The effects of simvastatin-loaded nanoliposomes on human multilineage liver fibrosis microtissue.

In this in vitro study, for the first time, we evaluate the effects of simvastatin-loaded liposome nanoparticles (SIM-LipoNPs) treatment on fibrosis-induced liver microtissues, as simvastatin (SIM) has shown potential benefits in the non-alcoholic fatty liver disease process. We developed multicellular liver microtissues composed of hepatic stellate cells, hepatoblastoma cells and human umbilical vein endothelial cells. The microtissues were supplemented with a combination of palmitic acid and oleic acid to develop fibrosis models. Subsequently, various groups of microtissues were exposed to SIM and SIM-LipoNPs at doses of 5 and 10 mg/mL. The effectiveness of the treatments was evaluated by analysing cell viability, production of reactive oxygen species (ROS) and nitric oxide (NO), the expression of Kruppel-like factor (KLF) 2, and pro-inflammatory cytokines (interleukin(IL)-1 α, IL-1 ß, IL-6 and tumour necrosis factor-α), and the expression of collagen I. Our results indicated that SIM-LipoNPs application showed promising results. SIM-LipoNPs effectively amplified the SIM-klf2-NO pathway at a lower dosage compatible with a high dosage of free SIM, which also led to reduced oxidative stress by decreasing ROS levels. SIM-LipoNPs administration also resulted in a significant reduction in pro-inflammatory cytokines and Collagen I mRNA levels, as a marker of fibrosis. In conclusion, our study highlights the considerable therapeutic potential of using SIM-LipoNPs to prevent liver fibrosis progress, underscoring the remarkable properties of SIM-LipoNPs in activating the KLF2-NO pathway and anti-oxidative and anti-inflammatory response.

Mononuclear phagocyte morphological response to chemoattractants is dependent on geranylgeranyl pyrophosphate.

Statins are used to treat hypercholesterolemia and function by inhibiting the production of the rate-limiting metabolite mevalonate. As such, statin treatment not only inhibits de novo synthesis of cholesterol but also isoprenoids that are involved in prenylation, the posttranslational lipid modification of proteins. The immunomodulatory effects of statins are broad and often conflicting. Previous work demonstrated that statins increased survival and inhibited myeloid cell trafficking in a murine model of sepsis, but the exact mechanisms underlying this phenomenon were unclear. Herein, we investigated the role of prenylation in chemoattractant responses. We found that simvastatin treatment abolished chemoattractant responses induced by stimulation by C5a and FMLP. The inhibitory effect of simvastatin treatment was unaffected by the addition of either farnesyl pyrophosphate (FPP) or squalene but was reversed by restoring geranylgeranyl pyrophosphate (GGPP). Treatment with prenyltransferase inhibitors showed that the chemoattractant response to both chemoattractants was dependent on geranylgeranylation. Proteomic analysis of C15AlkOPP-prenylated proteins identified several geranylgeranylated proteins involved in chemoattractant responses, including RHOA, RAC1, CDC42, and GNG2. Chemoattractant responses in THP-1 human macrophages were also geranylgeranylation dependent. These studies provide data that help clarify paradoxical findings on the immunomodulatory effects of statins. Furthermore, they establish the role of geranylgeranylation in mediating the morphological response to chemoattractant C5a.NEW & NOTEWORTHY The immunomodulatory effect of prenylation is ill-defined. We investigated the role of prenylation on the chemoattractant response to C5a. Simvastatin treatment inhibits the cytoskeletal remodeling associated with a chemotactic response. We showed that the chemoattractant response to C5a was dependent on geranylgeranylation, and proteomic analysis identified several geranylgeranylated proteins that are involved in C5a receptor signaling and cytoskeletal remodeling. Furthermore, they establish the role of geranylgeranylation in mediating the response to chemoattractant C5a.

Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS).

BACKGROUND: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. METHODS: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. RESULTS: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. CONCLUSIONS: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS.

Overcoming statin resistance in prostate cancer cells by targeting the 3-hydroxy-3-methylglutaryl-CoA-reductase.

