Effects Of Simvastatin Research Articles

A Drug-Drug Interaction Study to Evaluate the Impact of Simvastatin and Itraconazole on Erlotinib Pharmacokinetics in Rats by UPLC-MS/MS.

The goal of our study was to investigate the effects of single-dose simvastatin and itraconazole application on the pharmacokinetics of erlotinib in rats. Twenty-one male Sprague-Dawley rats were randomly divided into 3 groups, including erlotinib combined with simvastatin, erlotinib combined with itraconazole and erlotinib alone groups. The rats were given a single dose of 2 mg/kg simvastatin, 15 mg/kg itraconazole or 0.5% sodium carboxymethyl cellulose followed by 12 mg/kg erlotinib. The concentration of erlotinib in rat plasma was determined by UPLC-MS/MS. As internal standard, tinidazole was used for chromatographic analysis on the Kinetex C18 column (100×2.1 mm, 2.6 μm). Erlotinib was validated in the calibration range of 5-1000 ng/mL. The lower limit of quantification (LLOQ) was 5 ng/mL. The inter- and intra-day precisions for erlotinib were less than 10.56%, and the accuracies were in the range of 98.61-104.99%. The validated UPLC-MS/MS method was successfully applied to this study. Compared with the erlotinib alone group, the values of AUC0-t, AUC0-∞, Cmax, Vz/F and t1/2 in the simvastatin group showed no statistical differences among pharmacokinetic parameters (P>0.05). However, the values of AUC0-t, AUC0-∞ and Cmax, in the itraconazole group were approximately 1.32-fold, 1.32-fold and 1.34-fold higher, and the CL/F was lower than those in the erlotinib alone group; the difference was statistically significant (P<0.05). Simvastatin had no significant effect on the pharmacokinetics of erlotinib, whereas co-administration of itraconazole considerably increased the exposure of erlotinib. Therefore, we should pay more attention to the potential drug-drug interaction to ensure safety in cancer patient treatment.

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

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. 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. 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. We found a favorable effect of CGRPabs, amitriptyline, and simvastatin compared with beta blockers, while topiramate and clonidine were associated with poorer outcomes.

Simvastatin ameliorates synaptic plasticity impairment in chronic mild stress-induced depressed mice by modulating hippocampal NMDA receptor.

In our previous study, we showed simvastatin exerts an antidepressant effect and inhibits neuroinflammation. Given the role of synaptic impairment in depression development, we investigate the effect of simvastatin on synaptic plasticity in depression and the related mechanisms. Electrophysiological analysis, Golgi staining, and transmission electron microscope were performed to analyze the effect of simvastatin on synaptic impairment in depression. In addition, the localization and reactivity of N-methyl-D-aspartate receptor (NMDAR) subunits and the downstream signaling were investigated to explore the mechanism of simvastatin's effect on synaptic plasticity. Simvastatin ameliorated the reduction of the magnitude of long-term potentiation (LTP) in Schaffer collateral-CA1, restored hippocampal dendritic spine density loss, improved the number of spine synapses, reversed the reduction in BrdU-positive cells in chronic mild stress (CMS)-induced depressed mice, and ameliorated NMDA-induced neurotoxicity in hippocampal neurons. Dysfunction of NMDAR activity in the hippocampus is associated with depression. Simvastatin treatment reversed the surface expression and phosphorylation changes of NMDAR subunits in NMDA-treated hippocampal neurons and depressed mice. In addition, simvastatin further increased the levels of mature BDNF, activating TrkB-Akt-mTOR signaling, which is critical for synaptic plasticity. These findings suggest that simvastatin can improve the dysfunction of NMDAR and ameliorate hippocampal synaptic plasticity impairment in depressed mice.

