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For many years, statins have been the most commonly used drugs in cholesterol-lowering therapy. In addition to these therapeutic effects, statins exhibit other, pleiotropic effects that can be beneficial, but also harmful to cells and tissues. The aim of this research was to determine and compare the pleiotropic effects of structurally different statins: atorvastatin, simvastatin and rosuvastatin at different concentrations on hepatocellular carcinoma (HepG2) cells. The MTT assay was used to determine the cytotoxic effects of statins. The influence of statins on the production of reactive oxygen species (ROS) was determined by measuring fluorescent response of 2,7-dichlorofluorescein diacetate (DCFH-DA). The effect of statins on glucose production and excretion was determined with glucose production assay. The obtained results confirmed that all tested statins exhibit cytotoxic effects, increase the production of ROS as well as the production and excretion of glucose from HepG2 cells. It was observed that all the mentioned effects are more pronounced with lipophilic statins, atorvastatin and simvastatin compared to hydrophilic rosuvastatin. The less pronounced pleiotropic effects of rosuvastatin on HepG2 cells are probably due to differences in structure and solubility compared to atorvastatin and simvastatin. Transporter-dependent and a slower influx of rosuvastatin into cells compared to the tested lipophilic statins probably lead to a weaker accumulation of rosuvastatin in HepG2 cells, which results in less pronounced pleiotropic effects compared to lipophilic atorvastatin and simvastatin. [ABSTRACT FROM AUTHOR]

Apical periodontitis (AP) is an inflammatory dental disease caused by bacterial infections of the endodontic system. The correlation between AP and cardiovascular diseases. (CVD) has been consistently investigated. Statins are a class of drugs that are used to treat hypercholesterolemia and prevent atherosclerotic vascular diseases. They have other beneficial pleiotropic effects such as anti-inflammatory, antithrombotic, and antioxidant activities. The aim of this study was to evaluate the oral health status and prevalence of AP in patients treated with statins (Group S) in comparison with untreated patients (Group C) to understand whether the anti-inflammatory action of these drugs can influence the prevalence of AP. The records of seventy-nine patients (43 men and 36 women, mean age 68 ± 11 years, 1716 teeth) treated with statins and referred to the University clinic for dental evaluation were reviewed. Seventy patients free from systemic diseases and without therapy (39 men and 31 women, mean age 62 ± 9 years, 1720 teeth) constituted the control group. All subjects underwent complete oral, dental, and radiographic examinations to determine the presence and severity of AP. Periapical index (PAI) and decayed, missed, and filled teeth (DMFT) scores were obtained. AP was significantly less common in Group S (22,8%) than in Group C (50%) (P < 0.05). Furthermore, the mean value of the qualitative rank of the severity of AP (PAI score) was higher in Group C than in Group S (P ≤ 0.05). Our results suggest that statins can attenuate the prevalence of AP, which is associated to CVD. [ABSTRACT FROM AUTHOR]

Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect. Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction. Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF. Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis. [ABSTRACT FROM AUTHOR]

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Metabolic perturbations underlie a variety of cardiovascular disease states; yet, metabolic interventions to prevent or treat these disorders are sparse. Ketones carry a negative clinical stigma as they are involved in diabetic ketoacidosis. However, evidence from both experimental and clinical research has uncovered a protective role for ketones in cardiovascular disease. Although ketones may provide supplemental fuel for the energy-starved heart, their cardiovascular effects appear to extend far beyond cardiac energetics. Indeed, ketone bodies have been shown to influence a variety of cellular processes including gene transcription, inflammation and oxidative stress, endothelial function, cardiac remodeling, and cardiovascular risk factors. This paper reviews the bioenergetic and pleiotropic effects of ketone bodies that could potentially contribute to its cardiovascular benefits based on evidence from animal and human studies. [ABSTRACT FROM AUTHOR]

Stroke is the second leading cause of death and the third leading cause of disability worldwide. Diabetes mellitus and the associated hyperglycemia are important risk factors for acute ischemic stroke and are associated with poor prognosis. Neurovascular protection is an important therapeutic target to achieve in patients with stroke, especially in those receiving thrombolytic reperfusion therapy. Sodium glucose-linked cotransporter 2 (SGLT2) inhibitors are a novel class of antidiabetic agents that target SGLT2. Hyperglycemia exacerbates the neuronal damage through the SGLT2 transporter. The purpose of this narrative review is to discuss the pleiotropic effects of SGLT2 inhibitors and their role in the treatment and prevention of ischemic stroke in experimental and clinical studies. We searched the PubMed database using different term combinations from the date of inception to May 2019. Deselection methods were followed to exclude unrelated articles. The total number of articles included was 14. In experimental models, SGLT2 inhibitors have a protective mechanism against neuronal dysfunction and damage through various mechanisms. From a clinical perspective and based on current evidence, SGLT2 inhibitors reduce the risk of cardiovascular events, especially in patients with heart failure. SGLT inhibitors may have neurologic and/or vascular protective effect after acute ischemic stroke based on experimental studies. However, getting an accurate judgment of this effect is hard to achieve because only a few animal studies are available. Furthermore, and unlike animale studies, clinical studies provided uncertain answers on whether SGLT2 inhibitors would provide neuroprotective effect. In addition, several studies used combination of drugs along with SGLT2 inhibitors. It is unlikely that SGLT inhibitors have a positive or negative effect on stroke risk, but the question that remains unanswered is whether SGLT inhibitors can yield a protective effect after acute ischemic stroke. Future observational studies and registries may be the first step to help answer this question. [ABSTRACT FROM AUTHOR]

There has been no report about outcome of pitavastatin versus atorvastatin therapy in high-risk patients with hypercholesterolemia. Hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases (n = 664, age = 65, male = 54%, diabetes = 76%, primary prevention = 74%) were randomized to receive pitavastatin 2 mg/day (n = 332) or atorvastatin 10 mg/day (n = 332). Follow-up period was 240 weeks. The primary end point was a composite of cardiovascular death, sudden death of unknown origin, nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, or heart failure requiring hospitalization. The secondary end point was a composite of the primary end point plus clinically indicated coronary revascularization for stable angina. The mean low-density lipoprotein cholesterol (LDL-C) level at baseline was 149 mg/dL. The mean LDL-C levels at 1 year were 95 mg/dL in the pitavastatin group and 94 mg/dL in the atorvastatin group. There were no differences in LDL-C levels between both groups, however, pitavastatin significantly reduced the risk of the primary end point, compared to atorvastatin (pitavastatin = 2.9% and atorvastatin = 8.1%, HR, 0.366; 95% CI 0.170–0.787; P = 0.01 by multivariate Cox regression) as well as the risk of the secondary end point (pitavastatin = 4.5% and atorvastatin = 12.9%, HR = 0.350; 95%CI = 0.189–0.645, P = 0.001). The results for the primary and secondary end points were consistent across several prespecified subgroups. There were no differences in incidence of adverse events between the statins. Pitavastatin therapy compared with atorvastatin more may prevent cardiovascular events in hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases despite similar effects on LDL-C levels. • The study was a first, randomized, prospective trial of two statins therapy. • Pitavastatin reduced more cardiovascular events compared with atorvastatin. • There were no differences in cholesterol profiles between two statin groups. • This may suggest the action of statin beyond cholesterol-lowering effects. • We may reconsider how to use statins for high-risk patients. [ABSTRACT FROM AUTHOR]

