Simvastatin Impairs Insulin Secretion by Multiple Mechanisms in MIN6 Cells

Statins are widely used in the treatment of hypercholesterolemia and are efficient in the prevention of cardiovascular disease. Molecular mechanisms explaining statin-induced impairment in insulin secretion remain largely unknown. In the current study, we show that simvastatin decreased glucose-stimulated insulin secretion in mouse pancreatic MIN6 β-cells by 59% and 79% (p<0.01) at glucose concentration of 5.5 mmol/l and 16.7 mmol/l, respectively, compared to control, whereas pravastatin did not impair insulin secretion. Simvastatin induced decrease in insulin secretion occurred through multiple targets. In addition to its established effects on ATP-sensitive potassium channels (p = 0.004) and voltage-gated calcium channels (p = 0.004), simvastatin suppressed insulin secretion stimulated by muscarinic M3 or GPR40 receptor agonists (Tak875 by 33%, p = 0.002; GW9508 by 77%, p = 0.01) at glucose level of 5.5 mmol/l, and inhibited calcium release from the endoplasmic reticulum. Impaired insulin secretion caused by simvastatin treatment were efficiently restored by GPR119 or GLP-1 receptor stimulation and by direct activation of cAMP-dependent signaling pathways with forskolin. The effects of simvastatin treatment on insulin secretion were not affected by the presence of hyperglycemia. Our observation of the opposite effects of simvastatin and pravastatin on glucose-stimulated insulin secretion is in agreement with previous reports showing that simvastatin, but not pravastatin, was associated with increased risk of incident diabetes.     

The effect of 3-weeks stationary cardiac rehabilitation on plasma lipids level in 444 patients with coronary heart disease

The aim of this study was to investigate the effect of 3-weeks stationary cardiac rehabilitation on plasma lipids level in patients with CHD. The study included 444 consecutive patients (364 male and 80 female, mean age 58 +/- 9 year) with CHD who underwent 3-weeks stationary cardiac rehabilitation. Patients were divided into groups depending on their baseline levels of cholesterol and medication therapy: patients with normal (< 5 mmol/L, group I, 129 patients) and elevate plasma level of Total cholesterol (> 5 mmol/L, group II, 315 patients) and subgroups Ia and IIa (with statin in therapy), Ib and IIb (without statin in therapy). After 3-weeks cardiac rehabilitation, the levels of Total cholesterol 5.75 +/- 1.34 vs. 5.17 +/- 1.08 mmol/l; p < 0.001, triglycerides 2.04 +/- 1.33 vs. 1.81 +/- 1.06 mmol/L; p = 0.004, LDL-cholesterol 3.77 +/- 1.14 vs. 3.21 +/- 0.96 mmol/L; p < 0.001 were significantly lower while the level of HDL-cholesterol 0.94 +/- 0.28 vs. 0.99 +/- 0.27 mmol/L; p = 0.008 were significantly higher in comparison with the baseline values. Furthermore, we found significant changes in lipid profile at the end of rehabilitation in each group of patients compared with the baseline values. There were no significant differences in plasma lipids level between group of patients with or without statin in therapy at the end of rehabilitation. The results of this study suggest that moderate regular physical activity and diet alone or in combination with hypolipidemic drugs already after 3 weeks have a favourable effect on plasma lipids level and should be propagate in the prevention of CHD.     

