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1.
BMC Cardiovasc Disord ; 24(1): 245, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38730371

ABSTRACT

BACKGROUND: The 2013 ACC/AHA Guideline was a paradigm shift in lipid management and identified the four statin-benefit groups. Many have studied the guideline's potential impact, but few have investigated its potential long-term impact on MACE. Furthermore, most studies also ignored the confounding effect from the earlier release of generic atorvastatin in Dec 2011. METHODS: To evaluate the potential (long-term) impact of the 2013 ACC/AHA Guideline release in Nov 2013 in the U.S., we investigated the association of the 2013 ACC/AHA Guideline with the trend changes in 5-Year MACE survival and three other statin-related outcomes (statin use, optimal statin use, and statin adherence) while controlling for generic atorvastatin availability using interrupted time series analysis, called the Chow's test. Specifically, we conducted a retrospective study using U.S. nationwide de-identified claims and electronic health records from Optum Labs Database Warehouse (OLDW) to follow the trends of 5-Year MACE survival and statin-related outcomes among four statin-benefit groups that were identified in the 2013 ACC/AHA Guideline. Then, Chow's test was used to discern trend changes between generic atorvastatin availability and guideline potential impact. RESULTS: 197,021 patients were included (ASCVD: 19,060; High-LDL: 33,907; Diabetes: 138,159; High-ASCVD-Risk: 5,895). After the guideline release, the long-term trend (slope) of 5-Year MACE Survival for the Diabetes group improved significantly (P = 0.002). Optimal statin use for the ASCVD group also showed immediate improvement (intercept) and long-term positive changes (slope) after the release (P < 0.001). Statin uses did not have significant trend changes and statin adherence remained unchanged in all statin-benefit groups. Although no other statistically significant trend changes were found, overall positive trend change or no changes were observed after the 2013 ACC/AHA Guideline release. CONCLUSIONS: The 2013 ACA/AHA Guideline release is associated with trend improvements in the long-term MACE Survival for Diabetes group and optimal statin use for ASCVD group. These significant associations might indicate a potential positive long-term impact of the 2013 ACA/AHA Guideline on better health outcomes for primary prevention groups and an immediate potential impact on statin prescribing behaviors in higher-at-risk groups. However, further investigation is required to confirm the causal effect of the 2013 ACA/AHA Guideline.


Subject(s)
Guideline Adherence , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Interrupted Time Series Analysis , Practice Guidelines as Topic , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , United States , Time Factors , Retrospective Studies , Male , Female , Aged , Middle Aged , Treatment Outcome , Guideline Adherence/standards , Biomarkers/blood , Dyslipidemias/drug therapy , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/mortality , Dyslipidemias/epidemiology , Atorvastatin/therapeutic use , Atorvastatin/adverse effects , Cardiovascular Diseases/mortality , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/blood , Databases, Factual , Practice Patterns, Physicians'/standards , Cholesterol/blood , Medication Adherence , Drugs, Generic/therapeutic use , Drugs, Generic/adverse effects , Risk Assessment
2.
Int J Mol Sci ; 25(10)2024 May 15.
Article in English | MEDLINE | ID: mdl-38791422

ABSTRACT

The effectiveness of lipid-lowering therapies may be insufficient in high-risk cardiovascular patients and depends on the genetic variability of drug-metabolizing enzymes. Customizing statin therapy, including treatment with atorvastatin, may improve clinical outcomes. Currently, there is a lack of guidelines allowing the prediction of the therapeutic efficacy of lipid-lowering statin therapy. This study aimed to determine the effects of clinically significant gene variants of CYP2C19 on atorvastatin therapy in patients with acute coronary syndromes. In total, 92 patients with a confirmed diagnosis of ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI) were sequenced for target regions within the CYP2C19 gene on the Illumina Miniseq system. The CYP2C19 poor metabolizer phenotype (carriers of CYP2C19*2, CYP2C19*4, and CYP2C19*8 alleles) was detected in 29% of patients. These patients had significantly lower responses to treatment with atorvastatin than patients with the normal metabolizer phenotype. CYP2C19-metabolizing phenotype, patient age, and smoking increased the odds of undertreatment in patients (∆LDL-C (mmol/L) < 1). These results revealed that the CYP2C19 phenotype may significantly impact atorvastatin therapy personalization in patients requiring LDL lipid-lowering therapy.


