High-density lipoprotein and apolipoprotein A-I inhibit palmitate-induced translocation of toll-like receptor 4 into lipid rafts and inflammatory cytokines in 3T3-L1 adipocytes.

Saturated fatty acids (SFAs) activate toll-like receptor 4 (TLR4) signal transduction in macrophages and are involved in the chronic inflammation accompanying obesity. High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) produce anti-inflammatory effects via reverse cholesterol transport. However, the underlying mechanisms by which HDL and apoA-I inhibit inflammatory responses in adipocytes remain to be determined. Here we examined whether palmitate increases the translocation of TLR4 into lipid rafts and whether HDL and apoA-I inhibit inflammation in adipocytes. Palmitate exposure (250 µM, 24 h) increased interleukin-6 and tumor necrosis factor-α gene expressions and translocation of TLR4 into lipid rafts in 3T3-L1 adipocytes. Pretreatment with HDL and apoA-I (50 µg/mL, 6 h) suppressed palmitate-induced inflammatory cytokine expression and TLR4 translocation into lipid rafts. Moreover, HDL and apoA-I inhibited palmitate-induced phosphorylation of nuclear factor-kappa B. HDL showed an anti-inflammatory effect via ATP-binding cassette transporter G1 and scavenger receptor class B, member 1, whereas apoA-I showed an effect via ATP-binding cassette transporter A1. These results demonstrated that HDL and apoA-I reduced palmitate-potentiated TLR4 trafficking into lipid rafts and its related inflammation in adipocytes via these specific transporters.

Pravastatin improves postprandial endothelial dysfunction and hemorheological deterioration in patients with effort angina pectoris.

Postprandial hypertriglyceridemia and hyperglycemia may promote endothelial and hemorheological dysfunction. The present study investigated the effects of pravastatin on endothelial function and hemorheology in patients with stable angina pectoris (AP) before and after eating a test meal. We recruited 26 patients with stable AP who had impaired glucose tolerance and mild dyslipidemia and six healthy men as controls to assess endothelial function and hemorheological behavior. In each group, we measured forearm blood flow (FBF) during post-ischemic reactive hyperemia and obtained blood samples before and 2 h after the test meal. Pravastatin 20 mg/day was then commenced in the 26 AP patients. The above tests were repeated after 2 days and 6 months. Maximum FBF during hyperemia in the baseline fasting phase was significantly lower in the AP patients than in the controls (p < 0.05). Fasting and postprandial FBF during reactive hyperemia time-dependently improved after pravastatin treatment (p < 0.05 vs. baseline data for each phase). Pravastatin treatment for 6 months, but not for 2 days, inhibited leukocyte activation and improved hemorheological parameters. In conclusion, pravastatin treatment for 6 months improved fasting and postprandial endothelial and hemorheological dysfunction in AP patients.

Effects of pitavastatin on walking capacity and CD34+/133+ cell number in patients with peripheral artery disease.

This multi-center prospective non-randomized comparative study investigated the effects of pitavastatin in patients with peripheral artery disease (PAD) in terms of exercise tolerance capacities and peripheral CD34+/133+ cell numbers. At baseline, a peripheral blood test was administered to 75 patients with PAD, along with a treadmill exercise test using the Skinner-Gardner protocol to measure asymptomatic walking distance (AWD) and maximum walking distance (MWD). Each patient was assigned to a 6-month pitavastatin treatment group (n = 53) or a control group (n = 22), according to the patient's preference. The tests were repeated in both groups at 3 and 6 months. Baseline AWD and MWD correlated positively with the ankle-brachial pressure index (r = 0.342, p = 0.0032 and r = 0.324, p = 0.0054, respectively). Both AWD and MWD values improved at 3 and 6 months compared with baseline, and the degrees of their improvement were higher in the pitavastatin treatment group. CD34+/133+ cell numbers did not change over time or between groups. Eighty-seven percent of patients in the treatment group attained low-density lipoprotein cholesterol levels below 100 mg/dL after 3 months. The study shows that pitavastatin may be effective in increasing exercise tolerance capacity in patients with PAD.

Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review].

In pancreatic ß-cells, glucose-induced closure of the ATP-sensitive K+ (KATP) channel is an initial process triggering glucose-stimulated insulin secretion (GSIS). This KATP-channel dependent pathway has been believed to be a central mechanism for GSIS. However, since the resting membrane potential of cells is determined by the balance of the net result of current amplitudes in outward and inward directions, it must be taken into consideration that not only KATP channel inhibition but also inward current via the basal opening of non-selective cation channels (NSCCs) plays a crucial role in membrane potential regulation. The basal activity of NSCCs is essential to effectively evoke depolarization in concert with KATP channel closure that is dependent on glucose metabolism. The present study summarizes recent findings regarding the roles of NSCCs in GSIS and GTP-binding protein coupled receptor-(GPCR) operated potentiation of GSIS.

Suppression of coronary atherosclerosis by helix B surface Peptide, a nonerythropoietic, tissue-protective compound derived from erythropoietin.

Erythropoietin (EPO), a type I cytokine originally identified for its critical role in hematopoiesis, has been shown to have nonhematopoietic, tissue-protective effects, including suppression of atherosclerosis. However, prothrombotic effects of EPO hinder its potential clinical use in nonanemic patients. In the present study, we investigated the antiatherosclerotic effects of helix B surface peptide (HBSP), a nonerythropoietic, tissue-protective compound derived from EPO, by using human umbilical vein endothelial cells (HUVECs) and human monocytic THP-1 cells in vitro and Watanabe heritable hyperlipidemic spontaneous myocardial infarction (WHHLMI) rabbits in vivo. In HUVECs, HBSP inhibited apoptosis (≈70%) induced by C-reactive protein (CRP), a direct mediator of atherosclerosis. By using a small interfering RNA approach, Akt was shown to be a key molecule in HBSP-mediated prevention of apoptosis. HBSP also attenuated CRP-induced production of tumor necrosis factor (TNF)-α and matrix metalloproteinase-9 in THP-1 cells. In the WHHLMI rabbit, HBSP significantly suppressed progression of coronary atherosclerotic lesions as assessed by mean cross-sectional stenosis (HBSP 21.3 ± 2.2% versus control peptide 38.0 ± 2.7%) and inhibited coronary artery endothelial cell apoptosis with increased activation of Akt. Furthermore, TNF-α expression and the number of M1 macrophages and M1/M2 macrophage ratio in coronary atherosclerotic lesions were markedly reduced in HBSP-treated animals. In conclusion, these data demonstrate that HBSP suppresses coronary atherosclerosis, in part by inhibiting endothelial cell apoptosis through activation of Akt and in association with decreased TNF-α production and modified macrophage polarization in coronary atherosclerotic lesions. Because HBSP does not have the prothrombotic effects of EPO, our study may provide a novel therapeutic strategy that prevents progression of coronary artery disease.

Association of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes.

BACKGROUND: Osteoprotegerin is a member of the tumor necrosis factor-related family and inhibits RANK stimulation of osteoclast formation as a soluble decoy receptor. The goal of this study was to determine the relationship of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes. METHODS: The subjects were 124 patients with type 2 diabetes mellitus, including 88 males and 36 females with a mean (± SD) age of 65.6 ± 8.2 years old. Serum levels of osteoprotegerin, osteocalcin, fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D3 and adiponectin were measured by ELISA. Vascular calcification in the cervical artery was examined by ultrasound sonography. The subjects were divided into 4 quartiles depending on serum osteoprotegerin levels. RESULTS: Vascular calcification was significantly higher in the 4th quartile and significantly lower in the 1st quartile of serum osteoprotegerin levels, compared to other quartiles. There were no differences in serum osteoprotegerin and vascular calcification among patients with different stages of diabetic nephropathy, but serum FGF23 levels were elevated in those with stage 4 diabetic nephropathy. Simple regression analysis showed that serum osteoprotegerin levels had significant positive correlations with age, systolic blood pressure and serum adiponectin levels, and significant negative correlations with BMI and serum 25-hydroxyvitamin D3. CONCLUSIONS: These findings suggest that elevated serum osteoprotegerin may be involved in vascular calcification independently of progression of diabetic nephropathy in patients with type 2 diabetes.

