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Blood Jul 2017
Topics: Atorvastatin; Humans; Lung Neoplasms; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 28751357
DOI: 10.1182/blood-2017-06-788455 -
Cell Communication and Signaling : CCS May 2023Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain-Barré syndrome in...
BACKGROUND
Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain-Barré syndrome in adults. Like other flaviviruses, ZIKV depends on cholesterol to facilitate its replication; thus, cholesterol has been proposed as a therapeutic target to treat the infection using FDA-approved statins. Cholesterol is stored in intracellular lipid droplets (LD) in the form of cholesterol esters and can be regulated by autophagy. We hypothesize that the virus hijacks autophagy machinery as an early step to increase the formation of LD and viral replication, and that interference with this pathway will limit reproduction of virus.
METHODS
We pretreated MDCK cells with atorvastatin or other inhibitors of autophagy prior to infection with ZIKV. We measured viral expression by qPCR for NS1 RNA and immunofluorescence for Zika E protein.
RESULTS
Autophagy increases in virus-infected cells as early as 6 h post infection (hpi). In the presence of atorvastatin, LD are decreased, and cholesterol is reduced, targeting key steps in viral replication, resulting in suppression of replication of ZIKV is suppressed. Other both early- and late-acting autophagy inhibitors decrease both the number of LD and viral replication. Bafilomycin renders cholesterol is inaccessible to ZIKV. We also confirm previous reports of a bystander effect, in which neighboring uninfected cells have higher LD counts compared to infected cells.
CONCLUSIONS
We conclude that atorvastatin and inhibitors of autophagy lead to lower availability of LD, decreasing viral replication. We conclude that bafilomycin A1 inhibits viral expression by blocking cholesterol esterification to form LD. Video Abstract.
Topics: Humans; Atorvastatin; Autophagy; Lipid Metabolism; Virus Replication; Zika Virus; Zika Virus Infection; Madin Darby Canine Kidney Cells; Animals; Dogs
PubMed: 37208782
DOI: 10.1186/s12964-022-01026-8 -
European Journal of Medical Research Sep 2023Atorvastatin is regarded as the most frequently prescribed statin worldwide for dyslipidemia. However, clinical response and risk of adverse effects to statin therapy... (Review)
Review
INTRODUCTION
Atorvastatin is regarded as the most frequently prescribed statin worldwide for dyslipidemia. However, clinical response and risk of adverse effects to statin therapy are associated with genetic variations. Numerous research linked statins pharmacokinetics (PK) variations to genetic polymorphisms in cytochromes P450 (CYPs) metabolic enzymes.
OBJECTIVE
This article reviews the association between CYP3A4/5 genetic variations and response to atorvastatin therapy globally, which includes atorvastatin PK, and the risk for adverse reactions, with a hint to the Egyptians.
METHODS
Up to March 30, 2022, electronic medical databases like PubMed, Web of Science, MEDLINE, and Egyptian Knowledge Bank (EKB) were searched. All articles that highlighted the relationship between CYP3A4/5 genetic polymorphisms and atorvastatin efficacy/safety profile were included in this review.
RESULTS
Initially, 492 articles were retrieved after an exhaustive search. There were 24 articles included according to the inclusion criteria. Findings of association studies of CYP3A4/5 genetic polymorphisms with response to atorvastatin varied among different ethnicities. CYP3A4*1B was associated with better therapeutic outcomes after atorvastatin therapy in Chileans and vice versa in Americans. Caucasians with myalgia while using atorvastatin were at significant risk of suffering severe muscle damage if they were carriers of CYP3A5*3/*3. As far as we can report for the Egyptian population, the impact of CYP3A4/5 genetic variations on the response to atorvastatin therapy was understudied.
CONCLUSION
More pharmacogenetic studies amongst diverse populations worldwide, like the Egyptian population, are necessary to detect further atorvastatin-gene interactions.
Topics: Humans; Atorvastatin; Cytochrome P-450 CYP3A; Egypt; Genotype; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Polymorphism, Genetic; Treatment Outcome
PubMed: 37759317
DOI: 10.1186/s40001-023-01038-1 -
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 -
Iranian Journal of Kidney Diseases Jul 2023Contrast-induced nephropathy (CIN) is an important issue in patients with cardiovascular disorders undergoing angiography, especially in patients with kidney failure.... (Randomized Controlled Trial)
Randomized Controlled Trial
Preventive Effects of Nicorandil and Atorvastatin in Contrastinduced Nephropathy in Patients with Renal Dysfunction Undergoing Coronary Artery Angiography: A Double Blind, Randomized, Controlled Clinical Trial.
INTRODUCTIONS
Contrast-induced nephropathy (CIN) is an important issue in patients with cardiovascular disorders undergoing angiography, especially in patients with kidney failure. The purpose of the present study was to compare the preventive effects of nicorandil and atorvastatin on the incidence of CIN in patients with chronic kidney disease (CKD).