Subject(s)
Acute Coronary Syndrome , Atorvastatin , Cytochrome P-450 CYP2C19 , Humans , Cytochrome P-450 CYP2C19/genetics , Atorvastatin/therapeutic use , Female , Male , Acute Coronary Syndrome/drug therapy , Acute Coronary Syndrome/genetics , Middle Aged , Aged , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Alleles
3.
Medicine (Baltimore) ; 103(19): e38122, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38728464

ABSTRACT

BACKGROUND: Statins are the first-line treatment for dyslipidemia, which is a major modifiable risk factor for atherosclerotic cardiovascular disease. Studies have shown that in addition to the beneficial lipid-lowering effect, statins also exhibit a number of pleiotropic effects that may find application in other diseases, including osteoporosis. This study aimed to assess the effect of statins on bone turnover, as measured by the concentration of bone turnover markers, and to compare the effect of atorvastatin as a lipophilic statin and rosuvastatin as a hydrophilic statin. METHODS: This study included 34 postmenopausal women aged < 65 years with newly diagnosed dyslipidemia requiring statin therapy. Patients were randomly assigned to receive a statin drug. Statins were initiated at standard doses of 5 to 10 mg of rosuvastatin and 20 mg of atorvastatin. The levels of C-terminal telopeptide of type I collagen as a bone resorption marker and N-terminal propeptide of procollagen type I as a marker of bone formation, lipid concentrations and other biochemical parameters were assessed at baseline and after 6 and twelve months of treatment. RESULTS: There were no statistically significant differences between the levels of bone turnover markers before and 6 months after statin implementation (P > .05) - for all patients or subgroups according to statin use. Analysis of the results showed that after 12 months, there was a statistically significant decrease in N-terminal propeptide of procollagen type I concentration in all subjects (P = .004). By statin subgroup, a statistically significant decrease in N-terminal propeptide of procollagen type I was observed only in patients receiving rosuvastatin (P = .012) and not in those receiving atorvastatin (P = .25). Moreover, changes in bone turnover markers did not correlate with changes in lipid concentrations. CONCLUSIONS: These results may indicate the superiority of atorvastatin over rosuvastatin in inhibiting adverse changes in bone turnover in postmenopausal women. Confirmed by studies involving a larger population, the observed differences might find particular applications in clinical practice, and the choice of atorvastatin over rosuvastatin for women could be considered in the early postmenopausal period to reduce the risk of osteoporosis and subsequent osteoporotic fractures.


Subject(s)
Atorvastatin , Bone Remodeling , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Postmenopause , Rosuvastatin Calcium , Humans , Rosuvastatin Calcium/therapeutic use , Rosuvastatin Calcium/administration & dosage , Female , Atorvastatin/therapeutic use , Atorvastatin/pharmacology , Middle Aged , Bone Remodeling/drug effects , Postmenopause/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Biomarkers/blood , Collagen Type I/blood , Osteoporosis, Postmenopausal/drug therapy , Dyslipidemias/drug therapy , Dyslipidemias/blood
4.
Respir Res ; 25(1): 213, 2024 May 18.
Article in English | MEDLINE | ID: mdl-38762465

ABSTRACT

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.


Subject(s)
Diet, High-Fat , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Mice, Inbred C57BL , Mice, Transgenic , Obesity , Pulmonary Fibrosis , Animals , Male , Diet, High-Fat/adverse effects , Obesity/drug therapy , Obesity/metabolism , Mice , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Pulmonary Fibrosis/prevention & control , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/drug therapy , PCSK9 Inhibitors , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Mice, Obese , Proprotein Convertase 9/metabolism , Proprotein Convertase 9/genetics , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Bronchial Hyperreactivity/prevention & control , Bronchial Hyperreactivity/drug therapy , Bronchial Hyperreactivity/metabolism , Bronchial Hyperreactivity/physiopathology , Antibodies, Monoclonal, Humanized
5.
Medicine (Baltimore) ; 103(21): e37883, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38788020

ABSTRACT

BACKGROUND: Hyperlipidemia is a common feature of chronic diseases. The aim of this work was designed to assess the role of probiotics (Lactobacillus casei Zhang, Bifidobactetium animalis subsp. lactis V9, and Lactobacillus plantarum P-8) in the treatment of hyperlipidemia. METHODS: Thirty three patients with hyperlipidemia were randomly divided into a probiotic group (n = 18) and a control group (n = 15). The probiotic group was administered probiotics (2 g once daily) and atorvastatin 20 mg (once daily), and the control group was administered a placebo (2 g once daily) and atorvastatin 20 mg (once daily). Serum and fecal samples were gathered for subsequent analyses. RESULTS: Time had a significant effect on the total cholesterol (TC), triglycerides (TG), and low-density lipoprotein-cholesterol (LDL-C) levels in the probiotic and control groups (P < .05). The gut microbial abundance in the probiotic group was markedly higher than that in the control group following 3-month probiotic treatment (P < .05). At the phylum level, probiotics exerted no notable effects on the relative abundance of Firmicutes, Bacteroidetes, and Actinobacteria but elevated that of Tenericutes and reduced Proteobacteria. At the genus level, probiotics increased the relative abundance of Bifidobacterium, Lactobacillus, and Akkermansia, and decreased that of Escherichia, Eggerthella, and Sutterella relative to the control group in months 1, 2, and 3 (P < .05). CONCLUSIONS: Probiotics optimize the gut microbiota structure and decrease the amount of harmful bacteria in patients with hyperlipidemia. Probiotics can influence the composition of gut microorganisms and increase their diversity and abundance in vivo. It is recommended to use probiotics combined with atorvastatin to treat patients with hyperlipidemia.