Inhibition of insulin secretion from rat pancreatic islets by dexmedetomidine and medetomidine, two sedatives frequently used in clinical settings.

The aim of this study was to determine whether dexmedetomidine (DEX) and medetomidine (MED), α2-adrenergic agonists clinically used as sedatives, influence insulin secretion from rat pancreatic islets. Islets were isolated from adult male Wistar rats after collagenase digestion. Static incubation was used to determine effects of DEX or MED on insulin secretion and ionic-channel currents of ß-cells. Results indicate that both drugs dose-dependently inhibit insulin secretion, DEX more potently than MED. The inhibitory effects were attenuated by addition of yohimbine or by pretreatment of rats with pertussis toxin (PTX). 10 nM DEX decreased the current amplitude of voltage-dependent Ca2+ channels, but this did not occur when the N-type Ca2+ channel blocker ω-conotoxin was added. In the presence of tetraethylammonium, a classical voltage-gated K+ channel (Kv channel) blocker, the magnitude of inhibition of insulin secretion by MED was reduced. However, when tolbutamide, a specific blocker of the ATP-sensitive K+ channel (KATP channel), was present, the magnitude of MED inhibition of insulin secretion was not influenced, suggesting that Kv-channel activity alteration, but not that of KATP channels, is involved in MED-associated insulin secretory inhibition. The Kv-channel currents were increased during 1 nM MED exposure at membrane potentials ranging from -30 mV to -10 mV, where action potentials were generated in response to glucose stimulation. These results indicate that DEX and MED inhibit insulin secretion through an α2-adrenoceptor and PTX-sensitive GTP-binding protein pathway that eventually involves Kv channel activation and Ca2+ channel inhibition.

Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin.

Erythropoietin (EPO), originally identified for its critical hormonal role in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of tissues, including the heart, by preventing apoptosis. However, EPO also has undesirable effects, such as thrombogenesis. In the present study, we investigated whether a helix B-surface peptide (HBSP), a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin, protects cardiomyocytes from apoptosis in vitro and in vivo. In cultured neonatal rat cardiomyocytes, HBSP clearly inhibited apoptosis (approximately 80%) induced by TNF-alpha, which was comparable with the effect of EPO, and activated critical signaling pathways of cell survival, including Akt, ERK1/2, and STAT3. Among these pathways, Akt was shown to play an essential role in HBSP-induced prevention of apoptosis, as assessed by using a small interfering RNA approach. In the dilated cardiomyopathic hamster (J2N-k), whose cardiac tissues diffusely expressed TNF-alpha, HBSP also inhibited apoptosis (approximately 70%) and activated Akt in cardiomyocytes. Furthermore, the levels of serum creatine kinase activity and of cardiac expression of atrial natriuretic peptide, a marker of chronic heart failure, were down-regulated in animals treated with HBSP. These data demonstrate that HBSP protects cardiomyocytes from apoptosis and leads to a favorable outcome in failing hearts through an Akt-dependent pathway. Because HBSP does not have the undesirable effects of EPO, it could be a promising alternative for EPO to treat cardiovascular diseases, such as myocardial infarction and heart failure.

An ultrasensitive enzymatic method for measuring mevalonic acid in serum.

