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FASEB Journal : Official Publication of... Apr 2022Neuronal apoptosis is one of the main pathological processes of hypoxic-ischemic brain damage (HIBD) and is involved in the development of hypoxic-ischemic...
Neuronal apoptosis is one of the main pathological processes of hypoxic-ischemic brain damage (HIBD) and is involved in the development of hypoxic-ischemic encephalopathy (HIE) in neonates. Atorvastatin has been found to have neuroprotective effects in some nervous system diseases, but its role in regulating the pathogenesis of neonatal HIBD remains elusive. Thus, this study aimed to explore the effects and related mechanisms of atorvastatin on the regulation of neuronal apoptosis after HIBD in newborn rats. The rat HIBD model and the neuronal oxygen glucose deprivation (OGD) model were established routinely. Atorvastatin, cAMP inhibitor (SQ22536), and BDNF inhibitor (ANA-12) were used to treat HIBD rats and OGD neurons. Cerebral infarction, learning and memory ability, cAMP/PKA/p-CREB/BDNF signaling molecules, and apoptosis-related indicators (TUNEL, cleaved caspase-3, and Bax/Bcl2) were then examined. In vivo, atorvastatin reduced cerebral infarction, improved learning and memory ability, decreased the number of TUNEL-positive neurons, inhibited the expression of cleaved caspase-3 and Bax/Bcl2, and activated the cAMP/PKA/p-CREB/BDNF pathway in the cerebral cortex after HIBD. In vitro, atorvastatin also decreased the apoptosis-related indicators and activated the cAMP/PKA/p-CREB/BDNF pathway in neurons after OGD. Furthermore, inhibition of cAMP or BDNF attenuated the effect of atorvastatin on the reduction of neuronal apoptosis, suggesting that atorvastatin inhibits HIBD-induced neuronal apoptosis and alleviates brain injury in neonatal rats mainly by activating the cAMP/PKA/p-CREB/BDNF pathway. In conclusion, atorvastatin may be developed as a potential drug for the treatment of neonatal HIE.
Topics: Animals; Animals, Newborn; Apoptosis; Atorvastatin; Brain-Derived Neurotrophic Factor; Caspase 3; Cerebral Infarction; Hypoxia; Hypoxia-Ischemia, Brain; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; bcl-2-Associated X Protein
PubMed: 35303316
DOI: 10.1096/fj.202101654RR -
JAMA Neurology Nov 2018Chronic subdural hematoma (CSDH) is a trauma-associated condition commonly found in elderly patients. Surgery is currently the treatment of choice, but it carries a... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Chronic subdural hematoma (CSDH) is a trauma-associated condition commonly found in elderly patients. Surgery is currently the treatment of choice, but it carries a significant risk of recurrence and death. Nonsurgical treatments remain limited and ineffective. Our recent studies suggest that atorvastatin reduces hematomas and improves the clinical outcomes of patients with CSDH.
OBJECTIVE
To investigate the safety and therapeutic efficacy of atorvastatin to nonsurgically treat patients with CSDH.
DESIGN, SETTING, AND PARTICIPANTS
The Effect of Atorvastatin on Chronic Subdural Hematoma (ATOCH) randomized, placebo-controlled, double-blind phase II clinical trial was conducted in multiple centers in China from February 2014 to November 2015. For this trial, we approached 254 patients with CSDH who received a diagnosis via a computed tomography scan; of these, 200 (78.7%) were enrolled because 23 patients (9.1%) refused to participate and 31 (12.2%) were disqualified.
INTERVENTIONS
Patients were randomly assigned to receive either 20 mg of atorvastatin or placebo daily for 8 weeks and were followed up for an additional 16 weeks.
MAIN OUTCOMES AND MEASURES
The primary outcome was change in hematoma volume (HV) by computed tomography after 8 weeks of treatment. The secondary outcomes included HV measured at the 4th, 12th, and 24th weeks and neurological function that was evaluated using the Markwalder grading scale/Glasgow Coma Scale and the Barthel Index at the 8th week.
