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Objective: To determine whether pre-hospital statin use is associated with lower renal replacement therapy requirement and/or death during intensive care unit stay. Methods: Prospective cohort analysis. We analyzed 670 patients consecutively admitted to the intensive care unit of an academic tertiary-care hospital. Patients with ages ranging from 18 to 80 years admitted to the intensive care unit within the last 48 hours were included in the study. Results: Mean age was 66±16.1 years old, mean body mass index 26.6±4/9kg/m2 and mean abdominal circumference was of 97±22cm. The statin group comprised 18.2% of patients and had lower renal replacement therapy requirement and/or mortality (OR: 0.41; 95%CI: 0.18-0.93; p=0.03). The statin group also had lower risk of developing sepsis during intensive care unit stay (OR: 0.42; 95%CI: 0.22-0.77; p=0.006) and had a reduction in hospital length-of-stay (14.7±17.5 days versus 22.3±48 days; p=0.006). Statin therapy was associated with a protective role in critical care setting independently of confounding variables, such as gender, age, C-reactive protein, need of mechanical ventilation, use of pressor agents and presence of diabetes and/or coronary disease. Conclusion: Statin therapy prior to hospital admission was associated with lower mortality, lower renal replacement therapy requirement and sepsis rates. [ABSTRACT FROM AUTHOR]

The sole unifying feature of Archaea is the use of isoprenoid-based glycerol lipid ethers to compose cellular membranes. The branched hydrocarbon tails of archaeal lipids are synthesized via the polymerization of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), but many questions still surround the pathway(s) that result in production of IPP and DMAPP in archaeal species. Isotopic-labeling strategies argue for multiple biological routes for production of mevalonate, but biochemical and bioinformatic studies support only a linear pathway for mevalonate production. Here, we use a combination of genetic and biochemical assays to detail the production of mevalonate in the model archaeon Thermococcus kodakarensis. We demonstrate that a single, linear pathway to mevalonate biosynthesis is essential and that alternative routes of mevalonate production, if present, are not biologically sufficient to support growth in the absence of the classical mevalonate pathway resulting in IPP production from acetyl-CoA. Archaeal species provide an ideal platform for production of high-value isoprenoids in large quantities, and the results obtained provide avenues to further increase the production of mevalonate to drive isoprenoid production in archaeal hosts. [ABSTRACT FROM AUTHOR]

Abstract Objectives The pleiotropic effect of hydroxymethylglutaryl-CoA reductase inhibitors (statins) might have a beneficial effect in sepsis through several mechanisms. The aim was to assess the efficacy and safety of statins, compared with placebo, for the treatment of sepsis in adults. Methods We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2017, Issue 12), OVID MEDLINE (from 1966 to January 2018), Embase (Ovid SP, from 1974 to January 2018), and LILACS (from 1986 to January 2018). We also searched the trial registries ISRCTN and ClinicalTrials.gov to January 2018. The eligibility criteria were randomized controlled trials comparing the treatment of statins versus placebo in adult patients who were hospitalized due to sepsis. Participants were adults (16 years and older) hospitalized because of sepsis or who developed sepsis during admission. Interventions were treatment with hydroxymethylglutaryl-CoA reductase inhibitors (statins) versus no treatment or placebo. We performed a systematic review of all randomized controlled trials published until January 2018, assessing the efficacy and safety of statins in sepsis treatment. Two primary outcomes were assessed: 30-day overall mortality and deterioration to severe sepsis during management. Secondary outcomes were hospital mortality, need for mechanical ventilation and drug related adverse events. Results Fourteen trials evaluating 2628 patients were included. Statins did not reduce 30-day all-cause mortality neither in all patients (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.83–1.10), nor in a subgroup of patients with severe sepsis (RR 0.97, 95% CI 0.84–1.12). The certainty of evidence for both outcomes was high. There was no change in the rate of adverse events between study arms (RR 1.24, 95% CI 0.94 to 1.63). The certainty of evidence for this outcome was high. Conclusions The use of statin therapy in adults for the indication of sepsis is not recommended. [ABSTRACT FROM AUTHOR]

Talinum triangulare leaf flavonoid extract (TTFE) was evaluated for its effects on streptozotocin‐hyperglycemia and associated complications especially as it relates to dyslipidemia, lipid peroxidation, and renal dysfunction in rats. Two normoglycemic rat groups designated: control (administered distilled water) and control + TTFE (administered 10 mg/kg b.w. TTFE) and two streptozotocin‐induced (STZ) diabetic rat groups designated: STZ‐control (administered distilled water) and STZ + TTFE (administered 10 mg/kg TTFE). The treatment was given orally once daily for 21 consecutive days. Body weight and insulin concentration showed significant improvement while blood glucose, uric acid, creatinine, and total bilirubin concentrations were significantly reduced in diabetic rats administered TTFE compared to diabetic untreated rats. Furthermore, triglycerides, total cholesterol, LDL‐cholesterol, and malondialdehyde concentrations were significantly lowered in diabetic rats administered TTFE compared with diabetic untreated rats. Key enzymes involved in carbohydrate breakdown and cholesterol synthesis, α‐amylase and 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) reductase, respectively, were significantly inhibited in TTFE‐treated diabetic rats compared to diabetic control. Results presented in this study suggest that administration of TTFE for 21 days normalized STZ‐induced hyperglycemia and its associated dyslipidemia by a mechanism involving inhibition of α‐amylase and HMG‐CoA reductase activities, respectively, in rats. The study describes the potential antihyperglycemic effect of Talinum triangulare leaf flavonoid extract in streptozotocin‐induced diabetic rats. In addition to restoring blood glucose level in diabetic rats, significant improvement in blood lipid profile, as well as upregulation of antioxidant enzyme activities, was also observed. The extract was also observed to inhibit alpha‐amylase and 3‐hydroxy‐3‐methylglutaryl‐CoA reductase activities thus providing possible mechanistic justification for its observed antihyperglycemic and antilipidemic activities, respectively. [ABSTRACT FROM AUTHOR]

Copyright of Biomédica: Revista del Instituto Nacional de Salud is the property of Instituto Nacional de Salud of Colombia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Accelerated ubiquitination and subsequent endoplasmic reticulum (ER)-associated degradation (ERAD) constitute one of several mechanisms for feedback control of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This ERAD is initiated by the accumulation of certain sterols in ER membranes, which trigger binding of reductase to ER membrane proteins called Insigs. Insig-associated ubiquitin ligases facilitate ubiquitination of reductase, marking the enzyme for extraction across the ER membrane through a reaction that is augmented by nonsterol isoprenoids. Once extracted, ubiquitinated reductase becomes dislocated into the cytosol for degradation by 26S proteasomes. In this review, we will highlight several advances in the understanding of reductase ERAD, which includes the discovery for a role of the vitamin K 2 synthetic enzyme UBIAD1 in the reaction and demonstration that sterol-accelerated ERAD significantly contributes to feedback regulation of reductase and cholesterol metabolism in livers of whole animals. [ABSTRACT FROM AUTHOR]

Previous studies have shown that cowpea protein positively interferes with cholesterol metabolism. In this study, we evaluated the ability of the fraction containing peptides of <3 kDa, as well as that of the Gln-Asp-Phe (QDF) peptide, derived from cowpea β-vignin protein, to inhibit HMG-CoA reductase activity. We established isolation and chromatography procedures to effectively obtain the protein with a purity above 95%. In silico predictions were performed to identify peptide sequences capable of interacting with HMG-CoA reductase. In vitro experiments showed that the fraction containing peptides of <3 kDa displayed inhibition of HMG-CoA reductase activity. The tripeptide QDF inhibits HMG-CoA reductase (IC 50  = 12.8 μM) in a dose-dependent manner. Furthermore, in silico studies revealed the binding profile of the QDF peptide and hinted at the molecular interactions that are responsible for its activity. Therefore, this study shows, for the first time, a peptide from cowpea β-vignin protein that inhibits HMG-CoA reductase and the chemical modifications that should be investigated to evaluate its binding profile. [ABSTRACT FROM AUTHOR]