We have developed a simple, precise, and ultrasensitive enzymatic method for measuring serum mevalonic acid (MVA) concentration, which is thought to be a good indicator of the in vivo cholesterol biosynthesis rate. This assay is based on an enzyme cycling reaction and makes use of HMG-CoA reductase (HMGR), thio-NAD, NADH, and CoA. MVA participates in the HMGR cycling reaction, and its level is measured based on the production of thio-NADH, which is determined from the change in absorbance at 405 nm. To achieve high specificity, we used mevalonate kinase (MVK) in addition to HMGR. Only substrates able to participate in both the HMGR cycling reaction and the MVK reaction are measured as MVA. The detection limit for MVA is 0.4 ng/ml (2.7 nmol/l), and the calibration curve for MVA is linear up to 44 ng/ml (300 nmol/l). Regression analysis with 40 serum samples showed the accuracy of quantifying MVA with this enzymatic assay to be comparable to that using LC-MS/MS (correlation: y = 0.83x + 0.24; r = 0.97). This procedure is simple, precise, and robust. It is also rapid and has a high throughput, making it potentially useful for clinical applications.

Latent associations of low serum amylase with decreased plasma insulin levels and insulin resistance in asymptomatic middle-aged adults.

BACKGROUND: Low serum amylase is likely to be associated with obesity and metabolic abnormalities, which are often accompanied by impaired insulin action. However, it is unclear whether low serum amylase is associated with impaired insulin action in clinical settings. Therefore, we investigated the associations of low serum amylase with plasma insulin levels, and obesity-related parameters, including leptin. RESEARCH DESIGN AND METHODS: We measured serum amylase, plasma insulin, obesity-related parameters such as leptin, cardiometabolic risk factors, and anthropometric parameters in a cross-sectional study of 54 asymptomatic subjects (mean age 48.6 ± 7.6 years) who were not being treated for diabetes. RESULTS: Body mass index (BMI) and plasma glucose at 120 min after a 75-g oral glucose tolerance test (OGTT) were significantly higher in subjects with low serum amylase (< 60 IU/l, n = 21) than in those with normal-to-high serum amylase (n = 33) (P = 0.04 and P = 0.004, respectively). In univariate correlation analysis, serum amylase was significantly correlated with BMI alone (r = -0.39, P = 0.004). By contrast, multivariate logistic analysis showed that each 1-SD increase in quantitative insulin sensitivity check index, and each 1-SD decrease in plasma insulin OGTT at 0 and 60 min, homeostasis model assessment of insulin resistance (HOMA)-R, and HOMA-ß were significantly associated with low serum amylase, particularly after adjusting for BMI. When subjects were divided into three groups according to HOMA-R, serum amylase levels were significantly lower in subjects with HOMA-R > 2.5 (n = 23) compared with subjects with HOMA-R 1.6-2.5 (n = 10) (61.1 ± 13.6 U/ml versus 76.9 ± 20.5 U/ml, Bonferroni test, P = 0.02), but not compared with subjects with HOMA-R<1.6 (n = 21; 62.7 ± 17.6 U/ml). Similar trends were observed when subjects were divided according to plasma leptin and fasting plasma insulin levels. CONCLUSIONS: These results suggest that after adjusting for BMI, low serum amylase is associated with decreased basal insulin levels and insulin secretion, as well as high insulin resistance. The nature of these associations remains to be elucidated in further studies.

Association of subcutaneous and visceral fat mass with serum concentrations of adipokines in subjects with type 2 diabetes mellitus.

The goal of the study was to examine the association of subcutaneous and visceral fat mass with serum concentrations of adipokines in 130 subjects with type 2 diabetes mellitus. The levels of serum high sensitivity C-reactive protein (HS-CRP), adiponectin, high-molecular-weight (HMW) adiponectin, interleukin-18, and retinol-binding protein 4 were measured. Percentage body fat was determined by dual energy X-ray absorptiometry, and subcutaneous and visceral fat areas were measured by abdominal CT. HS-CRP had significant positive correlations with percentage body fat and subcutaneous fat area, and a particularly significant positive correlation with visceral fat area. Serum adiponectin had a negative correlation with the subcutaneous and visceral fat areas, with the strongest correlation with the visceral fat area. Similar results were obtained for HMW adiponectin. Serum adiponectin had a negative correlation with visceral fat area in subjects with a visceral fat area < 100 cm², but not in those with a visceral fat area ≥ 100 cm². In contrast, serum HS-CRP showed a positive correlation with visceral fat area in subjects with visceral fat area ≥ 100 cm², but not in those with a visceral fat area < 100 cm². These findings indicate that an increased visceral fat area is associated with inflammatory changes, and that inflammatory reactions may alter the functional properties of visceral fat in type 2 diabetes mellitus.