RESULTS
One hundred ninety-six patients received treatment (169 men [86.2%]; median [SD] age, 63.6 [14.2] years). The baseline HV and clinical presentations were similar between patients who were taking atorvastatin (98 [50%]) and the placebo (98 [50%]). After 8 weeks, the HV reduction in patients who were taking atorvastatin was 12.55 mL more than those taking the placebo (95% CI, 0.9-23.9 mL; P = .003). Forty-five patients (45.9%) who were taking atorvastatin significantly improved their neurological function, but only 28 (28.6%) who were taking the placebo did, resulting in an adjusted odds ratio of 1.957 for clinical improvements (95% CI, 1.07-3.58; P = .03). Eleven patients (11.2%) who were taking atorvastatin and 23 (23.5%) who were taking the placebo underwent surgery during the trial for an enlarging hematoma and/or a deteriorating clinical condition (hazard ratio, 0.47; 95% CI, 0.24-0.92; P = .03). No significant adverse events were reported.
CONCLUSIONS AND RELEVANCE
Atorvastatin may be a safe and efficacious nonsurgical alternative for treating patients with CSDH.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02024373.
Topics: Aged; Atorvastatin; China; Double-Blind Method; Female; Hematoma, Subdural, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Outcome Assessment, Health Care
PubMed: 30073290
DOI: 10.1001/jamaneurol.2018.2030 -
The Annals of Pharmacotherapy Oct 2021
Topics: Atorvastatin; Gynecomastia; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male
PubMed: 33472378
DOI: 10.1177/1060028021988994 -
Andrologia Jul 2022Atorvastatin may be an effective treatment for erectile dysfunction (ED). The purpose of this meta-analysis was to determine whether atorvastatin therapy is effective in... (Meta-Analysis)
Meta-Analysis Review
Atorvastatin may be an effective treatment for erectile dysfunction (ED). The purpose of this meta-analysis was to determine whether atorvastatin therapy is effective in the treatment of ED. All published research on atorvastatin in the treatment of ED patients in EMBASE, PubMed, Web of Science and Cochrane were investigated till 30 October 2021. A meta-analysis of randomized controlled trials (RCTs) was done to investigate the efficacy of atorvastatin and placebo in the treatment of ED. Moreover, we also performed a meta-analysis based on single-arm trials (SATs) to explore the atorvastatin treatment on the efficacy of ED. In a meta-analysis based on RCTs, the weighted mean difference of the change of International Index for Erectile Function-5 (IIEF-5) score in the atorvastatin treatment group with or without treatment was 4.53 (95 per cent confidence interval [CI] of 3.28-5.79) higher than in the control group. In an SAT-based meta-analysis, the ES of the change in IIEF-5 score in the atorvastatin treatment group before and after treatment was 3.22 (95 per cent CI of 1.32-5.12). Atorvastatin is an effective therapeutic drug for patients with ED. However, we expect that more multicentre clinical trials will be conducted to support this assertion.
Topics: Atorvastatin; Erectile Dysfunction; Humans; Male; Penile Erection; Treatment Outcome
PubMed: 35224753
DOI: 10.1111/and.14408 -
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 -
Journal of AOAC International May 2019Atorvastatin, a lipid-regulating drug, was the best-selling drug in the world in the early 2000s. Thus, monitoring of this drug is important because it is accessible to... (Review)
Review
Atorvastatin, a lipid-regulating drug, was the best-selling drug in the world in the early 2000s. Thus, monitoring of this drug is important because it is accessible to a large portion of the population. In addition, its quality control is fundamental to provide quality medicines. Method of analysis can be the first step in the rational use of pharmaceuticals. In this context, a critical review of analytical methods present in the literature and official compendia for the pharmaceutical quality control of atorvastatin was made. Among the analytical methods most used in the evaluation of atorvastatin, HPLC is highlighted, followed by HPLC coupled to MS, and spectrophotometry in UV. Tablets are the most studied pharmaceutical samples, and plasma is the most studied biological matrix. In the literature, studies with atorvastatin-based pharmaceutical products are more common than biological materials. Acetonitrile is the organic solvent most commonly used in the methods surveyed to evaluate atorvastatin. Currently, awareness of the impact that the analytical choice has on the health of the operator and the environment is growing. Therefore, the suitability of existing methods for the determination of atorvastatin can be made to adhere to the current analytical chemistry. In this way, the analytical, environmental, and human consciousness will remain united. Although the literature shows interesting methods from an economic and environmental point of view, such as UV, Vis miniaturized, and TLC, they can still be improved to meet the requirements of the current sustainable analytical chemistry.