Heat shock proteins (HSP or stress proteins) are intracellular molecules that participate in physiological cell metabolism and growth, although they are known to be involved in many stress conditions. Statins inhibit the action of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA), which is important in the synthesis of cholesterol and essential isoprenoid intermediates, thereby lowering circulating low-density lipoprotein cholesterol (LDL), a major risk factor for cardiovascular disease (CVD). This review provides new insights into the mechanisms of action of statins in the regulation of HSPs. A better understanding of this involvement can help in development of new and more effective treatment strategies for CVD. [ABSTRACT FROM AUTHOR]

Plants respond to drought stress in the form of various physio-biochemical and molecular changes at both cellular and molecular levels. Drought stress causes the destruction of cell membranes by disintegration of membrane lipids. One of the major groups of membrane lipids that plays important role in preserving the integrity of cell membranes is phytosterols. HMG-CoA reductase (HMGR) is the principal enzyme in the biosynthesis of plant sterols, synthesized via mevalonic acid pathway. Phospholipid: sterol acyltransferase (PSAT) is another important enzyme that plays an important role in turnover of phytosterols into steryl esters and helps maintain homeostasis of membrane lipids. In this study, the expression of both HMGR and PSAT genes in drought sensitive (IR64) and drought tolerant (N22) rice cultivars under applied drought conditions were found to be elevated. The increase in expression of these genes was proportional to the level of severity of applied drought stress. This is substantiated by the negative correlation of HMGR and PSAT expression to relative water content (RWC) and membrane stability index (MSI). Expression of PSAT was also found to be positively correlated to ABA content and HMGR expression. [ABSTRACT FROM AUTHOR]

5‐Hydroxy‐3‐methylglutaryl‐CoA reductase inhibitors (statins) have beneficial effects in patients with heart failure (HF), regardless of serum cholesterol levels. However, their synergic effects with angiotensin II receptor blocker (ARB) remain to be established. We assessed the existence and potential underlying mechanisms of the effects of combined ARB [losartan (LOS)] and statin [simvastatin (SIM)] on cardiac function in rats and mice with load‐induced HF. Salt‐loaded Dahl salt‐sensitive (DS) rats were treated with vehicle, LOS, SIM, or LOS + SIM for 8 weeks. To mimic load‐induced HF in vitro, cultured neonatal rat cardiomyocytes (NRCM) were cyclically stretched. We also investigated the effect of LOS + SIM on pressure overload‐induced HF using mice with transverse aortic constriction (TAC). LOS + SIM improved left ventricular (LV) function and reduced LV hypertrophy more than the monotherapies in both salt‐loaded DS rats and TAC‐operated mice. LV‐tissue increases in Rho kinase and matrix metalloproteinase‐9 activity were decreased to a greater extent by LOS + SIM than by LOS and SIM monotherapies. Plasma levels of Exp‐3174, a LOS metabolite, were higher in LOS + SIM‐treated DS rats than in LOS‐treated rats. Stretch‐induced hypertrophy of NRCM pretreated with SIM + Exp‐3174 was significantly attenuated from that with LOS, Exp‐3174, SIM, or LOS + SIM. SIM administration significantly enhanced mitophagy in mouse hearts after TAC. However, LOS + SIM reduced mitophagy, and the salutary effect of SIM in mouse hearts after TAC was abolished in AT1R−/− mice. In conclusion, LOS and SIM have beneficial myocardial effects on load‐induced HF via differential pleiotropic effects. Thus, combination therapy of these drugs thus has potential as a therapeutic strategy for HF. [ABSTRACT FROM AUTHOR]

Cholesterol biosynthesis is tightly regulated in the cell. For example, high sterol concentrations can stimulate degradation of the rate-limiting cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, HMGCR). HMGCR is broken down by the endoplasmic reticulum membrane-associated protein complexes consisting of insulin-induced genes (Insigs) and the E3 ubiquitin ligase gp78. Here we found that HMGCR degradation is partially blunted in Chinese hamster ovary (CHO) cells lacking gp78 (gp78-KO). To identify other ubiquitin ligase(s) that may function together with gp78 in triggering HMGCR degradation, we performed a small-scale short hairpin RNA-based screening targeting endoplasmic reticulum-localized E3s. We found that knockdown of both ring finger protein 145 (Rnf145) and gp78 genes abrogates sterol-induced degradation of HMGCR in CHO cells. We also observed that RNF145 interacts with Insig-1 and -2 proteins and ubiquitinates HMGCR. Moreover, the tetrapeptide sequence YLYF in the sterol-sensing domain and the Cys-537 residue in the RING finger domain were essential for RNF145 binding to Insigs and RNF145 E3 activity, respectively. Of note, amino acid substitutions in the YLYF or of Cys-537 completely abolished RNF145-mediated HMGCR degradation. In summary, our study reveals that RNF145, along with gp78, promotes HMGCR degradation in response to elevated sterol levels and identifies residues essential for RNF145 function. [ABSTRACT FROM AUTHOR]

Statins are Hydroxymethylglutaryl‑coenzyme A reductase inhibitors, which are typically used to lower blood cholesterol. Additional beneficial effects, including improvement to pulmonary arterial hypertension (PAH), have also been confirmed. However, the mechanisms underlying this improvement have not yet been clarified. The present study was conducted to determine if fluvastatin was protective against experimental PAH development and to investigate the potential effects of fluvastatin on caveolin‑1 (cav‑1) expression. Rats were randomized to either receive a single subcutaneous injection of monocrotaline (MCT; 60 mg/kg; MCT group) or a single subcutaneous injection of MCT (60 mg/kg) followed by an oral gavage of fluvastatin (10 mg/kg) once daily until day 42 (M + F group). Rats in the MCT group received an equivalent volume of saline following the MCT injection. Six additional rats were given an equivalent volume of saline throughout as a control measure. PAH associated variables and cav‑1 protein expression were measured in each group at various times during the experimental period. Hemodynamic and morphometric analysis revealed that M + F rats developed moderate, delayed PAH. Cav‑1 western blot analysis demonstrated that cav‑1 expression was not significantly different in fluvastatin treated rats; however, MCT injured rats given saline had markedly reduced cav‑1 expression. It was concluded that fluvastatin may protect against PAH development and ameliorate MCT induced inhibition of cav‑1 expression in rats. [ABSTRACT FROM AUTHOR]

Immune-mediated necrotizing myopathy (IMNM) associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies occurs in patients both with and without history of statin-intake. The mechanisms of muscle fiber degeneration in this condition remain unknown. We studied pathological changes in muscle biopsies from three patients lacking history of statin-intake. Ultrastructural observations showed accumulation of degenerating mitochondria, glycogen granules and autophagic vacuoles, forming large composites in three cases, along with various nonspecific changes. The autophagic vacuoles often contained remnants of mitochondria, indicating mitophagy. Furthermore, upregulation of B-cell lymphoma 2/adenovirus E1B 19 kD-interacting protein 3 (BNIP3), a protein involved in mitophagy, was observed in two cases examined. In three cases of sporadic inclusion body myositis, two polymyositis, and three IMNM with anti-signal recognition particle antibody, BNIP3 was upregulated less frequently, and ultrastructural change of mitophagy was rarely seen. These findings suggested that mitophagy plays an important role in muscle fiber degeneration in IMNM with anti-HMGCR autoantibodies. [ABSTRACT FROM AUTHOR]