Hyponatremia is the valuable manifestation for initiating diagnosis of hypopituitarism in elderly.

The present study was undertaken to determine clinical features of hypopituitarism in elderly subjects. Thirty-one elderly patients with hypopituitarism were enrolled. They were 19 males and 12 females, with the ages of 70.7±5.4 years ranging from 62 to 80 years. High prevalence of hyponatremia (80.6%) and hypoglycemia (29.0%) was found, and it was totally different from that in hypopituitarism from general population. There were two groups of hyponatremia derived from their clinical courses, namely, acute deterioration of hyponatremia and chronically persistent hyponatremia. Analysis for deficient hormones clearly showed that ACTH deficiency was highly found in 30 of 31 patients. There was no difference in serum cortisol levels between the hyponatremic and normonatremic patients. Despite hypoosmolality, plasma arginine vasopressin (AVP) was apparently high in the hyponatremic patients compared with in the normonatremic ones. The present study indicates that hyponatremia is the valuable finding for initiating diagnosis of hypopituitarism, and that augmented release of AVP may be involved in developing hyponatremia in elderly patients with hypopituitarism.

Prompt increases in retinol-binding protein 4 and endothelial progenitor cells during acute exercise load in diabetic subjects.

The present study was undertaken to determine whether acute exercise load alters serum retinol-binding protein 4 (RBP4) and numbers of endothelial progenitor cells (EPC) in diabetic subjects. Sixty-two subjects with type 2 diabetes mellitus were enrolled in the present study. They were 50 males and 12 females with the ages of 65.1±8.1 (mean ± SD) years. Cardio-pulmonary exercise stress test (CPX) was carried out, and the numbers of EPC and serum RBP4 levels before and after the CPX were measured. RBP4 is a cytokine synthesized in hepatocytes, white adipose tissues and skeletal muscles, and serum RBP4 was determined by ELISA. EPC was determined as CD34(+)/133(+) cells by FACS. The subjects were subgrouped into two groups with or without nephropathy. Serum RBP4 levels promptly increased from 48.2±4.3 (mean±SEM) to 54.3±4.2 µg/mL after the CPX (mean exercise time of 8 min) in the diabetic subjects without nephropathy (p=0.0006), but did not in those with nephropathy. There was a positive correlation between changes in serum RBP4 during the exercise and estimated glomerular filtration rate (r=0.30, p=0.018). Also, an acute exercise load promptly increased the number of EPCs in the diabetic subjects with and without nephropathy. These findings suggest that a prompt increase in exercise-induced RBP4 is retarded by progression of nephropathy, and that an exercise-induced mobilization of EPCs could maintain endothelial cells in diabetic subjects.

A novel mechanism of imeglimin-mediated insulin secretion via the cADPR-TRP channel pathway.

