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Zoledronate (ZOL) inhibits farnesyl pyrophosphate synthase leading to intracellular accumulation of isopentenyl pyrophosphate/triphosphoric acid 1-adenosin-5′-yl ester 3-(3-methylbut-3-enyl) ester (IPP/ApppI). Cytotoxic Vγ9Vδ2 T cells have been shown to recognize IPP/ApppI in breast cancer cells. Further, human breast cancer cells have been shown to differ remarkably in their ZOL treatment induced IPP/ApppI production and responses to that. In this communication we analysed the responsiveness of prostate cancer cells PC-3 and DU-145, Caki-2 renal carcinoma cells and U87MG glioblastoma cells to ZOL treatment, and the subsequent activation of Vγ9Vδ2 T-cell cytotoxicity. Of the cell lines tested, PC-3 cells were not susceptible to Vγ9Vδ2 T-cell cytotoxicity due to low activity of the mevalonate pathway and low amount of IPP formed. However, the resistance of PC-3 cells to Vγ9Vδ2 T-cell cytotoxicity could be abrogated by upregulation of the mevalonate pathway through cholesterol depletion. [ABSTRACT FROM AUTHOR]

In the present investigation, we have performed ligand based analyses (QSAR (binary classification and multiple linear regression (MLR) analyses), pharmacophore studies and fingerprint analysis) on a data set comprised of 249 HMG CoA reductase (HMGR) inhibitors. The QSAR and the pharmacophore analyses explained that the polar features present in the molecules determine the observed HMGR inhibitory activity of the compounds. The binary classification study performed with bundle of descriptors such as PEOE_PC-, GCUT_PEOE-0, GCUT_PEOE-3, MNDO_LUMO, VSA_Pol and V_surf-ID7 descriptors in model A and TPSA, LogP(o/w), LogS, Wienerpol, A_don and A_acc descriptors belong to the model B. The binary classification study provided acceptable statistical parameter values for accuracy, sensitivity, specificity, precision, Matthew's correlation coefficient (MCC), goodness of fit score (GH score), F-score (the harmonic mean of precision and sensitivity), enrichment factor, etc., against both models (A and B), which demonstrated that these models predict the activities of the compounds (as active and inactive) significantly. The sum of ranking difference (SRD) was calculated using statistical parameters derived from the models (MLR-QSAR and binary QSAR models). The %SRD reveals that the model 5 in MLR-QSAR and the binary models A1, B1 and A2 are significant among the developed models. Further protein ligand interaction fingerprints (PLIF) and the pharmacophore studies also revealed that the hydrogen bond acceptor, hydrogen bond donor and ionic interactions are involved in the protein ligand interaction to elicit the activity of the molecules. In order to support the findings from the analyses, the MACCS fingerprints of the data set were calculated and which explain that the polar functional groups/fragments in the molecules are important for the inhibitory activity. The results retrieved from these analyses will be useful for the development of novel molecules for the inhibition of HMGR enzyme. [ABSTRACT FROM AUTHOR]

A clerodane diterpene, 16 α -Hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (compound 1 ) isolated from Polyalthia longifolia had previously been reported as a new structural class of HMG-CoA reductase inhibitor apart from statins. Statins are known to be anti-adipogenic in nature. The distant structural similarity between compound 1 and lovastatin (polyketide class of compound) prompted us to investigate effects of diterpene compound 1 on adipogenesis and thereby obesity. High content microscopy proved diterpene compound 1 exhibits better anti-adipogenic activity and less toxicity in differentiating adipocytes. Moreover, it reduced expression levels of PPARγ, C/EBPα and GLUT4 during differentiation in a time and concentration dependent manner. Diterpene compound 1 during early differentiation reduced MDI induced-Akt/mTOR phosphorylation and expression of cell cycle proteins, and thereby halted mitotic clonal expansion, the decisive factor in early adipogenesis. Further, its anti-adipogenic activity was validated in murine mesenchymal cell-line C3H10T1/2 and human mesenchymal stem cell models of adipogenic differentiation. When compound 1 was administered along with HFD, for another 8 weeks in 2 month HFD fed overweight mice (with BMI > 30 and impaired glucose tolerance), it attenuated weight gain and epididymal fat accumulation. It improved body glucose tolerance, reduced HFD induced increase in total cholesterol and leptin/adiponectin ratio. All these effects were comparable with standard anti-obesity drug Orlistat with added edge of potently decreasing circulating triglyceride levels comparable with normal chow fed group. Histological analysis shows that compound 1 inhibit adipocyte hypertrophy and decreased steatosis in hepatocytes. Both in vivo and in vitro results demonstrate a potential value of compound 1 as a novel anti-adipogenic and anti-obesity agent. [ABSTRACT FROM AUTHOR]

In Estonia, HMG-CoA reductase inhibitors are widely used to modify lipid levels but there are no current data on additional medicines prescribed alongside the statins. The aim of this study was to identify the frequency of potential clinically relevant interactions at a national level among an outpatient population treated with statins between January and June 2008, based on the prescription database of the Estonian Health Insurance Fund. This retrospective prevalence study included 203,646 outpatients aged 50 years or older, of whom 29,367 received statin therapy. The study analysed individuals who had used at least one prescription medicine for a minimum of 7 days concomitantly with statins. Potential drug interactions were analysed using Epocrates online, Stockley's Drug Interactions, and the drug interaction database developed in Estonia. Statins metabolised by the CYP3A4 isoenzyme were prescribed to 64% of all statin users. Medicines known to have potentially clinically significant interactions with statins were prescribed to 4.6% of patients. The drugs prescribed concomitantly most often with simvastatin were warfarin (5.7%) and amiodarone (3.9%), whereas digoxin (1.2%) and ethinylestradiol (2%) were prescribed with atorvastatin. Potential interactions were not detected in the treatment regimens of rosuvastatin, pravastatin, and fluvastatin users. [ABSTRACT FROM AUTHOR]

Background: Considering the increasing incidence of coronary artery stenosis and its related complications, the importance of its etiology and inconsistent reports we aimed to determine the relationship between oxysterol, serum levels and severity of coronary atherosclerosis and effect of statins on oxysterol. Methods: A total of 85 patients referred to Taleghani Hospital, Tehran, Iran during 2011-2012 with coronary artery stenosis more than 75%, as determined by angiography, participated in the current study. Their demographic information and history of smoking and taking atorvastatin was carefully recorded. Two milliliters of venous blood was obtained from each patient. The serum oxysterol level of samples was measured using the enzyme-linked immunosorbent assay (ELISA) method. Statistical analysis was performed using SPSS v.19. Results: Eighty five patients completed the study. Mean age of patients was 64.4 years; 51 (60%) were male; 55 (68%) had acute coronary syndrome and 30 (32%) had chronic stable angina. Mean±SD of plasma level of oxysterol was 24.8±0.2 pmol/ml. The normal range of oxysterol level was 13pmol/ml. Mean±SD of plasma oxysterol level in patients under statin therapy was 24.4±2.1 pmol/ml. In patients without receiving statins, plasma oxysterol level was 26.38±1.6pmol/ml. Conclusion: Findings of the present study indicated significant correlation between serum oxysterol and severity of coronary artery stenosis. It also demonstrated that receiving atorvastatin is associated with significant reduction of plasma oxysterol level. [ABSTRACT FROM AUTHOR]