Currently, there is no standard therapy for non-alcoholic fatty liver disease (NAFLD), and statins have been developed as a first-line pharmaceutical therapeutic option for NAFLD-associated dyslipidemia. However, prolonged statins therapy has side effects, as statins inhibit HMG-CoA reductase, an enzyme at the very beginning of the mevalonate pathway. Here, we found that zoledronic acid (ZA), an inhibitor of farnesyl diphosphate synthase in the downstream mevalonate pathway, could attenuate hepatic lipid accumulation and improve liver injury in both high-fat diet-induced C57BL/6J mice and ob/ob mice. Moreover, the hepatic lipid metabolism was largely inhibited after ZA administration in high-fat diet-induced obese mice. Mechanically, ZA inhibited SREBP-1c-mediated de novo lipogenesis through suppressing RhoA activation via decreasing farnesyl diphosphate and geranylgeranyl diphosphate levels. In conclusion, our data provide a novel application of ZA in improving hepatic steatosis. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials on the post-admission use of statins in sepsis patients have not shown a survival benefit. Whether preadmission use of statins would confer any beneficial effects in sepsis patients has not been well studied.Methods: We conducted a population-based cohort study on a national health insurance claims database between 1999 and 2011. Sepsis patients were identified by ICD-9 codes compatible with the third International consensus definitions for sepsis. Use of statin was defined as the cumulative use of any statin for more than 30 days before the indexed sepsis admission. We determined the association between statin use and sepsis outcome by multivariate-adjusted Cox proportional hazard models and propensity score matched analysis. To minimize baseline imbalance between statin users and non-statin users, we matched/adjusted for social economic status, comorbidities, proxies for healthy lifestyle, health care facility utilization, and use of medications.Results: We identified 52 737 sepsis patients, of which 3599 received statin treatment. Statins use was associated with a reduced 30-day mortality after multivariable adjustment (HR 0.86, 95% CI, 0.78-0.94) and propensity score matching (HR, 0.88; 95% CI, 0.78-0.99). On subgroup analysis, the beneficial effects of statins were not significant in patients receiving ventilator support or requiring ICU admission.Conclusions: In this national cohort study, preadmission statin therapy before sepsis development was associated with a 12% reduction in mortality when compared with patients who never received a statin. There were no consistent beneficial effects of statins in all patient subgroups. [ABSTRACT FROM AUTHOR]

Background: The anti-inflammatory effects of statins have been suggested to relieve postoperative pain. This retrospective study tested the association between the perioperative routine use of statins in therapeutic doses, and opioid requirements and pain scores, after hip replacement surgery.Methods: With IRB approval, data was obtained for adult patients who had elective hip replacement surgery under spinal anaesthesia at Cleveland Clinic between 2005 and 2015. Patients were compared using a joint hypothesis framework. We used the inverse probability of treatment weighting method to control for observed confounding factors (a total of 26).Results: We included 611 statin users and 780 non-statin users. Pain score during the initial 72 h after surgery was 0.07 higher (95% CI: -0.02, 0.17) in statin users (noninferiority test in both directions P<0.001). The estimated ratio of geometric means in the cumulative i.v. morphine equivalent opioid consumption was 1.01 (95% CI: 0.93, 1.10) for statin vs non-statin users (noninferiority test P=0.001 in the hypothesized direction and<0.001 in the other direction) during the initial 72 h after surgery. The statin and non-statin patients were deemed equivalent on postoperative opioid consumption and pain score.Conclusions: This is the first large retrospective clinical study that investigates the effects of statin use on postoperative pain and opioid consumption. We observed no difference between statin users and non-users during the initial 72 h after hip surgery. Our findings do not support the routine use of statins as part of an analgesic regimen. [ABSTRACT FROM AUTHOR]

Statins, cholesterol lowering drugs, have been demonstrated to exert beneficial effects in other conditions such as primary and progressing neurodegenerative diseases beyond their original role. Observation that statins ameliorate the neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS) and cerebral ischemic stroke, the neuroprotective effects of these drugs are thought to be linked to their anti-inflammatory, anti-oxidative, and anti-excitotoxic properties. Despite the voluminous literature on the clinical advantages of 3-hydroxy-3-methylglutaryl Co-enzyme A reductase (HMGCR) inhibitors (statins) in cardiovascular system, the neuroprotective effects and the underlying mechanisms are little understood. Hence, the present review tries to provide a critical overview on the statin-induced neuroprotection, which are presumed to be associated with the ability to reduce cholesterol, Amyloid-β and apolipoprotein E (ApoE) levels, decrease reactive oxygen and nitrogen species (ROS and RNS) formation, inhibit excitotoxicity, modulate matrix metalloproteinases (MMPs), stimulate endothelial nitric oxide synthase (eNOS), and increase cerebral blood perfusion. This review is also aimed to illustrate that statins protect neurons against the neuro-inflammatory processes through balancing pro-inflammatory/anti-inflammatory cytokines. Ultimately, the beneficial role of statins in ameliorating the development of PD, AD, MS and cerebral ischemic stroke has been separately reviewed. [ABSTRACT FROM AUTHOR]

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In 50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients presented after one year of age. Six patients died prior to data collection. Long-term neurological complications were common. Half of the patients had a normal cognitive development while the remainder showed psychomotor deficits. We identified seven novel HMGCL mutations. In agreement with previous reports, no clear genotype-phenotype correlation could be found. This is the largest cohort of HMGCLD patients reported so far, demonstrating that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important. [ABSTRACT FROM AUTHOR]

Background: Latex from the dandelion species Taraxacum brevicorniculatum contains many high-value isoprenoid end products, e.g. triterpenes and polyisoprenes such as natural rubber. The isopentenyl pyrophosphate units required as precursors for these isoprenoids are provided by the mevalonate (MVA) pathway. The key enzyme in this pathway is 3- hydroxy-methyl-glutaryl-CoA reductase (HMGR) and its activity has been thoroughly characterized in many plant species including dandelion. However, two enzymes acting upstream of HMGR have not been characterized in dandelion latex: ATP citrate lyase (ACL), which provides the acetyl-CoA utilized in the MVA pathway, and acetoacetyl- CoA thiolase (AACT), which catalyzes the first step in the pathway to produce acetoacetyl-CoA. Here we isolated ACL and AACT genes from T. brevicorniculatum latex and characterized their expression profiles. We also overexpressed the well-characterized HMGR, ACL and AACT genes from Arabidopsis thaliana in T. brevicorniculatum to determine their impact on isoprenoid end products in the latex. Results: The spatial and temporal expression profiles of T. brevicorniculatum ACL and AACT revealed their pivotal role in the synthesis of precursors necessary for isoprenoid biosynthesis in latex. The overexpression of A. thaliana ACL and AACT and HMGR in T. brevicorniculatum latex resulted in the accumulation of all three enzymes, increased the corresponding enzymatic activities and ultimately increased sterol levels by ~5-fold and pentacyclic triterpene and cis-1,4-isoprene levels by ~2-fold. Remarkably high levels of the triterpene precursor squalene were also detected in the triple-transgenic lines (up to 32 mg/g root dry weight) leading to the formation of numerous lipid droplets which were observed in root crosssections. Conclusions: We could show the effective expression of up to three transgenes in T. brevicorniculatum latex which led to increased enzymatic activity and resulted in high level squalene accumulation in the dandelion roots up to an industrially relevant amount. Our data provide insight into the regulation of the MVA pathway in dandelion latex and can be used as a basis for metabolic engineering to enhance the production of isoprenoid end products in this specialized tissue. [ABSTRACT FROM AUTHOR]

