(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Obesity

Small dense low-density lipoprotein (sdLDL), which are often associated with obesity, are considered as the most atherogenic and have been shown to impair endothelial function. It is not known whether reduction of sdLDL by pharmacological intervention can improve endothelial function. Thirty-four consecutive postmenopausal women with >/=5.70 mmol/L total cholesterol were placed into either an overweight (body mass index [BMI] >/= 25.0, n = 22) or a normal-weight (BMI < 25.0, n = 12) group, and forearm blood flow (FBF) was measured using strain-gauge plethysmography during reactive hyperemia before and after fluvastatin treatment. At baseline, the peak FBF during reactive hyperemia in the overweight group was less than that in the normal-weight group (mean +/- SD, 13.6 +/- 4.4 v 22.2 +/- 4.0 mL/min/100 mL, P <.01). The maximal FBF after nitroglycerin was similar in both groups. In the stepwise multiple regression analysis, only the concentration of sdLDL was the predictor for peak FBF (standard coefficient = -0.517, P =.0115). The nonsignificant parameters for the correlations in the model were age, BMI, systolic blood pressure, the homeostasis model assessment of insulin resistance (HOMA-IR), hemoglobin A(1c) (HbA(1c)), and LDL-cholesterol. Fluvastatin treatment was associated with the recovery of the peak FBF in the overweight group but it did not influence that of the normal-weight group. Changes in sdLDL fractions by fluvastatin correlated well with the peak FBF recovery. These results suggested that an increased sdLDL was linked to endothelial dysfunction in overweight postmenopausal women and fluvastatin treatment improved endothelial dysfunction by decreasing the atherogenic sdLDL fraction in this population.

Topics: Aged; Anticholesteremic Agents; Blood Flow Velocity; Case-Control Studies; Cholesterol; Endothelium, Vascular; Fatty Acids, Monounsaturated; Female; Fluvastatin; Forearm; Humans; Hypercholesterolemia; Hyperemia; Indoles; Lipids; Lipoproteins, LDL; Middle Aged; Obesity; Particle Size; Postmenopause; Time Factors

The aim of this study was to assess obese patients with hypercholesterolemia whom were prescribed a standardized diet, comparing the action of orlistat, fluvastatin, orlistat with fluvastatin, and placebo on anthropometric measurements, blood pressure (BP), and lipid profile.. This was a 1-year, randomized, double-blind, placebo-controlled trial. The patients were prescribed a controlled-energy diet and were randomly allocated to receive placebo, orlistat 120 mg TID (O group), fluvastatin 80 mg/d (F group), or olistat 120 mg TID with fluvastatin 80 mg/d (OF group). Clinical measurements (body weight, body mass index [BMI], waist circumference, and BP) and lipid profile assessment (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TGs]) were performed at baseline and after 6 months and 1 year of treatment.. The study included 99 obese patients with hypercholesterolemia (48 men and 51 women; mean [SD] age, 51 [9] years). There were no significant differences between groups in baseline demographic, BP, or plasma lipid values. Three patients dropped out (2 women in the O group and 1 man in the OF group) due to adverse events related to orlistat treatment, including gastrointestinal events (oily spotting and fecal urgency). Ninety-six patients completed the study. There were significant differences from baseline (mean [SD]) in BMI, waist circumference reduction (WCR), and body weight loss (BWL) at 6 months in the OF group (29.9 [1.1] kg/m(2), 2.7 [0.8] cm, and 7.4 [0.9] kg, respectively; all P < 0.05), and BMI, WCR, and BWL at 1 year in the O group (29.0 [1.0] kg/m(2), 3.0 [1.0] cm, and 8.6 [1.0] kg, respectively; all P < 0.02), the F group (29.3 [1.6] kg/m(2), 2.4 [1.0] cm, and 8/0 [1.0] kg, respectively; all P < 0.05), and the OF group (28.4 [0.6] kg/m(2), 4.0 [0.6] cm, and 11.4 [1.0] kg, respectively; all P < 0.01). Significant reductions from baseline in systolic and diastolic BP were observed at 1 year in the O and F groups (all P < 0.05) and the OF group (both P < 0.01). At 6 months, there were significant reductions from baseline in TC and LDL-C in the F group (both P < 0.05) and in TC, LDL-C, and TGs in the OF group (P < 0.02, P < 0.02, and P < 0.05, respectively), as well as a significant increase in HDL-C in the OF group (P < 0.02). At 1 year, there were significant reduction from baseline in TC in the O, F, and OF groups (P < 0.05 and P < 0.01, respectively), LDL-C (P < 0.05, P < 0.02, and P < 0.01, respectively), and TGs (P < 0.02, P < 0.05, and P < 0.02, respectively). Also at 1 year, HDL-C was significantly higher than baseline in the F and OF groups (P < 0.02 and P < 0.01, respectively).. Improvements in clinical and lipid-profile parameters were found at 1 year with all 3 treatments.