Plants of chilli Capsicum annuum L. CM334 show a high level of resistance to Phytophthora capsici, but are susceptible to Nacobbus aberrans; such resistance has been associated with capsidiol accumulation, a sesquiterpene phytoalexin. In the present study the expression of hydroxymethylglutaryl- CoA reductase 2 gene (HMG2, associated with sesquiterpene phytoalexins biosynthesis) in CM334 chilli roots inoculated with N. aberrans and in combination with P. capsici, was determined by qRT-PCR. The levels of HMG2 transcripts were significantly reduced (p⩽0.05) from -1.57 to -1.28- fold in the interaction CM334/N. aberrans; whereas in roots inoculated only with the oomycete, the accumulation of transcripts occurred earlier and at higher levels (1.52 to 3.54-fold). In plants inoculated with both pathogens, the expression was higher compared with those inoculated with the nematode only (p⩽0.05), but generally lower than the expression observed in roots of plants inoculated with the oomycete alone. The expression of the HMG2 gene associated with defense was reduced in CM334 chilli plants infected by N. aberrans. [ABSTRACT FROM AUTHOR]

Statins have been shown to possess properties that go beyond their lipid-lowering effects. These agents act on the mevalonate pathway and inhibit synthesis of cholesterol, geranylgeranyl pyrophosphate, and farnesyl pyrophosphate, which are necessary for posttranslational modification of the Rho, Rac, and Ras superfamily of proteins. Early phase studies have demonstrated that this modulation of cellular signaling can ultimately exert pro-apoptotic, anti-angiogenic, and immunomodulatory effects, and might even restore chemosensitivity in several hematologic cancers. Nonetheless, these promising preclinical results have not yet migrated from the bench to the bedside as their effectiveness as adjuvant agents in hematologic malignancies is currently uncertain. In the present review, we summarize the existing evidence stemming from preclinical and clinical studies pertaining to the use of statins as adjuvant therapies in hematologic malignancies, and discuss the new insights gained from the ongoing translational research. [ABSTRACT FROM AUTHOR]

We aimed to examine the association between preoperative use of statins and postoperative acute kidney injury ( AKI) in patients undergoing major surgery by performing a systemic review and meta-analysis. MEDLINE and EMBASE, from inception to April 2013, and the reference lists of related articles were searched for relevant studies. Trials comparing preoperative statin therapy with no preoperative statin in patients undergoing major surgery were included. Outcome measures of interest were the risk of cumulative postoperative AKI and postoperative AKI requiring renal replacement therapy ( RRT). Fixed or random effect meta-analysis was performed to derive summary effect estimates. In five randomized controlled trials ( RCTs) and 19 observational studies, comprising a total of 989 173 patients undergoing major surgery, 112 840 patients (11.41%) received preoperative statin therapy. The specific type, dosage, and duration of statin therapy were not available in most studies. Preoperative statin therapy was associated with a significant risk reduction for cumulative postoperative AKI (weighted summary odds ratio ( OR) 0.87, 95% CI 0.79 to 0.95). The effect of risk reduction was also significant when considering postoperative AKI requiring RRT ( OR 0.80, 95% CI 0.72 to 0.90). When restricting the analysis to the five RCTs, preoperative statin therapy did not show significant protective effect on postoperative AKI ( OR 0.49, 95% CI 0.22 to 1.09). In patients undergoing major surgery, preoperative statin therapy could associate with a reduced risk for postoperative AKI. However, considerable heterogeneity existed among included studies. Future randomized trials were warranted for this critical clinical question. [ABSTRACT FROM AUTHOR]

The atomic electrostatic potentials calculated by the CHELPG method have been shown to be sensitive indicators of the gas phase and solution properties of the statins. Solvation free energies in water, n-octanol and n-octane have been determined using the SMD solvent model. The percentage hydrophilicity and hydrophobicity (or lipophilicity) of the statins in solution have been determined using (a) the differences in solvation free energies between n-octanol and n-octane as a measure of hydrophilicity, and the solvation energy in octane as a measure of hydrophobicity (b) the sum of the atomic electrostatic charges on the hydrogen bonding and polar bonding nuclei of the common pharmacophore combined with a solvent measure of hydrophobicity, and (c) using the buried surface areas after statin binding to HMGCR to calculate the hydrophobicity of the bound statins. The data suggests that clinical definitions of statins as either “hydrophilic” or “lipophilic” based on experimental partition coefficients are misleading. An estimate of the binding energy between rosuvastatin and HMGCR has been made using: (a) a coulombic electrostatic interaction model, (b) the calculated desolvation and resolvation of the statin in water, and (c) the first shell transfer solvation energy as a proxy for the restructuring of the water molecules immediately adjacent to the active binding site of HMGCR prior to binding. Desolvation and resolvation of the statins before and after binding to HMGCR are major determinants of the energetics of the binding process. An analysis of the amphiphilic nature of lovastatin anion, acid and lactone and fluvastatin anion and their abilities to cross the blood brain barrier has indicated that this process may be dominated by desolvation and resolvation effects, rather than the statin molecular size or statin–lipid interactions within the bilayer. The ionization energy and electron affinity of the statins are sensitive physical indicators of the ease that the various statins can undergo endogenous oxidative metabolism. The absolute chemical hardness is also an indicator of the stability of the statins, and may be a useful indicator for drug design. [ABSTRACT FROM AUTHOR]

Density functional theory (B3LYP-6-31G(d)) was performed to study the effect of molecular and electronic structures, of 2-cyclopropyl-4-thiophenyl-quinoline mevalonolactones as potential hypocholesterolemic inhibitors, on their biological activities and discuss the correlation between the inhibition efficiency and quantum chemical parameters. Molecular docking was performed to investigate the mode of interactions between the investigated inhibitors and the active sites of the target Hydroxymethylglutaryl-Coenzyme A(HMG-CoA) reductase. The results could suggest further structural modifications to discover more potent and selective HMG-CoA reductase inhibitors. The catalytic active sites of HMGR have a positive electrostatic potential which is complemented with a negative electrostatic potential of the investigated drugs to form a stabilized complex. The presence of lipophobic groups, such as quinoline nucleus, cyclopropyl and substituted thiophenyl groups as well as a lactone moiety, is important for binding to the active sites. A good correlation between the experimental and theoretical data confirms that the quantum chemical methods and molecular docking studies are successful tools for enriching screening experiments aimed at the discovery of novel bioactive compounds. [ABSTRACT FROM AUTHOR]

Statins, inhibitors of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase enzyme, are molecules of fungal origin. By inhibiting a key step in the sterol biosynthetic pathway statins are powerful cholesterol lowering medications and have provided outstanding contributions to the prevention of cardiovascular disease. Their detection in mycetes traces back to close to 40 years ago: there were, originally, widely opposing views on their therapeutic potential. From then on, intensive pharmaceutical development has led to the final availability in the clinic of seven statin molecules, characterized by differences in bioavailability, lipo/hydrophilicity, cytochrome P-450 mediated metabolism and cellular transport mechanisms. These differences are reflected in their relative power (mg LDL-cholesterol reduction per mg dose) and possibly in parenchymal or muscular toxicities. The impact of the antagonism of statins on a crucial step of intermediary metabolism leads, in fact, both to a reduction of cholesterol biosynthesis as well as to additional pharmacodynamic (so called “pleiotropic”) effects. In the face of an extraordinary clinical success, the emergence of some side effects, e.g. raised incidence of diabetes and cataracts as well as frequent muscular side effects, have led to increasing concern by physicians. However, also in view of the present relatively low cost of these drugs, their impact on daily therapy of vascular patients is unlikely to change. [ABSTRACT FROM AUTHOR]