HMG-CoA reductase ( HMGR) is a key enzyme in the mevalonate pathway for sterols and cytosolic isoprenoid production. Although HMGR kinases from spinach, barley, and cauliflower tissues have been strongly suggested as members of SNF1-related protein kinases 1 (Sn RK1), the phosphorylation and inactivation of HMGR by plant Sn RK1s has not been demonstrated. In this study, we elucidated that AKIN10, an Arabidopsis Sn RK1, acts as an HMGR kinase. The recombinant AKIN10 phosphorylates and inactivates At HMGR1S using recombinant GRIK1 as the AKIN10 activator. In contrast, AKIN10- GRIK1 fails to inactivate At HMGR1S-S577A, suggesting that this is achieved through Ser577 phosphorylation. Moreover, phosphorylation is detected not only in At HMGR1S but also in At HMGR1S-S577A, suggesting the presence of a novel regulatory mechanism of plant HMGR. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia and statin use have been unevenly associated with clinical change in Alzheimer's disease dementia. In this longitudinal study, 192 consecutive outpatients with late-onset Alzheimer's disease dementia were stratified according to APOE haplotypes, and followed for one year to investigate associations of lipid profile variations and lipophilic statin therapy with changes in cognition, caregiver burden, basic and instrumental functionality. Overall, 102 patients (53.1%) carried APOE4+ haplotypes and 90 (46.9%) carried APOE4- haplotypes; 189 patients (98.4%) used either a cholinesterase inhibitor, or Memantine, or both; 144 patients had dyslipidemias and 143 of them received statin therapy. Total cholesterol, LDL-cholesterol, Mini-Mental State Examination scores, and functional independence scores were significantly lower at the end of the follow-up, while Clinical Dementia Rating sum-of-boxes scores were higher. Exclusively for APOE4- carriers, rising LDL-cholesterol levels were associated with a trend toward improvements in the Index of Independence in Activities of Daily Living ( β = 0.010; ρ = 0.16), whereas rising HDL-cholesterol levels were associated with lowered scores ( β = −0.051; ρ = 0.04). Lipophilic statin therapy had non-significant protective effects over Clinical Dementia Rating sum-of-boxes score variations only for APOE4- carriers. APOE4- haplotypes might enhance lipid availability to protect neuronal membranes, thus overcoming their supposed dysfunction in cholesterol metabolism, while APOE4+ carriers have inefficient neural repair mechanisms. In conclusion, APOE haplotypes seem to influence the protective effects of lipid profile variations for patients with Alzheimer's disease dementia, but current evidence is insufficient to propose lipid-lowering drugs as specific anti-dementia therapy. [ABSTRACT FROM AUTHOR]

Porcine circovirus type 2 (PCV2) is the smallest DNA virus, which causes porcine circovirus diseases and porcine circovirus-associated diseases (PCVD/PCVAD). Due the small size of viral genomic DNA, PCV2 replication predominantly relies on the host factors. In this study, effects of PKC and HMGCR on PCV2 infection were evaluated using real time PCR and western blot. We found that PKC and HMGCR participated in different stages of PCV2 infection. HMGCR works on the early stage of the infection to inhibit the virus infection, while PKC enhances the infection at the late stage. Furthermore, PKC enhances PCV2 replication by activating JNK1/2 and inactivating HMGCR via regulating phosphorylation of these two proteins, while HMGCR can suppress phosphorylation of JNK1/2. The results in the present study will provide new sights in the pathogenesis of PCV2 infection, as well as interactions between host factors during PCV2 infection. [ABSTRACT FROM AUTHOR]

Background Statin pretreatment has been associated with reduced infarct volume in nonlacunar strokes. The effect of statins on functional outcomes of strokes related to atrial fibrillation (AF) is unknown. We aimed to define the influence of prestroke statin use on functional outcome in AF. Methods We assembled a cohort of consecutive ischemic stroke patients from 2006 to 2010. All patients underwent CT or MRI and were adjudicated by site investigators. AF was confirmed by electrocardiogram in 100% of patients. Site neurologists blinded to the study hypothesis affirmed the type of stroke and assessed the severity of disability at the time of hospital discharge. The frequency of death at 30-days was calculated. Results Ischemic stroke ( n = 1030) resulted in a severe neurological deficit or death (modified Rankin scale ≥ 4) at 30 days in 711 patients (69%). Using multivariable logistic regression models adjusting for factors associated with statin treatment and factors associated with functional outcome, prestroke statin use was associated with a 32% reduction in frequency of severe stroke (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.50–0.92; P = 0.011). Other independent factors associated with severe stroke included older age, female sex, non-White race, diabetes mellitus, prior ischemic stroke, prior venous thromboembolism, and dementia. Conclusion Ischemic strokes in AF are associated with high mortality and morbidity. Statin use at time of stroke onset among patients with AF was associated in this study with less severe stroke and warrant validation. [ABSTRACT FROM AUTHOR]

Background: Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown.Methods: We used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol-lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes.Results: Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes.Conclusions: In this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive. (Funded by the Medical Research Council and the National Heart, Lung, and Blood Institute.). [ABSTRACT FROM AUTHOR]

The pathogenesis of the muscular symptoms and recurrent rhabdomyolysis that are commonly manifested in patients with mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiencies is still unknown. In this study we investigated the effects of the major long-chain monocarboxylic 3-hydroxylated fatty acids (LCHFA) accumulating in these disorders, namely 3-hydroxytetradecanoic (3HTA) and 3-hydroxypalmitic (3HPA) acids, on important mitochondrial functions in rat skeletal muscle mitochondria. 3HTA and 3HPA markedly increased resting (state 4) and decreased ADP-stimulated (state 3) and CCCP-stimulated (uncoupled) respiration. 3HPA provoked similar effects in permeabilized skeletal muscle fibers, validating the results obtained in purified mitochondria. Furthermore, 3HTA and 3HPA markedly diminished mitochondrial membrane potential, NAD(P)H content and Ca 2+ retention capacity in Ca 2+ -loaded mitochondria. Mitochondrial permeability transition (mPT) induction probably underlie these effects since they were totally prevented by cyclosporin A and ADP. In contrast, the dicarboxylic analogue of 3HTA did not alter the tested parameters. Our data strongly indicate that 3HTA and 3HPA behave as metabolic inhibitors, uncouplers of oxidative phosphorylation and mPT inducers in skeletal muscle. It is proposed that these pathomechanisms disrupting mitochondrial homeostasis may be involved in the muscle alterations characteristic of MTP and LCHAD deficiencies. [ABSTRACT FROM AUTHOR]

Statins are HMG-CoA reductase inhibitors that are used to decrease the blood levels of low-density lipoprotein (LDL). In addition, they have been shown to exert pleiotropic protective effects in the absence of LDL-lowering activity. The present study investigated the effects of lovastatin on global gene expression in human umbilical vein endothelial cells (HUVECs), in order to further explore its ability to protect against oxidized (ox)-LDL-induced cytotoxicity. HUVECs were treated with lovastatin for 2-24 h, and gene expression patterns were analyzed using cDNA microarrays. The results suggested that numerous genes were regulated by lovastatin, including certain genes associated with cell survival, such as PTK2B, BCL2 and MAP3K3. In particular, PTK2B, which has been shown to exert anti-apoptotic effects against ox-LDL-induced cell injury, was upregulated by lovastatin. Knockdown of PTK2B was able to attenuate ox-LDL-induced cell injury, and this was associated with decreased levels of phosphorylated-AKT and eNOS, and inhibition of mitochondrial-dependent apoptosis. In conclusion, the results of the present study suggested that lovastatin protects against ox-LDL-induced cell injury, potentially via the upregulation of PTK2B, which regulates the anti-apoptosis signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated.Methods: We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case-control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH.Results: A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones.Conclusions: Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions. [ABSTRACT FROM AUTHOR]

