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The Journal of Biological Chemistry Mar 2022Alzheimer's disease is characterized by the presence of extraneuronal amyloid plaques composed of amyloid-beta (Aβ) fibrillar aggregates in the brains of patients. In... (Meta-Analysis)
Meta-Analysis
Alzheimer's disease is characterized by the presence of extraneuronal amyloid plaques composed of amyloid-beta (Aβ) fibrillar aggregates in the brains of patients. In mouse models, it has previously been shown that atorvastatin (Ator), a cholesterol-lowering drug, has some reducing effect on the production of cerebral Aβ. A meta-analysis on humans showed moderate effects in the short term but no improvement in the Alzheimer's Disease Assessment Scale-Cognitive Subscale behavioral test. Here, we explore a potential direct effect of Ator on Aβ42 aggregation. Using NMR-based monomer consumption assays and CD spectroscopy, we observed a promoting effect of Ator in its original form (Ator-calcium) on Aβ42 aggregation, as expected because of the presence of calcium ions. The effect was reversed when applying a CaCO-based calcium ion scavenging method, which was validated by the aforementioned methods as well as thioflavin-T fluorescence assays and transmission electron microscopy. We found that the aggregation was inhibited significantly when the concentration of calcium-free Ator exceeded that of Aβ by at least a factor of 2. The H-N heteronuclear single quantum correlation and saturation-transfer difference NMR data suggest that calcium-free Ator exerts its effect through interaction with the KLVF binding site on the Aβ peptide via its aromatic rings as well as hydroxyl and methyl groups. On the other hand, molecular dynamics simulations confirmed that the increasing concentration of Ator is necessary for the inhibition of the conformational transition of Aβ from an α-helix-dominant to a β-sheet-dominant structure.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Atorvastatin; Calcium; Humans; Mice; Peptide Fragments
PubMed: 35104501
DOI: 10.1016/j.jbc.2022.101662 -
The Cochrane Database of Systematic... Jul 2020Asthma is a common chronic respiratory disease. People with asthma have inflammation of their airways that causes recurrent episodes of wheezing, breathlessness and...
BACKGROUND
Asthma is a common chronic respiratory disease. People with asthma have inflammation of their airways that causes recurrent episodes of wheezing, breathlessness and chest tightness, with or without a cough. Statins possess multiple therapeutic effects, including lowering lipid levels in the blood. Statins are reported to have a potential role as an adjunct treatment in asthma. However, comprehensive evidence of the benefits and harms of using statins is required to facilitate decision making.
OBJECTIVES
To assess the benefits and harms of statins as an adjunct therapy for asthma in adults and children.
SEARCH METHODS
We searched for studies in the Cochrane Airways Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid SP and Embase Ovid SP, from their inception dates We handsearched the proceedings of major respiratory conferences. We also searched clinical trials registries for completed, ongoing and unpublished studies, and scanned the reference lists of included studies and relevant reviews to identify additional studies. The search is current to 7 February 2020.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) with a parallel-group design that assessed statins for at least 12 weeks' duration. We considered all participants with a clinical diagnosis of asthma to be eligible, regardless of age, sex, disease severity and previous or current treatment. We planned to include studies reported as full text, those published as abstract only, and unpublished data.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened and selected the studies, extracted outcome data and intervention characteristics from included studies, and assessed risk of bias according to standard Cochrane methodological procedures. We resolved any disagreement through discussion.
MAIN RESULTS
We found only one trial involving a total of 60 people living with asthma. The trial compared the effect of atorvastatin with a placebo (dummy treatment containing lactose) in treating people with chronic asthma. The trial did not report data for the primary outcomes or adverse events. There was uncertainty about the relative effect on forced expiratory volume in one second (FEV) and peak expiratory flow (PEF) in the atorvastatin group compared with the placebo group. The study did not report serious adverse effects for the interventions. The included study had internal discrepancies in its reported data.
AUTHORS' CONCLUSIONS
The evidence was of very low certainty, so we are unable to draw conclusions about the effectiveness and safety of statins to treat asthma. High-quality RCTs are needed to assess the effect of statins on people with asthma. Well-designed multicentre trials with larger samples and longer duration of treatment are required, which assess outcomes such as adverse events, hospital utilisation and costs, to provide better quality evidence. Future studies that include subgroups of obese people with asthma are also required.
Topics: Anti-Asthmatic Agents; Asthma; Atorvastatin; Forced Expiratory Volume; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Peak Expiratory Flow Rate
PubMed: 32668027
DOI: 10.1002/14651858.CD013268.pub2 -
BMC Medicine Mar 2023Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSC-EV) have a superior cardiac repair effect on...
Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway.
BACKGROUND
Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSC-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSC-EV.