Background: GP78 is a membrane-anchored ubiquitin ligase mediating the degradation of 3-hydroxy-3-methylglutaryl- CoA coenzyme A reductase (HMGCR) and Insig-1, which was very essential for the synthesis of cholesterol process. Cholesterol levels have a causal role in the development of cardiovascular disease. The aim of the present study was to assess the association between the human gp78 gene polymorphism and coronary artery disease (CAD) in a Han and Uygur population of China. Methods: We used two independent case-control studies: a Han population (602 CAD patients and 572control subjects) and a Uygur population (374 CAD patients and 376control subjects). All CAD patients and controls were genotyped for the same three single nucleotide polymorphisms (SNPs) (rs731119, rs2617849and rs2440472) of gp78 gene by a Real-time PCR instrument. Results: In the Han population, for total and men, the distribution of SNP3 (rs2440472) alleles and the dominant model (AA vs AG + GG) and recessive model (GG vs AG + AA) showed a significant difference between CAD and control participants (for allele: P = 0.003 and P = 0.002, respectively; for dominant model: P = 0.041 and P = 0.026, respectively; for recessive model: p = 0.004 and p = 0.004, respectively).The significant difference in both the two models was retained after adjustment for covariates (for dominant model OR:0.760, 95% confidence interval [CI]:0.584-0.99, P = 0.042; OR:0.686, 95% CI: 0.498-0.946, P = 0.022, respectively; for recessive model OR: 1.451, 95% CI: 1.067-1.974, P = 0.018; OR: 1.789, 95% CI: 1.219-2.627, P = 0.000). Our data was also assessed via haplotype-based case-control studies. For the Han population, for total, The G-T-G haplotype in CAD was significantly higher than that in the control group (P = 0.02), and the G-C-A haplotype in CAD was significantly lower than that in the control group (P = 0.0443), And for man, the G-T-G haplotype in CAD was significantly higher than that in the control group (P = 0.0048). Conclusions: The GG genotype and G allele of rs2440472 in gp78 gene could be a risk genetic marker of CAD in Han population in China. [ABSTRACT FROM AUTHOR]

For the first time, structural informationregarding the role ofsimvastatin in bone anabolism is described, and a bone-specific statinis introduced. Polyaspartate-conjugated simvastatin was synthesizedby solid-phase synthesis with the assistance of microwave irradiation.It displays significant bone targeting and bone formation with lesstoxicity than simvastatin. [ABSTRACT FROM AUTHOR]

Objective Our goal was to evaluate the effects of simvastatin on endometrial cancer cell lines and primary cultures of endometrial cancer cells. Methods Cell proliferation in the ECC-1 and Ishikawa endometrial cancer cell lines and primary cultures of endometrial cancer cells was assessed by MTT assay. Apoptosis and cell cycle were detected by Annexin V assay and propidium iodide staining, respectively. Reactive oxygen species and cell adhesion were assessed using ELISA assays. Invasion was analyzed using a transwell invasion assay. Mitochondrial DNA damage was confirmed using qPCR. The effects of simvastatin on the AKT/mTOR and MAPK pathways were determined by Western blotting. Results Simvastatin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines and 5/8 primary cultures of endometrial cancer cells. Simvastatin treatment resulted in G1 cell cycle arrest, a reduction in the enzymatic activity of HMG-CoA, induction of apoptosis as well as DNA damage and cellular stress. Treatment with simvastatin resulted in inhibition of the MAPK pathway and exhibited differential effects on the AKT/mTOR pathway in the ECC-1 and Ishikawa cells. Minimal change in AKT phosphorylation was seen in both cell lines. An increase in phosphorylated S6 was seen in ECC-1 and a decrease was seen in Ishikawa. Treatment with simvastatin reduced cell adhesion and invasion (p < 0.01) in both cell lines. Conclusion Simvastatin had significant anti-proliferative and anti-metastatic effects in endometrial cancer cells, possibly through modulation of the MAPK and AKT/mTOR pathways, suggesting that statins may be a promising treatment strategy for endometrial cancer. [ABSTRACT FROM AUTHOR]

The maturation status of dendritic cells determines whether interacting T cells are activated or if they become tolerant. Previously we could induce T cell tolerance by applying a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (HMGCRI) atorvastatin, which also modulates MHC class II expression and has therapeutic potential in autoimmune disease. Here, we aimed at elucidating the impact of this therapeutic strategy on T cell differentiation as a consequence of alterations in dendritic cell function. We investigated the effect of HMGCRI during differentiation of peripheral human monocytes and murine bone marrow precursors to immature DC in vitro and assessed their phenotype. To examine the stimulatory and tolerogenic capacity of these modulated immature dendritic cells, we measured proliferation and suppressive function of CD4+ T cells after stimulation with the modulated immature dendritic cells. We found that an HMGCRI, atorvastatin, prevents dendrite formation during the generation of immature dendritic cells. The modulated immature dendritic cells had a diminished capacity to take up and present antigen as well as to induce an immune response. Of note, the consequence was an increased capacity to differentiate naïve T cells towards a suppressor phenotype that is less sensitive to proinflammatory stimuli and can effectively inhibit the proliferation of T effector cells in vitro. Thus, manipulation of antigen-presenting cells by HMGCRI contributes to an attenuated immune response as shown by promotion of T cells with suppressive capacities. [ABSTRACT FROM AUTHOR]

Background: An association between tumor-specific HMG-CoA reductase (HMGCR) expression and good prognosis has previously been demonstrated in breast and ovarian cancer. In this study, the expression, clinicopathological correlates and prognostic value of HMGCR expression in colorectal cancer was examined. Findings: Immunohistochemical expression of HMGCR was assessed in tissue microarrays with primary tumours from 557 incident cases of colorectal cancer in the Malmö Diet and Cancer Study. Pearson's Chi Square test was applied to explore the associations between HMGCR expression and clinicopathological factors and other investigative biomarkers. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the relationship between HMGCR expression and cancer-specific survival (CSS) according to negative vs positive HMGCR expression. A total number of 535 (96.0%) tumours were suitable for analysis, of which 61 (11.4%) were HMGCR negative. Positive cytoplasmic HMGCR expression was associated with distant metastasis-free disease at diagnosis (p = 0.002), lack of vascular invasion (p = 0.043), microsatellite-instability (p = 0.033), expression of cyclin D1 (p = <0.001) and p21 (p = <0.001). Positive HMGCR expression was significantly associated with a prolonged CSS in unadjusted Cox regression analysis in the entire cohort (HR = 1.79; 95% CI 1.20-2.66) and in Stage III-IV disease (HR = 1.71; 95% CI 1.09-2.68), but not after adjustment for established clinicopathological parameters. Conclusions: Findings from this prospective cohort study demonstrate that HMGCR is differentially expressed in colorectal cancer and that positive expression is associated with favourable tumour characteristics and a prolonged survival in unadjusted analysis. The utility of HMGCR as a predictor of response to neoadjuvant or adjuvant statin treatment in colorectal cancer merits further study. Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2115647072103464. [ABSTRACT FROM AUTHOR]

The enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA-R) is the fundamental target for the treatment of hypercholesterolemia nowadays. The HMG-CoA-R clinical active site inhibitors (statins) are among the most widespread and profitable drugs ever sold but their side effects (myopathies, sometimes severe) still limit their use, which makes the finding of alternatives to statins a field of intense research. In this line, we address here a new strategy for inhibiting the homotetrameric HMG-CoA-R. The enzyme consists of a "dimer of dimers', each dimer having two active sites. We pursue here the inhibition of enzyme oligomerization, through drug binding to the dimer interface. We have computationally mutated 232 interfacial residues by alanine and calculated the loss in binding free energy among the monomers that build up each dimer of the homotetramer. This led to the identification of the (ten) key residues for the formation of the active dimer (Glu528, Ile531, Met534, Tyr644, Glu665, Asn686, Lys692, Lys735, Met742, and Val863). The results show that these residues are located in two specific spots of the protein with a cleft shape, whose shape and size is favorable for small drug binding. It is expectable that small molecules specifically bound to these druggable pockets will have a major effect on the oligomerization of the protein or/and in active site formation. This paves the way for the discovery of new families of inhibitors of HMG-CoA-R. [ABSTRACT FROM AUTHOR]