Prostate cancer is the most prevalent malignancy in men. While diagnostic and therapeutic interventions have substantially improved in recent years, disease relapse, treatment resistance, and metastasis remain significant contributors to prostate cancer-related mortality. Therefore, novel therapeutic approaches are needed. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway which plays an essential role in cholesterol homeostasis. Numerous preclinical studies have provided evidence for the pleiotropic antitumor effects of statins. However, results from clinical studies remain controversial and have shown substantial benefits to even no effects on human malignancies including prostate cancer. Potential statin resistance mechanisms of tumor cells may account for such discrepancies. In our study, we treated human prostate cancer cell lines (PC3, C4-2B, DU-145, LNCaP) with simvastatin, atorvastatin, and rosuvastatin. PC3 cells demonstrated high statin sensitivity, resulting in a significant loss of vitality and clonogenic potential (up to - 70%; p < 0.001) along with an activation of caspases (up to 4-fold; p < 0.001). In contrast, C4-2B and DU-145 cells were statin-resistant. Statin treatment induced a restorative feedback in statin-resistant C4-2B and DU-145 cells through upregulation of the HMGCR gene and protein expression (up to 3-folds; p < 0.01) and its transcription factor sterol-regulatory element binding protein 2 (SREBP-2). This feedback was absent in PC3 cells. Blocking the feedback using HMGCR-specific small-interfering (si)RNA, the SREBP-2 activation inhibitor dipyridamole or the HMGCR degrader SR12813 abolished statin resistance in C4-2B and DU-145 and induced significant activation of caspases by statin treatment (up to 10-fold; p < 0.001). Consistently, long-term treatment with sublethal concentrations of simvastatin established a stable statin resistance of a PC3SIM subclone accompanied by a significant upregulation of both baseline as well as post-statin HMGCR protein (gene expression up to 70-fold; p < 0.001). Importantly, the statin-resistant phenotype of PC3SIM cells was reversible by HMGCR-specific siRNA and dipyridamole. Our investigations reveal a key role of a restorative feedback driven by the HMGCR/SREBP-2 axis in statin resistance mechanisms of prostate cancer cells.

Low-density lipoprotein cholesterol response to statins according to comorbidities and co-medications: A population-based study.

BACKGROUND: The response of low-density lipoprotein cholesterol (LDL-C) to statin therapy is variable, and may be affected by the presence of co-morbid conditions or the use of concomitant medications. Systematic variation in the response to statins based on these factors could affect the selection of the statin treatment regimen in population subgroups. We investigated whether common comorbidities and co-medications had clinically important effects on statin responses in individual patients. METHODS: This register-based cohort study included 89,006 simvastatin or atorvastatin initiators with measurements of pre-statin and on-statin LDL-C levels, in Denmark, 2008-2018. We defined statin response as the percentage reduction in LDL-C, and used linear regression to estimate percentage reduction differences (PRD) according to 175 chronic comorbidities and 99 co-medications. We evaluated both the statistical significance (P-values corrected for multiple testing) and the clinical importance (PRD of 5 percentage points or more) of the observed associations. RESULTS: Concomitant use of oral blood-glucose lowering drugs, which included metformin in 96% of treated individuals, was associated with a greater response to statin therapy that was both statistically significant and clinically important, with a PRD of 5.18 (95% confidence interval: 4.79 to 5.57). No other comorbidity or co-medication reached the prespecified thresholds for a significant, clinically important effect on statin response. Overall, comorbidities and co-medications had little effect on statin response, and altogether explained only 1.7% of the total observed population variance. CONCLUSION: Most of the studied comorbidities and co-medications did not have a clinically important effect on statin response, suggesting no need to modify treatment regimens. However, use of metformin was associated with a significantly enhanced LDL-C response to statins, suggesting that lower statin doses may be effective in patients taking metformin.

Statins affect human iPSC-derived cardiomyocytes by interfering with mitochondrial function and intracellular acidification.