Subject(s)
Atorvastatin , Gastrointestinal Microbiome , Hyperlipidemias , Probiotics , Humans , Atorvastatin/administration & dosage , Atorvastatin/therapeutic use , Probiotics/administration & dosage , Probiotics/therapeutic use , Hyperlipidemias/drug therapy , Double-Blind Method , Male , Female , Middle Aged , Gastrointestinal Microbiome/drug effects , Adult , Treatment Outcome , Triglycerides/blood , Cholesterol, LDL/blood , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/therapeutic use , Lactobacillus plantarum , Feces/microbiology , Aged , Combined Modality Therapy
6.
Lipids Health Dis ; 23(1): 106, 2024 Apr 14.
Article in English | MEDLINE | ID: mdl-38616260

ABSTRACT

BACKGROUND: Dyslipidemia, a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), is influenced by genetic variations, particularly those in the low-density lipoprotein receptor (LDLR) gene. This study aimed to elucidate the effects of LDLR polymorphisms on baseline serum lipid levels and the therapeutic efficacy of atorvastatin in an adult Han population in northern China with dyslipidemia. METHODS: In this study, 255 Han Chinese adults receiving atorvastatin therapy were examined and followed up. The 3' untranslated region (UTR) of the LDLR gene was sequenced to identify polymorphisms. The associations between gene polymorphisms and serum lipid levels, as well as changes in lipid levels after intervention, were evaluated using the Wilcoxon rank sum test, with a P < 0.05 indicating statistical significance. Assessment of linkage disequilibrium patterns and haplotype structures was conducted utilizing Haploview. RESULTS: Eleven distinct polymorphisms at LDLR 3' UTR were identified. Seven polymorphisms (rs1433099, rs14158, rs2738466, rs5742911, rs17249057, rs55971831, and rs568219285) were correlated with the baseline serum lipid levels (P < 0.05). In particular, four polymorphisms (rs14158, rs2738466, rs5742911, and rs17249057) were in strong linkage disequilibrium (r2 = 1), and patients with the AGGC haplotype had higher TC and LDL-C levels at baseline. Three polymorphisms (rs1433099, rs2738467, and rs7254521) were correlated with the therapeutic efficacy of atorvastatin (P < 0.05). Furthermore, carriers of the rs2738467 T allele demonstrated a significantly greater reduction in low-density lipoprotein cholesterol (LDL-C) levels post-atorvastatin treatment (P = 0.03), indicating a potentially crucial genetic influence on therapeutic outcomes. Two polymorphisms (rs751672818 and rs566918949) were neither correlated with the baseline serum lipid levels nor atorvastatin's efficacy. CONCLUSIONS: This research outlined the complex genetic architecture surrounding LDLR 3' UTR polymorphisms and their role in lipid metabolism and the response to atorvastatin treatment in adult Han Chinese patients with dyslipidemia, highlighting the importance of genetic profiling in enhancing tailored therapeutic strategies. Furthermore, this investigation advocates for the integration of genetic testing into the management of dyslipidemia, paving the way for customized therapeutic approaches that could significantly improve patient care. TRIAL REGISTRATION: This multicenter study was approved by the Ethics Committee of Xiangya Hospital Central South University (ethics number K22144). It was a general ethic. In addition, this study was approved by The First Hospital of Hebei Medical University (ethics number 20220418).