Significance: HMG-CoA reductase inhibitors (statins) lower serum cholesterol concentrations and are beneficial in the primary and secondary prevention of coronary heart disease. The positive clinical effects have only partially been reproduced with other lipid-lowering interventions suggesting potential statin effects in addition to cholesterol lowering. In experimental models, direct beneficial cardiovascular effects that are mediated by the inhibition of isoprenoids have been documented, which serve as lipid attachments for intracellular signaling molecules such as small Rho guanosine triphosphate-binding proteins, whose membrane localization and function are dependent on isoprenylation. Recent Advances: Rac1 GTPase is an established master regulator of cell motility through the cortical actin reorganization and of reactive oxygen species generation through the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Critical Issues: Observations in cells, animals, and humans have implicated the activation of Rac1 GTPase as a key component of cardiovascular pathologies, including the endothelial dysfunction, cardiac hypertrophy and fibrosis, atrial fibrillation, stroke, hypertension, and chronic kidney disease. However, the underlying signal transduction remains incompletely understood. Future Directions: Based on the recent advance made in Rac1 research in the cardiovascular system by using mouse models with transgenic overexpression of activated Rac1 or conditional knockout, as well as Rac1-specific small molecule inhibitor NSC 23766, the improved understanding of the Rac1-mediated effects statins may help to identify novel therapeutic targets and strategies. Antioxid. Redox Signal. 20, 1238-1250. [ABSTRACT FROM AUTHOR]

Introduction: Statins (or HMG-CoA reductase inhibitors) have become drug of choice for raised Low-Density Lipoprotein Cholesterol (LDL-C) in treating. Of these, Atorvastatin, because of its prolonged 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibition has been considered for alternate day therapy in primary prevention of (CHD). Objectives: To compare the efficacy and safety of daily versus alternate day 10 mg Atorvastatin on reduction of lipid levels in patients of dyslipidemia and to evaluate the number of patients reaching the target Low-Density Lipoprotein (LDL) goals in these groups. Methodology: In this comparative, randomized, parallel group, non-blinded study, 100 naïve dyslipidemic patients in low to moderate risk group as per NCEP ATP (III) Guidelines were divided in two groups. Group A (n=50) received Atorvastatin 10 mg every alternate day for three months and Group B (n=50) received Atorvastatin 10 mg daily for three months. Apart from general examination and baseline investigations, lipid profile was also done. Efficacy was assessed by the percentage reduction in LDL and attainment of LDL goals as per NCEP ATP III Guidelines at the end of the study. Safety of the medication was assessed. Results: Atorvastatin 10 mg daily produced a significant reduction in Total Cholesterol (TC), LDL, Very Low Density Lipoprotein (VLDL) as compared to Atorvastatin 10 mg alternate day. The increase in the HDL level was also greater with a daily dose as compared to alternate day (but not statistically significant). In Low risk category 86.12 % patients (n=31) on daily dose reached their LDL-C goal vis-a-vis 66.67% (n=18) of patients on alternate day therapy. In the moderate risk category 100 % of daily Atorvastatin patients (n=10) achieved their LDL-C goal versus 33.33% patients (n=4) on alternate day therapy. Adverse events with alternate day therapy (n=4) were less as compared with daily treatment (n=10). Conclusion: Atorvastatin 10 mg daily was found to be safe and efficacious in patients with dyslipidemia compared to an alternate day therapy. [ABSTRACT FROM AUTHOR]

Highlights: [•] Relative contribution of MEP and MVA pathways to isoprenoids of cotton studied. [•] Isotopically-labeled intermediates fed to cotton seedlings. [•] Both pathways contribute to the formation of all classes of terpenoids. [•] Pathway contribution varied strongly among organs. [•] Differences between the labeling of intermediates and products sometimes large. [Copyright &y& Elsevier]

Purpose: Conflicting evidence has suggested that statins possess chemopreventive properties against prostate cancer (PCa). Therefore, we examined the association between statin use and risk of PCa in a Denmark-based case-control study. Materials and methods: We identified 42,480 patients diagnosed with incident PCa during 1997-2010 from a national cancer registry. Five age-matched population controls (n = 212,400) were selected for each case using risk-set sampling. Statin use from 1996 to the index date was obtained from the National Prescription Registry. Odds ratios (ORs) adjusted for age, comorbidity, non-steroidal anti-inflammatory drug use, and educational level for PCa associated with statin use, were computed using conditional logistic regression. Analyses were stratified by duration of statin use (0-1, 2-4, 5-9, or ⩾10 years), stage of PCa (localized or advanced), and type of statin used (lipophilic or hydrophilic). Results: In total, 7915 patients (19%) and 39,384 controls (19%) redeemed statin prescriptions prior to the index date. Overall, statin users had a 6% lower risk of PCa compared with non-users [adjusted OR (ORa), 0.94; 95% confidence interval (CI), 0.91-0.97]. Risk estimates did not differ substantially by duration or type of statin used. Slightly larger statin use-associated risk reductions were observed for advanced PCa (ORa, 0.90; 95% CI, 0.85-0.96) and with statin use ⩾10 years (ORa, 0.78; 95% CI, 0.65-0.95). Conclusion: Statin use was associated with a risk reduction overall (6%) and, specifically with advanced PCa (10%). Differences in diagnostic measures and residual confounding by socioeconomic parameters may have influenced our results. [ABSTRACT FROM AUTHOR]

Enterocytes are the only cell type that must balance the de novo synthesis and absorption of cholesterol, although the coordinate regulation of these processes is not well understood.Our previous studies demonstrated that enterocytes respond to the pharmacological blockade of cholesterol absorption by ramping up de novo sterol synthesis through activation of sterol regulatory element-binding protein-2 (SREBP-2). Here, we genetically disrupt both Insig1 and Insig2 in the intestine, two closely related proteins that are required for the feedback inhibition of SREBP and HMG-CoA reductase (HMGR). This double knock-out was achieved by generating mice with an intestine-specific deletion of Insig1 using Villin-Cre in combination with a germ line deletion of Insig2. Deficiency of both Insigs in enterocytes resulted in constitutive activation of SREBP and HMGR, leading to an 11-fold increase in sterol synthesis in the small intestine and producing lipidosis of the intestinal crypts. The intestine-Herived cholesterol accumulated in plasma and liver, leading to secondary feedback inhibition of hepatic SREBP2 activity. Pharmacological blockade of cholesterol absorption was unable to further induce the already elevated activities of SREBP-2 or HMGR in Insig-deficient enterocytes. These studies confirm the essential role of Insig proteins in the sterol homeostasis of enterocytes. [ABSTRACT FROM AUTHOR]

Abstract: Statins reduce the risk of death from cardiovascular disease in millions of people worldwide. Recent pharmacovigilance data has suggested that people taking statins have an increased risk of psychiatric adverse events such as amnesia and anxiety. This study aimed to investigate the possibility of statin-induced amnesia through animal models of memory and learning. We conducted extracellular field recordings of synaptic transmission in area CA1 of hippocampal slices to examine the effects of acute cholesterol lowering with lipid lowering drugs. We also assessed the effect of six weeks of simvastatin (2mg/kg/d) and atorvastatin (1mg/kg/d) treatment using the Morris water maze. Long Term Potentiation (LTP) was significantly diminished in the presence of 3µM atorvastatin or simvastatin and by the cholesterol sequestering agent methyl-β-cyclodextrin (MBCD). The effects were reversed in the MBCD but not the statin treated slices by the addition of cholesterol. In the water maze, statin treatment did not cause any deficits in the first five days of reference memory testing, but statin treated guinea pigs preformed significantly worse than control animals in a working memory test. The deficits observed in our experiments in water maze performance and hippocampal LTP are suggestive of statin induced changes in hippocampal plasticity. The effects on LTP are independent of cholesterol regulation, and occur at concentrations that may be relevant to clinical use. Our results may help to explain some of the behavioural changes reported in some people after beginning statin treatment. [Copyright &y& Elsevier]