The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus

Statins decrease triglycerides (TGs) in addition to decreasing low density lipoprotein-cholesterol. Although the mechanism for the latter effect is well understood, it is still unclear how TG decrease is achieved with statin therapy. Because hypertriglyceridemia is common in obese patients with type 2 diabetes mellitus, we studied triglyceride-rich lipoprotein triglyceride (TRL-TG) turnover in 12 such subjects using stable isotopically labeled glycerol. The diabetic subjects were studied after 12 weeks of placebo and after a similar course of therapy with simvastatin (80 mg daily) in a single-blind design. The results were compared with those from six nonobese nondiabetic control subjects. Simvastatin therapy reduced serum TGs by 35% in the diabetic subjects. Compared with the control subjects, TRL-TG secretion was almost 2-fold higher in the diabetic subjects (45.4 +/- 4.9 vs. 24.4 +/- 1.9 micromol/min; P < 0.002) and was unaffected by simvastatin therapy. However, TRL-TG clearance was significantly increased in the diabetic subjects during simvastatin treatment compared with placebo (0.25 +/- 0.03 vs. 0.16 +/- 0.02 pools/h; P < 0.002). This change was accompanied by a 49% increase in preheparin plasma lipase activity (P < 0.03) and a 21% increase in postheparin LPL activity (P < 0.01). Together, these findings provide strong evidence that the effect of statins on serum TGs is related to an increase in LPL activity, resulting in accelerated delipidation of TRL particles. The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus.     

A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma

Statins, the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, are effective serum cholesterol-lowering agents in clinical practice, and they may also have anti-inflammatory properties. Asthma is characterized by chronic eosinophilic inflammation in the airways, which is thought to be regulated by the activity of T lymphocytes. We therefore examined the anti-inflammatory activity of simvastatin in a murine model of allergic asthma. In mice previously sensitized to OVA, simvastatin treatment, either orally or i.p., reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid in response to inhaled OVA challenge. Simvastatin therapy i.p. was also associated with a reduction in IL-4 and IL-5 levels in bronchoalveolar lavage fluid and, at higher doses, a histological reduction in inflammatory infiltrates in the lungs. OVA-induced IL-4, IL-5, IL-6, and IFN-gamma secretion was reduced in thoracic lymph node cultures from simvastatin-treated mice. Simvastatin treatment did not alter serum total IgE or OVA-specific IgG1 and IgG2a levels. These data demonstrate the therapeutic potential of statin-sensitive pathways in allergic airways disease.     

Infection with Toxoplasma gondii does not Alter TNFalpha and IL-6 Secretion by A human Astrocytoma Cell Line

The secretion of tumour necrosis factor-alpha (TNFalpha), interleukin-1alpha (IL-alpha) and interleukin-6 (IL-6) by a human astrocytoma cell fine was studied 1 h, 3 h, 6 h and 24 h after infection with tachyzoites from three Toxoplasma gondii strains (virulent, RH; cystogentc, 76K and Prugniaud strains). The astrocytoma cell fine constitutively secreted TNFalpha and IL-6, but no IL-1alpha. A positive control was obtained by stimulation with phorbol esters inducing a significant increase (p < 0.05) in TNFalpha and IL- 6 secretion but not in IL-1alpha, while lipopolysaccharide (alone and after priming), interferon gamma, ionophore A 23187 and sera positive to T. gondii did not induce any increase in cytokine levels. None of the tachyzoites, whatever their virulence, induced a significant increase in cytokine production at any time in the study. Tachyzoites did not inhibit the secretion induced by phorbol esters.     