Accumulation of sterols in endoplasmic reticulum membranes stimulates the ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which catalyzes a ratelimiting step in synthesis of cholesterol. This ubiquitination marksHMGCRfor proteasome-mediated degradation and constitutes one of several mechanisms for feedback control of cholesterol synthesis. Mechanisms for sterol-accelerated ubiquitination and degradation of HMGCR have been elucidated through the study of cultured mammalian cells. However, the extent to which these reactions modulate HMGCR and contribute to control of cholesterol metabolism in whole animals is unknown. Here, we examine transgenic mice expressing in the liver the membrane domain of HMGCR (HMGCR (TM1-8)), a region necessary and sufficient for sterol-accelerated degradation, and knock-in mice in which endogenous HMGCR harbors mutations that prevent sterol-induced ubiquitination. Characterization of transgenic mice revealed that HMGCR (TM1-8) is appropriately regulated in the liver of mice fed a high cholesterol diet or chow diet supplemented with theHMGCRinhibitor lovastatin. Ubiquitination-resistant HMGCR protein accumulates in the liver and other tissues disproportionately to its mRNA, indicating that sterol-accelerated degradation significantly contributes to feedback regulation of HMGCR in vivo. Results of these studies demonstrate that HMGCR is subjected to sterol-accelerated degradation in the liver through mechanisms similar to those established in cultured cells. Moreover, these studies designate sterol-accelerated degradation of HMGCR as a potential therapeutic target for prevention of atherosclerosis and associated cardiovascular disease. [ABSTRACT FROM AUTHOR]

Objective: In this study we report the development of a simple, rapid and efficient capillary electrophoresis method for the simultaneous determination of atorvastatin, fluvastatin, lovastatin and simvastin. Methods: Capillary zone electrophoresis proved to be efficient for the simultaneous separation of atorvastatin and fluvastatin, but could not resolve the determination of lovastatin and simvastatin. The simultaneous separation of all four statins was achieved by applying a micellar electrokinetic chromatographic method, after transforming lovastatin and simvastatin in β-hydroxyl acid forms through alkaline hydrolysis. The optimum electrophoretic conditions and analytical parameters were investigated and the analytical performances of the method were verified with regard to linearity, precision, accuracy, LOD and LOQ. Results: The optimum electrophoretic separation conditions were: 25 mM sodium tetraborate with 25 mM sodium dodecyl sulphate buffer electrolyte at pH 9.5, applied voltage + 25 kV, separation temperature 25 °C, injection pressure/time 50 mbar/1 minutes, UV detection at 230 nm. Using the optimized electrophoretic conditions we succeeded in the simultaneous determination of the four statins in approximately 3 minutes, the order of migration being: atorvastatin, fluvastatin, lovastatin, simvastatin. The proposed method has been applied to the determination of the analytes in pharmaceutical tablets formulations. Conclusions: The capillary electrophoretic method developed in the present work proved to be suitable for the routine analysis of statins and can be adopted as quality control protocol in pharmaceutical analysis. [ABSTRACT FROM AUTHOR]

The present study was designed to evaluate the effect of sinapic acid, a bioactive phenolic acid on high blood pressure associated cardiac dysfunction, kidney fibrosis and lipid alterations in N ω -nitro- l -arginine methyl ester hydrochloride ( l -NAME) induced hypertensive rats. Sinapic acid was administered to rats orally at a dosage of 40 mg/kg everyday for a period of 4 weeks. Sinapic acid treatment significantly decreased mean arterial pressure, left ventricular end diastolic pressure, organ weights (liver and kidney), lipid peroxidation products in tissues (liver and kidney), activities of hepatic marker enzymes and the levels of renal function markers in serum of l -NAME rats. Sinapic acid treatment also significantly increased the level of plasma nitric oxide metabolites, and enzymatic and non-enzymatic antioxidants in tissues of l -NAME rats. Tissue damage was assessed by histopathological examination. Alterations in plasma angiotensin-converting enzyme activity, level of plasma lipoproteins and tissue lipids were corrected by sinapic acid treatment in l -NAME rats. Sinapic acid treatment significantly decreased the activity of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase in plasma and liver, whereas the activity of lecithin cholesterol acyl transferase was significantly increased in the plasma of hypertensive rats. Docking result showed the interaction between sinapic acid and HMG-CoA reductase. Sinapic acid has shown best ligand binding energy of −5.5 kcal/M. Moreover, in chick embryo model, sinapic acid improved vessel density on chorioallantoic membrane. These results of the present study concludes that sinapic acid acts as a protective agent against hypertension associated cardiac dysfunction, kidney fibrosis and lipid alterations. [ABSTRACT FROM AUTHOR]

Objectives: Physically active adults may be especially vulnerable to the adverse muscular side effects of statins. We determined if short-term cessation of statin therapy would improve aerobic exercise performance in middle-aged adults engaged in regular aerobic exercise training. Methods: Physically active middle-aged adults on statin therapy ≥6 mo (n = 16; 58 ± 10 y) or not taking lipid-lowering medications (controls) (n = 19; 51 ± 9 y) completed a peak oxygen consumption (VO2peak) and time to exhaustion test on a cycle ergometer 2-7 d apart. Tests were repeated following 1 mo of statin cessation or a 1 mo period for controls. Questionnaires were administered to assess exercise history and muscle complaints. Results: Statin users reported little or no muscle complaints and participation in aerobic exercise was similar between groups (p≥0.13). The lower VO2peak (37.3 ± 9.0 vs. 43.1 ± 4.9 ml/kg/min; p = 0.02) and time to exhaustion (21.9 ± 4.4 vs. 26.0 ± 6.3 min; p = 0.04) in statin users versus controls did not persist after controlling for age (p≥0.08). Aerobic exercise performance did not change with 1 mo of statin cessation (p≥0.54). No changes were observed in controls when tests were repeated 1 mo later (p≥0.38). Conclusion: Short-term cessation of statin therapy does not alter maximal aerobic capacity or aerobic endurance in physically active middle-aged adults with few or no statin muscle complaints. [ABSTRACT FROM AUTHOR]

Abstract The HMG-CoA reductase inhibitor (statin), which reduces serum cholesterol, has been demonstrated in the control of immune responses and may potentially play an important role in the regulation of acute and chronic rejection in organ transplantations. We investigated the graft-protective effect of a kind of statin, pravastatin, in the survival of fully major histocompatibility complex--mismatched murine cardiac allograft transplantation. Fully vascularized heterotopic hearts from C57BL/6 donors were transplanted into CBA recipients through microsurgical techniques. CBA recipients transplanted with a C57BL/6 heart received oral administration of 40, 120, or 400 μg/kg/day of pravastatin from the day of transplantation to 7 days afterward. Immunohistochemical staining studies were performed to determine whether intimal formation of coronary arteries in the transplanted cardiac allografts was preserved and also to conduct morphometric analysis. Untreated CBA recipients rejected C57BL/6 cardiac grafts acutely (median survival time [MST] 7 days). CBA recipients exposed with 40 and 120 μg/kg/day of pravastatin had a small prolonged allograft survival (MSTs of 10 and 9 days, respectively). However, the MST of CBA recipients exposed to 400 μg/kg/day of pravastatin was significantly effective for allograft survival (MST 50 days). Immunohistochemical staining assessments on 4 weeks after grafting showed suppression of intimal hyperplasia in allograft coronary arteries. Pravastatin could induce the prolongation of fully major histocompatibility complex--mismatched cardiac allograft through the protection of the coronary artery. Highlights • We investigated the effects of pravastatin in murine cardiac transplantation. • Pravastatin-treated CBA had significantly prolonged allograft survival. • Histologic studies from the pravastatin-treated group showed graft protective effects. [ABSTRACT FROM AUTHOR]

