, and WHtR measured in health examinations. The incidence of CKD was determined at annual medical examinations over a six-year period. The hazard ratios for CKD were calculated using proportional hazard models, and the χ2 statistic was used to compare the strengths of the associations. Results The mean BMI (kg/m2), WC (cm), and WHtR were 23.6, 84.3, and 0.49 for men and 22.3, 79.7, and 0.50 for women, respectively. The incidence of CKD (/1,000 person-years) was 18.1 for men and 8.4 for women. In men, positive linear associations were observed between the BMI, WC, and WHtR and the risk of CKD, even after adjusting for the presence of metabolic abnormalities (p for trend <0.001, 0.012, and 0.023, respectively). In women, a linear association was observed only between the WHtR and CKD, not the BMI or WC (p for trend =0.042, 0.057, and 0.186). The χ2 statistics were the highest for the BMI in both men and women. Conclusion The BMI, WC, and WHtR were linearly associated with the risk of CKD independently of metabolic abnormalities in men, while the associations were weaker or not significant in women. The BMI was the most strongly associated with the incidence of CKD in both men and women.

Expression of human apoAII in transgenic rabbits leads to dyslipidemia: a new model for combined hyperlipidemia.

OBJECTIVE: Apolipoprotein AII (apoAII) is the second major apolipoprotein in high-density lipoprotein (HDL). However, the physiological functions of apoAII in lipoprotein metabolism have not been fully elucidated. METHODS AND RESULTS: We generated human apoAII transgenic (Tg) rabbits, a species that normally does not have an endogenous apoAII gene. Plasma levels of human apoAII in Tg rabbits were approximately 30 mg/dL, similar to the plasma levels in healthy humans. The expression of human apoAII in Tg rabbits resulted in increased levels of plasma triglycerides, total cholesterol, and phospholipids accompanied by a marked reduction in HDL-cholesterol levels compared with non-Tg littermates. Analysis of lipoprotein fractions showed that hyperlipidemia exhibited by Tg rabbits was caused by elevated levels of very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins. Furthermore, postheparin lipoprotein lipase activity significantly decreased in Tg rabbits compared with non-Tg rabbits. CONCLUSIONS: These results indicate that apoAII plays an important role in both VLDL and HDL metabolism, possibly through the inhibition of lipoprotein lipase activity. ApoAII Tg rabbits may become a new model for the study of human familial combined hyperlipidemia.

Detailed analysis of lipolytic enzymes in a Japanese woman of familial lipoprotein lipase deficiency - Effects of pemafibrate treatment.

BACKGROUND: We present here a 72-y-old Japanese woman with lipoprotein lipase (LPL) deficiency and analyzed her lipolytic enzymes in detail before and after pemafibrate treatment. METHODS: She had a serum triglycerides (TG) of 22.6 mmol/l at a medical checkup at the age of 52 y. She was referred to our hospital at the age of 61 y. Her serum lipoprotein lipase (LPL) concentration was extremely low, suggesting the clinical diagnosis of LPL deficiency. She experienced an event of acute pancreatitis at the age of 65 y. RESULTS: Next-generation sequencing analysis revealed a homozygous nonsense mutation in the LPL gene, c.1277G > A (p.Trp409Ter). Her serum TG, LPL and hepatic lipase (HL) concentrations were 15.0 mmol/l, 23 ng/ml and 66 ng/ml, respectively. Fifteen minutes after intravenous heparin injection (30 U/kg), her serum TG, LPL and HL concentrations turned to 14.1 mmol/l, 20 ng/ml and 660 ng/ml, respectively. Eight weeks of pemafibrate treatment (0.2 mg/day) caused a modest reductions in serum TG (15.02 â†’ 13.58 mmol/l) and considerable increases in preheparin HL (66 â†’ 76 ng/ml) and PHP-HL (660 â†’ 1118 ng/ml) concentrations and PHP-HL activities (253 â†’ 369U/l) despite almost no effect on LPL concentrations and activities. CONCLUSIONS: These findings suggest that HL may contribute to the reduction of plasma TG in LPL deficiency.

Synthesis and reversible control of the fluorescent properties of a divalent tin dipyrromethene.

A fluorescent chlorostannylene bearing a dipyrromethene ligand was synthesized. Its fluorescence quantum yield was low, Phi(f) = 0.04, probably because of the existence of the lone-pair orbital energetically close to the pi orbital. However, its fluorescence emission was increased to Phi(f) = 0.42 by dechlorination using silver triflate. The resulting cationic species reverted again to the chlorostannylene upon reaction with tetrabutylammonium chloride, with a corresponding weakening of the fluorescence.