Hyperlipidemia is associated with altered levels of insulin-like growth factor-I

Previous studies revealed altered levels of the circulating insulin-like growth factor-I (IGF-I) and of its binding protein-3 (IGFBP-3) in subjects with coronary atherosclerosis, metabolic syndrome and premature atherosclerosis. Hyperlipidemia is a powerful risk factor of atherosclerosis. We expected IGF-I and IGFBP-3 alterations in subjects with moderate/severe hyperlipidemia but without any clinical manifestation of atherosclerosis. Total IGF-I and IGFBP-3 were assessed in 56 patients with mixed hyperlipidemia (MHL; cholesterol >6.0 mmol/l, triglycerides >2.0 mmol/l), in 33 patients with isolated hypercholesterolemia (IHC; cholesterol >6.0 mmol/l, triglycerides <2.0 mmol/l), and in 29 healthy controls (cholesterol<6.0 mmol/l, triglycerides<2.0 mmol/l). The molar ratio of IGF-I/IGFBP-3 was used as a measure of free IGF-I. IHC subjects differed from controls by lower total IGF-I (164+/-60 vs. 209+/-73 ng/ml, p=0.01) and IGF-I /IGFBP-3 ratio (0.14+/-0.05 vs. 0.17+/-0.04, p=0.04). Compared to controls, MHL subjects had lower total IGF-I (153+/-54 ng/ml, p=0.0002) and IGFBP-3 (2.8+/-0.6 mg/ml, p<0.0001), but higher IGF-I/IGFBP-3 ratio (0.25+/-0.06, p<0.0001). Differences remained significant after the adjustment for clinical and biochemical covariates, except for triglycerides. Patients with both IHC and MHL have lower total IGF-I compared to controls. The mechanism is presumably different in IHC and MHL. Because of prominent reduction of IGFBP-3 in patients with MHL, they have reduced total IGF-I despite the actual elevation IGF-I/IGFBP-3 ratio as a surrogate of free IGF-I.     

Bicarbonate supplementation via lactate efflux improves anaerobic and cognitive performance in elite combat sport athletes

The aim of this study was the assessment of sodium bicarbonate supplementation (NaHCO₃ ^-) on anaerobic and cognitive performance, assuming ergogenic effect of HCO₃ by improving buffering capacity and greater lactate efflux, which may have indirect effect on circulating neurotrophin level (e.g BDNF, IGF-1) and memory. Sixteen well-trained judo athletes completed a randomized trial of either a NaHCO₃ ^- (EG) (5000 mg x 2/day/90 min before training)or placebo for 21 days (CG). Before and after treatment, athletes completed double Wingate test (Wt) protocol following which they performed perceived Working Memory test (pWM). Results suggested significant increase in Upper Limb Total Work (with p = 0.011), Mean Power (with p = 0.001), post exercise LA concentration (from 15.51 mmol/L to 18.10 mmol/L with p = 0.01) and HCO3_rest concentrations (from 27.37 mmol/l to 28.91 mmol/l with p = 0.001), when compared to baseline values in EG. The analysis showed statistically significant increase in values for IGF-1 (with p = 0.001) and decrease for cortisol and BDNF (with p = 0.001) in EG and CG, when pre and post exercise values were compared. We also revealed statistically significant decrease in values for display time after ingestion of HCO₃ between pre and post exercise (with p = 0.002) In conclusion, the lack of a substantial relationship between exerkines (IGF-1, BDNF) and memory in the present study might suggest that exercise induced lactate levels is dominant mechanism improving working memory in well-train athletes.     

Erythrocyte antioxidant enzymes in hypertensive patients receiving lisinopril monotherapy or combined lisinopril plus simvastatin therapy

Statins and angiotensin-converting enzyme (ACE) inhibitors have beneficial impact on the serum cholesterol and blood pressure. It is supposed that statins and ACE inhibitors may modify the antioxidative status in erythrocytes. The study objective was to compare the effects of two treatments, lisinopril alone versus lisinopril plus simvastatin, on erythrocyte antioxidant enzyme activities. The study involved 32 patients with arterial hypertension, their initial serum total cholesterol, LDL-cholesterol and triglycerides were within the normal range. Patients of two groups, each of 16 subjects, were treated with lisinopril (10 mg/day) or with lisinopril (10 mg/day) plus simvastatin (20 mg/day). Before and after the ambulatory therapy for 3 and 6 months, activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR) were determined in purified erythrocytes. All treated patients had significantly higher catalase activity (by 79.3–106.5%, p < 0.0001) and significantly lower GPx activity (by 20.7–30.6%, p < 0.001) as compared to the baselines. The same results were obtained in both groups (lisinopril and lisinopril + simvastatin), after both periods (3 and 6 month) of treatments. SOD activity increased only in the lisinopril group and only after 6 months (p = 0.0345). No changes of GR activity were observed under all conditions studied. Thus, the lisinopril monotherapy and combined lisinopril plus simvastatin therapy exhibit specific, pronounced and equipotent effects on antioxidant enzymes in human erythrocytes. Peroral administration of lisinopril or lisinopril plus simvastatin may protect erythrocytes and other tissues against oxidative damage.     