Statins are effective drugs in reducing cardiovascular morbidity and mortality by inhibiting cholesterol synthesis. These effects are primarily beneficial for the patient's vascular system. A significant number of statin users suffer from muscle complaints probably due to mitochondrial dysfunction, a mechanism that has recently been elucidated. This has raised our interest in exploring the effects of statins on cardiac muscle cells in an era where the elderly and patients with poorer functioning hearts and less metabolic spare capacity start dominating our patient population. Here, we investigated the effects of statins on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-derived CMs). hiPSC-derived CMs were exposed to simvastatin, atorvastatin, rosuvastatin, and cerivastatin at increasing concentrations. Metabolic assays and fluorescent microscopy were employed to evaluate cellular viability, metabolic capacity, respiration, intracellular acidity, and mitochondrial membrane potential and morphology. Over a concentration range of 0.3-100 µM, simvastatin lactone and atorvastatin acid showed a significant reduction in cellular viability by 42-64%. Simvastatin lactone was the most potent inhibitor of basal and maximal respiration by 56% and 73%, respectively, whereas simvastatin acid and cerivastatin acid only reduced maximal respiration by 50% and 42%, respectively. Simvastatin acid and lactone and atorvastatin acid significantly decreased mitochondrial membrane potential by 20%, 6% and 3%, respectively. The more hydrophilic atorvastatin acid did not seem to affect cardiomyocyte metabolism. This calls for further research on the translatability to the clinical setting, in which a more conscientious approach to statin prescribing might be considered, especially regarding the current shift in population toward older patients with poor cardiac function.

Unveiling the association between HMG-CoA reductase inhibitors and bladder cancer: a comprehensive analysis using Mendelian randomization, animal models, and transcriptomics.

This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA.

Dantrolene and coenzyme Q10 as a suggested combination therapy to statin-induced myopathy in high fat diet rats: A possible interference with ROS/ TGF-ß / Smad4 signaling pathway.

One of the major hitches for statins' utilization is the development of myotoxicity. Versatile studies reported that the underlining molecular mechanisms including coenzyme Q10 (CoQ10)/ubiquinone depletion, as well as the disturbance in the cytoplasmic Ca2+ homeostasis. Therefore, we investigated the consequences of supplementing CoQ10 and dantrolene, a cytoplasmic Ca2+ reducing agent, in combination with simvastatin. This adjuvant therapy normalized the simvastatin-mediated elevation in serum ALT, AST, CK-MM, as well as tissue Ca2+ content, in addition to suppressing the simvastatin-mediated oxidative stress in simvastatin-treated rats, while having no effect upon statin-induced antihyperlipidemic effect. Additionally, the combination inhibited the simvastatin-induced TGF-ß/ Smad4 pathway activation. Collectively, the current study emphasizes on the potential utilization of dantrolene and CoQ10 as an adjuvant therapy to statins treatment for improving their side effect profile.

Overcoming Resistance in Prostate Cancer Therapy Using a DZ-Simvastatin Conjugate.

Prostate cancer (PC), particularly its metastatic castration-resistant form (mCRPC), is a leading cause of cancer-related deaths among men in the Western world. Traditional systemic treatments, including hormonal therapy and chemotherapy, offer limited effectiveness due to tumors' inherent resistance to these therapies. Moreover, they often come with significant side effects. We have developed a delivery method using a tumor-cell-specific heptamethine carbocyanine dye (DZ) designed to transport therapeutic agents directly to tumor cells. This research evaluated simvastatin (SIM) as the antitumor payload because of its demonstrated chemopreventive effects on human cancers and its well-documented safety profile. We designed and synthesized a DZ-SIM conjugate for tumor cell targeting. PC cell lines and xenograft tumor models were used to assess tumor-cell targeting specificity and killing activity and to investigate the corresponding mechanisms. DZ-SIM treatment effectively killed PC cells regardless of their androgen receptor status or inherent therapeutic resistance. The conjugate targeted and suppressed xenograft tumor formation without harming normal cells of the host. In cancer cells, DZ-SIM was enriched in subcellular organelles, including mitochondria, where the conjugate formed adducts with multiple proteins and caused the loss of transmembrane potential, promoting cell death. The DZ-SIM specifically targets PC cells and their mitochondria, resulting in a loss of mitochondrial function and cell death. With a unique subcellular targeting strategy, the conjugate holds the potential to outperform existing chemotherapeutic drugs. It presents a novel strategy to circumvent therapeutic resistance, offering a more potent treatment for mCRPC.