The Russian Farm-Fox Experiment is the best known experimental study in animal domestication. By subjecting a population of foxes to selection for tameness alone, Dimitry Belyaev generated foxes that possessed a suite of characteristics that mimicked those found across domesticated species. This 'domestication syndrome' has been a central focus of research into the biological pathways modified during domestication. Here, we chart the origins of Belyaev's foxes in eastern Canada and critically assess the appearance of domestication syndrome traits across animal domesticates. Our results suggest that both the conclusions of the Farm-Fox Experiment and the ubiquity of domestication syndrome have been overstated. To understand the process of domestication requires a more comprehensive approach focused on essential adaptations to human-modified environments. The 'domestication syndrome' has been a central focus of research into the biological processes underlying domestication. The Russian Farm-Fox Experiment was the first to test whether there is a causal relationship between selection for tameness and the domestication syndrome. Historical records and genetic analysis show that the foxes used in the Farm-Fox Experiment originated from fur farms in eastern Canada and that most traits attributed to the behavioral selection for tameness predated the experiment, undermining a central pillar of support for the domestication syndrome. The overall weight of evidence, including data from other species, does not unambiguously support the existence of the domestication syndrome in animals. Competing theories to explain domestication syndrome should be reconsidered after the traits themselves are more clearly connected to the early stages of domestication. [ABSTRACT FROM AUTHOR]

The effects of statins in prevention of venous thromboembolism (VTE) is not well established. To examine the risks of first-time VTE in a cohort of patients initiating statin treatment and in a matched general population comparison cohort. We conducted a nationwide, population-based, matched cohort study based on data from Danish health registries. The study period was 1 January 2005–31 December 2015. We identified statin initiators (without VTE, myocardial infarction, or ischemic stroke) and sex-, age-, and calendar year-matched (1,3) individuals from the general population (without statin use, VTE, myocardial infarction, or ischemic stroke). We computed cumulative risks and comorbidity-adjusted hazard ratios (HRs) of VTE, myocardial infarction, and ischemic stroke. Among 601,011 statin initiators and 1,803,033 matched population cohort members during 2005–2015, the cumulative risk after 11 years was 2.8% for VTE (both cohorts), 4.7% vs. 2.9% for myocardial infarction, and 7.1% vs. 5.2 for ischemic stroke. After adjustment, statin use was associated with a slightly decreased risk of VTE (adjusted HR: 0.95 [95% CI: 0.92–0.97]), driven by a reduced risk of unprovoked VTE (adjusted HR: 0.92 [95% CI: 0.89–0.95]). The reduced risks of VTE were more pronounced among patients who had an imaging examination performed. The adjusted HRs were elevated for myocardial infarction and ischemic stroke. Statin initiation was associated with a reduced risk of VTE, with no indication of a healthy-user effect. Based on available evidence, statins have weak thromboprophylactic effects. [ABSTRACT FROM AUTHOR]

• LiHsp83-SAG1 line presented all photosynthetic pigments significantly diminished and the PSII efficiency were strongly reduced. • The expression of CHLI , RSSU and LHCa/b genes did not show significant differences between LiHsp83-SAG1 and control plants. • After the heat treatment, LiHsp83-SAG1 plants showed an important alleviation of their phenotype and an evident recovery of the PSII function. • This is the first report where demonstrated that a transplastomic line performs much better at higher temperatures. Previously, we showed that transplastomic tobacco plants expressing the LiHsp83-SAG1 fusion protein displayed a chlorotic phenotype and growth retardation, while plants expressing the SAG1 and GRA4 antigens alone did not. We conducted a comprehensive examination of the metabolic and photosynthetic parameters that could be affecting the normal growth of LiHsp83-SAG1 plants in order to understand the origin of these pleiotropic effects. These plants presented all photosynthetic pigments and parameters related to PSII efficiency significantly diminished. However, the expression of CHLI , RSSU and LHCa/b genes did not show significant differences between LiHsp83-SAG1 and control plants. Total protein, starch, and soluble sugar contents were also greatly reduced in LiHsp83-SAG1 plants. Since Hsp90 s are constitutively expressed at much higher concentrations at high temperatures, we tested if the fitness of LiHsp83-SAG1 over-expressing LiHsp83 would improve after heat treatment. LiHsp83-SAG1 plants showed an important alleviation of their phenotype and an evident recovery of the PSII function. As far as we know, this is the first report where it is demonstrated that a transplastomic line performs much better at higher temperatures. Finally, we detected that LiHsp83-SAG1 protein could be binding to key photosynthesis-related proteins at 37 °C. Our results suggest that the excess of this molecular chaperone could benefit the plant in a possible heat shock and prevent the expected denaturation of proteins. However, the LiHsp83-SAG1 protein content was weakly decreased in heat-treated plants. Therefore, we cannot rule out that the alleviation observed at 37 °C may be partially due to a reduction of the levels of the recombinant protein. [ABSTRACT FROM AUTHOR]

Summary In addition to lowering cholesterol levels, statins have pleiotropic effects, particularly anti-inflammatory, antiangiogenic, and antifibrotic, that may be beneficial in some chronic inflammatory conditions. Statins have only recently been investigated as a potential treatment option in chronic liver diseases because of concerns related to their safety in patients with impaired liver function. A number of experimental studies in animal models of liver diseases have shown that statins decrease hepatic inflammation, fibrogenesis and portal pressure. In addition, retrospective cohort studies in large populations of patients with cirrhosis and pre-cirrhotic conditions have shown that treatment with statins, with the purpose of decreasing high cholesterol levels, was associated with a reduced risk of disease progression, hepatic decompensation, hepatocellular carcinoma development, and death. These beneficial effects persisted after adjustment for disease severity and other potential confounders. Finally, a few randomised controlled trials have shown that treatment with simvastatin decreases portal pressure (two studies) and mortality (one study). Statin treatment was generally well tolerated but a few patients developed severe side effects, particularly rhabdomyolysis. Despite these promising beneficial effects, further randomised controlled trials in large series of patients with hard clinical endpoints should be performed before statins can be recommended for use in clinical practice. [ABSTRACT FROM AUTHOR]

• A single dominant Morc locus controls mottled fruit rind color in WI7632 cucumber. • Abnormal chloroplasts at particular fruit rind areas lead to the mottled fruit rind color of WI7632. • A 4895-bp PAV contributes to the genetic variation of Morc locus. • Morc locus plays pleiotropic effects on cucumber fruit external qualities. Rind color and pattern is the crucial fruit trait that preferentially affects the commercial consumption of cucumber (Cucumis sativus L.). Knowing the genetic architecture of fruit rind color and pattern is essential for improving cucumber external qualities. However, the genetic basis of cucumber fruit rind patterns is still unclear, especially for the phenotypic variation of mottled or unmottled (uniform) fruit rind color. To explore the genetic architecture of mottled fruit rind color in cucumber, we constructed F 2 segregating populations using two cucumber inbred lines WI7632 and XNS16–1 showing green mottled rind color and white uniform rind color, respectively. Inheritance analysis revealed that the mottled rind color in WI7632 is genetically controlled by a dominant locus Morc (Mottled rind color). Chlorophyll content determination and chloroplast observation show that the mottled fruit rind color in WI7632 might be due to the decrease of chlorophyll synthesis caused by abnormal chloroplast development at particular fruit rind areas. Fine genetic mapping delimited the Morc locus into a 29.5-kb physical region on chromosome 5, which included only one candidate gene CsaV3_5G028870 encoding a C 2 H 2 -type zinc finger transcription factor. Sequence alignment showed that CsaV3_5G028870 and its flanking region (4895-bp in size) were missed in unmottled XNS16–1. Transcriptome profiling revealed that Morc might regulate the biosynthesis balance of heme and chlorophyll. Furthermore, the pleiotropic effects and diverse functions of Morc locus on determining multiple cucumber fruit's external qualities were discussed. [ABSTRACT FROM AUTHOR]