METHODS
In this clinical trial study, 270 patients with renal insufficiency nominated for angiographic procedures were randomly divided into three groups (each group, n = 90): hydration group (1000 mL saline), hydration + atorvastatin group (80 mg/d for 3 days), and hydration + nicorandil group (10 mg 3 times/d for 3 days). Serum creatinine (Cr) and blood urea nitrogen (BUN) levels as well as glomerular filtration rate (GFR) were evaluated before and 72 hours after the intervention.
RESULTS
At the end of the study, serum Cr and BUN levels in all three groups showed a significant increase compared to the pre-intervention levels, which were significantly higher in the control group than the other two groups. The amount of GFR also significantly decreased following the intervention in all three groups, with the decline being significantly more pronounced in the control group than in other two groups. No significant differences were found in serum concentrations of Cr and BUN as well as GFR levels between nicorandil and atorvastatin groups at the end of the study.
CONCLUSION
Nicorandil and atorvastatin administration showed preventive effects on CIN in CKD patients undergoing angiography, but there was no significant difference between the two drugs. DOI: 10.52547/ijkd.7348.
Topics: Humans; Nicorandil; Atorvastatin; Coronary Vessels; Coronary Angiography; Renal Insufficiency; Renal Insufficiency, Chronic
PubMed: 37634247
DOI: No ID Found -
Endocrinology, Diabetes & Metabolism May 2022Cardiovascular disease (CVD) is the leading cause of mortality in people with Type 2 diabetes mellitus (T2DM). Statins reduce low-density lipoproteins and positively...
INTRODUCTION
Cardiovascular disease (CVD) is the leading cause of mortality in people with Type 2 diabetes mellitus (T2DM). Statins reduce low-density lipoproteins and positively affect CVD outcomes. Statin type and dose have differential effects on glycaemia and risk of incident T2DM; however, the impact of gender, and of individual drugs within the statin class, remains unclear.
AIM
To compare effects of simvastatin and atorvastatin on lipid and glycaemic control in men and women with and without T2DM, and their association with incident T2DM.
METHODS
The effect of simvastatin and atorvastatin on lipid and glycaemic control was assessed in the T2DM DiaStrat cohort. Prescribed medications, gender, age, BMI, diabetes duration, blood lipid profile and HbA1c were extracted from Electronic Care Record, and compared in men and women prescribed simvastatin and atorvastatin. Analyses were replicated in the UKBiobank in those with and without T2DM. The association of simvastatin and atorvastatin with incident T2DM was also investigated in the UKBiobank. Cohorts where matched for age, BMI and diabetes duration in men and women, in the UKBioBank analysis, where possible.
RESULTS
Simvastatin was associated with better LDL (1.6 ± 0.6 vs 2.1 ± 0.9 mmol/L, p < .01) and total cholesterol (3.6 ± 0.7 vs 4.2 ± 1.0 mmol/L, p < .05), and glycaemic control (62 ± 17 vs 67 ± 19 mmol/mol, p < .059) than atorvastatin specifically in women in the DiaStrat cohort. In the UKBiobank, both men and women prescribed simvastatin had better LDL (Women: 2.6 ± 0.6 vs 2.6 ± 0.7 mmol/L, p < .05; Men: 2.4 ± 0.6 vs 2.4 ± 0.6, p < .01) and glycaemic control (Women:54 ± 14 vs 56 ± 15mmol/mol, p < .05; Men, 54 ± 14 vs 55 ± 15 mmol/mol, p < .01) than those prescribed atorvastatin. Simvastatin was also associated with reduced risk of incident T2DM in both men and women (p < .0001) in the UKBiobank.
CONCLUSIONS
Simvastatin is associated with superior lipid and glycaemic control to atorvastatin in those with and without T2DM, and with fewer incident T2DM cases. Given the importance of lipid and glycaemic control in preventing secondary complications of T2DM, these findings may help inform prescribing practices.
Topics: Atorvastatin; Biological Specimen Banks; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glycemic Control; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Simvastatin; United Kingdom
PubMed: 35243827
DOI: 10.1002/edm2.326 -
Biomedicine & Pharmacotherapy =... Dec 2023Statins are highly prevalent in patients with coronary artery disease. Statins exert their anti-inflammatory effects on the vascular wall and circulating levels of...
Statins are highly prevalent in patients with coronary artery disease. Statins exert their anti-inflammatory effects on the vascular wall and circulating levels of pro-inflammatory cytokines. However, increasing attention revealed the exacerbation of macrophage inflammation induced by statins, and a clear mechanistic explanation of whether the detrimental effects of statins on macrophage inflammatory phenotypes outweigh the beneficial effects is has not yet been established. Here, RNA-sequencing and RT-qPCR analyses demonstrated that statins significantly upregulated EphA2, Nlrp3, IL-1β and TNF-α expression in macrophages. Mechanistically, we found that atorvastatin reduced KLF4 binding to the EphA2 promoter using KLF4-chromatin immunoprecipitation, suppressed HDAC11-mediated deacetylation and subsequently led to enhanced EphA2 transcription. The 4D-label-free proteomics analysis further confirmed the upregulated EphA2 and inflammatory signals. Furthermore, the proinflammatory effect of atorvastatin was neutralized by an addition of recombinant Fc-ephrinA1, a selective Eph receptor tyrosine kinase inhibitor (ALW-II-41-27) or EphA2-silencing adenovirus (siEphA2). In vivo, EphA2 was identified a proatherogenic factor and apoE mice placed on a high-fat diet following gastric gavage with atorvastatin exhibited a consistent elevation in EphA2 expression. We further observed that the transfection with siEphA2 in atorvastatin-treated mice significantly attenuated atherosclerotic plaque formation and abrogated statin-orchestrated macrophages proinflammatory genes expression as compared to that in atorvastatin alone. Increased plaque stability index was also observed following the addition of siEphA2, as evidenced by increased collagen and smooth muscle content and diminished lipid accumulation and macrophage infiltration. The data suggest that blockage of EphA2 provides an additional therapeutic benefit for further improving the anti-atherogenic effects of statins.