Background: Older patients with longstanding type 1 diabetes have high cardiovascular disease (CVD) risk such that statin therapy is recommended independent of prior CVD events. We aimed to determine self-reported CVD prevention guideline adherence in patients with longstanding diabetes. Research design and methods: 309 Canadians with over 50 years of type 1 diabetes completed a medical questionnaire for presence of lifestyle and pharmacological interventions, stratified into primary or secondary CVD prevention subgroups based on absence or presence of self-reported CVD events, respectively. Associations with statin use were analyzed using multivariable logistic regression. Results: The 309 participants had mean ± SD age 65.7 ± 8.5 years, median diabetes duration 54.0 [IQR 51.0, 59.0] years, and HbA1c of 7.5 ± 1.1% (58 mmol/mol). 159 (52.7%) participants reported diet adherence, 296 (95.8%) smoking avoidance, 217 (70.5%) physical activity, 218 (71.5%) renin-angiotensin-system inhibitor use, and 220 (72.1%) statin use. Physical activity was reported as less common in the secondary prevention subgroup, and current statin use was significantly lower in the primary prevention subgroup (65.5% vs. 84.8%, p = 0.0004). In multivariable logistic regression, the odds of statin use was 0.38 [95% CI 0.15-0.95] in members of the primary compared to the secondary prevention subgroup, adjusting for age, sex, hypertension history, body mass, HbA1c, cholesterol, microvascular complications, acetylsalicylic acid use, and renin-angiotensin system inhibitor use. Conclusion: Despite good self-reported adherence to general CVD prevention guidelines, against the principles of these guidelines we found that statin use was substantially lower in those without CVD history. Interventions are needed to improve statin use in older type 1 diabetes patients without a history of CVD. [ABSTRACT FROM AUTHOR]

Objective. This study was aimed to determine the effect of Anethum graveolens extract and Anethum graveolens (dill) tablet on lipid profile, liver enzymes, and gene expression and enzymatic activity of HMG-CoA reductase in high cholesterol fed hamsters. Materials and Methods. Golden Syrian male hamsters (130 ± 10 g) were randomly divided into 6 groups (n=6) and received daily the following: group 1 received chow + 2% cholesterol + 0.5% cholic acid (HCD), groups 2 and 3 received HCD diet plus 100 and 200 mg/kg hydroalcoholic extract of dill, respectively, and groups 4 and 5 received HCD diet plus 100 and 200 mg/kg dill tablet, respectively. Group 6 received only chow. After 1 month feeding serum biochemical factors were determined. HMG-CoA reductase mRNA level was measured (real-time PCR) and its activity was determined spectrophotometrically. Results. Compared with hypercholesterolemic group 1, lipid profile, blood glucose, and liver enzymes significantly decreased in all dill tablet or dill extract treated groups (p<0.05). The changes in HMG-CoA reductase gene expression level and enzyme activity significantly reduced in animals that received 200 mg/kg of extract or tablet. Conclusion. Dill extract and dill tablet showed potential hypocholesterolemic properties in hamsters by inhibition of HMG-CoA reductase activity. [ABSTRACT FROM AUTHOR]

A stable HMG-CoA reductase (HMGR) reaction in vitro was developed by a sensitive, selective and precise liquid chromatography–tandem mass spectrometry (LC–MS/MS) method. The optimized enzyme reaction condition contained 1.5 μg of HMGR, 20 nM of NADPH with 50 min of reaction time. The method was validated by several intra- and inter-day assays. The production transitions of m / z 147.0/59.1 and m / z 154.0/59.1 were used to detect and quantify mevalonolactone (MVAL) and MVAL-D 7 , respectively. The accuracy and precision of the method were evaluated over the concentration range of 0.005–1.000 μg/mL for MVAL and 0.010–0.500 μg/mL for lovastatin acid in three validation batch runs. The lower limit of quantitation was found to be 0.005 μg/mL for MVAL and 0.010 μg/mL for lovastatin acid. Intra-day and inter-day precision ranged from 0.95% to 2.39% and 2.26% to 3.38% for MVAL, 1.46% to 3.89% and 0.57% to 5.10% for lovastatin acid, respectively. The results showed that the active ingredients in Xuezhikang capsules were 12.2 and 14.5 mg/g, respectively. This assay method could be successfully applied to the quality control study of Xuezhikang capsule for the first time. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is one of the most severe forms of leishmaniasis which is fatal if left untreated. Sterol biosynthetic pathway in Leishmania is currently being explored for its therapeutic potential. In the present study, we have evaluated the antileishmanial efficacy of mevastatin, a known inhibitor of 3-hydroxy-3-methyl glutaryl-CoA reductase (HMGR) enzyme. Mevastatin inhibited Leishmania donovani promastigotes and intracellular amastigotes with an 50 % inhibitory concentration (IC) value of 23.8 ± 4.2 and 7.5 ± 1.1 μM, respectively, without exhibiting toxicity towards host cell line. Mevastatin also inhibited recombinant L. donovani HMGR ( LdHMGR) enzyme activity with an IC value of 42.2 ± 3.0 μM. Kinetic analysis revealed that the inhibition of recombinant LdHMGR activity by mevastatin was competitive with HMG-CoA. Mevastatin-treated parasites exhibited 66 % reduction in ergosterol levels with respect to untreated parasites. Incubation of mevastatin-treated L. donovani promastigotes with ergosterol resulted in revival of cell growth, whereas cholesterol supplementation failed to cause reversal in cell death. To further prove the specificity of mevastatin for HMGR enzyme, HMGR-overexpressing parasites were used which showed almost threefold resistance to mevastatin. It also induced morphological changes in the parasite accompanied by lipid body accumulation. Hence, antileishmanial effect of mevastatin was due to the inhibition of HMGR, which eventually leads to reduction in ergosterol levels and hence parasite death. The present study may have implications in the treatment of visceral form of leishmaniasis. [ABSTRACT FROM AUTHOR]

Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, are widely used in the management of different diseases beyond their primary indication for lowering cholesterol. Previous studies have demonstrated the neuroprotective effects of simvastatin in different animal models. In the present study, we examined the effects of simvastatin (30, 60, 100 and 300 mg/kg, p.o.) on the development and expression of morphine-induced tolerance and dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10 mg/kg, s.c.) for 5 consecutive days. Tolerance was evaluated by the hot-plate test and physical dependence by naloxone challenge, on the sixth day. The results showed that oral administration of simvastatin produced antinociceptive activity in a dose-dependent way. Co-administration of simvastatin with morphine did not affect the acute morphine-induced analgesia (10 mg/kg, s.c.). However, repeated co-administration of simvastatin with morphine significantly attenuated the development of tolerance to the analgesic effect of morphine and inhibited the naloxone (5 mg/kg, s.c.)-precipitated withdrawal signs (jumping and body weight loss). Also, simvastatin at doses of 100 and 300 mg/kg attenuated the expression of morphine-induced tolerance and dependence. These data indicated that, while simvastatin can alleviate both development and expression of morphine-induced tolerance, it cannot enhance morphine-induced antinociception. Taken together, simvastatin may be used as an adjutant therapeutic agent in combination with morphine and or other opioids in patients with severe chronic pain. [ABSTRACT FROM AUTHOR]

