-
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 -
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 -
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 -
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 -
Medicine Dec 2020Atorvastatin and aspirin have been used in treating different forms of epilepsy. However, their effect on post-stroke epilepsy (PSE) still needs to be validated by...
OBJECTIVE
Atorvastatin and aspirin have been used in treating different forms of epilepsy. However, their effect on post-stroke epilepsy (PSE) still needs to be validated by large-scale clinical studies. In addition, their impact on the use of the antiepileptic drug levetiracetam for post-stroke epilepsy remains to be explored. Thus, the aim of this study was to further evaluate the effect of atorvastatin and aspirin on PSE and their effect on the usage of the antiepileptic drug levetiracetam in PSE patients.
METHODS
Patients, aged 65 to 85 years, with newly diagnosed post-ischemic stroke epilepsy from August 30, 2014 to August 30, 2018 were included in the study, with the exclusion of those with coexisting conditions.
RESULTS
Initially, 1321 patients were included, and 780 remained in the study at the 1-year follow-up. During the study, atorvastatin treatment with or without aspirin reduced the number of clinical epileptic episodes in PSE patients. It also reduced the dosage of levetiracetam and achieved better control of epilepsy compared to levetiracetam mono-treatment. Aspirin co-treatment with levetiracetam did not result in a significant improvement. However, the combination of aspirin with atorvastatin significantly reduced the number of seizures compared to atorvastatin treatment alone.
CONCLUSION
Atorvastatin and aspirin co-treatment with levetiracetam can reduce epilepsy in PSE patients and reduce the dosage of levetiracetam required for effective control of PSE.
Topics: Aged; Aged, 80 and over; Anticonvulsants; Aspirin; Atorvastatin; Cerebral Infarction; Drug Therapy, Combination; Epilepsy; Female; Humans; Levetiracetam; Male; Severity of Illness Index; Stroke
PubMed: 33327318
DOI: 10.1097/MD.0000000000023577 -
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 -
Asian Pacific Journal of Cancer... Apr 2021The statin drug Atorvastatin (AT) used for cholesterol reduction and Ganoderma lucidum (Gl) mushroom extract exhibited satisfactory antitumor activities towards various...
BACKGROUND
The statin drug Atorvastatin (AT) used for cholesterol reduction and Ganoderma lucidum (Gl) mushroom extract exhibited satisfactory antitumor activities towards various types of cancer.
OBJECTIVE
The present study was designed to evaluate the apoptotic and antiangiogenic effects of Atorvastatin and/or Ganoderma lucidum against Ehrlich solid tumor inoculated in female mice.
MATERIALS AND METHODS
Atorvastatin (AT) or/and Ganoderma lucidum (Gl) extract were administered to mice bearing tumor alternatively for 28 days after 10 days of tumor cells inoculation. Mice were divided into 5 equal groups as follows: Control (C): Normal mice, Ehrlich (E): mice injected in thigh with EAC cells, (E+AT): mice bearing solid tumor that received an intraperitoneal dose of Atorvastatin (10 mg/kg). Group (4): (E+Gl): mice bearing solid tumor that received an oral dose of Ganoderma lucidum (28 mg/kg) Group (5): (E+AT+Gl): mice bearing solid tumor that received intraperitoneal dose of Atorvastatin and oral dose of Ganoderma lucidum.
RESULTS
showed that administration of Atorvastatin and/or Ganoderma lucidum to mice bearing tumor, reduced tumor size, increased MDA level and decreased GSH, SOD and CAT levels in tumor tissues. Histopathological study showed high attenuation in tumor cells associated with antiangiogenesis illustrated by extravasation of blood vessels between tumor cells. Immunohistochemical study demonstrated high reduction of the angiogenic marker Vascular endothelial growth factor (VEGF) with remarkable increase of the apoptotic protein markers cytochrome-c and caspase-3. Conclusion: Atorvastatin and Ganoderma lucidum may have anticancer, apoptotic and antiangiogenic activities by reducing tumor growth in Ehrlich solid tumor. Their antitumor effect is exerted through the antiangiogenesis effect in tumor cells which is confirmed by the decrease of the angiogenic marker (VEGF protein) as well as by inducing significant increase in the apoptotic protein markers cytochrome-c and caspase-3. It is noticeable that the antitumor activity is ameliorated by the combination of the two treatments.
Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Atorvastatin; Caspase 3; Disease Models, Animal; Drugs, Chinese Herbal; Female; Mice; Reishi; Vascular Endothelial Growth Factor A
PubMed: 33906301
DOI: 10.31557/APJCP.2021.22.4.1095 -
Medicine Nov 2023We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness of low-intensity atorvastatin 5 mg and ezetimibe 10 mg combination therapy compared with moderate-intensity atorvastatin 10 mg monotherapy: A randomized, double-blinded, multi-center, phase III study.
BACKGROUND
We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients requiring cholesterol-lowering therapy.