Subject(s)
Dyslipidemias , Polymorphism, Genetic , Adult , Humans , Atorvastatin/therapeutic use , 3' Untranslated Regions/genetics , Cholesterol, LDL , Dyslipidemias/drug therapy , Dyslipidemias/genetics , China
7.
Int J Mol Sci ; 25(8)2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38674010

ABSTRACT

The solute carrier organic anion transporter family member 1B1 (SLCO1B1) encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in SLCO1B1, such as *5, cause altered systemic exposure to statins and therefore affect statin outcomes, with potential pharmacogenetic applications; yet, evidence is inconclusive. We studied common and rare SLCO1B1 variants in up to 64,000 patients from UK Biobank prescribed simvastatin or atorvastatin, combining whole-exome sequencing data with up to 25-year routine clinical records. We studied 51 predicted gain/loss-of-function variants affecting OATP1B1. Both SLCO1B1*5 alone and the SLCO1B1*15 haplotype increased LDL during treatment (beta*5 = 0.08 mmol/L, p = 6 × 10-8; beta*15 = 0.03 mmol/L, p = 3 × 10-4), as did the likelihood of discontinuing statin prescriptions (hazard ratio*5 = 1.12, p = 0.04; HR*15 = 1.05, p = 0.04). SLCO1B1*15 and SLCO1B1*20 increased the risk of General Practice (GP)-diagnosed muscle symptoms (HR*15 = 1.22, p = 0.003; HR*20 = 1.25, p = 0.01). We estimated that genotype-guided prescribing could potentially prevent 18% and 10% of GP-diagnosed muscle symptoms experienced by statin patients, with *15 and *20, respectively. The remaining common variants were not individually significant. Rare variants in SLCO1B1 increased LDL in statin users by up to 1.05 mmol/L, but replication is needed. We conclude that genotype-guided treatment could reduce GP-diagnosed muscle symptoms in statin patients; incorporating further SLCO1B1 variants into clinical prediction scores could improve LDL control and decrease adverse events, including discontinuation.


Subject(s)
Biological Specimen Banks , Exome Sequencing , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Liver-Specific Organic Anion Transporter 1 , Humans , Liver-Specific Organic Anion Transporter 1/genetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Exome Sequencing/methods , United Kingdom , Male , Female , Middle Aged , Aged , Simvastatin/therapeutic use , Treatment Outcome , Atorvastatin/therapeutic use , Polymorphism, Single Nucleotide , UK Biobank
8.
Neuroradiology ; 66(7): 1113-1122, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38587561

ABSTRACT

PURPOSE: To develop and validate a prediction model based on imaging data for the prognosis of mild chronic subdural hematoma undergoing atorvastatin treatment. METHODS: We developed the prediction model utilizing data from patients diagnosed with CSDH between February 2019 and November 2021. Demographic characteristics, medical history, and hematoma characteristics in non-contrast computed tomography (NCCT) were extracted upon admission to the hospital. To reduce data dimensionality, a backward stepwise regression model was implemented to build a prognostic prediction model. We calculated the area under the receiver operating characteristic curve (AUC) of the prognostic prediction model by a tenfold cross-validation procedure. RESULTS: Maximum thickness, volume, mean density, morphology, and kurtosis of the hematoma were identified as the most significant predictors of good hematoma dissolution in mild CSDH patients undergoing atorvastatin treatment. The prediction model exhibited good discrimination, with an area under the curve (AUC) of 0.82 (95% confidence interval [CI], 0.74-0.90) and good calibration (p = 0.613). The validation analysis showed the AUC of the final prognostic prediction model is 0.80 (95% CI 0.71-0.86) and it has good prediction performance. CONCLUSION: The imaging data-based prediction model has demonstrated great prediction accuracy for good hematoma dissolution in mild CSDH patients undergoing atorvastatin treatment. The study results emphasize the importance of imaging data evaluation in the management of CSDH patients.


Subject(s)
Atorvastatin , Hematoma, Subdural, Chronic , Tomography, X-Ray Computed , Humans , Atorvastatin/therapeutic use , Female , Hematoma, Subdural, Chronic/diagnostic imaging , Hematoma, Subdural, Chronic/drug therapy , Male , Tomography, X-Ray Computed/methods , Aged , Prognosis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Middle Aged , Retrospective Studies , Aged, 80 and over , Predictive Value of Tests
9.
Clin Cancer Res ; 30(11): 2370-2376, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38573708