Development of a sila-Friedel-Crafts reaction and its application to the synthesis of dibenzosilole derivatives.

An intramolecular sila-Friedel-Crafts reaction was developed and applied to the synthesis of dibenzosilole derivatives. This reaction proceeds under mild conditions to afford the target in relatively high yield, indicating its availability as a versatile synthetic method. The synthesis of trisilasumanene, a silicon analogue of sumanene, was achieved using the present reaction.

Formation of prebeta1-HDL during lipolysis of triglyceride-rich lipoprotein.

Prebeta1-HDL, a putative discoid-shaped high-density lipoprotein (HDL) is known to participate in the retrieval of cholesterol from peripheral tissues. In this study, to clarify potential sources of this lipoprotein, we conducted heparin injection on four Japanese volunteer men and found that serum triglyceride (TG) level decreased in parallel with the increase in serum nonesterified fatty acids and plasma lipoprotein lipase (LPL) protein mass after heparin injection. Plasma prebeta1-HDL showed considerable increases at 15 min after the heparin injection in all of the subjects. In contrast, serum HDL-C levels did not change. Gel filtration with fast protein liquid chromatography system (FPLC) study on lipoprotein profile revealed that in post-heparin plasma, low-density lipoprotein and alphaHDL fractions did not change, whereas there was a considerable decrease in very low-density lipoprotein (VLDL) fraction and an increase in prebeta1-HDL fraction when compared with those in pre-heparin plasma. We also conducted in vitro analysis on whether prebeta1-HDL was produced during VLDL lipolysis by LPL. One hundred microliters of VLDL extracted from pooled serum by ultracentrifugation was incubated with purified bovine milk LPL at 37 degrees C for 0-120 min. Prebeta1-HDL concentration increased in a dose dependent manner with increased concentration of added LPL in the reaction mixture and with increased incubation time, indicating that prebeta1-HDL was produced during lipolysis of VLDL by LPL. Taken these in vivo and in vitro analysis together, we suggest that lipolysis of VLDL particle by LPL is an important source for formation of prebeta1-HDL.

Detection of biologically important anions in aqueous media by dicationic azaborines bearing ammonio or phosphonio groups.

New cationic triarylboranes bearing ammonio or phosphonio groups on the periphery were synthesized from a common intermediate, a dibromodibenzoazaborine. These cationic molecules are soluble in highly polar organic solvents as well as water, and they exhibit strong light absorption and photoluminescence emission in water. Complexation of the cationic azaborines with fluoride and cyanide ions in aqueous media proceeded and could be monitored by NMR, UV/Vis, and fluorescence spectroscopy.

Synthesis and reactivity of a bis(dimesitylboryl)azaborine and its fluoride sensing ability.

An azaborine bearing two dimesitylboryl groups on its periphery showed very strong light absorption and moderate photo-luminescence emission; the reaction of the title compound with fluoride ion resulted in multi-step fluoride ion complexation on the boron atoms of the dimesitylboryl groups, producing mono- and bisfluoroborates.

Residual Effect of Sodium Glucose Cotransporter 2 Inhibitor, Tofogliflozin, on Body Weight After Washout in Japanese Men With Type 2 Diabetes.

BACKGROUND: We investigated the potential mechanism underlying body weight reduction by the sodium glucose cotransporter 2 (SGLT2) inhibitor, tofogliflozin, during treatment and after subsequent washout. METHODS: Ten Japanese men with type 2 diabetes (average age: 66.3 years) were orally administered tofogliflozin (20 mg/day) for 8 weeks followed by a subsequent 8-week washout period (16 weeks). RESULTS: Significant reductions were observed in blood glucose, hemoglobin A1c (HbA1c), uric acid, body weight and waist circumference with an increase in high-molecular weight (HMW) adiponectin at 8 weeks. We also evaluated these markers at 16 weeks and found that unlike HbA1c and uric acid, body weight and HMW adiponectin did not return to baseline levels. To clarify the potential mechanism underlying the body weight reduction during treatment with tofogliflozin (8 weeks) and after washout (at 16 weeks), we investigated the correlations between changes from baseline (0 week) in body weight and those in waist circumference (or HMW adiponectin). The changes in body weight between 0 weeks versus 8 weeks were not significantly correlated with those in waist circumference or HMW adiponectin. In contrast, changes in body weight between 0 and 16 weeks did show a significant correlation to those in waist circumference and HMW adiponectin. CONCLUSION: The body weight reduction caused by tofogliflozin may be due to several factors as well as fat reduction at 8 weeks, but is most likely due to fat reduction alone after a subsequent 8 weeks of washout of this agent.