Differential regulation of cytokine and chemokine production in lipopolysaccharide-induced tolerance and priming

LPS pretreatment of human pro-monocytic THP-1 cells induces tolerance to secondary LPS stimulation with reduced TNFalpha production. However, secondary stimulation with heat-killed Staphylococcus aureus (HKSa) induces priming as evidenced by augmented TNFalpha production. The pro-inflammatory cytokine, IFNgamma, also abolishes suppression of TNFalpha in LPS tolerance. The effect of LPS tolerance on HKSa and IFNgamma-induced inflammatory mediator production is not well defined. We hypothesized that LPS, HKSa and IFNgamma differentially regulate pro-inflammatory mediators and chemokine production in LPS-induced tolerance. THP-1 cells were pretreated for 24 h with LPS (100 ng/ml) or LPS (100 ng/ml) + IFNgamma (1 microg/ml). Cells were subsequently stimulated with LPS or HKSa (10 microg/ml) for 24 h. The production of the cytokines TNFalpha, IL-6, IL-1beta, and GMCSF and the chemokine IL-8 were measured in supernatants. LPS and HKSa stimulated TNFalpha (3070 +/- 711 pg/ml and 217 +/- 9 pg/ml, respectively) and IL-6 (237 +/- 8.9 pg/ml and 56.2 +/- 2.9 pg/ml, p < 0.05, n = 3, respectively) in control cells compared to basal levels (< 25 pg/ml). LPS induced tolerance to secondary LPS stimulation as evidenced by a 90% (p < 0.05, n = 3) reduction in TNFalpha. However, LPS pretreatment induced priming to HKSa as demonstrated by increased TNFalpha (2.7 fold, from 217 to 580 pg/ml, p < 0.05, n = 3 ). In contrast to suppressed TNFalpha, IL-6 production was augmented to secondary LPS stimulation (9 fold, from 237 to 2076 pg/ml, p < 0.01, n = 3) and also primed to HKSa stimulation (62 fold, from 56 to 3470 pg/ml, p < 0.01, n = 3). LPS induced IL-8 production and to a lesser extent IL-1beta and GMCSF. LPS pretreatment did not affect secondary LPS stimulated IL-8 or IL-1beta, although HKSa stimulation augmented both mediators. In addition, IFNgamma pretreatment reversed LPS tolerance as evidenced by increased TNFalpha levels while IL-6, IL-1beta, and GMCSF levels were further augmented. However, IL-8 production was not affected by IFNgamma. These data support our hypothesis of differential regulation of cytokines and chemokines in gram-negative- and gram-positive-induced inflammatory events. Such changes may have implications in the pathogenesis of polymicrobial sepsis.     

Effect of the prostaglandin E1 analog enisoprost on glucose and lipid metabolism in patients with type II diabetes mellitus.