METHODS
MSC-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSC-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo.
RESULTS
MSC-EV significantly reduced the amount of CD68 total macrophages and increased CD206 M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01-0.0001). On day 28, MSC-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSC-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSC-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSC-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy.
CONCLUSIONS
We uncovered a novel mechanism that MSC-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.
Topics: Rats; Animals; Atorvastatin; Myocardial Infarction; Extracellular Vesicles; MicroRNAs; Mesenchymal Stem Cells; Macrophages; STAT1 Transcription Factor
PubMed: 36927608
DOI: 10.1186/s12916-023-02778-x -
International Journal of Molecular... Oct 2021Electroporation is influenced by the features of the targeted cell membranes, e.g., the cholesterol content and the surface tension of the membrane. The latter is...
Electroporation is influenced by the features of the targeted cell membranes, e.g., the cholesterol content and the surface tension of the membrane. The latter is eventually affected by the organization of actin fibers. Atorvastatin is a statin known to influence both the cholesterol content and the organization of actin. This work analyzes the effects of the latter on the efficacy of electroporation of cancer cells. In addition, herein, electroporation was combined with calcium chloride (CaEP) to assess as well the effects of the statin on the efficacy of electrochemotherapy. Cholesterol-rich cell lines MDA-MB231, DU 145, and A375 underwent (1) 48 h preincubation or (2) direct treatment with 50 nM atorvastatin. We studied the impact of the statin on cholesterol and actin fiber organization and analyzed the cells' membrane permeability. The viability of cells subjected to PEF (pulsed electric field) treatments and CaEP with 5 mM CaCl was examined. Finally, to assess the safety of the therapy, we analyzed the N-and E-cadherin localization using confocal laser microscopy. The results of our investigation revealed that depending on the cell line, atorvastatin preincubation decreases the total cholesterol in the steroidogenic cells and induces reorganization of actin nearby the cell membrane. Under low voltage PEFs, actin reorganization is responsible for the increase in the electroporation threshold. However, when subject to high voltage PEF, the lipid composition of the cell membrane becomes the regulatory factor. Namely, preincubation with atorvastatin reduces the cytotoxic effect of low voltage pulses and enhances the cytotoxicity and cellular changes induced by high voltage pulses. The study confirms that the surface tension regulates of membrane permeability under low voltage PEF treatment. Accordingly, to reduce the unfavorable effects of preincubation with atorvastatin, electroporation of steroidogenic cells should be performed at high voltage and combined with a calcium supply.
Topics: Anticholesteremic Agents; Antineoplastic Agents; Apoptosis; Atorvastatin; Calcium; Cell Membrane; Cell Membrane Permeability; Cell Proliferation; Cholesterol; Electrochemotherapy; Electroporation; Humans; Neoplasms; Tumor Cells, Cultured
PubMed: 34681903
DOI: 10.3390/ijms222011245 -
Molecular Pharmaceutics Sep 2021Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic...
Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [F]atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [F]Atorvastatin was synthesized via a previously optimized F-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats ( = 7 for both groups), and for subsequent biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [F]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [F]atorvastatin was 38 ± 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [F]atorvastatin kinetics in the liver. A strong correlation (R > 0.93) between quantitative (the radiotracer's unidirectional net rate of influx between compartments) and semi-quantitative liver's SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of for monitoring [F]atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [F]atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [F]atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.
Topics: Animals; Atorvastatin; Female; Fluorine Radioisotopes; Hepatobiliary Elimination; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Molecular Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Wistar; Sex Factors; Tissue Distribution
PubMed: 34351158
DOI: 10.1021/acs.molpharmaceut.1c00305 -
Journal of the American Heart... Sep 2023Background We aimed to compare statin monotherapy and upfront combination therapy of statin and ezetimibe in patients with acute coronary syndromes (ACSs). Methods and... (Observational Study)
Observational Study
Intensive Statin Therapy Versus Upfront Combination Therapy of Statin and Ezetimibe in Patients With Acute Coronary Syndrome: A Propensity Score Matching Analysis Based on the PL-ACS Data.