ABSTRACT

PURPOSE: Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT; NCT01988571) randomized patients with breast cancer or lymphoma receiving anthracyclines to atorvastatin 40 mg daily or placebo. We evaluated the effects of atorvastatin on oxidative and nitrosative stress biomarkers, and explored whether these biomarkers could explain the lack of effect of atorvastatin on LVEF (left ventricular ejection fraction) in PREVENT. PATIENTS AND METHODS: Blood samples were collected and cardiac MRI was performed before doxorubicin initiation and at 6 and 24 months. Thirteen biomarkers [arginine-nitric oxide metabolites, paraoxonase-1 (PON-1) activity, and myeloperoxidase] were measured. Dimensionality reduction using principal component analysis was used to define biomarker clusters. Linear mixed-effects models determined the changes in biomarkers over time according to treatment group. Mediation analysis determined whether biomarker clusters explained the lack of effect of atorvastatin on LVEF. RESULTS: Among 202 participants with available biomarkers, median age was 53 years; 86.6% had breast cancer; median LVEF was 62%. Cluster 1 levels, reflecting arginine methylation metabolites, were lower over time with atorvastatin, although this was not statistically significant (P = 0.081); Cluster 2 levels, reflecting PON-1 activity, were significantly lower with atorvastatin (P = 0.024). There were no significant changes in other biomarker clusters (P > 0.05). Biomarker clusters did not mediate an effect of atorvastatin on LVEF (P > 0.05). CONCLUSIONS: Atorvastatin demonstrated very modest effects on oxidative/nitrosative stress biomarkers in this low cardiovascular risk population. Our findings provide potential mechanistic insight into the lack of effect of atorvastatin on LVEF in the PREVENT trial.


Subject(s)
Atorvastatin , Biomarkers , Breast Neoplasms , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Nitrosative Stress , Oxidative Stress , Humans , Female , Middle Aged , Oxidative Stress/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Nitrosative Stress/drug effects , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Male , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Aged , Adult , Doxorubicin/adverse effects , Aryldialkylphosphatase/metabolism , Arginine
10.
J Control Release ; 369: 591-603, 2024 May.
Article in English | MEDLINE | ID: mdl-38582336

ABSTRACT

Ischemia stroke is one of the leading causes of death and disability worldwide. Owing to the limited delivery efficiency to the brain caused by the blood-brain barrier (BBB) and off-target effects of systemic treatment, it is crucial to develop an in situ drug delivery system to improve the therapeutic effect in ischemic stroke. Briefly, we report a multifunctional in situ hydrogel delivery system for the co-delivery of reactive oxygen species (ROS)-responsive nanoparticles loaded with atorvastatin calcium (DSPE-se-se-PEG@AC NPs) and ß-nerve growth factor (NGF), which is expected to remodel pathological microenvironment for improving cerebral ischemia injury. The in vitro results exhibited the multifunctional hydrogel scavenged oxygen-glucose deprivation (OGD)-induced free radical, rescued the mitochondrial function, and maintained the survival and function of neurons, hence reducing neuronal apoptosis and neuroinflammation, consequently relieving ischemia injury in hippocampal neurons cell line (HT22). In the rat ischemia stroke model, the hydrogel significantly minified cerebral infarction by regulating inflammatory response, saving apoptotic neurons, and promoting angiogenesis and neurogenesis. Besides, the hydrogel distinctly improved the rats' neurological deficits after cerebral ischemia injury over the long-term observation. In conclusion, the in-situ hydrogel platform has demonstrated promising therapeutic effects in both in vitro and in vivo studies, indicating its potential as a new and effective therapy.


Subject(s)
Atorvastatin , Brain Ischemia , Hydrogels , Rats, Sprague-Dawley , Animals , Hydrogels/administration & dosage , Brain Ischemia/drug therapy , Male , Atorvastatin/administration & dosage , Atorvastatin/therapeutic use , Atorvastatin/pharmacology , Cell Line , Reactive Oxygen Species/metabolism , Nanoparticles/administration & dosage , Brain/drug effects , Brain/pathology , Brain/metabolism , Nerve Growth Factor/administration & dosage , Mice , Neurons/drug effects , Neurons/pathology , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/therapeutic use , Neuroprotective Agents/pharmacology , Rats , Apoptosis/drug effects , Polyethylene Glycols/chemistry , Polyethylene Glycols/administration & dosage , Drug Delivery Systems , Ischemic Stroke/drug therapy , Ischemic Stroke/pathology
11.
Eur J Histochem ; 68(2)2024 Apr 12.
Article in English | MEDLINE | ID: mdl-38619020

ABSTRACT

Aortic valve calcification (AVC) is a common cardiovascular disease and a risk factor for sudden death. However, the potential mechanisms and effective therapeutic drugs need to be explored. Atorvastatin is a statin that can effectively prevent cardiovascular events by lowering cholesterol levels. However, whether atorvastatin can inhibit AVC by reducing low-density lipoprotein (LDL) and its possible mechanism of action require further exploration. In the current study, we constructed an in vitro AVC model by inducing calcification of the valve interstitial cells. We found that atorvastatin significantly inhibited osteogenic differentiation, reduced the deposition of calcium nodules in valve interstitial cells, and enhanced autophagy in calcified valve interstitial cells, manifested by increased expression levels of the autophagy proteins Atg5 and LC3B-II/I and the formation of smooth autophagic flow. Atorvastatin inhibited the NF-κB signalling pathway and the expression of inflammatory factors mediated by NF-κB in calcified valve interstitial cells. The activation of the NF-κB signalling pathway led to the reversal of atorvastatin's effect on enhancing autophagy and alleviating valve interstitial cell calcification. In conclusion, atorvastatin inhibited the NF-κB signalling pathway by upregulating autophagy, thereby alleviating valve interstitial cell calcification, which was conducive to improving AVC.