Comparative retention and effectiveness of migraine preventive treatments: A nationwide registry-based cohort study.

BACKGROUND AND PURPOSE: Little is known about the comparative effects of migraine preventive drugs. We aimed to estimate treatment retention and effectiveness of migraine preventive drugs in a nationwide registry-based cohort study in Norway between 2010 and 2020. METHODS: We assessed retention, defined as the number of uninterrupted treatment days, and effectiveness, defined as the reduction in filled triptan prescriptions during four 90-day periods after the first preventive prescription, compared to a 90-day baseline period. We compared retention and efficacy for different drugs against beta blockers. Comparative retention was estimated with hazard ratios (HRs), adjusted for covariates, using Cox regression, and effectiveness as odds ratios (ORs) using logistic regression, with propensity-weighted adjustment for covariates. RESULTS: We identified 104,072 migraine patients, 81,890 of whom were female (78.69%) and whose mean (standard deviation) age was 44.60 (15.61) years. Compared to beta blockers, botulinum toxin (HR 0.43, 95% confidence interval [CI] 0.42-0.44) and calcitonin gene-related peptide pathway antibodies (CGRPabs; HR 0.63, 95% CI 0.59-0.66) were the least likely to be discontinued, while clonidine (HR 2.95, 95% CI 2.88-3.02) and topiramate (HR 1.34, 95% CI 1.31-1.37) were the most likely to be discontinued. Patients on simvastatin, CGRPabs, and amitriptyline were more likely to achieve a clinically significant reduction in triptan use during the first 90 days of treatment, with propensity score-adjusted ORs of 1.28 (95% CI 1.19-1.38), 1.23 (95% CI 0.79-1.90), and 1.13 (95% CI 1.08-1.17), respectively. CONCLUSIONS: We found a favorable effect of CGRPabs, amitriptyline, and simvastatin compared with beta blockers, while topiramate and clonidine were associated with poorer outcomes.

Unravelling effects of phytochemicals from buckwheat on cholesterol metabolism and lipid accumulation in HepG2 cells and its validation through gene expression analysis.

BACKGROUND: The objective of this research was to elucidate the hypocholesterolemic effects of a bioactive compound extracted from buckwheat, and to delineate its influence on the regulatory mechanisms of cholesterol metabolism. The compound under investigation was identified as quercetin. MATERIAL AND RESULTS: In vitro experiments conducted on HepG2 cells treated with quercetin revealed a significant reduction in intracellular cholesterol accumulation. This phenomenon was rigorously quantified by assessing the transcriptional activity of key genes involved in the biosynthesis and metabolism of cholesterol. A statistically significant reduction in the expression of HMG-CoA reductase (HMGCR) was observed, indicating a decrease in endogenous cholesterol synthesis. Conversely, an upregulation in the expression of cholesterol 7 alpha-hydroxylase (CYP7A1) was also observed, suggesting an enhanced catabolism of cholesterol to bile acids. Furthermore, the study explored the combinatory effects of quercetin and simvastatin, a clinically utilized statin, revealing a synergistic action in modulating cholesterol levels at various dosages. CONCLUSIONS: The findings from this research provide a comprehensive insight into the mechanistic pathways through which quercetin, a phytochemical derived from buckwheat, exerts its hypocholesterolemic effects. Additionally, the observed synergistic interaction between quercetin and simvastatin opens up new avenues for the development of combined therapeutic strategies to manage hyperlipidemia.

Degree of serum LDL cholesterol reduction by simvastatin and ezetimibe is dependent on baseline LDL cholesterol concentration but not on baseline values and changes in cholesterol synthesis and absorption parameters.