Application of the mlo -based resistance in barley against powdery mildew attacks is a major success in crop breeding, since it confers durable disease resistance. Resistance caused by mutations in the Mlo gene seems to be ubiquitous across a range of species. This work addresses the introduction of mlo -based resistance into hexaploid wheat, which is complicated by the occurrence of three homoeologous genes: Mlo-A1, Mlo-B1 and Mlo-D1. EMS-generated mutant plants were screened for mutations in the three homoeologues. We selected and combined 6, 8, and 4 mutations, respectively, to obtain triple homozygous mlo mutant lines. Twenty-four mutant lines showed highly effective resistance towards attack by the powdery mildew pathogen under field conditions. All 18 mutations appeared to contribute to resistance; however, they had different effects on the occurrence of symptoms such as chlorotic and necrotic spots, which are pleiotropic to the mlo -based powdery mildew resistance. We conclude that to obtain highly effective powdery mildew resistance in wheat and to avoid detrimental pleiotropic effects, all three Mlo homoeologues should be mutated; however, at least one of the mutations should be of the weaker type in order to alleviate strong pleiotropic effects from the other mutations. • A range of different mutations in the three Mlo homoeologues in wheat can contribute to powdery mildew resistance. • Simultaneous mutations in all three Mlo homoeologues provide highly effective powdery mildew resistance in the field. • Strong mutations in all three Mlo homoeologues lead to severe pleiotropic effects, i.e. necrosis/chlorosis. • Weak mutations in one Mlo homoeologue can alleviate the pleiotropic effects from strong mutations in other homoeologues. • mlo mutations can be combined in wheat to obtain highly effective powdery mildew resistance without pleiotropic effects. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is a major cause of death globally. Addressing cardiovascular risk factors, particularly dyslipidemia, represents the most robust clinical strategy towards reducing the CVD burden. Statins inhibit 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and represent the main therapeutic approach for lowering cholesterol and reducing plaque formation/rupture. The protective effects of statins extend beyond lowering cholesterol. MicroRNAs (miRNAs or miRs), small noncoding regulatory RNAs, likely mediate the positive pleiotropic effects of statins via modulation of lipid metabolism, enhancement of endothelial function, inhibition of inflammation, improvement of plaque stability, and immune regulation. miRNAs are implicated in statin-related interindividual variations in therapeutic response, directly via HMG-CoA reductase, or indirectly through targeting cytochrome P450 3A (CYP3A) functionality and proprotein convertase subtilisin/kexin type9 (PCSK9) biology. Highlights miRs have been suggested to mediate pleiotropic effects of statins, including improvement of endothelial function as well as anti-inflammatory and immunomodulatory activities. miRs have been suggested to be implicated in the variations in the statin response. This role might be, at least in part, mediated via interaction of miRs with cytochrome P450 isoenzymes that are involved in statin metabolism. Upregulation of selected miRs by statins might enhance plaque stability by modulating multiple pathways, namely, repression of angiogenesis, atherosclerosis-related cell proliferation, monocyte migration, platelet adhesion, and the coagulation cascade. [ABSTRACT FROM AUTHOR]

Background Lipoprotein(LP)-apheresis is the treatment of choice in patients suffering from severe familial hypercholesterolemia. A wide range of mechanisms has been claimed to be responsible for the known clinical benefit. Methods Patients suffering from heterozygous familial hypercholesterolemia undergoing LP-apheresis either with direct adsorption of lipoproteins (DALI) or dextran sulfate (DS) were examined. A total volume of 10 l blood was exchanged. Non-lipid effects, mainly concerning endothelial function (circulating endothelial cells, circulating endothelial progenitor cells, flow-mediated vasodilation, microalbuminuria) as well as left ventricular ejection fraction and homocysteine were assessed. Results A single LP-apheresis session improves paradox contractile response in statin intolerant patients, but not in those on regular statin therapy. In contrast, over a 6-months follow-up after treatment initiation, all the examined parameters (circulating endothelial cells, circulating endothelial progenitor cells, flow mediated vasodilatation, homocysteine, microalbuminuria and left ventricular ejection fraction) improved. When available, a comparison between DS vs. DALI was performed. In none of the subgroups a significant difference was noted. Discussion These findings indicate that beyond the well known lipid/lipoprotein lowering action the broad spectrum of functional tests examined reflecting mainly endothelial function is significantly improved by LP-apheresis treatment on the long-term and seems to be a key underlying reason for the clinical improvement seen in these patients. [ABSTRACT FROM AUTHOR]

Because cholesterol-independent effects of statins are difficult to determine in patients, we studied these pleiotropic effects in apolipoprotein E-deficient (ApoE −/− ) mice with a mutation in the fibrillin-1 gene (Fbn1 C1039G +/− ). These mice develop exacerbated atherosclerosis and spontaneous plaque ruptures, accompanied by myocardial infarctions (MI) and sudden death. ApoE −/− Fbn1 C1039G +/− mice were fed a Western diet (WD). At week 10 of WD, mice were divided in a control (WD), atorvastatin (10 mg/kg/day + WD) and cholesterol withdrawal group (cholW, normal chow). The latter was included to compare the effects of atorvastatin with dietary lipid lowering. Fifteen weeks later, the mice were sacrificed. CholW, but not atorvastatin, reduced plasma cholesterol. Survival increased from 50% to 90% both in cholW and atorvastatin treated mice. CholW as well as atorvastatin treatment increased plaque collagen and fibrous cap thickness, but they did not affect the amount of plaque macrophages and T cells. MMP-2 and MMP-9 activity was significantly lower and the expression of MMP-12, TNF-α and IL-1β was strongly reduced in both treatment groups. Blood monocytes and neutrophils returned to baseline levels (ApoE −/− mice before the onset of atherosclerosis). Importantly, atorvastatin but not cholW significantly reduced coronary stenosis (from 50 to 28%) and the occurrence of MI (from 43 to 10%). In conclusion, independent of cholesterol lowering, atorvastatin significantly reduced mortality, plaque vulnerability and inflammation to the same extent as cholW. In addition, atorvastatin but not cholW reduced coronary stenosis and the occurrence of MI. These data unequivocally illustrate the significance of the pleiotropic effects of atorvastatin in the prevention of cardiovascular morbidity and mortality. [ABSTRACT FROM AUTHOR]

In the family of chlorophyll binding proteins, single helix small CAB-like proteins (SCPs) are found in all organisms performing oxygenic photosynthesis. Here, we investigated the function of these stress-inducible proteins in the cyanobacterium Synechocystis sp. PCC 6803. We compared physiological, proteome and transcriptome traits of a Photosystem I (PSI) deletion strain, which constitutively induces SCPs, and a PSI-less/ScpABCDE − without SCPs. The SCP mutant cells were larger in size, showed irregular thylakoid structure and differed in cell-surface morphology. Deletion of scp genes strongly affected the carbon (C) and nitrogen (N) balance, resulting in accumulation of carbohydrates and a decrease in N-rich compounds (proteins and chlorophyll). Data from transcriptomic and metabolomic experiments revealed a role of SCPs in the control of chlorophyll biosynthesis. Additionally, SCPs diminished formation of reactive oxygen species, thereby preventing damage within Photosystem II. We conclude that the lack of SCP-function to remove free chlorophyll under stress conditions has a large impact on the metabolism of the entire cell. [ABSTRACT FROM AUTHOR]