Subject(s)
Aortic Valve Stenosis , Aortic Valve/pathology , Calcinosis , NF-kappa B , Osteogenesis , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Autophagy
12.
Pharm Dev Technol ; 29(3): 236-247, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38451055

ABSTRACT

Cancer ranks as one of the most challenging illnesses to deal with because progressive phenotypic and genotypic alterations in cancer cells result in resistance and recurrence. Thus, the creation of novel medications or alternative therapy approaches is mandatory. Repurposing of old drugs is an attractive approach over the traditional drug discovery process in terms of shorter drug development duration, low-cost, highly efficient and minimum risk of failure. In this study Atorvastatin, a statin drug used to treat abnormal cholesterol levels and prevent cardiovascular disease in people at high risk, was introduced and encapsulated in cubic liquid crystals as anticancer candidate aiming at sustaining its release and achieving better cellular uptake in cancer cells. The cubic liquid crystals were successfully prepared and optimized with an entrapment effieciency of 73.57% ±1.35 and particle size around 200 nm. The selected formulae were effectively doped with radioactive iodine 131I to enable the noninvasive visualization and trafficking of the new formulae. The in vivo evaluation in solid tumor bearing mice was conducted for comparing131I-Atorvastatin solution,131I-Atorvastatin loaded cubosome and 131I-Atorvastatin chitosan coated cubosome. The in vivo biodistribution study revealed that tumor radioactivity uptake of 131I-Atorvastatin cubosome and chitosan coated cubosome exhibited high accumulation in tumor tissues (target organ) scoring ID%/g of 5.67 ± 0.2 and 5.03 ± 0.1, respectively 1h post injection compared to drug solution which recorded 3.09 ± 0.05% 1h post injection. Concerning the targeting efficiency, the target/non target ratio for 131I-Atorvastatin chitosan coated cubosome was higher than that of 131I-Atorvastatin solution and 131I ATV-loaded cubosome at all time intervals and recorded T/NT ratio of 2.908 2h post injection.


Subject(s)
Breast Neoplasms , Chitosan , Thyroid Neoplasms , Humans , Mice , Animals , Female , Atorvastatin/therapeutic use , Breast Neoplasms/drug therapy , Chitosan/chemistry , Tissue Distribution , Iodine Radioisotopes , Particle Size , Drug Delivery Systems
13.
Acta Pharmacol Sin ; 45(6): 1316-1320, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38459255

ABSTRACT

Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg-1·d-1) and fenofibrate (100 mg·kg-1·d-1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia.


Subject(s)
Atherosclerosis , Disease Models, Animal , Hyperlipidemia, Familial Combined , Mice, Inbred C57BL , Mice, Transgenic , Animals , Atherosclerosis/drug therapy , Humans , Mice , Hyperlipidemia, Familial Combined/drug therapy , Hyperlipidemia, Familial Combined/genetics , Apolipoprotein C-III/genetics , Male , Proprotein Convertase 9/genetics , Proprotein Convertase 9/metabolism , Hypolipidemic Agents/therapeutic use , Hypolipidemic Agents/pharmacology , Triglycerides/blood , Diet, High-Fat , Atorvastatin/therapeutic use , Atorvastatin/pharmacology
15.
Sci Rep ; 14(1): 3559, 2024 02 12.
Article in English | MEDLINE | ID: mdl-38347043

ABSTRACT

This study aimed to investigate the predictive factors of therapeutic efficacy for chronic subdural hematoma (CSDH) patients receiving atorvastatin combined with dexamethasone therapy by using clinical imaging characteristics in conjunction with computed tomography (CT) texture analysis (CTTA). Clinical imaging characteristics and CT texture parameters at admission were retrospectively investigated in 141 CSDH patients who received atorvastatin combined with dexamethasone therapy from June 2019 to December 2022. The patients were divided into a training set (n = 81) and a validation set (n = 60). Patients in the training data were divided into two groups based on the effectiveness of the treatment. Univariate and multivariate analyses were performed to assess the potential factors that could indicate the prognosis of CSDH patients in the training set. The receiver operating characteristic (ROC) curve was used to analyze the predictive efficacy of the significant factors in predicting the prognosis of CSDH patients and was validated using a validation set. The multivariate analysis showed that the hematoma density to brain parenchyma density ratio, singal min (minimum) and singal standard deviation of the pixel distribution histogram, and inhomogeneity were independent predictors for the prognosis of CSDH patients based on atorvastatin and dexamethasone therapy. The area under the ROC curve between the two groups was between 0.716 and 0.806. As determined by significant factors, the validation's accuracy range was 0.816 to 0.952. Clinical imaging characteristics in conjunction with CTTA could aid in distinguishing patients with CSDH who responded well to atorvastatin combined with dexamethasone.