AIMS/INTRODUCTION: Imeglimin is a novel oral hypoglycemic agent that improves blood glucose levels through multiple mechanisms of action including the enhancement of glucose-stimulated insulin secretion (GSIS), however, the details of this mechanism have not been clarified. In the process of GSIS, activation of the transient receptor potential melastatin 2 (TRPM2) channel, a type of non-selective cation channel (NSCCs) in ß-cells, promotes plasma membrane depolarization. The present study aimed to examine whether imeglimin potentiates GSIS via the TRPM2 channel in ß-cells. MATERIALS AND METHODS: Pancreatic islets were isolated by collagenase digestion from male wild-type and TRPM2-knockout (KO) mice. Insulin release and nicotinamide adenine dinucleotide (NAD+ ) production in islets were measured under static incubation. NSCC currents in mouse single ß-cells were measured by patch-clamp experiments. RESULTS: Batch-incubation studies showed that imeglimin enhanced GSIS at stimulatory 16.6 mM glucose, whereas it did not affect basal insulin levels at 2.8 mM glucose. Imeglimin increased the glucose-induced production of NAD+ , a precursor of cADPR, in islets and the insulinotropic effects of imeglimin were attenuated by a cADPR inhibitor 8-Br-cADPR. Furthermore, imeglimin increased NSCC current in ß-cells, and abolished this current in TRPM2-KO mice. Imeglimin did not potentiate GSIS in the TRPM2-KO islets, suggesting that imeglimin's increase of NSCC currents through the TRPM2 channel is causally implicated in its insulin releasing effects. CONCLUSIONS: Imeglimin may activate TRPM2 channels in ß-cells via the production of NAD+ /cADPR, leading to the potentiation of GSIS. Developing approaches to stimulate cADPR-TRPM2 signaling provides a potential therapeutic tool to treat type 2 diabetes.

Voltage-dependent metabolic regulation of Kv2.1 channels in pancreatic beta-cells.

Voltage-gated potassium channels (Kv channels) play a crucial role in formation of action potentials in response to glucose stimulation in pancreatic beta-ells. We previously reported that the Kv channel is regulated by glucose metabolism, particularly by MgATP. We examined whether the regulation of Kv channels is voltage-dependent and mechanistically related with phosphorylation of the channels. In rat pancreatic beta-cells, suppression of glucose metabolism with low glucose concentrations of 2.8mM or less or by metabolic inhibitors decreased the Kv2.1-channel activity at positive membrane potentials, while increased it at potentials negative to -10 mV, suggesting that modulation of Kv channels by glucose metabolism is voltage-dependent. Similarly, in HEK293 cells expressing the recombinant Kv2.1 channels, 0mM but not 10mM MgATP modulated the channel activity in a manner similar to that in beta-cells. Both steady-state activation and inactivation kinetics of the channel were shifted toward the negative potential in association with the voltage-dependent modulation of the channels by cytosolic dialysis of alkaline phosphatase in beta-cells. The modulation of Kv-channel current-voltage relations were also observed during and after glucose-stimulated electrical excitation. These results suggest that the cellular metabolism including MgATP production and/or channel phosphorylation/dephosphorylation underlie the physiological modulation of Kv2.1 channels during glucose-induced insulin secretion.

Effects of submaximal exercise on blood rheology and sympathetic nerve activity.

BACKGROUND: To explore the acute effects of submaximal exercise on blood rheology and sympathetic nerve activity. METHODS AND RESULTS: The effects of exercise (20 or 80 Watts (W)) on blood rheology and sympathetic nerve activity were assessed in 10 healthy Japanese men. Blood sampling and heart rate variability (HRV) recording were performed during 20-min supine rest and standing ergometric exercise (20 W for 10 min, 80 W for 10 min) and recovery. Blood passage time across the microchannels (diameter, 7 microm) as a parameter of blood rheology, and the number of adhesive leukocytes on microchannel terraces as a parameter of leukocyte activation were measured. Sympathetic nerve activity was evaluated by plasma noradrenalin levels and the ratio of low-frequency (LF)/high-frequency (HF) by spectral analysis of HRV. Compared with values while supine at rest, significant increases in hematocrit, leukocyte count, noradrenalin level and blood passage time were seen after strenuous ergometer exercise at 80 W (P<0.01 each). The LF/HF ratio and nitric oxide metabolites tended to be increased with 80 W exercise. CONCLUSIONS: Strenuous exercise dynamically alters blood rheological parameters, probably by changes in hematocrit and sympathetic nerve activity.