OBJECTIVE: We questioned whether the baseline status of low-density lipoprotein cholesterol (LDL-C), cholesterol synthesis and absorption, and the changes in these parameters determine the change in serum LDL-C under statin or ezetimibe treatment or under combination treatment. MATERIALS AND METHODS: 37 mildly hypercholesterolemic healthy male subjects were studied under placebo, simvastatin (20 mg/d), ezetimibe (10 mg/d), and combination treatment. We correlated the change of LDL-C (ΔLDL-C) under treatment with the placebo end values of LDL-C (baseline), whole-body cholesterol synthesis, and hepatic cholesterol synthesis (serum lathosterol to cholesterol ratio) as well as fractional absorption rate (FAR) of cholesterol and serum campesterol to cholesterol ratio. The change in serum LDL-C was also correlated with the changes in synthesis and absorption parameters. RESULTS: ΔLDL-C was highly negatively related to baseline LDL-C under ezetimibe (p < 0.0001), simvastatin (p < 0.0001), and combination treatment (p < 0.0001). Under combination treatment, LDL-C lowering appears possible from baseline values of 10 mg/dL upwards, while ΔLDL-C was independent of the baseline value (-50 to -60%). ΔLDL-C was positively associated with placebo FAR under ezetimibe (p = 0.0106) and combination treatment (p = 0.0457). No associations were found between ΔLDL-C and baseline values for synthesis nor between ΔLDL-C and changes in synthesis and absorption surrogate markers. CONCLUSION: Under ezetimibe, simvastatin, and combination treatment, ΔLDL-C is predominantly dependent on the baseline LDL-C concentration. We hypothesize that the concentration gradient between serum LDL-C and hepatic cellular cholesterol determines the efficiency of serum LDL-C lowering. Combination treatment is the preferred treatment.

A systematic review of case series and clinical trials investigating systemic oral or injectable therapies for the treatment of vitiligo.

AIMS AND OBJECTIVES: The purpose of this study is to investigate the effectiveness and safety of oral and injectable systemic treatments, such as methotrexate, azathioprine, cyclosporine, tofacitinib, baricitinib, corticosteroids, statins, zinc, apremilast, etc., for treating vitiligo lesions. METHOD: Databases including PubMed, Scopus, and Web of Science were meticulously searched for studies spanning from 2010 to August 2023, focusing on systemic oral and injectable therapies for vitiligo, using comprehensive keywords and search syntaxes tailored to each database. Key data extracted included study design, treatment efficacy, patient outcomes, patient satisfaction, and safety profiles. RESULTS: In a total of 42 included studies, oral mini-pulse corticosteroid therapy (OMP) was the subject of six studies (14.2%). Minocycline was the focus of five studies (11.9%), while methotrexate, apremilast, and tofacitinib each were examined in four studies (9.5%). Antioxidants and Afamelanotide were the subjects of three studies each (7.1%). Cyclosporine, simvastatin, oral zinc, oral corticosteroids (excluding OMP) and injections, and baricitinib were each explored in two studies (4.8%). Azathioprine, mycophenolate mofetil, and Alefacept were the subjects of one study each (2.4%). CONCLUSION: Systemic treatments for vitiligo have been successful in controlling lesions without notable side effects. OMP, Methotrexate, Azathioprine, Cyclosporine, Mycophenolate mofetil, Simvastatin, Apremilast, Minocycline, Afamelanotide, Tofacitinib, Baricitinib, Antioxidants, and oral/injectable corticosteroids are effective treatment methods. However, oral zinc and alefacept did not show effectiveness.

Simvastatin attenuates silica-induced pulmonary inflammation and fibrosis in rats via the AMPK-NOX pathway.

BACKGROUND: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms. METHODS: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway. RESULTS: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and transforming growth factor-ß1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions. CONCLUSIONS: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.

Effect of Statin Treatment in Patients with Aneurysmal Subarachnoid Hemorrhage: A Network Meta-Analysis.