METHODS
At 19 centers in Korea, 290 patients were randomized to 4 groups: atorvastatin 5 mg and ezetimibe 10 mg (A5E), ezetimibe 10 mg (E), atorvastatin 5 mg (A5), and atorvastatin 10 mg (A10). Clinical and laboratory examinations were performed at baseline, and at 4-week and 8-week follow-ups. The primary endpoint was percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. Secondary endpoints included percentage changes from baseline in additional lipid parameters.
RESULTS
Baseline characteristics were similar among the study groups. At the 8-week follow-up, percentage changes in LDL cholesterol levels were significantly greater in the A5E group (49.2%) than in the E (18.7%), A5 (27.9%), and A10 (36.4%) groups. Similar findings were observed regarding the percentage changes in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. Triglyceride levels were also significantly decreased in the A5E group than in the E group, whereas high-density lipoprotein levels substantially increased in the A5E group than in the E group. In patients with low- and intermediate-cardiovascular risk, 93.3% achieved the target LDL cholesterol levels in the A5E group, 40.0% in the E group, 66.7% in the A5 group, and 92.9% in the A10 group. In addition, 31.4% of patients in the A5E group, 8.1% in E, 9.7% in A5, and 7.3% in the A10 group reached the target levels of both LDL cholesterol < 70 mg/dL and reduction of LDL ≥ 50% from baseline.
CONCLUSIONS
The addition of ezetimibe to low-intensity atorvastatin had a greater effect on lowering LDL cholesterol than moderate-intensity atorvastatin alone, offering an effective treatment option for cholesterol management, especially in patients with low and intermediate risks.
Topics: Humans; Atorvastatin; Anticholesteremic Agents; Cholesterol, LDL; Hypercholesterolemia; Azetidines; Heptanoic Acids; Pyrroles; Drug Therapy, Combination; Ezetimibe; Cholesterol; Treatment Outcome; Double-Blind Method; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 38013289
DOI: 10.1097/MD.0000000000036122 -
Pathology Oncology Research : POR Jan 2020Atorvastatin is the most prescribed cholesterol-lowering statin, while caffeine enhances chemo-sensitivity and induces apoptosis of tumor cells through its DNA...
Atorvastatin is the most prescribed cholesterol-lowering statin, while caffeine enhances chemo-sensitivity and induces apoptosis of tumor cells through its DNA repair-inhibiting effect. The present study investigated the effects and mechanisms of atorvastatin and caffeine in combination on human prostate cancer cells cultured in vitro. Cell growth were determined by the trypan blue exclusion assay. The cell apoptosis and colony formation were determined by morphological assessment. The ability of cell migration and invasion were performed using a scratch wound-healing and Transwell assay. Tumorspheres were formed in suspension under the condition of non-adherence and serum-free medium. Finally, the western blot assay was used to determine the levels of proteins. The combination synergistically suppressed proliferation and induced apoptotic death. Meanwhile, the migration, invasion, and the formation of tumorspheres were significantly inhibited by the combination. We found that atorvastatin and caffeine in combination downregulated phospho-Akt, phospho-Erk1/2, anti-apoptotic Bcl-2 and Survivin protein levels. Results of the present study indicate treatment with the combination of caffeine and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.
Topics: Apoptosis; Atorvastatin; Caffeine; Cell Movement; Cell Proliferation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; PC-3 Cells; Phosphodiesterase Inhibitors; Prostatic Neoplasms
PubMed: 29796873
DOI: 10.1007/s12253-018-0415-7 -
Revista Medica Del Instituto Mexicano... Oct 2023Atorvastatin has been used in the management of dyslipidemia and little is known about the efficacy and safety of high-dose atorvastatin administration for secondary... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Atorvastatin has been used in the management of dyslipidemia and little is known about the efficacy and safety of high-dose atorvastatin administration for secondary prevention of Major Cardiovascular Events (MACE).
OBJECTIVE
To evaluate the impact of high-dose atorvastatin on secondary prevention of MACE and adverse events.
MATERIAL AND METHODS
A systematic review and meta-analysis of Pubmed, Embase, Bireme and Cochrane Library Plus databases was performed, with a time scope from 1990 to July 2022. Six randomized clinical trials were included with a total of 29,333 patients who were treated with 80 mg, 10 mg or placebo doses of Atorvastatin where the main outcomes evaluated were Major Cardiovascular Events (MACE), mortality and treatment safety.
RESULTS
In the comparative study between the use of Atorvastatin 80 mg and other therapies, a relative risk (RR) of 0.8 (95%CI 0.69-0.92) was found, representing a 20% reduction in risk (RRR) and a number needed to treat (NNT) of 30-55. In the analysis of adverse effects, an RR of 2.37 (95% CI 0.86-6.53) and a number needed to harm (NNH) of 14-19 were observed. The use of 80 mg atorvastatin is associated with similar adverse events at lower doses.
CONCLUSIONS
The use of atorvastatin 80 mg is effective in the secondary prevention of Major Cardiovascular Event (MACE). The drug has adverse events that should be taken into account in secondary prevention.
Topics: Humans; Atorvastatin; Cardiovascular Diseases
PubMed: 37934798
DOI: 10.5281/zenodo.8319748