Circulating CD34+/133+ progenitor cells in patients with stable angina pectoris undergoing percutaneous coronary intervention.

BACKGROUND: This study explored the clinical significance of CD34(+)/133(+) circulating progenitor cell (CPC) counts in patients with stable angina pectoris (AP) who underwent percutaneous coronary intervention (PCI). METHODS AND RESULTS: Subjects comprised 52 patients with stable AP requiring PCI and 50 control patients without AP. In the AP group, blood samples were taken before and 20 min and 24 h after PCI to measure CPC counts by fluorescence-activated cell sorter analysis. The baseline number of CPCs was smaller in the AP group than in controls. In the AP group, body mass index (BMI) correlated positively with the baseline number of CPCs and was an independent predictor of CPC count in multivariate regression analysis. Other conventional risk factors, daily exercise activity and statin administration showed no association with CPC count. CPC counts remained unchanged within 24 h after PCI. CONCLUSIONS: CPC counts in patients with AP are influenced by BMI, but not by other coronary risk factors. CPC counts remain unchanged within 24 h after PCI.

Decrease in malonyl-CoA and its background metabolic alterations in murine model of cancer cachexia.

The alterations of enzymatic activities involved in lipid degradation in cancer cachexia have not been fully elucidated. One of the two subclones of colon 26 adenocarcinoma, clone 20, with a potent ability to induce cachexia, or clone 5, without such an activity, was transplanted in to CDF-1 male mice. Murine livers were extirpated for analyses on the 14th day after tumor inoculation. The body weights and food intake of mice bearing clone 20 were all significantly lower than those of non-tumor bearing mice and mice bearing the clone 5 tumor. The decline of body weight was accompanied by a shrinkage of epididymal fat pads. Expression of spermidine/spermine N-1 acetyl transferase (SSAT) assessed by real-time PCR was significantly increased in cachectic mice. Conversely, acetyl-CoA carboxylase (ACC) measured by Western blotting and malonyl-CoA levels determined by malonyl-CoA:acetyl-CoA cycling procedures were decreased in cachectic mice. Indomethacin in drinking water reversed the clone 20 induced decrease in body and fat weight and food intake, and simultaneously negated the clone 20 induced increase of SSAT expressions and decrease of ACC and malonyl-CoA amounts. Because malonyl-CoA inhibits the rate-limiting step in the beta-oxidation of fatty acids, the decreased malonyl-CoA and the background metabolic alterations may contribute to the accelerated lipolysis of cancer cachexia.

Effects of pitavastatin on fasting and postprandial endothelial function and blood rheology in patients with stable coronary artery disease.

BACKGROUND: Because postprandial hypertriglyceridemia and hyperglycemia may promote atherosclerosis, the present study investigated the effects of a clinical dose of pitavastatin on endothelial function and blood rheology in patients with coronary artery disease (CAD) before and after eating a test meal. METHODS AND RESULTS: The 16 patients with stable CAD and mild dyslipidemia and 6 age-matched healthy men as controls were recruited. In each group, forearm blood flow (FBF) was measured during postischemic reactive hyperemia and blood samples were taken before and 2 h after the test meal. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also measured. The patients were started on pitavastatin 2 mg/day. The tests were repeated after 6 months. Maximum FBF during hyperemia in the baseline fasting phase was significantly lower in CAD patients than in control subjects (P=0.040). Fasting and postprandial FBF during reactive hyperemia significantly improved after pitavastatin treatment (P<0.05 vs baseline data for each phase) associated with reduced urine 8-OHdG, increased plasma adiponectin and improved lipid profile. No significant differences in baseline rheological parameters were seen between controls and CAD patients. CONCLUSIONS: Pitavastatin significantly improved fasting and postprandial dyslipidemia and endothelial dysfunction in CAD patients, partly via reducing oxidative stress and increasing plasma adiponectin, although rheological parameters remained unchanged.