BACKGROUND: There are knowledge gaps regarding the relative efficacy of statins for aneurysmal subarachnoid hemorrhage (aSAH). This study aims to examine the comparative effectiveness and determine the ranking of different statins with network meta­analysis in patients with aSAH. METHODS: MEDLINE, Embase, Pubmed, and Cochrane Central Register of Controlled Trials were searched from database inception until December 15, 2022. Outcomes included delayed cerebral ischemia (DCI), functional recovery, and mortality. Relative risk (RRs) ratios and associated 95% confidence intervals (CIs) were estimated. The values derived from surface under the cumulative ranking curve were obtained to rank the treatment hierarchy in the analysis. RESULTS: We identified 13 trials involving 1,885 patients. Atorvastatin 20 mg (RR 0.68, 95% CI 0.53-0.86), pravastatin 40 mg (RR 0.51, 95% CI 0.31-0.77), and simvastatin 80 mg (RR 0.54, 95% CI 0.40-0.70) were superior to the placebo in preventing DCI. Additionally, simvastatin 80 mg (RR 0.60, 95% CI 0.42-0.84) and pravastatin 40 mg (RR 0.56, 95% CI 0.32-0.93) were associated with a decreased risk of DCI than simvastatin 40 mg. Comparisons across treatment durations suggested that short-term (RR 0.62, 95% CI 0.50-0.76) statin therapy reduced risk of DCI. CONCLUSIONS: Simvastatin 80 mg might be the most effective intervention in reducing DCI. Additionally, short-term therapy might provide more benefits. Further research with longer follow-up is warranted to validate the current findings in patients with aSAH who are at high risk of DCI.

Statins-Their Role in Bone Tissue Metabolism and Local Applications with Different Carriers.

Statins, widely prescribed for lipid disorders, primarily target 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase competitively and reversibly, resulting in reduced low-density lipoprotein cholesterol (LDL-C). This mechanism proves effective in lowering the risk of lipid-related diseases such as ischemic cerebrovascular and coronary artery diseases. Beyond their established use, statins are under scrutiny for potential applications in treating bone diseases. The focus of research centers mainly on simvastatin, a lipophilic statin demonstrating efficacy in preventing osteoporosis and aiding in fracture and bone defect healing. Notably, these effects manifest at elevated doses (20 mg/kg/day) of statins, posing challenges for systematic administration due to their limited bone affinity. Current investigations explore intraosseous statin delivery facilitated by specialized carriers. This paper outlines various carrier types, characterizing their structures and underscoring various statins' potential as local treatments for bone diseases.

SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients.

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.

Effects of Atorvastatin and Simvastatin on the Bioenergetic Function of Isolated Rat Brain Mitochondria.

Little is known about the effects of statins, which are cholesterol-lowering drugs, on the bioenergetic functions of mitochondria in the brain. This study aimed to elucidate the direct effects of atorvastatin and simvastatin on the bioenergetics of isolated rat brain mitochondria by measuring the statin-induced changes in respiratory chain activity, ATP synthesis efficiency, and the production of reactive oxygen species (ROS). Our results in isolated brain mitochondria are the first to demonstrate that atorvastatin and simvastatin dose-dependently significantly inhibit the activity of the mitochondrial respiratory chain, resulting in a decreased respiratory rate, a decreased membrane potential, and increased ROS formation. Moreover, the tested statins reduced mitochondrial coupling parameters, the ADP/O ratio, the respiratory control ratio, and thus, the oxidative phosphorylation efficiency in brain mitochondria. Among the oxidative phosphorylation complexes, statin-induced mitochondrial impairment concerned complex I, complex III, and ATP synthase activity. The calcium-containing atorvastatin had a significantly more substantial effect on isolated brain mitochondria than simvastatin. The higher inhibitory effect of atorvastatin was dependent on calcium ions, which may lead to the disruption of calcium homeostasis in mitochondria. These findings suggest that while statins are effective in their primary role as cholesterol-lowering agents, their use may impair mitochondrial function, which may have consequences for brain health, particularly when mitochondrial energy efficiency is critical.