Background and aims There are no studies that compared the effects of different intensities of statin treatment on the long-term outcome of patients with recent ischemic stroke. We aimed to evaluate these effects. Methods We prospectively studied 436 consecutive patients who were discharged after acute ischemic stroke (39.2% males, age 78.6 ± 6.7 years). Statin treatment was categorized in equipotent doses of atorvastatin. One year after discharge, the functional status was assessed with the modified Rankin scale (mRS). Adverse outcome was defined as mRS between 2 and 6. The occurrence of ischemic stroke, myocardial infarction and death was recorded. Result Adverse outcome rates were lower in patients treated with atorvastatin 20 mg/day or more potent doses of statins than in patients treated with atorvastatin 10 mg/day (63.5, 38.2 and 48.2%, respectively; p = 0.004). In binary logistic regression analysis, independent predictors of adverse outcome were the mRS at discharge (relative risk (RR) 2.33, 95% confidence interval (CI) 1.77–3.07, p < 0.001) whereas more aggressive treatment with statins independently predicted favorable outcome (atorvastatin 20 vs. 10 mg/day, RR 0.30, 95% CI 0.11–0.87, p = 0.026; atorvastatin 40 mg/day or more potent dose of statins vs. atorvastatin 10 mg/day, RR 1.66, 95% CI 0.62–4.44, p = NS). The incidence of cardiovascular events and all-cause mortality showed a trend for being lower in patients treated with atorvastatin 40–80 mg/day or rosuvastatin 10–40 mg/day than in those treated with less potent doses of statins. Conclusion More aggressive statin treatment improves the long-term functional outcome of patients with acute ischemic stroke more than less aggressive treatment. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory ligand that terminates the lifecycle of the low-density lipoprotein (LDL) receptor (LDLR) thus affecting plasma LDL-cholesterol (LDL-C) levels. Recent evidence shows that in addition to the straightforward mechanism of action, there are more complex interactions between PCSK9, LDLR and plasma lipoprotein levels, including: (a) the presence of both parallel and reciprocal regulation of surface LDLR and plasma PCSK9; (b) a correlation between PCSK9 and LDL-C levels dependent not only on the fact that PCSK9 removes hepatic LDLR, but also due to the fact that up to 40% of plasma PCSK9 is physically associated with LDL; and (c) an association between plasma PCSK9 production and the assembly and secretion of triglyceride-rich lipoproteins. The effect of PCSK9 on LDLR is being successfully utilized toward the development of anti-PCSK9 therapies to reduce plasma LDL-C levels. Current biochemical research has uncovered additional mechanisms of action and interacting partners for PCSK9, and this opens the way for a more thorough understanding of the regulation, metabolism, and effects of this interesting protein. [ABSTRACT FROM AUTHOR]

Highlights: [•] Several weeds worldwide have evolved resistance in response to intense herbicide use. [•] Single-locus mutations and complex multigenic stress responses underlie resistance. [•] Large population sizes and standing genetic variation likely cause rapid evolution. [•] Future research should integrate genomic data, evolutionary ecology, and modeling. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Statin pleiotropy is still an evolving concept, and the lack of clarity on this subject is due at least in part to the lack of a definitive biomarker for statin pleiotropy. Using plasma mRNA analysis as a novel research tool for the non-invasive in vivo assessment of gene expression in vascular beds, we hypothesised that atorvastatin lowers the plasma mRNA level from statin pleiotropy-target genes, and the reduction is independent of the reduction of low-density lipoprotein cholesterol (LDL-C). Design and methods: Forty-four patients with stable angina received atorvastatin therapy (20mg/day, 10weeks). Plasma chemokine (C-C motif) ligand 2 (CCL2) and intercellular adhesion molecule-1 (ICAM1) mRNA levels and their protein concentrations (MCP-1, sICAM-1) were analysed before and after the treatment. Plasma vascular adhesion molecule-1 (sVCAM-1) concentrations were also analysed. Results: Atorvastatin lowered plasma mRNA levels (CCL2: −31.76%, p=0.037; ICAM1: −34.09%, p<0.001) and MCP-1 protein concentration (−18.88%, p=0.008) but did not lower sICAM-1 and sVCAM-1 protein concentrations, and the decreases appeared to be independent from the lowering of LDL-C. The plasma mRNA levels correlated with their protein concentrations following statin treatment only. Conclusion: Our results significantly strengthen the clinical evidence in support of statin pleiotropy. Furthermore, this unique simultaneous measurement of plasma mRNAs and their protein concentrations offers an advanced non-invasive in vivo assessment of the circulation pathology. [Copyright &y& Elsevier]

Abstract: Type 2 diabetes mellitus is a rising cause of cardiovascular morbidity and mortality. A number of studies have also identified diabetic patients as having increased risk for the development of cancer. Metformin is a widely prescribed antidiabetic drug with an established efficacy coupled with a favorable safety profile and low cost. An increasing number of studies have associated metformin treatment with a decrease of cancer risk. Moreover, metformin has also been associated with improved outcomes in cancer patients. These possible pleiotropic effects of metformin may establish metformin as a cancer prevention and treatment option. However, any favorable effects of metformin on cancer are not always corroborated by clinical trials. Larger studies are expected to better investigate the possible antineoplastic effects of metformin. [Copyright &y& Elsevier]

Abstract: In most patients only a few sessions of apheresis treatment are necessary to see the benefit. This is the case of immunological diseases when the production of a pathologic component is limited in time or in microcirculation disturbances when changes of vascular function may occur. In the first instance the acute effect is likely due to the removal of the corresponding antibody, while in the second case the improvement of the endothelium-dependent vasodilation and the reduction of blood viscosity play a major role. In long-term treatment, as in the case of patients affected by familial hypercholesterolemia, the chronic effects of apheresis may lead to the repair of morphological alterations in the vascular wall. We report the recovery from ulcers in two hemodialysis patients suffering from peripheral arterial disease as the result of twenty-two sessions of rheopheresis. The reasons that justify these chronic actions may involve pleiotropic effects that are different according to the apheresis technique used. [Copyright &y& Elsevier]

Abstract: Lipoprotein apheresis is a well-established extracorporeal treatment in modality of severe hyperlipoproteinemia. Besides the reduction of LDL cholesterol and modifications to physiology of lipoprotein and lipid metabolism, Lipoprotein apheresis may have crucial effects on many other atherogenic factors as vascular inflammation, rheology and gene expressions in blood cells. These different effects of lipoprotein apheresis treatments are reviewed with respect to oxidative stress in plasma, red and white blood cells and in consequence to progression of atherosclerosis. However, in consideration of these reviewed aspects as a factor of biocompatibility lipoprotein apheresis remains safe. [Copyright &y& Elsevier]

Abstract: Objective: This study was designed to investigate whether metformin affects monocyte secretory function in patients with impaired fasting glucose receiving chronic statin therapy. Materials/Methods: The study included 48 patients with impaired fasting glucose treated for at least three months with simvastatin (40mg daily). These patients were randomized to either metformin (3g daily) or placebo, which was administered together with simvastatin for 90days. Plasma lipids, glucose homeostasis markers, monocyte cytokine release and plasma C-reactive protein levels were determined before randomization and at the end of the treatment. Results: Compared to placebo, metformin reduced monocyte release of tumor necrosis factor-α, interleukin-1β, interleukin-6, monocyte chemoattractant protein-1 and interleukin-8, as well as decreased plasma C-reactive protein levels, which were accompanied by an improvement in insulin sensitivity. Conclusions: The obtained results suggest that metformin may inhibit monocyte secretory function and reduce systemic inflammation in statin-treated patients with prediabetes. Impaired fasting glucose patients with high cardiovascular risk may receive the greatest benefits from concomitant treatment with a statin and metformin. [Copyright &y& Elsevier]

Abstract: Objective: No previous study has investigated whether metformin produces any effect on lymphocyte secretory function in patients with glucose metabolism abnormalities. Methods: Sixty-two subjects with impaired fasting glucose (IFG) treated for at least 3 months with simvastatin were allocated into one of two groups receiving, respectively, metformin (3 g daily) or placebo for the following 90 days. Plasma lipids, glucose homeostasis markers, plasma C-reactive protein and intercellular adhesion molecule-1 levels, as well as lymphocyte release of proinflammatory cytokines were determined before randomization and at the end of the treatment. Results: Fifty-eight patients completed the study. Metformin, but not placebo, administered to simvastatin-treated IFG subjects reduced plasma levels of C-reactive protein, soluble intercellular adhesion molecule-1, as well as lymphocyte release of interleukin-2, interferon-γ and tumor necrosis factor-α, which was accompanied by the improvement in insulin sensitivity and a reduction in free fatty acid levels. Conclusions: The obtained results indicate that metformin potentiates lymphocyte-suppressing and systemic anti-inflammatory effects of simvastatin in subjects with IFG. These effects of statin–metformin combination therapy may play a role in the prevention and treatment of atherosclerosis and its complications in patients with early glucose metabolism abnormalities. [Copyright &y& Elsevier]