Subject(s)
Hematoma, Subdural, Chronic , Humans , Retrospective Studies , Atorvastatin/therapeutic use , Hematoma, Subdural, Chronic/diagnostic imaging , Hematoma, Subdural, Chronic/drug therapy , Tomography, X-Ray Computed , Dexamethasone/therapeutic use
16.
Leuk Lymphoma ; 65(6): 783-788, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38380861

ABSTRACT

STOP-CA was a multicenter, double-blind, randomized, placebo-controlled trial comparing atorvastatin to placebo in treatment-naïve lymphoma patients receiving anthracycline-based chemotherapy. We performed a preplanned subgroup to analyze the impact of atorvastatin on efficacy in patients with diffuse large B-cell lymphoma (DLBCL). Patients received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at standard doses for six 21-day cycles and were randomly assigned to receive atorvastatin 40 mg daily (n = 55) or placebo (n = 47) for 12 months. The complete response (CR) rate was numerically higher in the atorvastatin arm (95% [52/55] vs. 85% [40/47], p = .18), but this was not statistically significant. Adverse event rates were similar between the atorvastatin and placebo arms. In summary, atorvastatin did not result in a statistically significant improvement in the CR rate or progression-free survival, but both were numerically improved in the atorvastatin arm. These data warrant further investigation into the potential therapeutic role of atorvastatin added to anthracycline-based chemotherapies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Atorvastatin , Cyclophosphamide , Doxorubicin , Lymphoma, Large B-Cell, Diffuse , Prednisone , Rituximab , Vincristine , Humans , Atorvastatin/therapeutic use , Atorvastatin/administration & dosage , Atorvastatin/adverse effects , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Prednisone/therapeutic use , Prednisone/adverse effects , Prednisone/administration & dosage , Vincristine/therapeutic use , Vincristine/adverse effects , Rituximab/therapeutic use , Rituximab/adverse effects , Rituximab/administration & dosage , Doxorubicin/therapeutic use , Doxorubicin/adverse effects , Doxorubicin/administration & dosage , Cyclophosphamide/therapeutic use , Cyclophosphamide/adverse effects , Cyclophosphamide/administration & dosage , Male , Female , Middle Aged , Aged , Double-Blind Method , Treatment Outcome , Adult
17.
Mol Med Rep ; 29(3)2024 03.
Article in English | MEDLINE | ID: mdl-38299233

ABSTRACT

Metabolic dysfunction­associated steatotic liver disease (MASLD) is an increasingly significant global health burden for which there is currently no effective treatment. The present study aimed to explore the underlying mechanisms and investigate the effects of donafenib and atorvastatin in MASLD. The effects of donafenib and atorvastatin on the activity and lipid metabolism of HepG2 cells were analyzed in vitro. A rat model of MASLD was established induced by a high­fat diet in vivo. H&E and Oil red O staining were used to observe the improvement in MASLD, western blotting analysis was used to detect the expression of proteins related to fat metabolism and immunofluorescence was used to detect reactive oxygen species (ROS) levels. In vitro, donafenib and atorvastatin inhibited lipid accumulation in HepG2 cells. In vivo, donafenib and atorvastatin activated the AMP­activated protein kinase (AMPK) pathway, downregulated the expressions of proteins related to fatty acid synthesis (sterol regulatory element­binding protein­1, 3­hydroxy­3­methylglutaryl­CoA reductase and fatty acid synthase) and upregulated the expression of proteins related to fatty acid ß­oxidation (carnitine palmitoyl­transferase 1C and acyl­CoA oxidase). The levels of free fatty acids, cholesterol and triglycerides in the liver and serum decreased in all three treatment groups. Additionally, donafenib and atorvastatin reduced oxidative stress in the liver tissue and decreased ROS levels. Low­dose donafenib combined with atorvastatin improved MASLD by regulating fatty acid metabolism and reducing oxidative stress through activation of the AMPK signaling pathway.