Highlights: [•] We developed a fast, sensitive, and efficient method to determine HMGCR activity in different human cell lines. [•] MVL levels were determined using UPLC–MS/MS. [•] Lower limit of quantification was 0.12μg/l. [Copyright &y& Elsevier]

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (HMGR), an NADPH dependant enzyme catalyzes the synthesis of mevalonic acid from HMG-CoA required for isoprenoid biosynthesis. The HMGR gene from Leishmania donovani was cloned and expressed. Genome analysis of L. donovani revealed that HMGR gene having an open reading frame of 1305 bp encodes a putative protein of 434 amino acids. LdHMGR showed optimal activity at pH 7.2 and temperature 37 °C. Kinetic analysis of this enzyme revealed K m values of 35.7 ± 2.5 μM for (R,S)-HMG-CoA and 70 ± 7.9 μM for the cofactor NADPH. On tryptophan fluorescence quenching, the Stern Volmer constant (K sv), binding constant (K a) and protein:cofactor stoichiometry for interaction of NADPH cofactor with the enzyme were found to be 6.0 ± 0.7 M−1, 0.17 μM and 0.72 respectively. Polyclonal anti-rat HMGR antibody detected a band of ∼45 kDa in all phases of promastigote growth. Biophysical analysis of the secondary structure of LdHMGR confirmed the presence of 25.7 ± 0.35% alpha helicity. Thermal denaturation studies showed extreme stability of the enzyme with 60% helical structure retained at 90 °C. Statins (simvastatin and atorvastatin) and non-statin (resveratrol) effectively inhibited the growth of L. donovani promastigotes as well as the catalytic activity of the recombinant LdHMGR. Atorvastatin was found to be most potent antileishmanial inhibitor with an IC50 value of 19.4 ± 3.07 μM and a very lower concentration of 315.5 ± 2.1 nM was enough to cause 50% recombinant LdHMGR enzyme inhibition suggesting direct interaction with the rate limiting enzyme of the ergosterol biosynthetic pathway. Exogenous supplementation of ergosterol in case of atorvastatin and resveratrol treated cells caused complete reversal of growth inhibition whereas simvastatin was found to be ergosterol refractory. Cholesterol supplementation however, failed to overcome growth inhibition in all the cases. Overall our study emphasizes on exploring LdHMGR as a potential drug target for the development of novel antileishmanial agents. [ABSTRACT FROM AUTHOR]

The hypocholesterolemic effect of tomato juice has been investigated in an intervention study with rats, along with the possible inhibition effect of bioactive tomato compounds binding to the HMGCR enzyme. Two experimental groups (n = 8 Sprague-Dawley rats) were fed ad libitum for five weeks, with water or tomato juice provided to the control and intervention groups, respectively. Total, LDL and HDL cholesterol, and total triglycerides were analysed in plasma, and the lycopene content and the expression and activity of the enzyme HMGCR were determined in liver samples. A computational molecular modelling was carried out to determine the interactions between HMGCR and lycopene, chlorogenic acid and naringenin. Total, LDL and HDL cholesterol were significantly lower in the intervention group after the intake of tomato juice. In addition, a significant reduction in HMGCR activity was observed, although this was not accompanied by changes in gene expression. The molecular modelling showed that components of tomato can bind to the active site of the enzyme and compete with the ligand HMGCoA. Lycopene, from tomato juice, accumulates in the liver and can inhibit the activity of the rate-limiting enzyme of cholesterol biosynthesis, HMGCR. [ABSTRACT FROM AUTHOR]

3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a disorder biochemically characterized by the predominant accumulation of 3-hydroxy-3-methylglutarate (HMG), 3-methylglutarate (MGA), 3-methylglutaconate and 3-hydroxyisovalerate in tissues and biological fluids of the affected patients. Neurological symptoms and hepatopathy are commonly found in HL deficiency, especially during metabolic crises. Since the mechanisms of tissue damage in this disorder are not well understood, in the present study we evaluated the ex vivo effects of acute administration of HMG and MGA on important parameters of oxidative stress in cerebral cortex and liver from young rats. In vivo administration of HMG and MGA provoked an increase of carbonyl and carboxy-methyl-lysine formation in cerebral cortex, but not in liver, indicating that these metabolites induce protein oxidative damage in the brain. We also verified that HMG and MGA significantly decreased glutathione concentrations in both cerebral cortex and liver, implying a reduction of antioxidant defenses. Furthermore, HMG and MGA increased 2',7'-dichlorofluorescin oxidation, but did not alter nitrate and nitrite content in cerebral cortex and liver, indicating that HMG and MGA effects are mainly mediated by reactive oxygen species. HMG and MGA also increased the activities of superoxide dismutase and catalase in cerebral cortex and liver, whereas MGA decreased glutathione peroxidase activity in cerebral cortex. Our present data showing a disruption of redox homeostasis in cerebral cortex and liver caused by in vivo administration of HMG and MGA suggest that this pathomechanism may possibly contribute to the brain and liver abnormalities observed in HL-deficient patients. [ABSTRACT FROM AUTHOR]

HMG-CoA reductase (HMGR) is the target of statins, cholesterol-lowering drugs prescribed to millions of patients worldwide. More recent research indicates that HMGR could be a useful target in the development of antimicrobial agents. Over the last seven decades, researchers have proposed a series of increasingly complex reaction mechanisms for this biomedically important enzyme. [ABSTRACT FROM AUTHOR]

Type I polyketide synthases often use programmed β-branching, via enzymes of a 'hydroxymethylglutaryl-CoA synthase (HCS) cassette', to incorporate various side chains at the second carbon from the terminal carboxylic acid of growing polyketide backbones. We identified a strong sequence motif in acyl carrier proteins (ACPs) where β-branching is known to occur. Substituting ACPs confirmed a correlation of ACP type with β-branching specificity. Although these ACPs often occur in tandem, NMR analysis of tandem β-branching ACPs indicated no ACP-ACP synergistic effects and revealed that the conserved sequence motif forms an internal core rather than an exposed patch. Modeling and mutagenesis identified ACP helix III as a probable anchor point of the ACP-HCS complex whose position is determined by the core. Mutating the core affects ACP functionality, whereas ACP-HCS interface substitutions modulate system specificity. Our method for predicting β-carbon branching expands the potential for engineering new polyketides and lays a basis for determining specificity rules. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hydroxymethylglutaryl-Coenzyme A Reductase (HMGCR) catalyzes the rate-limiting step of cholesterol biosynthesis. This enzyme is the target of the widely available cholesterol lowering statins. In this population-based case–control study, the frequencies of -911 C>A polymorphism (rs3761740) of the HMGCR gene in patients with coronary heart disease (CHD) and healthy subjects were investigated and the correlations between the different genotypes and hypercholesterolemia with cardiovascular risk factors were analyzed. Methods: The HMGCR genotypes were determined in 365 patients with CHD and 365 controls by PCR–RFLP assay. Anthropometric measurements were measured in all participants. Results: There was no significant difference in the genotype frequencies of the HMGCR polymorphism between the male subjects of both patient and control groups, however, the HMGCR-CC genotype was found to be more frequent in female patients with CHD than female controls (p =0.002). The HMGCR-CC genotype showed higher total-cholesterol (TC) and LDL-cholesterol (LDL-C) levels than the CA+AA genotypes in male CHD patients (p =0.018). Due to this significant sex interaction, a multivariate analysis was conducted on the patient group. In the multivariate logistic regression analysis, the HMGCR-CC genotype was significantly associated with age<55 (OR=2.837, p =0.001) and TC≥5.18mmol/L (OR=1.970, p =0.027) in male subjects. However, this association was not observed in female patients (p >0.05). This analysis confirmed that the HMGCR-CC genotype was associated with elevated TC levels in male CHD patients with age<55years. Conclusion: These results suggest that age and sex modify the contribution of the HMGCR-911 polymorphism to fasting serum TC, LDL-C levels and risk of CHD. [Copyright &y& Elsevier]