Topics: Acetonitriles; Anticholesteremic Agents; Atorvastatin; Chemistry Techniques, Analytical; Drug Monitoring; Green Chemistry Technology; Humans; Occupational Health; Quality Control; Tablets
PubMed: 30563586
DOI: 10.5740/jaoacint.18-0200 -
Biomedicine & Pharmacotherapy =... Oct 2023As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular...
As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases.
Topics: Mice; Animals; Atorvastatin; Endothelial Cells; Ubiquitination; Ubiquitin-Protein Ligases; Mice, Knockout; Hypertension
PubMed: 37557013
DOI: 10.1016/j.biopha.2023.115228 -
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 2021Atorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of...
Atorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of Ate. Male Sprague Dawley (SD) rats were fed a high-fat diet for seven months and used as a hyperlipidemia model. The lipid level and liver function of the hyperlipidemia rats were studied by the levels of TG, TC, LDL, HDL, ALT, and AST in serum after intragastric administration with different doses of Ate. HE staining was used to observe the pathological changes of the rat liver and gastrocnemius muscle. The lipid deposits in the liver of rats were observed by staining with ORO. The genes in the rat liver were sequenced by RNA-sequencing. The results of the RNA-sequencing were further examined by qRT-PCR and western blotting. Biochemical test results indicated that Ate could obviously improve the metabolic disorder and reduce both the ALT and AST levels in serum of the hyperlipidemia rats. Pathological results showed that Ate could improve HFD-induced lipid deposition and had no muscle toxicity. The RNA-sequencing results suggested that Ate affected liver lipid metabolism and cholesterol, metabolism in the hyperlipidemia-model rats may vary via the PPAR-signaling pathway. The western blotting and qRT-PCR results demonstrated the Ate-regulated lipid metabolism in the hyperlipidemia model through the PPAR-signaling pathway and HMGCR expression. In brief, Ate can significantly regulate the blood lipid level of the model rats, which may be achieved by regulating the PPAR-signaling pathway and HMGCR gene expression.
Topics: Animals; Anticholesteremic Agents; Atorvastatin; Body Weight; Diet, High-Fat; Gene Expression Regulation; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipid Metabolism; Liver; Male; PPAR gamma; Rats, Sprague-Dawley; Signal Transduction; Rats
PubMed: 34681767
DOI: 10.3390/ijms222011107 -
Medical Oncology (Northwood, London,... Dec 2022Cancer is one of the most challenging diseases to manage. A sizeable number of researches are done each year to find better diagnostic and therapeutic strategies. At the... (Review)
Review
Cancer is one of the most challenging diseases to manage. A sizeable number of researches are done each year to find better diagnostic and therapeutic strategies. At the present time, a package of chemotherapy, targeted therapy, radiotherapy, and immunotherapy is available to cope with cancer cells. Regarding chemo-radiation therapy, low effectiveness and normal tissue toxicity are like barriers against optimal response. To remedy the situation, some agents have been proposed as adjuvants to improve tumor responses. Statins, the known substances for reducing lipid, have shown a considerable capability for cancer treatment. Among them, atorvastatin as a reductase (HMG-CoA) inhibitor might affect proliferation, migration, and survival of cancer cells. Since finding an appropriate adjutant is of great importance, numerous studies have been conducted to precisely unveil antitumor effects of atorvastatin and its associated pathways. In this review, we aim to comprehensively review the most highlighted studies which focus on the use of atorvastatin in cancer therapy.
Topics: Humans; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunotherapy; Radiation Oncology; Adjuvants, Immunologic; Neoplasms
PubMed: 36459301
DOI: 10.1007/s12032-022-01892-9