Abstract: Rodents are mostly controlled by using anticoagulant rodenticides to minimise adverse effects along the food production chain. Genetic resistance to anticoagulant compounds occurs in populations of Norway rats (Rattus norvergicus) and other rodents throughout the world. This can be problematic for control operations and put predators and scavengers at risk because resistant prey individuals carry high anticoagulant loads. Single nucleotide polymorphisms (SNPs) in the vitamin K reductase complex subunit 1 (VKORC1) gene that are associated with rodenticide resistance are related to several pleiotropic effects including increased vitamin K requirement. The uptake of dietary vitamin K available from food sources present on farms including corn silage and garden herbs may mitigate such effects. We tested the preference for food rich in vitamin K1/3 in Norway rats susceptible or resistant to bromadiolone due to the homozygous amino acid variant Tyr139Cys. We also studied the effect of vitamin K consumption from several food sources on blood clotting in bromadiolone resistant and susceptible Norway rats. There was no general preference of rats for food sources rich in vitamin K. Surprisingly, there was no effect of vitamin K uptake on blood clotting times. However, the consumption of 4 of 5 corn silages prevented the rise in blood clotting times that otherwise occurred in vitamin K deficient bromadiolone resistant rats. This seemed to be due to substances with vitamin K activity present in silage and may contribute to the sustaining and spreading SNPs that are related to rodenticide resistance. As corn silage is becoming increasingly available to rats due to the expansion in generating bio-energy from corn silage, there may be a future increase in the occurrence of anticoagulant resistant Norway rats and associated problems in agro-ecosystems. [Copyright &y& Elsevier]

Abstract: Background: The full impact of statins on patients with chronic heart failure (CHF) is unknown. Therefore, we aimed to evaluate the pleiotropic effects of rosuvastatin on vascular and tissue regeneration, its impact on endothelial function and hemodynamics in CHF. Methods: Forty-two patients with CHF (LVEF 30±1%) were randomized to 12weeks of oral rosuvastatin (40mg/d) or placebo. At baseline and at 12weeks, VEGF and oxidized LDL (oxLDL) were assessed by ELISA. Circulating endothelial progenitor cells (CPCs) were quantified using FACS. CPC function was determined by matrigel assay. Number of CD34+ stem cells and capillary density were measured in skeletal muscle (SM). Flow-mediated dilatation (FMD) and left ventricular (LV) function were determined by ultrasound. Results: Rosuvastatin increased VEGF by +43% (p =0.004 vs. placebo) and decreased oxLDL by −27% (p =0.04 vs. placebo). This was associated with an elevation in CPC count by +224% (p =0.04 vs. placebo) and an augmentation of CPC integrative capacity by +91% (p =0.03 vs. placebo). Capillary density increased by +14% (p <0.001 vs. placebo), which was associated with an enhanced homing of CD34+ stem cells. Rosuvastatin improved FMD by +163% (p <0.001 vs. placebo) and enhanced ejection fraction by +27% (p <0.001 vs. placebo). Conclusion: In CHF, rosuvastatin activates CPCs that contribute to neovascularisation and to the enhancement of endothelial function. Correction of vascular abnormalities leads in part to an increase in LV function. Therefore, rosuvastatin''s non-lipid effects may have the potential to promote endogenous tissue regeneration and improve LV performance in CHF. [Copyright &y& Elsevier]

Abstract: Background: Pharmaceutical stabilisation of the abdominal aortic aneurysm (AAA) wall can delay surgery and improve outcome. Observational studies indicate statins can be used to reduce AAA growth but mechanistic data are scarce. In this study, our aim was to determine the pleiotropic effects of different statins on AAA wall composition. Methods: We included 216 patients undergoing open AAA repair, of which 60 used simvastatin, 52 atorvastatin and 23 pravastatin. The AAA wall histology and protein expression (IL 1β,2,4,5,6,8,10,12, interferon-gamma (IFNγ), tumour necrosis factor (TNF)α,β, matrix metalloproteinase (MMP)2 and 9 activities, total MMP8,9 and cathepsin A and B levels) between statin users and non-users were compared as also among the use of different statins. Results: As far as histological inflammation goes, the AAA walls of statin users did not differ from those not using them. After multivariate adjustment for risk factors, pravastatin use was associated with tendencies of increased MMP8 (p = 0.022), active MMP9 (p = 0.040) and higher cathepsin B (p = 0.056) levels. The AAA walls of simvastatin and atorvastatin users showed no differences in proteases or cytokines in multivariate analyses. Conclusions: The use of statins was not associated with a decrease in protease levels or inflammation. The trends of elevated protease levels associated with pravastatin use suggest pleiotropic differences among the various statins, supporting the need for further research to target pharmaceutical AAA treatment. [Copyright &y& Elsevier]

Objectives: This meta-analysis was performed to determine the effects of various cholesterol-lowering treatments on the risk of stroke and its relationship with the extent of cholesterol lowering. Background: Statins reduce the incidence of stroke, and it has been proposed that such effect is independent of cholesterol lowering and is explained by alternative mechanisms. Methods: We performed a meta-analysis of randomized trials of cholesterol-lowering treatments in cardiovascular disease reporting on stroke, involving 266,973 patients investigated and a cumulative 946,582 person-years of exposure, and a meta-regression analysis of the extent of stroke reduction as a function of changes in total cholesterol. Results: The odds ratio (OR) for the incidence of stroke in actively treated groups versus controls was 0.88 (95% confidence interval: 0.83 to 0.94, p < 0.001). No treatment affected fatal strokes. Whereas statins decreased the risk of total stroke significantly (OR: 0.85, 95% confidence interval: 0.78 to 0.92; p < 0.001), the benefit of nonstatin interventions was smaller and not statistically significant (diet OR: 0.92, fibrates OR: 0.98, other treatments OR: 0.81). We found a significant relationship between percent reduction of total (and low-density lipoprotein) cholesterol and percent reduction of total strokes (p = 0.0017), with each 1% reduction of total cholesterol predicting a 0.8% relative risk reduction of stroke. We found no significant association between stroke reduction and changes of high-density lipoprotein cholesterol levels, and inconsistent associations with reduction of triglycerides. Conclusions: Among cholesterol-lowering treatments, statins are the most effective at decreasing the risk of total stroke, but their benefit is proportional to the percent reduction of total cholesterol and low-density lipoprotein cholesterol. No lipid-lowering intervention was associated with a reduction of fatal stroke. [Copyright &y& Elsevier]

Abstract: The effects of statins in chronic kidney disease (CKD) are incompletely understood. To date, no clinical trial has provided definitive evidence that cholesterol lowering treatments reduce cardiovascular morbidity and mortality in CKD patients. Moreover, existing preclinical data suggest both a renoprotective effect of statins (highlighted by reduction in the rate of the decline of GFR and reduction of proteinuria) and a harmful effect (mainly by accelerating renal fibrosis) in the long-term management of patients with CKD. Although several post-hoc analyses and meta-analyses of large randomized clinical trials of statins in cardiovascular disease have provided important insights into their role in affecting the rate of renal function deterioration in CKD, no randomized clinical study has directly addressed this issue in CKD patients. In this review, we discuss the preclinical and clinical evidence supporting the beneficial or harmful effects of statins in CKD patients and propose specific recommendations regarding their use in this patient population. [Copyright &y& Elsevier]