Simple and accurate spectrophotometric methods are presented for the determination of five 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors (statins), namely atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and simvastatin, in pharmaceutical preparations. The methods are based on the reaction of drugs as n-electron donor with 7,7,8,8-tetracyanoquinodimethane as π-acceptors to give highly colored complex species. All variables were studied in order to optimize the reaction conditions. Beer's law was obeyed in the concentration ranges 4-20 µg mL-1, 4-12 µg mL-1, 0.8-2.4 µg mL-1, 4-14 µg mL-1, and 2.5-20 µg mL-1 for atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and simvastatin, respectively. The proposed methods were successfully applied to the pharmaceutical preparations without any interference from excipients. [ABSTRACT FROM AUTHOR]

Highlights: [•] RSV particles mature as virus filaments. [•] Virus transmission occurs by virus filaments. [•] RSV filament formation is inhibited by lovastatin. [•] Lovastatin inhibits RSV transmission. [•] Hydroxymetylglutaryl coenzyme A reductase mediates virus transmission. [Copyright &y& Elsevier]

Red yeast rice (Monascus fermented rice) contains monacolin K (MK), an HMG-CoA reductase inhibitor. Red yeast rice (RYR) contains a variety of other potential biological active molecules. The objective of this study was to study the effects of a crude extract and a fraction that contained the red azaphilione pigments rubropunctamine and monascorubramine and compare this to pure monacolin K (MK) in a hepatocarcinoma cell line (HepG2). An MTT proliferation assay showed that RYR crude, MK, and fraction 4 (red pigments) reduced cell growth in a dose-dependent manner with 72h LC50 values of 0.734±0.015mg/mL for RYR crude, 8.842±1.703μg/mL for MK and 0.039±0.002mg/mL for fraction 4. Cell death was determined using three distinct flow cytometry assays for apoptosis (sub-G1 cell cycle analysis, TUNEL apoptosis assay and multi-caspase apoptosis assay). The TUNEL apoptosis assay after 72h of treatment showed a larger apoptotic cell accumulation after MK treatment (22.45±0.60%) and RYR crude extract (18.22±0.62%) compared to fraction 4 (7.29±0.09%). After 72h treatment, fraction 4 induced cellular senescence in a dose dependent manner. Cell had morphological changes and increase in β-galactosidase activity, a marker of senescence and causes irreversible growth arrest. This is the first report describing cellular senescence of red monascus pigments extract isolated from RYR. [ABSTRACT FROM AUTHOR]

BACKGROUND Agaricus bisporus mushrooms were able to lower cholesterol levels in hypercholesterolaemic rats and it was suggested that dietary fibre might inhibit cholesterol absorption. However, A. bisporus extracts were also able to inhibit the 3-hydroxy-3-methyl-glutaryl CoA reductase ( HMGCR, the key enzyme in the cholesterol biosynthetic pathway) and this might also contribute to the observed lowering of cholesterol levels in serum. RESULTS The methanol-water extracts obtained from A. bisporus were able to inhibit up to 60% the HMGCR activity using an in vitro assay. The HMGCR inhibitory capacities depended on cultivation conditions, strains, etc. The potential inhibitors were not statins, they might be β-glucans able to scavenge the substrate and impair the enzymatic reaction. They were present during all mushroom developmental stages and similarly distributed through all the tissues including the parts discarded as a by-product. Accelerated solvent extractions using 1:1 ethanol-water as pressurised solvent (10.7 MPa, 25°C, five cycles of 5 min) were more effective in the extraction of the HMGCiR inhibitor(s) than supercritical fluid extractions (9 MPa, 40°C) using CO2 with 10% ethanol. CONCLUSION A mushroom cultivation and two extraction procedures were optimised to obtain fractions from A. bisporus with high HMGCR inhibitory activities to design novel ingredients for hypocholesterolaemic functional foodstuffs. © 2013 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Abstract: Hydroxymethyl glutaryl CoA reductase is the key enzyme in cholesterol synthesis. A relationship was found between cholesterol and the development of many types of cancer. Atorvastatin is a hypolipidemic drug that may have a role in treatment of cancer. Moreover, atorvastatin was reported to decrease the resistance of cancer cells to many chemotherapeutic agents. The aim of this work was to study the effect of each of methotrexate (MTX) and atorvastatin alone and in combination on solid Ehrlich carcinoma (SEC) in mice. Fifty BALB/c mice were divided into five equal groups: control untreated group, SEC, SEC+MTX, SEC+atorvastatin, SEC+MTX+atorvastatin. Tumor volume, tissue glutathione reductase (GR), catalase, malondialdehyde (MDA), cholesterol and tumor necrosis factor alpha (TNF-α) were determined. A part of the tumor was examined for histopathological and immunohistochemical study. MTX or atorvastatin alone or in combination induced significant increase in tissue catalase and GR with significant decrease in tumor volume, tissue MDA, cholesterol and TNF-α and alleviated the histopathological changes with significant increase in p53 expression and apoptotic index compared to SEC group. In conclusion, the combination of MTX and atorvastatin had a better effect than each of MTX or atorvastatin alone against solid Ehrlich tumor in mice. [Copyright &y& Elsevier]

Background: The prescription of statins is an evidence-based treatment to reduce the risk of cardiovascular events in patients with elevated cardiovascular risk or with a cardiovascular disorder (CVD). In spite of this, many of these patients do not receive statins. Methods: We evaluated the impact of a brief educational intervention in cardiovascular prevention in primary care physicians' prescribing behaviour regarding statins beyond their participation in a randomised controlled trial (RCT). For this, prescribing data of all patients > 35 years who were counselled before and after the study period were analysed (each n > 75000). Outcome measure was prescription of Hydroxymethylglutaryl-CoA Reductase Inhibitors (statins) corresponding to patients' overall risk for CVD. Appropriateness of prescribing was examined according to different risk groups based on the Anatomical Therapeutic Chemical Classification System (ATC codes). Results: There was no consistent association between group allocation and statin prescription controlling for risk status in each risk group before and after study participation. However, we found a change to more significant drug configurations predicting the prescription of statins in the intervention group, which can be regarded as a small intervention effect. Conclusion: Our results suggest that an active implementation of a brief evidence-based educational intervention does not lead to prescription modifications in everyday practice. Physician's prescribing behaviour is affected by an established health care system, which is not easy to change. [ABSTRACT FROM AUTHOR]