Subject(s)
Metabolic Diseases , Non-alcoholic Fatty Liver Disease , Pyridines , Rats , Animals , Humans , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/complications , AMP-Activated Protein Kinases/metabolism , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Reactive Oxygen Species/metabolism , Diet, High-Fat/adverse effects , Liver/metabolism , Lipid Metabolism , Hep G2 Cells , Metabolic Diseases/complications
18.
Metabolism ; 153: 155794, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38301843

ABSTRACT

BACKGROUND: Glioblastoma is one of the deadliest tumors, and limited improvement in managing glioblastoma has been achieved in the past decades. The unmethylated promoter area of 6-O-Methylguanine-DNA Methyltransferase (MGMT) is a significant biomarker for recognizing a subset of glioblastoma that is resistant to chemotherapy. Here we identified MGMT methylation can also work as a specific biomarker to classify the lipid metabolism patterns between methylated and unmethylated glioblastoma and verify the potential novel therapeutic strategy for unmethylated MGMT glioblastoma. METHODS: Liquid Chromatograph Mass Spectrometer has been applied for non-targeted metabolome and targeted lipidomic profiling to explore the metabolism pattern correlated with MGMT promoter methylation. Transcriptome has been performed to explore the biological differences and the potential mechanism of lipid metabolism in glioblastoma samples. In vivo and ex vivo assays were performed to verify the anti-tumor activity of atorvastatin in the administration of glioblastoma. RESULTS: Multi-omics assay has described a significant difference in lipid metabolism between MGMT methylated and unmethylated glioblastoma. Longer and unsaturated fatty acyls were found enriched in MGMT-UM tumors. Lipid droplets have been revealed remarkably decreased in MGMT unmethylated glioblastoma. In vivo and ex vivo assays revealed that atorvastatin and also together with temozolomide showed significant anti-tumor activity, and atorvastatin alone was able to achieve better survival and living conditions for tumor-hosting mice. CONCLUSIONS: MGMT promoter methylation status might be a well-performed biomarker of lipid metabolism in glioblastoma. The current study can be the basis of further mechanism studies and implementation of clinical trials, and the results provide preclinical evidence of atorvastatin administration in glioblastoma, especially for MGMT unmethylated tumors.


Subject(s)
Brain Neoplasms , Glioblastoma , Animals , Mice , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/pathology , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Lipid Metabolism/genetics , Feasibility Studies , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , DNA Methylation , Biomarkers
19.
Cell Metab ; 36(2): 408-421.e5, 2024 02 06.
Article in English | MEDLINE | ID: mdl-38325336

ABSTRACT

Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.


Subject(s)
Glucose Intolerance , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Insulin Resistance , Microbiota , Humans , Animals , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Glucagon-Like Peptide 1 , Glucose Intolerance/drug therapy , Bile Acids and Salts , Ursodeoxycholic Acid/pharmacology , Ursodeoxycholic Acid/therapeutic use
20.
J Affect Disord ; 349: 342-348, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38199416

ABSTRACT

BACKGROUND: Depression is a common mental disorder. Some studies have demonstrated that people with diabetes are more likely to suffer from depression. Statins are an everyday use for diabetes. Trials of statin therapy have had conflicting findings on the potential risk of depression. METHODS: The National Health and Nutrition Examination Survey (NHANES) 2005-2018 was used to collect a representative sample. Weighted multivariate logistic regression models were used to evaluate odds ratios (ORs) and 95 % CIs for having depression symptoms. We performed stratified analyses to compare the effects of statins in subsamples with and without diabetes on depression symptoms. RESULTS: Statin use showed a significant and strong decreasing effect on having depression symptoms in participants with diabetes (aOR (adjusted OR) 0.59, p = 0.014) compared with that in non-diabetics (aOR 0.78, p = 0.128). Diabetic individuals with statin use for >5 years had a lower risk of having depression symptoms (aOR 0.42, p = 0.002) than those with shorter-term statin use (1-5 years, aOR 0.69, p = 0.111; <1 year: aOR 0.83, p = 0.646). Atorvastatin was more effective in decreasing depression symptoms either in diabetes (aOR 0.49, p = 0.018) or in non-diabetes (aOR 0.58, p = 0.033). LIMITATIONS: First, the dosage of statins cannot be obtained from NHANES datasets. Second, after being stratified, the number of participants for several statins was insufficient. Third, recall bias may exist in the survey. CONCLUSIONS: Diabetics with depression symptoms may benefit from long-term statin therapy. Atorvastatin and pravastatin should be recommended for diabetic patients with depression.


Subject(s)
Diabetes Mellitus , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Atorvastatin/therapeutic use , Nutrition Surveys , Depression/drug therapy , Depression/epidemiology , Diabetes Mellitus/drug therapy , Diabetes Mellitus/epidemiology
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