Short-term studies have suggested that analogs of prostaglandin E may have favorable effects on the carbohydrate and lipid metabolism in patients with type II diabetes mellitus. The present study was undertaken to investigate the long-term effects of a prostaglandin E1 analog on the regulation of glycemic control and plasma lipids. Twenty patients with type II diabetes received enisoprost, 300 mcg/day, for three months. Fasting serum glucose, glycosylated hemoglobin, insulin and C-peptide levels as well as triglyceride, total cholesterol, high density lipoprotein cholesterol and its subfractions, apolipoproteins B and AI and post-heparin lipoprotein lipase and hepatic triglyceride lipase activities were determined. During the first month, enisoprost treatment caused significant decreases in plasma glucose (baseline = 8.72 +/- 0.39 mmol/L, 4 week = 7.78 +/- 0.5 mmol/L, change = -0.94 +/- 0.28 mmol/L, p less than 0.01) and total cholesterol (baseline = 5.30 +/- 0.23 mmol/L, 4 week = 5.01 +/- 0.26 mmol/L, change = -0.28 +/- 0.06 mmol/L, p less than 0.05). The decrease in cholesterol level was due to a reduction in high density lipoprotein, specifically in high density lipoprotein2 fraction (baseline = 1.29 +/- 0.1 mmol/L, 4 week = 1.12 +/- 0.08 mmol/L, change = -0.018 +/- 0.04 mmol/L, p less than 0.05 for the former and baseline = 0.40 +/- 0.06 mmol/L, 4 week = 0.27 +/- 0.03 mmol/L, change = -0.12 +/- 0.03 mmol/L, p less than 0.05 for the latter): All of these values returned to the pretreatment levels despite continuation of enisoprost.(ABSTRACT TRUNCATED AT 250 WORDS)     

A specific inhibitor of cholesterol biosynthesis, BM15.766, reduces the expression of beta-secretase and the production of amyloid-beta in vitro

We have previously shown that statins reduce the production of amyloid-beta (Abeta) by both isoprenoid- and cholesterol-dependent mechanisms. These pathways contribute to the regulation of the dimerisation of BACE into its physiologically active form. Statins reduce cellular cholesterol levels by 20-40%; therefore, it is possible that the remaining cholesterol within the cell may play a significant role in the production of Abeta. Incubation of cells with the specific cholesterol biosynthesis inhibitor BM15.766 together with 50 micromol/L simvastatin and 400 micromol/L mevalonate reduced cellular cholesterol levels in a dose-dependent manner with increasing BM15.766 concentration (r = -0.9736, p = 0.0264). Furthermore, decreases in cellular cholesterol levels correlated with reductions in total Abeta production (r = 0.9683, p = 0.0317). A total of 2.5 micromol/L BM15.766 inhibited the dimerisation of BACE, whilst the expression of BACE monomer was reduced by 5 micromol/L BM15.766. BM15.766 treatment localised BACE predominantly within the Golgi, and reduced total BACE expression per cell. Similar changes were observed in the expression of the Golgi marker golgin-97, suggesting that reduced BACE expression may arise from a decrease in protein trafficking and an increase in degradation. By targeting cholesterol synthesis using specific cholesterol biosynthesis inhibitors, it is possible to reduce Abeta production without reducing protein isoprenylation.     

Late Antiretroviral Therapy (ART) Initiation Is Associated with Long-Term Persistence of Systemic Inflammation and Metabolic Abnormalities

Objectives

HIV-induced immunodeficiency is associated with metabolic abnormalities and systemic inflammation. We investigated the effect of antiretroviral therapy (ART) on restoration of insulin sensitivity, markers of immune activation and inflammation.

Methods

Immunological, metabolic and inflammatory status was assessed at antiretroviral therapy initiation and three years later in 208 patients from the ANRS-COPANA cohort. Patients were compared according to their pre-ART CD4⁺ cell count (group 1: ≤ 200/mm³, n = 66 vs. group 2: > 200/mm³, n = 142).