Abstract: Background: Rosuvastatin and pravastatin have differential hydrophilicity and potency to inhibit hydroxymethylglutaryl-CoA reductase that may be relevant to changes in adiponectin levels, insulin resistance, and the rate of new onset diabetes in large clinical studies. Therefore, we hypothesized that rosuvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients. Methods: This was a randomized, single-blind, placebo-controlled, parallel study. Age, gender, and body mass index were matched. Fifty-four patients were given placebo, rosuvastatin 10mg, or pravastatin 40mg, respectively once daily for 2months. Results: When compared with pravastatin therapy, rosuvastatin therapy significantly reduced total, LDL cholesterol, and apolipoprotein B levels (P <0.05 by post-hoc comparison), but comparably improved flow-mediated dilation after 2months. Interestingly, rosuvastatin therapy significantly increased fasting insulin (mean % changes; 28%, P =0.005). and HbA1c (1%, P =0.038) while decreasing plasma adiponectin levels (9%, P =0.010) and insulin sensitivity (assessed by QUICKI; 2%, P =0.007) when compared with baseline. By contrast, pravastatin therapy significantly decreased fasting insulin (8%, P =0.042), and HbA1c levels (1%, P =0.019) while increasing plasma adiponectin levels (36%, P =0.006) and insulin sensitivity (3%, P =0.005) when compared with baseline. Moreover, these differential effects were evident when outcomes of rosuvastatin and pravastatin therapy were directly compared (P =0.002 for insulin levels by ANOVA on Ranks, P =0.003 for adiponectin, P =0.003 for QUICKI, and P =0.010 for HbA1c by ANOVA). Conclusions: While significantly reducing lipoprotein profiles, rosuvastatin therapy had unwanted metabolic effects in hypercholesterolemic patients when compared with pravastatin therapy, that may be clinically relevant in patients prone to metabolic diseases. [Copyright &y& Elsevier]

A series of dual-actioncompounds were designed to target histonedeacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGR) by having a hydroxamate group essential for chelation withthe zinc ion in the active site of HDAC and the key structural elementsof statin for binding with both proteins. In our study, the statinhydroxamic acids prepared by a fused strategy are most promising incancer treatments. These compounds showed potent inhibitory activitiesagainst HDACs and HMGR with IC50values in the nanomolarrange. These compounds also effectively reduced the HMGR activityas well as promoted the acetylations of histone and tubulin in cancercells, but were not toxic to normal cells. [ABSTRACT FROM AUTHOR]

Abstract: Context: The association between 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and bone mineral density (BMD) is controversial because of conflicting findings from previous studies. Objective and design: The purpose of the present study was to evaluate the effect of statins on BMD reported in randomized and non-randomized controlled trials. We searched PubMed and Embase, using text, medical subject headings (MeSH) and keywords “bone mineral density” and “statins” or “HMG-CoA reductase inhibitors”. Our last PubMed and Embase queries were updated to August 2012. Data on participants, interventions, and outcomes from each study were abstracted independently by two authors. Results: Five case–control studies, six cohort studies and four randomized controlled trials (RCTs) met the inclusion criteria. Included studies involved 34,877 subjects (3824 in the intervention group and 31,053 in the control group) in 12 different countries with ages ranging from 44 to 66years. Statins significantly increased BMD at lumbar spine [standardized mean difference (SMD) 0.15, 95% CI 0.09–0.22], total hip (SMD 0.22, 95% CI 0.17–0.27) and femoral neck (SMD 0.19, 95% CI 0.09–0.29). We carried out subgroup analyses on selected populations of the cohorts. Statistically significant increases were also observed in the lumbar spine (SMD 0.12, 95% CI 0.04–0.21), total hip (SMD 0.23, 95% CI 0.17–0.28) and femoral neck BMD (SMD 0.22, 95% CI 0.08–0.36). Conclusion: The results of this study suggest that statins may help improve and maintain BMD at the lumbar spine, hip and femoral neck, especially in Caucasians and Asians. It also provides justification for prospective RCTs to evaluate the possible role of statins in BMD in different ethnic populations, such as Latin American and Africans. [Copyright &y& Elsevier]

Two-dimensional quantitative structure−activity relationship (2D-QSAR) models are useful in understanding how chemical structure is related to the biological activity of natural and synthetic chemicals. Also, they could be usefully employed for designing newer and better therapeutics. A 2D-QSAR study was performed for 52 compounds of a series of thiophenyl quinolines and α-asarone derivatives as potential hypocholesterolemic inhibitors using different types of physicochemical descriptors, which correlated significantly with the activity. Linear QSAR models were developed using multiple linear regression, where the genetic algorithm (genetic function approximation technique) was adopted for selecting the most appropriate descriptors. The results are discussed on the basis of regression data and the cross-validation technique. Model A is the best 2D-QSAR model describing the inhibition efficiency of HMG-CoA reductase with cross-validated squared correlation coefficient ( Q2 = 0.700) and the squared correlation coefficient ( R2 = 0.752), which is able to describe 70% of the variance in the experimental activity. The good agreement between the experimental and the predicted values of pIC50 (micromoles per litre) ( R = 0.876) confirms the reliability and the predictability of the proposed model. The results obtained from the present QSAR study explained the importance of the electronic, structural, spatial, and electrotopological descriptors in enhancing the biological activity of the investigated inhibitors. [ABSTRACT FROM AUTHOR]

Background: Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to have potentially useful anticancer effects against colorectal cancers in experimental studies, but clinical studies have shown inconsistent results on colorectal cancer incidence. Most colorectal cancers are believed to develop through the polyp-cancer sequence. We hypothesized that statins may protect against the development of adenomatous polyps, and this may contribute to the apparent cancer-protective effects. Objective: This study aims to compare previous statin use in patients with newly diagnosed adenomatous polyps against a control group without polyps. Method: A case-control study involving 264 patients attending for diagnostic colonoscopy at the Norfolk and Norwich University Hospital was used. Polyp cases were age and sex matched against controls with normal colonoscopies. Structured patient interviews and clinical notes were used to ascertain drug and risk factor. Logistic regression was used to compare statin exposure and correct for confounding factors. Results: There was a significant negative association between prior statin use and a diagnosis of adenomatous polyps [odds ratio (OR) = 0.40 (0.24-0.76)]. The association was significantly stronger with higher statin doses [≥40 mg simvastatin or equivalent; OR 0.33 (0.10-0.53)] or longer duration of use [>5 years; OR 0.36 (0.10-0.67)]. Statin use was negatively associated with both high- and low-risk polyps. Conclusions: Statins may have a protective effect against the development of adenomatous polyps. The negative association between statin use and polyp incidence showed a significant dose and duration relationship. [ABSTRACT FROM AUTHOR]

HMG-CoA-Reductase inhibitors, also known as statins, are currently the most powerful cholesterol-lowering drugs available on the market. Clinical trials and experimental evidence suggest that statins have anti-atherosclerotic effects. These are in part consequence of lipid lowering but also result from pleiotropic actions of the drugs. In this article, the anti-atherosclerotic actions of statins will be reviewed. [Copyright &y& Elsevier]

The article presents a study on the effects of increased inflammatory signaling of geranylgeranyltransferase type I (GGTase-I) deficient macrophages to the development of atherosclerosis at a low- density lipoprotein (LDL) receptor. The study uses genotype mice subjected to a Western -type diet of minimal cholesterol for certain period of time. The study concludes that GGTase-I activates RHOA which increases macrophage reverse cholesterol transport and reduces atherosclerosis development.