Anti-inflammatory potential of simvastatin and amfenac in ARPE-19 cells; insights in preventing re-detachment and proliferative vitreoretinopathy after rhegmatogenous retinal detachment surgery.

PURPOSE: Rhegmatogenous retinal detachment is a severe vision-threatening complication that can result into proliferative vitreoretinopathy (PVR) and re-detachment of the retina if recovery from surgery fails. Inflammation and changes in retinal pigment epithelial (RPE) cells are important contributors to the disease. Here, we studied the effects of simvastatin and amfenac on ARPE-19 cells under inflammatory conditions. METHODS: ARPE-19 cells were pre-treated with simvastatin and/or amfenac for 24 h after which interleukin (IL)-1α or IL-1ß was added for another 24 h. After treatments, lactate dehydrogenase release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) processing, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity, prostaglandin E2 (PGE2) level, and extracellular levels of IL-6, IL-8, monocytic chemoattractant protein (MCP-1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor, as well as the production of reactive oxygen species (ROS) were determined. RESULTS: Pre-treatment of human ARPE-19 cells with simvastatin reduced the production of IL-6, IL-8, and MCP-1 cytokines, PGE2 levels, as well as NF-κB activity upon inflammation, whereas amfenac reduced IL-8 and MCP-1 release but increased ROS production. Together, simvastatin and amfenac reduced the release of IL-6, IL-8, and MCP-1 cytokines as well as NF-κB activity but increased the VEGF release upon inflammation in ARPE-19 cells. CONCLUSION: Our present study supports the anti-inflammatory capacity of simvastatin as pre-treatment against inflammation in human RPE cells, and the addition of amfenac complements the effect. The early modulation of local conditions in the retina can prevent inflammation induced PVR formation and subsequent retinal re-detachment.

Effects of simvastatin on immunoreaction and inflammation in rats with asthma by regulating NOTCH signaling pathway.

To investigate the effect of simvastatin on the immunoreaction and inflammation in rats with asthma through the NOTCH signaling pathway, a total of 36 Sprague-Dawley (SD) rats were enrolled and randomly divided into the normal group (n=12), model group (n=12) and simvastatin group (n=12). The rats in the normal group were fed normally, those in the model group were prepared into models of asthma, and those in the simvastatin group were prepared into models of asthma and intervened with simvastatin. Next, the morphology of airway tissues was observed via hematoxylin-eosin (HE) staining assay. Besides, immunohistochemistry was employed to determine the expression of interferon-γ (INF-γ), and the relative protein expression levels of NOTCH2 and NOTCH3 were measured by Western blotting (WB). Additionally, enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction (qPCR) assay were carried out to detect the content of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) and the relative mRNA expression levels of INF-γ, IL-6 and TNF-α, respectively. HE staining results uncovered that the airway tissues displayed normal morphology in the normal group and disordered morphology and obvious inflammatory infiltration in the model group. In comparison with the model group, the simvastatin group exhibited significantly improved morphology of airway tissues. Based on immunohistochemistry, the average optical density of INF-γ positive expression was increased in the model group and simvastatin group compared with that in the normal group (P<0.05), and it was distinctly lower in the simvastatin group than that in the model group (P<0.05). The results of WB showed that compared with those in the normal group, the relative protein expression levels of NOTCH2 and NOTCH3 were elevated in model group and simvastatin group (P<0.05), whereas they were overtly reduced in simvastatin group compared with those in model group (P<0.05). It was found through ELISA that the model group and simvastatin group had raised content of IL-6 and TNF-α in comparison with the normal group (P<0.05), while the simvastatin group exhibited markedly decreased content of IL-6 and TNF-α in comparison with the model group (P<0.05). The results of qPCR revealed that the relative mRNA expression levels of INF-γ, IL-6 and TNF-α were distinctly up-regulated in the model group and simvastatin group compared with those in the normal group, displaying statistically significant differences (P<0.05), whereas they were markedly lowered in simvastatin group compared with those in the model group, showing statistically significant differences (P<0.05). Simvastatin represses the immunoreaction and inflammation in rats with asthma by down-regulating the NOTCH signaling pathway.