Results

Median CD4⁺ cell count increased in both groups after 3 years of successful ART but remained significantly lower in group 1 than in group 2 (404 vs 572 cells/mm³). Triglyceride and insulin levels were higher or tended to be higher in group 1 than in group 2 at ART initiation (median: 1.32 vs 0.97 mmol/l, p = 0.04 and 7.6 vs 6.8 IU, p = 0.09, respectively) and remained higher after three years of ART (1.42 vs 1.16 mmol/L, p = 0.0009 and 8.9 vs 7.2 IU, p = 0.01). After adjustment for individual characteristics and antiretroviral therapy regimens (protease inhibitor (PI), zidovudine), insulin levels remained significantly higher in patients with low baseline CD4⁺ cell count. Baseline IL-6, sCD14 and sTNFR2 levels were higher in group 1 than in group 2. Most biomarkers of immune activation/inflammation declined during ART, but IL-6 and hsCRP levels remained higher in patients with low baseline CD4⁺ cell count than in the other patients (median are respectively 1.4 vs 1.1 pg/ml, p = 0.03 and 2.1 vs 1.3 mg/ml, p = 0.07).

Conclusion

After three years of successful ART, low pretreatment CD4⁺ T cell count remained associated with elevated insulin, triglyceride, IL-6 and hsCRP levels. These persistent metabolic and inflammatory abnormalities could contribute to an increased risk of cardiovascular and metabolic disease.     

Statins directly suppress cytokine production in murine intraepithelial lymphocytes

Statins, inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are known not only as cholesterol-lowering agents but also as anti-inflammatory mediators. However, their regulatory effect on intestinal mucosal immunity remains unclear. The present study examined the possible direct effects of statin on intestinal intraepithelial lymphocytes (IELs), the front line cells of the intestinal mucosal immune system. Murine IELs were isolated from the small intestines of C57BL/6 mice. IELs activated with anti-CD3/CD28 monoclonal antibodies produced interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-4 in significant numbers; however, they did not produce IL-5. Both simvastatin and lovastatin suppressed IEL production of IFN-γ, TNF-α, IL-2, and IL-4 in a dose-dependent manner, whereas 48-h treatment with high concentrations (5 × 10^?5 M) of simvastatin and lovastatin did not affect the number of IELs. The suppressive effect of the simvastatin was significantly restored by the addition of mevalonate, farnesyl pyrophosphate ammonium salt, and geranylgeranyl pyrophosphate ammonium salt, which are downstream metabolites of HMG-CoA. These findings suggest that statins have direct suppressive effects on the production of T helper 1-cytokines and IL-4 in IELs; these effects are associated with inhibition of the mevalonate pathway to some extent.     

Relation of leptin and tumor necrosis factor alpha to body weight changes in patients with pulmonary tuberculosis

In this study we investigated whether leptin and TNFalpha levels change with improvement in body weight with antituberculotic therapy in active tuberculosis patients. 30 patients (8 females and 22 males) with active pulmonary tuberculosis formed the patient group, and 25 sex- and age-matched healthy subjects (8 females and 17 males) served as the control group. Body weight, body mass index (BMI) and serum leptin and plasma TNFalpha levels are measured before and in the sixth month of therapy in all patients. Before the initiation of therapy, BMI of the patients was significantly lower than BMI of the controls (20.2 +/- 1.6 vs. 25.2 +/- 2.7 kg/m(2), respectively; p < 0.05). After treatment, BMI of the patients increased significantly to 21.4 +/- 1.9 kg/m(2) (p < 0.05), but was still lower than that of the controls (p < 0.05). Pretreatment serum leptin (4.5 +/- 0.9 vs. 2.1 +/- 0.2 ng/ml, respectively; p < 0.05) and plasma TNFalpha (27.9 +/- 3.4 vs. 23.9 +/- 3.0 pg/ml, respectively; p < 0.05) levels of the patients were significantly higher than those of the controls. After treatment, serum leptin levels increased to 6.7 +/- 2.2 ng/ml, but this rise was not statistically significant (p > 0.05). Treatment did not result in any significant change in TNFalpha levels, either. Delta leptin was highly related to Delta BMI in patients with tuberculosis (r = 0.68, p = 0.02). In the pretreatment period, there was a significant correlation between leptin and TNFalpha levels in the whole patient group (r = 0.78, p < 0.001), and in female (r = 0.74, p < 0.001) and male patients separately (r = 0.74, p = 0.035). In conclusion, leptin and TNFalpha may be responsible for the weight loss in pulmonary tuberculosis patients, but their levels do not change with improvement in body weight with antituberculotic treatment.     