Key message: The HbCZF1 protein binds to the hmg1 promoter in yeast and this interaction was confirmed in vitro. The hmg1 promoter was activated in transgenic plants by HbCZF1. Abstract: Biosynthesis of natural rubber is known to be based on the mevalonate pathway in Hevea brasiliensis. The final step in the mevalonate production is catalyzed by the branch point enzyme, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), which shunts HMG-CoA into the isoprenoid pathway, leading to the synthesis of natural rubber. However, molecular regulation of HMGR expression is not known. To study the transcriptional regulation of HMGR, the yeast one-hybrid experiment was performed to screen the latex cDNA library using the hmg1 (one of the three HMGR in H. brasiliensis) promoter as bait. One cDNA that encodes the CCCH-type zinc finger protein, designated as HbCZF1, was isolated from H. brasiliensis. HbCZF1 interacted with the hmg1 promoter in yeast one-hybrid system and in vitro. HbCZF1 contains a 1110 bp open reading frame that encodes 369 amino acids. The deduced HbCZF1 protein was predicted to possess a typical C-X-C-X-C-H CCCH motif and RNA recognition motif. HbCZF1 was predominant in the latex, but little expression was detected in the leaves, barks, and roots. Furthermore, in transgenic tobacco plants, over-expression of HbCZF1 highly activated the hmg1 promoter. These results suggested that HbCZF1 may participate in the regulation of natural rubber biosynthesis in H. brasiliensis. [ABSTRACT FROM AUTHOR]

Key message: Protopanaxadiol (PPD) is an aglycone of dammarene-type ginsenoside and has high medicinal values. In this work, we reported the PPD production in transgenic tobacco co-overexpressing PgDDS and CYP716A47. Abstract: PPD is an aglycone of ginsenosides produced by Panax species and has a wide range of pharmacological activities. PPD is synthesized via the hydroxylation of dammarenediol-II (DD) by CYP716A47 enzyme. Here, we established a PPD production system via cell suspension culture of transgenic tobacco co-overexpressing the genes for PgDDS and CYP716A47. The concentration of PPD in transgenic tobacco leaves was 2.3-5.7 µg/g dry weight (DW), depending on the transgenic line. Leaf segments were cultured on medium with various types of hormones to induce callus. Auxin treatment, particularly 2,4-D, strongly enhanced the production of DD (783.8 µg g DW) and PPD (125.9 µg g DW). Treatment with 2,4-D enhanced the transcription of the HMG-Co reductase (HMGR) and squalene epoxidase genes. PPD production reached 166.9 and 980.9 µg g DW in a 250-ml shake flask culture and in 5-l airlift bioreactor culture, respectively. [ABSTRACT FROM AUTHOR]

Objective: Statins, or HMG-CoA reductase inhibitors, decrease cholesterol production. Because cholesterol is a precursor of the testosterone biosynthesis pathway, there is some concern that statins might lower serum testosterone levels. The objective of the present study was to investigate the association between the use of statins and serum testosterone levels in men. Design: Cross-sectional study within the prospective population-based Rotterdam Study. Subjects and methods: We included 4166 men with available data on total testosterone, non-sex hormone-binding globulin (SHBG)-bound testosterone, and medication use. Multivariable linear regression analysis was used to compare the differences in serum testosterone levels (nmol/l) between current, past, and never statin users. We considered dose and duration of use. Analyses were adjusted for age, BMI, cardiovascular disease, diabetes mellitus, hypertension, and estradiol levels. Results: We identified 577 current (mean age 64.1 years), 148 past (mean age 64.6 years), and 3441 never (mean age 64.6 years) statin users. Adjusted for all covariables, current statin use of 1-≤6 months or >6 months was significantly associated with lower total testosterone levels as compared to non-users (β -1.24, 95% CI -2.17, -0.31, and β -1.14, 95% CI -2.07, -0.20 respectively). Current use of 1-≤6 months was also associated with significantly lower non-SHBG-bound testosterone levels (β -.42, 95% CI -0.82, -0.02). There was a trend toward lower testosterone levels at higher statin doses both for total (Ptrend 2.9×10-5) and non-SHBG-bound (Ptrend 2.010×4) testosterone. No association between past statin use and testosterone levels was found. Conclusion:We showed that current use of statins was associated with significantly lower serum total and non-SHBG-bound testosterone levels. The clinical relevance of this association should be further investigated. [ABSTRACT FROM AUTHOR]

Background Statins inhibit hydroxymethylglutaryl-coenzyme A reductase, decrease plasma low-density lipoprotein cholesterol and reduce cardiovascular morbidity and mortality. They can also exert adverse effects, mostly affecting skeletal muscle, ranging from mild myalgia to rhabdomyolysis. Materials and methods Based on a PubMed search until December 2014, this review summarizes studies on statin effects on muscle mitochondrial morphology and function in the context of myopathy. Results Possible mechanisms of statin-induced myopathy include lower cholesterol synthesis and production of prenylated proteins, reduced dolichols and increased atrogin-1 expression. Statin-treated patients frequently feature decreased muscle coenzyme Q10 ( CoQ10) contents, suggesting that statins might impair mitochondrial function. In cell cultures, statins diminish muscle oxygen consumption, promote mitochondrial permeability transient pore opening and generate apoptotic proteins. Animal models confirm the statin-induced decrease in muscle CoQ10, but reveal no changes in mitochondrial enzyme activities. Human studies yield contradictory results, with decreased CoQ10, elevated lipids, decreased enzyme activities in muscle and impaired maximal oxygen uptake in several but not all studies. Some patients are susceptible to statin-induced myopathy due to variations in genes encoding proteins involved in statin uptake and biotransformation such as the solute carrier organic anion transporter family member 1B1 ( SLCO1B1) or cytochrome P450 ( CYP2D6, CYP3A4, CYP3A5). Carriers for carnitine palmitoyltransferase II deficiency and McArdle disease also present with higher prevalence of statin-induced myopathy. Conclusions Despite the widespread use of statins, the pathogenesis of statin-induced myopathy remains unclear, requiring prospective randomized controlled trials with intensive phenotyping also for identifying strategies for its risk assessment, prevention and treatment. [ABSTRACT FROM AUTHOR]

The competitive inhibitors of HMG-CoA reductase, popularly known as statins, exert pleiotropic effects, which result from the ability of statins to inhibit the synthesis of isoprenoids, which are fundamental for the functioning of proteins responsible for intracellular signaling. Some recent studies suggest an important role associated with the use of antineoplastic atorvastatin and rosuvastatin, the statins most widely used today. In this study, the Drosophila wing spot test was used to evaluate possible protective effects of atorvastatin and rosuvastatin against damage induced by DXR. Larvae were chronically treated with negative control (ethanol 5%), positive control (DXR 0.125 mg/mL) and five different concentrations of atorvastatin and rosuvastatin. The results demonstrated absence of a mutagenic effect for the two statins tested. The analysis of the descendants co-treated with DXR and atorvastatin/rosuvastatin revealed a modulatory effect of these statins on damage induced by DXR. This effect was verified in all concentrations tested in the descendants of the ST and HB crosses treated with rosuvastatin, and only in descendants of the HB cross treated with atorvastatin. Induction of apoptosis and antioxidant activity appear to be the main mechanisms involved in reducing the frequency of mutant spots and consequent modulation of the damage induced by DXR. [ABSTRACT FROM AUTHOR]