Abstract: Transgenic fish have been produced that have improved growth, disease resistance, survival in cold and body composition, have altered color, that can act as bioindicators for estrogenic pollutants and that can produce pharmaceutical proteins. The largest amount of transgenic research has focused on growth hormone transfer. A relatively small amount of research has focused on enhancing disease resistance, but significant enhancement has been accomplished. Pleiotropic effects from the transfer of other transgenes, particularly growth hormone gene can alter disease resistance in both positive and negative ways. Most negative effects for all transgenes appear to lower fitness traits, which is positive for biological containment. Transgenic fish appear to pose little environmental risk, but this research is not fully conclusive. To expedite commercialization and minimize environmental risk, transgenic sterilization research is underway. A large amount of functional genomics research has resulted in a much better understanding of gene expression when fish are experiencing disease epizootics. This information may allow the future design of more effective transgenic approaches to address disease resistance. [Copyright &y& Elsevier]

Ivabradine (IVA) reduces heart rate (HR) by inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in sinoatrial node. Studies suggest that IVA has other beneficial effects on cardiovascular system that are not related to its effect on HR such as prevention of endothelial injury and the antioxidant effects. In addition to sinoatrial node, HCN channels exist in other tissues and their expression pattern differs in certain pathologies such as hypertension and hypertrophy. We investigated the mechanism of IVA effect in the setting of streptozotocin (STZ)-induced cardiovascular damage. Direct effects of IVA and their mechanism on thoracic aorta as well as possible prevention of vascular dysfunction in diabetes were investigated in this study. The effects of IVA on vascular function were investigated in control and STZ-diabetic rats. Some control and diabetic rats were treated with IVA. IVA treatment prevented diabetes-induced increase in plasma p-selectin and vascular cell adhesion molecule-1 levels and the decrease in nitric oxide content in the aortas of diabetic animals. When added to isolated organ bath, IVA induced concentration-dependent relaxations in thoracic aorta. Pre-incubation with Nω-Nitro- L -arginine methyl ester reduced IVA-induced relaxations. Expression patterns of all isoforms of HCN proteins were affected by both diabetes and IVA treatment. IVA improves vascular function in diabetes and HCN channels support vascular activity against damaging effects of diabetes. IVA may be added to prevent diabetic cardiovascular dysfunction with these beneficial effects that are unrelated to its primary mechanism of action. [Display omitted] • In isolated organ bath, ivabradine induced concentration-dependent relaxations in rat aorta. • L-NAME reduced ivabradine-induced vascular relaxations. • Ivabradine prevented diabetes-induced increase in plasma p-selectin and VCAM-1. • Ivabradine prevented diabetes-induced decrease in NO in diabetic rat aorta. • Both diabetes and ivabradine affected HCN proteins in the vasculature. [ABSTRACT FROM AUTHOR]

• In RRMS we detected no benefit from statin treatment as add-on to IFN-β. • Combination of statins with IFN-β was safe and well-tolerated. • Potential beneficial effects in SPMS, CIS and ON warrant further evaluation in future RCTs. To assess whether statins (3‑hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) exert disease-modifying effects in multiple sclerosis (MS). A systematic review and meta-analysis was performed including randomized-controlled clinical trials (RCTs) on statin use in MS. A random-effects model was applied to calculate pooled estimates and odds ratios (ORs) with corresponding 95% confidence intervals (CIs), when comparing patients treated with statins alone or adjunct to disease modifying treatment (DMT) to non-statin-treated patients. We identified 7 RCTs including 789 patients with relapsing-remitting MS (RRMS), all of whom received additional DMT with IFN-β. Single identified RCTs in secondary-progressive MS (SPMS), clinically isolated syndrome (CIS) and optic neuritis (ON) were not meta-analyzed. In RRMS, add-on statin use was not associated with the risk of clinical relapse (OR=1.30, 95%CI: 0.90 1.87) or EDSS-progression from baseline, neither appeared related to the risk of new contrast-enhancing or T2 lesions (OR=1.28, 95%CI: 0.36 4.58), and the risk of whole-brain volume reduction on MRI. Add-on statins to IFN-β were safe and well-tolerated. In SPMS, stand-alone simvastatin led to significantly reduced annualized rate of whole-brain volume reduction. In CIS and ON, statins were associated with reduced risk for new T2 lesions and improved visual recovery, respectively. We detected no benefit from statin treatment as add-on to IFN-β in RRMS. However, a potential beneficial effect in SPMS, CIS and ON deserves independent confirmation and further evaluation within adequately powered RCTs. [ABSTRACT FROM AUTHOR]

Abstract: Background: Inflammation and oxidative stress have been associated with atrial fibrillation (AF). On the other hand, accumulating evidence suggests that statins may have antiarrhythmic effects due to pleiotropic properties. However, inconsistent results have been reported with respect to AF. Aims: We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) and observational studies to examine the association between statin use and development of AF. Methods: PubMed, Cochrane clinical trials database, and EMBASE were searched until November 2006. In addition, a manual search was performed using all review articles on this topic, reference lists of papers, and abstracts from conference reports. Of the 309 initially identified studies, 6 RCTs and 10 observational studies with 7041 patients were finally analyzed. Results: The analysis of RCTs showed no significant effect of statins on AF development (RR=0.76, 95% CI:0.55–1.05, P =0.09), and significant heterogeneity between individual studies (P =0.0008, I 2 =74.0%). Subgroup analysis revealed that differences in AF detection methodology may be the cause of heterogeneity. The analysis of observational studies demonstrated that statin use reduced the relative risk for AF by 23% (95% CI:0.70–0.85, Z =4.95, P <0.00001) without significant differences between the trials (P=0.08, I 2 =41.2%). This favorable effect was greatest in the post-operative patients (RR=0.61, 95% CI:0.49–0.76, Z =4.30, P <0.0001). Conclusion: Our meta-analysis suggests that statins may be effective in AF prevention especially in the post-operative setting. However, there are insufficient data for the widespread use of statins solely for AF prevention. Larger RCTs with long-term follow-up in different clinical settings, and more sensitive methods of arrhythmia detection are needed to clarify the impact of statins on AF. [Copyright &y& Elsevier]

Abstract: Background and aim: Little is known about the impact of gender on short-term effects of atorvastatin. We investigated the gender differences in the short-term lipid-lowering and pleiotropic effects of atorvastatin therapy. Methods and results: Seventy-two consecutive patients including 48 women with primary hypercholesterolemia, were assigned prospectively to treatment with atorvastatin (10mg/day) for 3months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS) as marker of lipid peroxide, fibrinolytic parameters, and endothelial function by flow-mediated vasodilation of the brachial artery (FMD), at baseline and after 3months of therapy. We assessed the impact of gender on temporal differences in these parameters. In men, atorvastatin decreased total, low-density lipoprotein (LDL), and small, dense LDL-cholesterol concentrations, and increased FMD after 3months. In women, atorvastatin decreased TBARS, triglyceride, and total, LDL, small, dense LDL, and remnant-like lipoprotein particle-cholesterol concentrations, and increased FMD after 3months. Fibrinolytic parameters did not change significantly in either men or women. With respect to the percent change in those parameters after 3months, TBARS (−17.6±12.4 vs. −0.4±18.8%, p <0.01) and small, dense LDL-cholesterol (−96.7±8.3 vs. −68.6±29.7%, p <0.01) decreased to a greater degree in women, although the relative changes in other parameters were similar between men and women. Conclusions: We found gender differences in some of the lipid altering changes, including TBARS and small, dense LDL-cholesterol concentrations, after short-term atorvastatin therapy, which were greater in women. However, short-term atorvastatin therapy may be beneficial in improving endothelial function equally in both men and women. [Copyright &y& Elsevier]

Abstract: Historically, the etiological link between hypercholesterolemia and stroke has been less clear than for coronary heart disease. The lack of association between cholesterol levels and stroke in most epidemiological and observational studies has brought about this controversy. Many recent, long-term clinical studies have confirmed that statin therapy results in a reduced risk of strokes, even in so-called “normocholesterolemic” patients. The magnitude of the effect is great. A large-scale analysis of more than 90,000 individuals showed that every 10% reduction in the concentration of LDL-cholesterol reduces the risk of stroke by 15.6%. The positive effect of statins on stroke depends mainly on LDL cholesterol reduction, but other non-lipid mechanisms, so-called “pleiotropic” effects, have been shown to play a role. This review seeks to summarize the role of statins in stroke prevention. Despite the fact that our understanding of the benefits of statins in stroke prevention is still evolving, we find marked room for improvement in stroke risk factor management. Internists must face this challenge and integrate this new knowledge into their daily clinical practice. [Copyright &y& Elsevier]