Background We aimed to compare statin monotherapy and upfront combination therapy of statin and ezetimibe in patients with acute coronary syndromes (ACSs). Methods and Results The study included consecutive patients with ACS included in the PL-ACS (Polish Registry of Acute Coronary Syndromes), which is a national, multicenter, ongoing, prospective observational registry that is mandatory for patients with ACS hospitalized in Poland. Data were matched using the Mahalanobis distance within propensity score matching calipers. Multivariable stepwise logistic regression analysis, including all variables, was next used in propensity score matching analysis. Finally, 38 023 consecutive patients with ACS who were discharged alive were included in the analysis. After propensity score matching, 2 groups were analyzed: statin monotherapy (atorvastatin or rosuvastatin; n=768) and upfront combination therapy of statin and ezetimibe (n=768 patients). The difference in mortality between groups was significant during the follow-up and was present at 1 (5.9% versus 3.5%; =0.041), 2 (7.8% versus 4.3%; =0.019), and 3 (10.2% versus 5.5%; =0.024) years of follow-up in favor of the upfront combination therapy, as well as for the overall period. For the treatment, rosuvastatin significantly improved prognosis compared with atorvastatin (odds ratio [OR], 0.790 [95% CI, 0.732-0.853]). Upfront combination therapy was associated with a significant reduction of all-cause mortality in comparison with statin monotherapy (OR, 0.526 [95% CI, 0.378-0.733]), with absolute risk reduction of 4.7% after 3 years (number needed to treat=21). Conclusions The upfront combination lipid-lowering therapy is superior to statin monotherapy for all-cause mortality in patients with ACS. These results suggest that in high-risk patients, such an approach, rather than a stepwise therapy approach, should be recommended.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Acute Coronary Syndrome; Ezetimibe; Propensity Score
PubMed: 37671618
DOI: 10.1161/JAHA.123.030414 -
Journal of Neuroinflammation Sep 2023Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the...
BACKGROUND
Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the risk of dementia through their pleiotropic effects rather than their cholesterol lowering effects. While AD is a leading cause of dementia, it is frequently found co-morbidly with cerebral small vessel disease and other vascular contributions to cognitive impairment and dementia (VCID), which are another leading cause of dementia. In this study, we determined if atorvastatin ameliorated hyperhomocysteinemia (HHcy)-induced VCID.
METHODS
Wild-type (C57Bl6/J) mice were placed on a diet to induce HHcy or a control diet each with or without atorvastatin for 14 weeks. Mice underwent novel object recognition testing before tissue collection. Plasma total cholesterol and total homocysteine as well as related metabolites were measured. Using qPCR and NanoString technology, we profiled glial cell-associated gene expression changes. Finally, microglial morphology, astrocyte end feet, and microhemorrhages were analyzed using histological methods.
RESULTS
Atorvastatin treatment of HHcy in mice led to no changes in total cholesterol but decreases in total homocysteine in plasma. While HHcy decreased expression of many glial genes, atorvastatin rescued these gene changes, which mostly occurred in oligodendrocytes and microglia. Microglia in HHcy mice with atorvastatin were trending towards fewer processes compared to control with atorvastatin, but there were no atorvastatin effects on astrocyte end feet. While atorvastatin treatment was trending towards increasing the area of microhemorrhages in HHcy mice in the frontal cortex, it only slightly (non-significantly) reduced the number of microhemorrhages. Finally, atorvastatin treatment in HHcy mice led to improved cognition on the novel object recognition task.
CONCLUSIONS
These data suggest that atorvastatin rescued cognitive changes induced by HHcy most likely through lowering plasma total homocysteine and rescuing gene expression changes rather than impacts on vascular integrity or microglial changes.
Topics: Animals; Mice; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperhomocysteinemia; Cognitive Dysfunction; Cognition; Alzheimer Disease; Dementia, Vascular; Homocysteine
PubMed: 37658433
DOI: 10.1186/s12974-023-02883-x -
Circulation. Genomic and Precision... Jun 2022Statin-associated muscle symptoms (SAMS) are the most frequently reported adverse events for statin therapies. Previous studies have reported an association between the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Statin-associated muscle symptoms (SAMS) are the most frequently reported adverse events for statin therapies. Previous studies have reported an association between the p.Val174Ala missense variant in and SAMS in simvastatin-treated subjects; however, evidence for genetic predictors of SAMS in atorvastatin- or rosuvastatin-treated subjects is currently lacking.
METHODS
ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; n=18 924) was a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of alirocumab (a PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor) in acute coronary syndrome patients receiving high-intensity statin therapy. The goal of this pharmacogenomic analysis was to identify genetic variants associated with atorvastatin- and rosuvastatin-mediated SAMS among ODYSSEY OUTCOMES subjects who consented to participate in the genetic study (n=11 880). We performed multi-ancestry exome-wide and genome-wide association studies and gene burden analysis across 2 phenotypes (clinical SAMS [n=10 617] and creatine kinase levels [n=9630]).
RESULTS
A novel genome-wide significant association for an intronic variant (rs6667912) located within (odds ratio [95% CI], 1.39 [1.24-1.55]; =3.71×10) for patients with clinical SAMS (cases=894, controls=9723) was identified. This variant is located ≈30 kb upstream of , a locus associated with severe SAMS. We replicated 2 loci, at and , previously associated with creatine kinase levels during statin treatment. No association was observed between p.Val174Ala (rs4149056) in and SAMS (odds ratio [95% CI], 1.03 [0.90-1.18]; =0.69).