Objective The study aimed to investigate the effect of concomitant use of atorvastatin or rosuvastatin on the pharmacokinetic and pharmacodynamic profile of centchroman, a non-steroidal female oral contraceptive. Methods A rat model was used to predict pharmacokinetic drug-drug interactions between centchroman and atorvastatin or rosuvastatin. A dried blood spot sampling technique followed by liquid chromatography-tandem mass spectrometry detection was employed for analysis of the pharmacokinetic interaction study samples. Sperm-positive female rats were investigated for postcoital contraceptive activity of centchroman with or without coadministration of atorvastatin or rosuvastatin. Results Coadministration of atorvastatin or rosuvastatin may increase the systemic availability of centchroman in blood, but it does not affect the pharmacodynamic profile of centchroman. Conclusion Atorvastatin or rosuvastatin may be prescribed with centchroman without compromising the contraceptive efficacy of centchroman. Chinese Abstract 摘要 目的 这项研究旨在调查同时使用阿托伐他汀或罗苏伐他汀时centchroman（一种非甾体女性口服避孕药）的药代动力学和药效情况。 方法 采用大鼠模型来预测centchroman与阿托伐他汀或罗苏伐他汀之间药物相互作用的药代动力学。随后采用干燥血斑点采样技术和液相色谱串联质谱检测用于样本的药代动力学相互作用的研究分析。对精子阳性的雌性大鼠，观察centchroman同时服用/不服用阿托伐他汀或瑞舒伐他汀的事后避孕效果。 结果 合用阿托伐他汀或瑞舒伐他汀可能会增加全身血液中的centchroman的生物利用率，但并不影响centchroman的药效。 结论 阿托伐他汀或瑞舒伐他汀并不影响centchroman的避孕效果 [ABSTRACT FROM AUTHOR]

The article presents a study which examines the hypolipidemic effects of Korean red ginseng water extract (KRGE) on hepatic lipid accumulation in HepG2 cells. It says that the cytotoxic effects of KRGE on HepG2 cells were examined and the triglyceride and cholesterol contents in HepG2 cells were measured. The results show that KRGE may reduce lipid accumulation by inhibition of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase and fatty acid synthase (FAS) expression in HepG2 cells.

Feedback regulation of cholesterol biosynthesis provides a mechanism to adapt to varying cholesterol input while maintaining rather constant serum and tissue cholesterol levels. The molecular mechanisms by which this occurs have been the subject of extensive investigation. This review focuses on the physiological mechanisms by which this regulation occurs. In animals that are sensitive to dietary cholesterol such as Golden Syrian hamsters, feedback regulation occurs mainly at the level of transcription of hepatic HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase). In animals like the Sprague Dawley rat that are resistant to the serum cholesterol raising action of dietary cholesterol, regulation occurs mainly at the level of translation efficiency of hepatic HMG-CoA reductase. Oxylanosterols were shown to effectively decrease translation of HMG-CoA reductase mRNA. Dietary cholesterol acts to significantly lower transcription of squalene epoxidase and lanosterol 14α demethylase favoring accumulation of the putative regulatory oxylanosterol-3β-hydroxylanosterol-8-en-32-al. Thus, decreased transcription of enzymes occurring late in the cholesterol biosynthetic pathway appears to result in decreased translation of hepatic HMG-CoA reductase mRNA. These findings indicate that pronounced physiological feedback regulation of cholesterol biosynthesis in cholesterol resistant animals occurs at the level of translational efficiency without substantial reduction in hepatic HMG-CoA reductase transcription. [ABSTRACT FROM AUTHOR]

Plant sterol esters are the popular cholesterol-lowering dietary supplements. In order to understand the role of fatty acid moieties in the cholesterol-lowering activity of plant sterol esters, the present study was to: (i) compare the cholesterol-lowering activity of sterol esters of sunflower oil (SSF) with that of sterol esters of canola oil (SCO); and (ii) to systematically investigate the effect of SSF and SCO on the gene expression of sterol transporters, enzymes, receptors and proteins involved in cholesterol metabolism in hamsters fed a high cholesterol diet. GC analysis showed that SSF and SCO had similar sterol profile but they had different fatty acid moieties. Results showed both SSF and SCO could equally reduce plasma cholesterol in a dose-dependent manner. Both SSF and SCO could inhibit the cholesterol absorption and enhance the excretion of bile acids. In the similar ways, dietary SSF and SCO could up-regulate hepatic cholesterol-7α-hydroxylase (CYP7A1) and down-regulate intestinal sterol transporter Niemann-Pick C1-like 1 (NPC1L1), acyl coenzyme A: cholesterol acyltransferase 2 (ACAT2) and hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). It was concluded that the fatty acid moieties had little effect on the cholesterol-lowering activity of SSF and SCO. Practical applications: Plant sterols are effective in reducing plasma cholesterol. Commercially, plant sterol esters of sunflower oil and plant sterol esters of canola oil are mostly used for this purpose. The present study found that SSF and SCO were equally effective in reducing plasma cholesterol in a dose-dependent manner regardless the significant difference in their fatty acid compositions. Fatty acid moieties have little effect on cholesterol-lowering potency of plant sterol esters. [ABSTRACT FROM AUTHOR]

Our previous study found that thyroid-stimulating hormone promoted sterol regulatory element-binding protein-2 (SREBP-2) expression and suppressed AMP-activated protein kinase (AMPK) activity in the liver, but it was unclear whether there was a direct link between TSH, AMPK and SREBP-2. Here, we demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of SREBP-2 and its target genes HMGCR and HMGCS, which are key enzymes in cholesterol biosynthesis, and suppressed the TSH-stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice. Furthermore, AMPK, an evolutionally conserved serine/threonine kinase, phosphorylated threonine residues in the precursor and nuclear forms of SREBP-2, and TSH interacted with AMPK to influence SREBP-2 phosphorylation. These findings may represent a molecular mechanism by which AMPK ameliorates the hepatic steatosis and hypercholesterolemia associated with high TSH levels in patients with subclinical hypothyroidism (SCH). [ABSTRACT FROM AUTHOR]

Background and purpose Statins display anti-inflammatory and anti-epileptogenic properties in animal models, and may reduce the epilepsy risk in elderly humans; however, a possible modulating role on outcome in patients with status epilepticus ( SE) has not been assessed. Methods This cohort study was based on a prospective registry including all consecutive adults with incident SE treated in our center between April 2006 and September 2012. SE outcome was categorized at hospital discharge into 'return to baseline', 'new disability' and 'mortality'. The role of potential predictors, including statins treatment on admission, was evaluated using a multinomial logistic regression model. Results Amongst 427 patients identified, information on statins was available in 413 (97%). Mean age was 60.9 (±17.8) years; 201 (49%) were women; 211 (51%) had a potentially fatal SE etiology; and 191 (46%) experienced generalized-convulsive or non-convulsive SE in coma. Statins (simvastatin, atorvastatin or pravastatin) were prescribed prior to admission in 76 (18%) subjects, mostly elderly. Whilst 208 (50.4%) patients returned to baseline, 58 (14%) died. After adjustment for established SE outcome predictors (age, etiology, SE severity score), statins correlated significantly with lower mortality (relative risk ratio 0.38, P = 0.046). Conclusion This study suggests for the first time that exposure to statins before an SE episode is related to its outcome, involving a possible anti-epileptogenic role. Other studies are needed to confirm this intriguing finding. [ABSTRACT FROM AUTHOR]