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Abstract: The effects of the transformation of a 4-coumarate:coenzyme A ligase (4CL) gene involved in lignin biosynthesis on the interactions between transgenic plants and soil microbiota were studied in silver birch (Betula pendula Roth). Although the genetic transformation did not lead to expected changes in wood chemistry, it had significant influence on root biomass and morphology. The transgenic lines had less root biomass and lower numbers of root tips than the wild-type birch. However, the transgenic lines formed normal ectomycorrhizas with Paxillus involutus (Batsch) Fr. and no differences between the transgenic lines and the wild-type birch were detected in the colonization by mycorrhizas in vitro. In a field trial, the decomposition of the transgenic and wild-type birch litter was equally rapid, and no marked differences were found between the transgenic lines and wild-type birch in total microbial biomass (SIR) or activity (basal respiration). The effects of the genetic transformation on the ergosterol content of the leaf litter were contradictory; the litter from one transgenic line had significantly higher ergosterol content and the litters from two other transgenic lines had significantly lower ergosterol content than the litter from wild-type birch. This study shows that the 4CL antisense transformation and the pleiotropic effects of the transformation on growth characteristics of birch did not disturb the formation of ectomycorrhizas with P. involutus and had no clear influence on the biodegradability of the leaf litter. [Copyright &y& Elsevier]

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) are the most effective and best-tolerated drugs to treat elevated levels of low-density lipoprotein cholesterol (LDL-C). In addition, they exhibit other effects unrelated to their lipid lowering effects (pleiotropic actions). In recent years, experimental and clinical evidence demonstrates that statins exert antiarrhythmic properties, reducing the recurrences of supraventricular and life-threatening ventricular arrhythmias both in patients with and without coronary artery disease (CAD). Thus, statins may constitute a novel therapeutic approach to cardiac arrhythmias. This article reviews the antiarrhythmic properties of statins as well as the possible mechanisms involved, including the lowering of LDL-C levels, the improvement of endothelial dysfunction and autonomic function, the stabilization of the atherosclerotic plaques, the antioxidant, antiinflammatory, antithrombotic and cardioprotective properties and the modulation of transmembrane ion fluxes. [Copyright &y& Elsevier]

Abstract: The short-term and small-dose pleiotropic effects of atorvastatin and influence on sex steroid production were investigated in 35 premenopausal and 71 postmenopausal hypercholesterolemic, hypertriglyceridemic women, as well as the temporal differences in these pleiotropic effects. Atorvastatin (10 mg daily) was given for 6 months and fasting lipid concentrations, high sensitive CRP, and coagulo-fibrinolytic parameters were measured at baseline and after 3 and 6 months of therapy. Atorvastatin reduced the low-density lipoprotein cholesterol, remnant-like particle lipoprotein cholesterol, and malondialdehyde-modified low-density lipoprotein cholesterol after 3 and 6 months in both pre- and postmenopausal women. Atorvastatin decreased significantly high-sensitivity C-reactive protein concentration (−47.6% and −58.0%, P <0.01) and tissue plasminogen activator/plasminogen activator inhibitor-1 ratio (−31.8% and −40.0%, P <0.001) after 6 months in pre- and postmenopausal women. There was no correlation between the pleiotropic effects and the improvement in the lipid profile. Furthermore, atorvastatin has no influence on sex steroid production in both pre- and postmenopausal period. The results indicate some short-term pleiotropic effects of small-dose atorvastatin therapy without influence of endocrinological status, which may be important with respect to the early benefits of statin therapy in the perimenopausal hyperlipidemic women. [Copyright &y& Elsevier]

Abstract: Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are potent cholesterol-lowering drugs. In addition to their cholesterol-lowering properties, statins exert a number of so-called ‘pleiotropic’, vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, stabilisation of atherosclerotic plaques, regulation of progenitor cells, inhibition of inflammatory responses and immunomodulatory actions. Pleiotropic actions of statins may have potential clinical impact in vascular disease beyond cholesterol lowering. The ongoing Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), for example, tests the effects of statins in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol (LDL-C) and elevated high-sensitivity C-reactive protein (hs-CRP). Additionally, previous studies have shown that although cholesterol is not an established stroke risk factor, statin therapy is associated with a reduction in the incidence of strokes. It is known that sudden withdrawal of statin treatment may acutely impair vascular function and increase morbidity and mortality in patients with vascular disease. Furthermore, the anti-inflammatory effects of statins may have clinical impact in a number of non-vascular conditions including multiple sclerosis and rheumatoid arthritis. [Copyright &y& Elsevier]

Abstract: Background: Oxidative stress contributes to endothelial dysfunction, an important step to the pathogenesis of atherosclerosis and coronary events. Latest studies revealed the existence of pleiotropic and especially antioxidant properties of statins. We sought to examine the effects of pravastatin on lipid peroxidation and endothelial function, independently from lipid-lowering, in patients with unstable angina (UA). Methods: Thirty-seven patients (males), 64.46±9.09 years, suffering from UA enrolled in the study. Patients were not on statin medication before admission and they received after randomization either 40 mg pravastatin daily (group A, n=20), or placebo (group B, n=17). Malondialdehyde (MDA) concentration, an index of lipid peroxidation and plaque instability, flow-mediated dilatation (FMD) of the brachial artery and blood lipids were measured on the second day of hospitalization and 10 days later. Results: MDA decreased significantly in both groups (A, p=0.008; B, p=0.003). FMD increased significantly in group A (p=0.007), whereas in group B it did not change. Serum lipids remained unaltered in all three groups. Conclusions: Pravastatin administration improved FMD within 10 days and this favorable effect occurred before any significant reduction in blood lipids, revealing its pleiotropic effects during the early phase of an acute coronary syndrome. Circulating lipid peroxidation products in patients with UA decreased significantly during the same period independently of endothelial function and pravastatin therapy. [Copyright &y& Elsevier]

Abstract: Although not currently indicated for chronic heart failure (CHF), statins have been associated with improved outcome in retrospective analysis. However, statin therapy reduces plasma levels of coenzyme Q10 (ubiquinone), which may have adverse effects on heart failure states. We hypothesized that atorvastatin treatment improves endothelial function in patients with chronic heart failure independent of LDL-cholesterol alterations. Furthermore, we assessed how reductions in coenzyme Q10 levels impact on potentially improved endothelial function. Twenty-four patients with stable, symptomatic heart failure (New York Heart Association Class II or III) and a left ventricular ejection fraction &#60;40% were randomised to 40mg atorvastatin or placebo for 6 weeks and crossed over to the other treatment arm for a further 6 weeks, after a 2-week wash out. Forearm resistance vessel function was assessed by venous occlusion plethysmography during infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and N G–monomethyl-l-arginine (l-NMMA) into the brachial artery. Atorvastatin treatment lowered triglycerides, LDL-cholesterol and coenzyme Q10 levels (all p &#60;0.001) and improved endothelium-dependent vasodilatation during acetylcholine infusion (p =0.015). Endothelium-dependent forearm blood flow improvements correlated with reductions in coenzyme Q10 levels (p =0.011), but not with LDL-cholesterol levels (p =0.084). Coenzyme Q10 remained the significant variable predicting improvement in NO dependent endothelial function after adjusting for LDL-cholesterol levels (p =0.041). In conclusion, short-term atorvastatin therapy improved endothelial function in chronic heart failure patients. Further studies are required to determine whether coenzyme Q10 reductions are limiting the maximum favourable effects of statin therapy on the microcirculation. [Copyright &y& Elsevier]