The effect of weight loss on serum concentration of interleukine-6 (IL-6) and insulin resistance

INTRODUCTION: Interleukine-6 (IL-6) is one of the cytokines, excreting by adipocytes, which increases in obesity. These cytokines participate in very complicated mechanisms of developing insulin resistance that accompany obesity. The aim of the study was to: 1) evaluate the influence of weight loss on insulin resistance and serum concentration of IL-6, 2) evaluate the hypothetical association between serum concentration of IL-6 and the improvement of insulin sensitivity in obese women after weight loss. MATERIAL AND METHODS: The study involved 27 obese women (age 40.3 +/- 11.1 year; BMI 37.4 +/- 5.2 kg/m(2)) with insulin resistance diagnosed using HOMA index, without concomitant diseases and without any medication. All the patients participated in complex weight reduction treatment (diet, physical activity and psychotherapy). Before and after weight reduction therapy weight and height were measured, body composition was determined using bioimpedance analysis. Serum concentration of glucose was determined by enzymatic procedure, serum concentration of insulin was measured by radioimmunoassay, serum concentration of IL-6 was measured by ELISA. HOMA index was calculated with formula. RESULTS: The mean weight loss after 3-month was 9.2 +/- 4.5 kg (approximately 10% of initial weight). After weight reduction significant decreases in HOMA index, insulin and IL-6 concentrations was observed. However, no correlations between changes in insulin concentrations, HOMA index and decrease of IL-6 concentration were showed. We observed significant correlations between DeltaHOMA and DeltaBMI (r = 0.48; p = 0.012) and Delta percentage fat mass (r = 0.39; p < 0.05). CONCLUSIONS: A moderate weight loss improves insulin sensitivity and decreases serum concentrations of IL-6. However improvement of insulin sensitivity is the effect of fat mass reduction and does not change serum concentration of IL-6.     

A Curcumin‐Based 1‐Week Triple Therapy for Eradication of Helicobacter pylori Infection: Something to Learn From Failure?

BACKGROUND: Curcumin is the principal element of turmeric powder extracted from the root of Curcuma longa. Studies on curcumin have demonstrated some anti-Helicobacter pylori activity as well as immunomodulating properties. N-acetylcysteine and lactoferrin with their respective mucolytic and antibacterial activities might also be effective in H. pylori eradication therapy. AIM: To determine if a 7-day non-antibiotic therapy comprised of curcumin, lactoferrin, N-acetylcysteine, and pantoprazole was effective for eradication of H. pylori infection and reduction of gastric inflammation, assessed by serum pepsinogens and relief of symptoms. SUBJECTS AND METHODS: Twenty-five consecutive H. pylori-positive patients (12 males, mean age 50 +/- 12 years, range 31-76) with functional dyspepsia were enrolled. Patients were administered for 7 days curcumin 30 mg b.i.d., bovine lactoferrin 100 mg b.i.d., N-acetylcysteine 600 mg b.i.d., and pantoprazole 20 mg b.i.d. H. pylori status and upper gastrointestinal symptoms were assessed by (13)C-urea breath test and a scale of upper gastrointestinal symptoms intensity (absent, mild, moderate, and severe), as well as a blood test for serum pepsinogens (sPGI, sPGII), gastrin-17 (G-17), and anti-H. pylori IgG (IgG-Hp) at baseline (T0) and after 2 months (T1). RESULTS: Three of 25 patients (12%) were cured of H. pylori infection. A significant decrease in the overall severity of symptoms (T0: 6, interquartile range [IQR]: 4.5-8; T1: 2, IQR: 2-3; p < or = .001), and sPGII (T0: 16 microg/L, IQR: 13-22; T1: 10 microg/L, IQR: 8-16; p < or = .001) and sPGI (T0: 82 microg/L, IQR: 67-97; T1: 74 microg/L, IQR: 62-94; p = .02) levels were observed after 2 months of the treatment. IgG and G-17 values did not significantly decrease after 2 months. CONCLUSIONS: This novel therapy was not effective for H. pylori eradication. However, despite the bacterium persistence, significant improvement of dyspeptic symptoms and reduction of serologic signs of gastric inflammation were observed after 2 months at the end of the 7-day treatment schedule.     