Topics: Humans; Mice; Animals; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Atherosclerosis; Macrophages; Plaque, Atherosclerotic; Inflammation
PubMed: 37984301
DOI: 10.1016/j.biopha.2023.115885 -
Revista Medica Del Instituto Mexicano... Mar 2023Dyslipidemia is a risk factor for the development of atherosclerosis and ischemic heart disease. Statins are safe drugs that are part of the routine treatment in...
BACKGROUND
Dyslipidemia is a risk factor for the development of atherosclerosis and ischemic heart disease. Statins are safe drugs that are part of the routine treatment in patients with Acute Myocardial Infarction (AMI), however, rhabdomyolysis associated with severe myonecrosis due to statins can occur and associated complications such as acute kidney injury increase mortality. The main objective of this article is to report the case of a critically ill patient with AMI who presented severe statin-associated rhabdomyolysis documented with muscle biopsy.
DESCRIPTION OF THE CASE
A 54-year-old man who presented with AMI, cardiogenic shock, and cardiorespiratory arrest requiring cardiopulmonary resuscitation, fibrinolysis, and successful salvage coronary angiography. However, he presented severe rhabdomyolysis associated with atorvastatin that required suspension of the drug and multi-organ support in a Coronary Care Unit.
CONCLUSIONS
The prevalence of statin-associated rhabdomyolysis is low, however, the late elevation of CPK above 10 times its upper normal value in those patients with successful percutaneous coronary angiography should promptly draw attention, generate a diagnostic approach towards non-traumatic acquired causes of rhabdomyolysis and assess the suspension of statins.
Topics: Male; Humans; Middle Aged; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Infarction; Risk Factors; Rhabdomyolysis
PubMed: 37207311
DOI: No ID Found -
Journal of the American College of... May 2020
Topics: Atorvastatin; Cholesterol, LDL; Humans; Risk Factors
PubMed: 32209335
DOI: 10.1016/j.jacc.2020.03.033 -
Experimental Biology and Medicine... Dec 2021High levels of blood glucose and lipids are well-known risk factors for heart diseases. Bee venom is a natural product that has a potent hypoglycemic, hypolipidemic,...
High levels of blood glucose and lipids are well-known risk factors for heart diseases. Bee venom is a natural product that has a potent hypoglycemic, hypolipidemic, anti-inflammatory, and antioxidant effects. The current study aimed to determine the bee venom effects on cardiac dysfunction compared to combined therapy of metformin and atorvastatin in diabetic hyperlipidemic rats. The median lethal dose of bee venom was estimated, and then 50 adult male albino rats were categorized into five groups. One group was fed a standard diet and served as a negative control, while the other groups were given nicotinamide and streptozotocin injections to induce type 2 diabetes. After confirming diabetes, the rats were fed a high-fat diet for four weeks. The four groups were divided as follows: one group served as a positive control, whereas the other three groups were treated with bee venom (0.5 mg/kg), bee venom (1.23 mg/kg), and combined therapy of metformin (60 mg/kg) and atorvastatin (10 mg/kg), respectively, for four weeks. Upon termination of the experiment, blood samples and heart tissue were obtained. Administration of bee venom using both doses (0.5 and 1.23 mg/kg) and combined therapy of metformin and atorvastatin revealed a significant decrease in the concentrations of glucose, total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, troponin I, creatine kinase, and lactate dehydrogenase activities. Moreover, a significant decrease had been detedcted in malondialdehyde, nuclear factor-kappa-β levels, and relative mRNA expression of vascular cell adhesion molecule-1 and galectin-3 in heart tissue compared to the positive control ( < 0.0001). Furthermore, there was a significant increase in bodyweight levels of insulin, high-density lipoprotein cholesterol, and total antioxidant capacity in heart tissue compared to the positive control ( < 0.0001). The results indicate that bee venom can ameliorate cardiac dysfunction through attenuating oxidative stress and downregulating the NF-κβ signaling pathway.
Topics: Animals; Atorvastatin; Bee Venoms; Diabetes Mellitus, Experimental; Diet, High-Fat; Heart; Hyperlipidemias; Male; Metformin; Rats
PubMed: 34550826
DOI: 10.1177/15353702211045924