Background: It is unclear whether there are temporal differences for the pleiotropic effects for different members of the statin class. The present study investigated differences in the short- and intermediate-term pleiotropic effects of statins in hypercholesterolemic patients. Methods: Thirty-five hypercholesterolemic patients were randomly treated with either atorvastatin or cerivastatin for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS), fibrinolytic parameters, and flow-mediated dilation of the brachial artery (FMD) at baseline and after 2 weeks and 3 months of therapy. Results: After 2 weeks of therapy, atorvastatin decreased the low density lipoprotein (LDL) cholesterol, small, dense LDL cholesterol (34±22 vs. 18±20%, P<0.01), remnant-like particles (RLP) cholesterol (8.8±6.0 vs. 5.1±2.6 mg/ml, P<0.01), and TBARS (3.3±1.0 vs. 3.1±0.9 nmol/ml, P<0.05), and cerivastatin decreased LDL cholesterol. After 3 months of therapy, atorvastatin decreased small dense LDL cholesterol (8±13%, P<0.0001) additionally, and cerivastatin decreased small, dense LDL cholesterol (51±11 vs. 12±22%, P<0.0001) and plasminogen activator inhibitor type 1 (68±32 vs. 51±21 ng/ml, P<0.05). FMD increased significantly in both groups after 2 weeks, although the relative change in FMD was greater with cerivastatin therapy after 2 weeks than atorvastatin therapy (60±78 vs. 23±26%, P<0.05). However, FMD was the same for both groups after 3 months (58±65 vs. 66±61%, NS), because atorvastatin additionally increased FMD. There was no correlation between these pleiotropic effects and the improvement in the lipid profile for either group. Conclusions: These findings suggest that the degree of pleiotropic effect as well as the time course for the effect are different among members of the statin class of drugs. [Copyright &y& Elsevier]

Rosuvastatin (Crestor®, AstraZeneca) is a new synthetic statin that exhibits a number of highly desirable pharmacologic characteristics. The drug has a high affinity for the active site of 3-hydroxy-3-methylglutaryl coenzyme A (HMG–CoA) reductase and exhibits greater potency in inhibiting enzyme activity and cholesterol synthesis in vitro than other statins. The effects of rosuvastatin are selective for hepatic cells, and there is minimal uptake of the drug by nonhepatic tissues. The vast majority of biologic activity of the drug is associated with the parent compound, which does not appear to undergo extensive metabolism. Hepatic metabolism appears to be minimal, and there is little evidence of metabolic interaction with cytochrome P450 3A4. In an early-phase study, rosuvastatin produced large and dose-related decreases in low-density lipoprotein (LDL) cholesterol of up to 65% in hypercholesterolemic patients. Rosuvastatin should constitute an important addition to current lipid-lowering interventions. [Copyright &y& Elsevier]

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, are administered as first line therapy for hypercholesterolemia, both in primary and secondary prevention. There is a growing body of evidence showing that beyond their lipid-lowering effect, statins have a number of additional beneficial properties. Pitavastatin is a unique lipophilic statin with a strong effect on lowering plasma total cholesterol and triacylglycerol. It has been reported to have pleiotropic effects such as decreasing inflammation and oxidative stress, regulating angiogenesis and osteogenesis, improving endothelial function and arterial stiffness, and reducing tumor progression. Based on the available studies considering the risk of statin-associated muscle symptoms it seems to be also the safest statin. The unique lipid and non-lipid effects of pitavastatin make this molecule a particularly interesting option for the management of different human diseases. In this review, we first summarized the lipid effects of pitavastatin and then strive to unravel the diverse pleiotropic effects of this molecule. [ABSTRACT FROM AUTHOR]

• This is the first study for evaluating the meta-analysis of GWAS and gene network analysis across countries for milk production traits in Holstein cows. • 770 significant SNPs associated with milk production traits were detected across countries. • The most significant lead SNPs for milk production traits were identified on BTA14. These SNPs were rs109421300 SNP near the DGAT1 gene, rs109146371 SNP near the PPP1R16A gene, rs134432442 SNP near the CPSF1 gene, rs109968515 SNP near the CYHR1 gene, and rs111018678 SNP near the TRAPPC9 gene. • Lead SNPs with pleiotropic effects for milk production traits (e.g., rs109421300 and rs109350371 SNPs) were detected in multi-trait meta-analysis. • Regulation of cation channel activity, ion channel complex, and phosphoric diester hydrolase activity were the most significant enriched GO terms for milk production traits. A large number of genome-wide association studies (GWAS) in livestock, especially in dairy cows, provide favorable conditions to integrate multiple independent studies. Methods such as meta-analysis provide the identification of effective QTLs with higher precision and power. A meta-analysis for milk production traits between different countries was conducted using the GWAS summary statistics (i.e., P-value, sample size, allele effects, and etc.) in Holstein cows. In the present study, METAL software was used for the weighted Z-score model. Gene network analysis was used as a complementary method to improve our knowledge of the genome structure of milk production traits and was implemented through the STRING plug-in in Cytoscape software. The Cytoscape ClueGO plug-in was also used for GO enrichment in order to identify biological process, cellular component, and molecular function associated with genomic regions. The aim of this study was to improve the power of QTLs detection and identify the biological mechanisms associated with milk production traits. Data were obtained from 26 published studies from 2010 to 2019. A total of 2,072 SNPs were identified for milk production traits, of which 1,583 SNPs were significant (P < 0.05). Meta-analysis identified 9 QTLs for milk yield, 36 QTLs for fat percentage, and 10 QTLs for protein percentage. Some QTLs were confirmed on BTA14, e.g., BTA14:1801116 close to the DGAT1 gene (milk yield, P = 2.6 × 10 − 131 ; fat percentage, P = 4.8 × 10 − 347 ; protein percentage, P = 7.6 × 10 − 24 ) and BTA14:1651311 close to the PPP1R16A gene (milk yield, P = 2.3 × 10 − 162 ; fat percentage, P = 3.5 × 10 − 153 ). We identified pleiotropic effects of lead SNPs for milk production traits, e.g., one SNP (rs109421300) at BTA14 had pleiotropic effects on milk yield, fat percentage, and protein percentage traits. The most important SNPs for studied traits across countries implicated to network scoring and visualization were including: rs109421300 (DGAT1 gene) for milk yield, fat percentage, and protein percentage; rs109146371 (PPP1R16A gene) for milk yield and fat percentage; rs109968515 (CYHR1 gene) for milk yield and fat percentage; rs134432442 (CPSF1 gene) for fat percentage; rs111018678 (TRAPPC9 gene) for protein percentage. Significant pathways involved in milk production traits through GO term enrichment analysis for biological process, cellular component, and molecular function included: regulation of cation channel activity (P = 1.6 × 10 − 2 ), ion channel complex (P = 1.4 × 10 − 2 ), and phosphoric diester hydrolase activity (P = 1.1 × 10 − 3 ) for milk yield; negative regulation of organ growth (P = 8.2 × 10 − 3 ), transmembrane transporter complex (P = 1.6 × 10 − 3 ), and potassium ion transmembrane transporter activity (P = 8.8 × 10 − 3 ) for fat percentage; mRNA polyadenylation (P = 1.2 × 10 − 2 ), mRNA cleavage factor complex (P = 9.8 × 10 − 4 ), and phosphoric diester hydrolase activity (P = 5.3 × 10 − 3 ) for protein percentage, respectively. Thus, the combination of GWAS summary statistics through a powerful methodology such as meta-analysis will assist us to accurately identify QTLs, potential candidate genes, and biological mechanisms. This kind of studies will help us to have better understanding of QTL regions and genome structure for milk production traits and improve genomic evaluations in Holstein cows. To the best of our knowledge, this is the first meta-analysis of GWAS and GO enrichment across countries for milk production traits in Holstein cows. [ABSTRACT FROM AUTHOR]