Simvastatin attenuates release of neutrophilic and remodeling factors from primary bronchial epithelial cells derived from stable lung transplant recipients

Obliterative bronchiolitis (OB), the major cause of chronic lung allograft dysfunction, is characterized by airway neutrophilia, inflammation, and remodeling, with progressive fibroproliferation and obliteration of small airways that ultimately leads to patient death. Statins have potential anti-inflammatory effects and have been demonstrated to confer a survival advantage in lung transplant patients. We postulated that the beneficial effects of simvastatin in lung transplantation are in part due to inhibition of the epithelial production of key mediators of neutrophil chemotaxis, inflammation, and airway remodeling. Our objective was to assess the effect of simvastatin on a unique population of primary bronchial epithelial cells (PBECs) derived from stable lung allografts, with specific reference to airway neutrophilia and remodeling. PBEC cultures were stimulated with IL-17 or transforming growth factor (TGF)-beta, with and without simvastatin. Supernatant levels of factors critical to driving airway neutrophilia and remodeling were measured. IL-17 upregulated IL-8, IL-6, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and VEGF, whereas TGF-beta increased IL-6, GM-CSF, matrix metalloproteinase (MMP)-2, and MMP-9. Simvastatin attenuated effects of both IL-17 and TGF-beta. We have demonstrated the ability of simvastatin to attenuate release of airway neutrophilic and remodeling mediators and to inhibit their upregulation by TGF-beta and IL-17. These data illustrate the potential of simvastatin to alleviate neutrophilic airway inflammation and remodeling in the transplanted lung and may have additional relevance to other neutrophilic airway conditions, such as chronic obstructive pulmonary disease.     

Studies on the antibacterial effects of statins--in vitro and in vivo

Background

Statin treatment has been associated with a beneficial outcome on respiratory tract infections. In addition, previous in vitro and in vivo experiments have indicated favorable effects of statins in bacterial infections.

Aim

The aim of the present study was to elucidate possible antibacterial effects of statins against primary pathogens of the respiratory tract.

Methods

MIC-values for simvastatin, fluvastatin and pravastatin against S. pneumoniae, M. catarrhalis and H. influenzae were determined by traditional antibacterial assays. A BioScreen instrument was used to monitor effects of statins on bacterial growth and to assess possible synergistic effects with penicillin. Bacterial growth in whole blood and serum from healthy volunteers before and after a single dose of simvastatin, fluvastatin and penicillin (positive control) was determined using a blood culture system (BactAlert).

Findings

The MIC-value for simvastatin against S pneumoniae and M catarrhalis was 15 µg/mL (36 mmol/L). Fluvastatin and Pravastatin showed no antibacterial effect in concentrations up to 100 µg/mL (230 µmol/L). Statins did not affect growth or viability of H influenzae. Single doses of statins given to healthy volunteers did not affect growth of pneumococci, whereas penicillin efficiently killed all bacteria.

Conclusions

Simvastatin at high concentrations 15 µg/mL (36 µmol/L) rapidly kills S pneumoniae and M catarrhalis. However, these concentrations by far exceed the concentrations detected in human blood during simvastatin therapy (1–15 nmol/L) and single doses of statins given to healthy volunteers did not improve antibacterial effects of whole blood. Thus, a direct bactericidal effect of statins in vivo is probably not the mechanism behind the observed beneficial effect of statins against various infections.