CONCLUSIONS
This study comprises the largest discovery exome-wide and genome-wide association study for atorvastatin- or rosuvastatin-mediated SAMS to date. These novel genetic findings may provide biological/mechanistic insight into this drug-induced toxicity, and help identify at-risk patients before selection of lipid-lowering therapies.
Topics: Acute Coronary Syndrome; Antigens, CD; Atorvastatin; Cholesterol, LDL; Creatine Kinase; Genome-Wide Association Study; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Membrane Proteins; Muscles; PCSK9 Inhibitors; Pharmacogenomic Testing; Receptors, Immunologic; Rosuvastatin Calcium
PubMed: 35543701
DOI: 10.1161/CIRCGEN.121.003503 -
Asian Pacific Journal of Cancer... Mar 2022Atorvastatin is commonly used as a lipid lowering drug. The emerging interest in statins as anticancer agents is based on their pleiotropic effects on cancer cells....
OBJECTIVE
Atorvastatin is commonly used as a lipid lowering drug. The emerging interest in statins as anticancer agents is based on their pleiotropic effects on cancer cells. Among the statins, atorvastatin, and in cancers, breast malignancies have received less attention in preclinical investigations. In order to enhance the efficacy of cancer treatment, adjuvant, less expensive therapeutic strategies have been recently noticed. In this case, we investigated the in-vitro effect of atorvastatin on viability and migration of MCF7 breast cancer cell line.
METHODS
We tested the cytotoxicity of atorvastatin on breast cancer cells survival by MTT assay. Annexin-V / PI staining and then flow cytometry of cancer cells in addition to quantitative real-time PCR tests quantified the apoptosis and necrosis of cancer cells. We figured out the impact of atorvastatin on cancer cell migration capability through scratch-wound healing assay and transwell migration examination. Inverted light microscope and fluorescent imaging displayed the morphological changes following treatment of MCF7 cells with atorvastatin.
RESULT
We resulted that atorvastatin can trigger MCF7 cancer cells to undergo necrosis and caspase-dependent apoptosis based on the viable/dead cell number, mitotic cell cycle, gene expression, and morphological assays. The results were dose- and time-dependent and the half- maximal inhibitory concentration of atorvastatin for cancer cells' viability inhibition was 9.1 μM/L(nM/mL). Moreover, the migration of MCF7 cells were inhibited in the treated group as we figured out in two- and three-dimensional migration methods.
CONCLUSION
In-vitro inspection of drug-cancer cell interactions paves the way for future in-vivo research studies. These in-vitro results revealed that atorvastatin has anti-viability and anti-migration effects on breast cancer cells.
Topics: Apoptosis; Atorvastatin; Breast Neoplasms; Cell Movement; Female; Humans; MCF-7 Cells
PubMed: 35345358
DOI: 10.31557/APJCP.2022.23.3.867 -
Hepatology Communications Dec 2023Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal pressure and thus the risk of complications and mortality. We aimed to investigate the effects of atorvastatin on hospital admissions, mortality, inflammation, and lipidomics in cirrhosis with portal hypertension.
METHODS
We performed a double-blinded, randomized, placebo-controlled clinical trial among patients with cirrhosis and portal hypertension. Atorvastatin (10-20 mg/d) was administered for 6 months. We measured splanchnic hemodynamics, analyzed inflammatory markers, and performed lipidomics at baseline and after 6 months.
RESULTS
Seventy-eight patients were randomized, with 38 patients allocated to atorvastatin and 40 patients to placebo. Fifty-nine patients completed 6 months of intervention. Comparisons between changes in each group were calculated. Liver-related complications and mortality were similar between the groups. The HVPG and Model for End-stage Liver Disease score did not change between groups (p=0.95 and 0.87, respectively). Atorvastatin decreased 3 of 42 inflammatory markers, CD62-L-selectin, matrix metalloproteinases-2, and TNF-α (p-values: 0.005, 0.011, and 0.023, respectively), while lipidomics was not significantly changed.
CONCLUSIONS
In patients with cirrhosis, atorvastatin was safe to use, but did not reduce mortality, the risk of liver-related complications, or the HVPG. Atorvastatin induced minor anti-inflammatory effects and minor effects on lipids during a 6-month treatment period.
Topics: Humans; Anti-Inflammatory Agents; Atorvastatin; End Stage Liver Disease; Hypertension, Portal; Liver Cirrhosis; Severity of Illness Index; Double-Blind Method
PubMed: 38051553
DOI: 10.1097/HC9.0000000000000332