Topics: Anthropometry; Anti-Obesity Agents; Blood Pressure; Diet, Reducing; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lactones; Lipids; Male; Middle Aged; Obesity; Orlistat; Treatment Outcome

Brown adipose tissue (BAT), an organ that burns energy through uncoupling thermogenesis, is a promising therapeutic target for obesity. However, there are still no safe anti-obesity drugs that target BAT in the market. In the current study, we performed large scale screening of 636 compounds which were approved by Food and Drug Administration (FDA) to find drugs that could significantly increase uncoupling protein 1 (

Topics: Adipose Tissue, Brown; Animals; Anti-Obesity Agents; Cells, Cultured; Energy Metabolism; Fluvastatin; Humans; Male; Mice; Mice, Inbred C57BL; Obesity; Uncoupling Protein 1

Obesity is associated with ~40% of cancer diagnoses but there are currently no effective preventive strategies, illustrating a need for chemoprevention. We previously demonstrated that fibroblast growth factor 2 (FGF2) from adipose tissue stimulates malignant transformation, as measured by growth in soft agar, the gold-standard in vitro transformation assay. Because the soft agar assay is unsuitable for high throughput screens (HTS), we developed a novel method using 3D growth in ultra-low attachment conditions as an alternative to growth in agar to discover compounds that inhibit transformation. Treating non-tumorigenic, skin epithelial JB6 P

Topics: Animals; Antineoplastic Agents; Cell Culture Techniques; Cell Proliferation; Cell Transformation, Neoplastic; Drug Screening Assays, Antitumor; Fibroblast Growth Factor 2; Fibroblasts; Fluvastatin; High-Throughput Screening Assays; Humans; Mice; Models, Biological; Neoplasms; Obesity; Podophyllotoxin; Skin

Statins can reduce reproductive damage induced by obesity or high-fat diet (HFD), but the specific regulatory mechanisms are largely unknown. Since mTOR/p70s6k sinaling promotes spermatogonia proliferation and spermatogenesis, we hypothesized that this pathway will be involved in the protective effects of statin in HFD-induced reproductive dysfunction.. Male Sprague Dawley rats (3 weeks old) were randomly divided into a control group (standard diet), HFD group, and a fluvastatin group (HFD + fluvastatin at 6mg/kg, once daily by oral gavage). After 8 weeks, body weight was obtain and rats were sacrificed. Weights of the testes, gross morphology, sperm parameters, circulating levels of sex hormones, lipid levels, and tissue mTOR, p-P70s6k were measured. Another set of male rats were treated with rapamycin or vehicle. Flow cytometry was used to detect the spermatogonia marker c-kit and cell cycle. p-P70s6k expression was analyzed by Western blot.. HFD not only results in rat obesity but also leads to spermatogenetic damage and fluvastatin was able to partially block the effects of HFD. Fluvastatin also partially reversed the suppression of mTOR and p-p70s6k expresson.. Our data suggest that fluvastatin has protective effects on reproductive function in obese male rats most probably through enhanced signaling of mTOR.

Topics: Animals; Body Weight; Cells, Cultured; Diet, High-Fat; Estradiol; Fatty Acids, Monounsaturated; Fluvastatin; Indoles; Lipids; Luteinizing Hormone; Male; Obesity; Protective Agents; Proto-Oncogene Proteins c-kit; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Spermatogenesis; Spermatogonia; Testis; Testosterone; TOR Serine-Threonine Kinases

Statins reduce lipid levels and are widely prescribed. Statins have been associated with an increased incidence of type 2 diabetes, but the mechanisms are unclear. Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/caspase-1 inflammasome, promotes insulin resistance, a precursor of type 2 diabetes. We showed that four different statins increased interleukin-1β (IL-1β) secretion from macrophages, which is characteristic of NLRP3 inflammasome activation. This effect was dose dependent, absent in NLRP3(-/-) mice, and prevented by caspase-1 inhibition or the diabetes drug glyburide. Long-term fluvastatin treatment of obese mice impaired insulin-stimulated glucose uptake in adipose tissue. Fluvastatin-induced activation of the NLRP3/caspase-1 pathway was required for the development of insulin resistance in adipose tissue explants, an effect also prevented by glyburide. Fluvastatin impaired insulin signaling in lipopolysaccharide-primed 3T3-L1 adipocytes, an effect associated with increased caspase-1 activity, but not IL-1β secretion. Our results define an NLRP3/caspase-1-mediated mechanism of statin-induced insulin resistance in adipose tissue and adipocytes, which may be a contributing factor to statin-induced development of type 2 diabetes. These results warrant scrutiny of insulin sensitivity during statin use and suggest that combination therapies with glyburide, or other inhibitors of the NLRP3 inflammasome, may be effective in preventing the adverse effects of statins.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Carrier Proteins; Caspase 1; Fatty Acids, Monounsaturated; Fluvastatin; Glyburide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammasomes; Insulin Resistance; Interleukin-1beta; Macrophages; Male; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity

The male Wistar rats were kept at high fat diet for 90 days and subjected to partial abdominal aortic constriction (PAAC) at 62nd and continued up to 90th day. Similarly, rats were kept at high fat diet for 90 days and subjected to chronic swimming training (CST) at 46th day and continued up to 90th day. Obesity was assessed by % age change in body weight, WHR ratio and adiposity index whereas cardiac hypertrophy was assessed by using index of cardiac hypertrophy, i.e., left ventricular weight, left ventricular weight to body weight, (LVW/BW), left ventricular wall thickness (LVWT), cardiomyocyte diameter, LV, protein content and collagen content. Further, mean arterial blood pressure (MABP) was also recorded. Oxidative stress was assessed by measuring the levels of thiobarbituric acid reactive species (TBARS), levels of superoxide anion generation and levels of reduced glutathione in left ventricular tissue. The PAAC and CST increased the index of cardiac hypertrophy. Moreover, PAAC has significantly increased MABP. Fluvastatin, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, significantly attenuated PAAC induced left ventricular cardiac hypertrophy and MABP whereas no significant change was observed in CST-induced cardiac hypertrophy. Furthermore, fluvastatin significantly attenuated the oxidative stress by decreasing the levels of TBARS and superoxide anion generation and increasing the levels of reduced glutathione. These results suggest that fluvastatin prevented the PAAC-induced cardiac hypertrophy.

Topics: Animals; Aorta, Abdominal; Blood Glucose; Collagen; Constriction; Dietary Fats; Dietary Sucrose; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated; Fluvastatin; Glutathione; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertrophy, Left Ventricular; Indoles; Lipid Peroxidation; Lipids; Male; Muscle Proteins; Obesity; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Wistar; Superoxides; Swimming; Ventricular Remodeling

To study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta to adrenomedullin (AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Deltatension at 10(-7) mol/l AM; LZ, -85.1 +/- 3.1%; OZ, -50.7 +/- 2.5%; OZ + Flu, -75.6 +/- 2.7%). Expression of endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in response to AM (10(-7) mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity): LZ, 2.3 +/- 0.4; OZ, 1.0 +/- 0.2; OZ + Flu, 1.8 +/- 0.3; Akt phosphorylation (relative intensity): LZ, 2.3 +/- 0.2; OZ, 1.0 +/- 0.3; OZ + Flu, 1.9 +/- 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTPgammaS-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca(2+) sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca(2+) sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.

Topics: Adrenomedullin; Angiotensin II; Animals; Aorta; Calcium; Diabetic Angiopathies; Endothelium, Vascular; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Obesity; Peptides; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; rho GTP-Binding Proteins; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Renal transplantation is associated with an increased risk for premature cardiovascular disease. We analyzed the data in the placebo arm of Assessment of Lescol in Renal Transplantation (ALERT) to improve our understanding of the relationship between cardiovascular risk factors and outcomes in this unique population.. We performed Cox survival analysis for myocardial infarction, cardiac death, and noncardiac death in 1,052 patients recruited to the placebo arm of ALERT. These subjects were aged 30 to 75 years, had stable graft function at least 6 months after transplantation, had a serum total cholesterol level between 155 and 348 mg/dL (4 and 9 mmol/L), and were receiving cyclosporine-based immunosuppression.. The results confirm previous studies. In multivariate analysis, preexisting coronary heart disease (hazard ratio [HR], 3.69; P < 0.001), total cholesterol level (HR, 1.55 per 50 mg/dL; P = 0.0045), and prior acute rejection (HR, 2.36; P = 0.0023) were independent risk factors. Conversely, independent risk factors for cardiac death were age (HR, 1.58 per decade; P = 0.0033), diabetes (HR, 3.35; P = 0.0002), ST-T changes on the ECG (HR, 3.17; P = 0.0004), and serum creatinine level (HR, 2.65 per milligram per deciliter; P < 0.0001).. This analysis confirms that renal transplant recipients share risk factors for myocardial infarction and cardiac death with the general population. However, the pattern of risk factors and their relationship with outcomes is atypical, highlighting the unique nature of cardiovascular risk in transplant recipients.

Topics: Adult; Aged; Cardiovascular Diseases; Creatinine; Death, Sudden, Cardiac; Diabetes Mellitus; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Immunosuppressive Agents; Indoles; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mortality; Myocardial Infarction; Obesity; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Factors; Smoking; Survival Analysis

Topics: Administration, Oral; Anticholesteremic Agents; Cyclosporine; Dermatologic Agents; Drug Synergism; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hyperlipoproteinemia Type II; Immunosuppressive Agents; Indoles; Lipoproteins, LDL; Middle Aged; Obesity; Psoriasis