Abstract: 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. [Copyright &y& Elsevier]

HMG-CoA reductase inhibitors, commonly known as statins, are some of the most widely prescribed medications worldwide and have been shown to be effective at lowering cholesterol in numerous long-term prospective trials, yet there are significant limitations to their use. First, patients receiving statin therapy have relatively low levels of medication adherence compared with other drug classes. Next, numerous statin formulations are available, each with its own unique safety and efficacy profile, and it may be unclear to prescribers which treatment is optimal for their patients. Finally, statins have class-wide side effects of myopathy and rhabdomyolysis that have resulted in a product recall and dosage limitations. Recent evidence suggests that two genomic markers, KIF6 and SLCO1B1, may inform the therapy choice of patients initiating statins. Given the prevalence of statin usage, their potential health advantages and their overall cost to the healthcare system, there could be significant clinical benefit from creating personalized treatment regimens. Ultimately, if this approach is effective it may encourage higher OPEN ACCESS adoption of generic statins when appropriate, promote adherence, lower rates of myopathy, and overall achieve higher value cardiovascular care. This paper will review the evidence for personalized prescribing of statins via KIF6 and SLCO1B1 and consider some of the implications for testing these markers as part of routine clinical care. [ABSTRACT FROM AUTHOR]

Abstract: To investigate the effect of maternal dietary protein on hepatic cholesterol metabolism in offspring pigs and to detect underlying epigenetic mechanisms, 14 primiparous purebred Meishan sows were fed standard-protein (SP, n=7) or low-protein (LP, 50% of SP, n=7) diets during pregnancy and lactation, respectively. LP piglets showed significantly lower body weight and liver weight at weaning, associated with decreased liver and serum cholesterol content. Hepatic SREBP2, HMGCR and CYP7α1 mRNA expressions were all up-regulated in LP piglets, as well as SREBP2 protein content and HMGCR enzyme activity, compared to SP piglets, while the mRNA expression of LDLR, FXR, LXR and CYP27α1 was not altered. Hepatic activation of HMGCR gene transcription in LP piglets was associated with promoter hypomethylation, together with decreased histone H3, H3 lysine 9 monomethylation (H3K9me1) and H3 lysine 27 trimethylation (H3K27me3) and increased H3 acetylation. No CpG islands were predicted in the CYP7α1 promoter, and the augmented CYP7α1 transcription in LP piglets was associated with decreased H3, H3K9me1 and H3K27me3. No alterations were detected for hepatic expression of microRNAs predicted to target 3′-UTR of HMGCR or CYP7α1 gene. These results indicate that maternal low-protein diet during gestation and lactation affects hepatic cholesterol metabolism in weaning piglets by modifying the epigenetic regulation of HMGCR and CYP7α1 genes, which implicates possible long-term consequences in cholesterol homeostasis later in adult life. [Copyright &y& Elsevier]

Nasutitermes takasagoensis soldiers defend their colonies using characteristic diterpenes. Diterpenes are thought to be synthesized in the frontal gland cells surrounding the gland reservoir. To identify the genes involved in diterpene synthesis, a cDNA library was prepared from the frontal gland cells and exhaustively sequenced using a 454 pyrosequencer ( GS Junior; Roche, Branford, CT, USA). A total of 50 290 clean sequences were assembled into 1111 contigs, which were grouped into 774 genes (isogroups). Based on sequence similarity with known proteins, we identified seven genes encoding the following four enzymes associated with diterpene synthesis: 3-hydroxy-3-methylglutaryl coenzyme A ( HMG- CoA) synthase ( HMGS), HMG- CoA reductase ( HMGR), farnesyl diphosphate synthase, and geranylgeranyl diphosphate synthases. The expression levels of two enzymes, HMGS and HMGR, involved in the mevalonate pathway were examined, assuming that the site of the defensive terpenoid synthesis strongly activates the mevalonate pathway, which produces a precursor of terpenoids. Real-time quantitative reverse-transcriptase PCR confirmed significantly higher expression of HMGS and HMGR in the heads of soldiers. We then divided the head into three parts and found that the expression levels of HMGS and HMGR were significantly higher in the part containing class 1 secretory cells of the frontal gland. Overall, the results suggested that the mevalonate pathway for diterpene synthesis occurs in class 1 cells around the frontal gland reservoir. [ABSTRACT FROM AUTHOR]

Abstract: Statins are inhibitors of 3-hydroxy-methylglutaryl (HMG) CoA reductase. They exhibit effects beyond cholesterol reduction, including anticancer activity. This review presents the effects of statins in vitro and their possible molecular anticancer mechanisms and critically discusses the data regarding the role of statins in cancer prevention. Finally, this review focuses on the use of statins combined with other chemotherapeutics to increase the effectiveness of cancer treatments. Despite rare and inconclusive clinical data, the preclinical results strongly suggest that such combined treatment could be a promising new strategy for the treatment of certain tumor types. [Copyright &y& Elsevier]

This study presents a design of a highly potent and competitive inhibitory peptide for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). HMGR is the major regulatory enzyme of cholesterol biosynthesis and the target enzyme of many investigations aimed at lowering the rate of cholesterol biosynthesis. In previous studies, the two hypocholesterolemic peptides (LPYP and IAVPGEVA) were isolated and identified from soy protein. Based on these peptide sequences, a number of peptides were designed previously by using the correlation between the conformational flexibility and bioactivity. The design method that was applied in previous studies was slightly modified for the purpose of the current research and 12 new peptides were designed and synthesized. Among all peptides, SFGYVAE showed the highest ability to inhibit HMGR. A kinetic analysis revealed that this peptide is a competitive inhibitor of HMG-CoA with an equilibrium constant of inhibitor binding ( K) of 12 ± 0.4 nM. This is an overall 14,500-fold increase in inhibitory activity compared to the first isolated LPYP peptide from soybeans. Conformational data support a conformation of the designed peptides close to the bioactive conformation of the previously synthesized active peptides. [ABSTRACT FROM AUTHOR]

HMG-CoA reductase catalyzes the four-electron reduction of HMG-CoA to mevalonate and is an enzyme of considerable biomedical relevance because of the impact of its statin inhibitors on public health. Although the reaction has been studied extensively using X-ray crystallography, there are surprisingly no computational studies that test the mechanistic hypotheses suggested for this complex reaction. Theozyme and quantum mechanical (QM)/molecular mechanical (MM) calculations up to the B3LYP/6-31g(d,p)//B3LYP/6-311++g(2d,2p) level of theory were employed to generate an atomistic description of the enzymatic reaction process and its energy profile. The models generated here predict that the catalytically important Glu83 is protonated prior to hydride transfer and that it acts as the general acid or base in the reaction. With Glu83 protonated, the activation energies calculated for the sequential hydride transfer reactions, 21.8 and 19.3 kcal/mol, are in qualitative agreement with the experimentally determined rate constant for the entire reaction (1 s-1 to 1 min-1). When Glu83 is not protonated, the first hydride transfer reaction is predicted to be disfavored by >20 kcal/mol, and the activation energy is predicted to be higher by >10 kcal/mol. While not involved in the reaction as an acid or base, Lys267 is critical for stabilization of the transition state in forming an oxyanion hole with the protonated Glu83. Molecular dynamics simulations and MM/Poisson-Boltzmann surface area free energy calculations predict that the enzyme active site stabilizes the hemithioacetal intermediate better than the aldehyde intermediate. This suggests a mechanism in which cofactor exchange occurs before the breakdown of the hemithioacetal. Slowing the conversion to aldehyde would provide the enzyme with a mechanism to protect it from solvent and explain why the free aldehyde is not observed experimentally. Our results support the hypothesis that the pKa of an active site acidic group is modulated by the redox state of the cofactor. The oxidized cofactor and deprotonated Glu83 are closer in space after hydride transfer, indicating that indeed the cofactor may influence the pKa of Glu83 through an electrostatic interaction. The enzyme is able to catalyze the transfer of a hydride to the structurally and electronically distinct substrates by maintaining the general shape of the active site and adjusting the electrostatic environment through acid-base chemistry. Our results are in good agreement with the well-studied hydride transfer reactions catalyzed by liver alcohol dehydrogenase in calculated energy profile and reaction geometries despite different mechanistic functionalities. [ABSTRACT FROM AUTHOR]