Simvastatin retards cartilage degradation and subchondral bone deterioration induced by a high-fat diet in mice

ABSTRACT To evaluate the effects of simvastatin on the degeneration of cartilage and subchondral bone in a mice model of osteoarthritis (OA) induced by obesity. Thirty male 3-month-old C57BL/6J mice were randomized into three groups: mice with normal diet + vehicle (distilled water) (Control), mice with High-fat diet + vehicle (HFD), mice with HFD + Simvastatin (HFD+S). HFD+S group were treated with simvastatin (10 mg/kg/day) for 12 weeks. The pathology of OA was assessed by histomorphology analyses, immunohistochemistry, micro-computed tomography, and enzyme-linked immunosorbent assay. Histomorphological analysis revealed that OA was significantly exacerbated by the HFD-induced obesity and markedly alleviated by the simvastatin intervention. In details, simvastatin ameliorated the abnormal metabolic status and cartilage lesions, significantly increased aggrecan and collagen-II expression and decreased the expression of MMP-13 and leptin in cartilage. Furthermore, the results of micro-CT analysis revealed that the HFD+S group exhibited higher BMD, BV/TV, and Tb.N values but a lower Tb.Sp value than that of the HFD group. Serum glucose, leptin, and IL-1β concentrations were significantly correlated with the OARSI score. Histomorphological analysis revealed that OA was significantly exacerbated by the HFD-induced obesity and markedly alleviated by the simvastatin intervention. In details, simvastatin ameliorated the abnormal metabolic status and cartilage lesions, significantly increased aggrecan and collagen-II expression and decreased the expression of MMP-13 and leptin in cartilage. Furthermore, the results of micro-CT analysis revealed that the HFD+S group exhibited higher BMD, BV/TV, and Tb.N values but a lower Tb.Sp value than that of the HFD group. Serum glucose, leptin, and IL-1β concentrations were significantly correlated with the OARSI score. The HFD-induced obesity aggravates articular degeneration and deterioration in subchondral bone, which could be improved by the intervention of simvastatin, suggesting that simvastatin may be a potential candidate for amelioration of the progression of obesity induced-OA.

Exploring the Synergistic Effect of Simvastatin in Oral Health Applications: A Literature Review.

Statins are the first line of treatment for hyperlipidaemia. Along with lowering lipids, it also lowers mortality and cardiovascular risk. Statins play a major role in maintaining the homeostasis of the oral cavity via a number of different mechanisms. It includes regeneration of dentin and pulp by differentiation and increased development of mineralized tissue via the bone morphogenetic proteins (BMP)-2 Pathway. It shows effective bone health by leading to osteogenic differentiation mesenchymal stem cells, by facilitating epithelization process in wound healing, anti-inflammatory, antioxidant, antimicrobial, antiviral, and fungicidal properties. To the finest of the information we have, there have been very few comprehensive studies that have investigated the effects of statin drugs on various aspects of dental and oral health. As a result, the main objective of this reviewwas to examine the effect of statins onoral health applications. According to the findings of our extensive review, statins have noteworthy and promising effects on several aspects oforal health, including dental pulp cells, chronic periodontitis, alveolar bone loss, orthodontic tooth movement, and so on. Nevertheless, it is concluded that local or even systemic administration of simvastatin should be regarded as an innovative, easily accessible, and safe therapeutic agent that has a significant impact on enhancing the oral health.

Simvastatin inhibits proliferation and promotes apoptosis of oral squamous cell carcinoma through KLF2 signal

ObjectivesThis study aimed to explore the role and specific mechanism of the cholesterol-lowering drug simvastatin in inhibiting oral squamous cell carcinoma (OSCC). MethodsThe proliferation, apoptosis, and migration levels of OSCC cells were detected by CCK8, quantitative real-time polymerase chain reaction, Western blot, colony formation, TdT-mediated dUTP Nick-End Labeling assay, and wound healing assay. The inhibitory effect of simvastatin in vivo was detected by a mouse xenograft tumor model. Immunohistochemistry and immunofluorescence staining were used to assess the KLF2 and β-catenin expressions in cells and tissues. ResultsKLF2 expression in OSCC cells and tissues was downregulated. The addition of KLF2 inducer, GGTI298, inhibited the proliferation and migration of OSCC cells. Simvastatin played a role in inhibiting the proliferation and promoting the apoptosis of OSCC cells. Moreover, it inhibited β-catenin expression and promoted KLF2 expression in OSCC cells. KLF2 siRNA reversed the effect of simvastatin on the proliferation and apoptosis of OSCC cells. ConclusionsKLF2, as a tumor suppressor gene, may be an important marker for diagnosing and treating OSCC. Simvastatin inhibits the progression of OSCC by regulating the KLF2 signal.

Inhibitory Effects of Simvastatin on IL-33-Induced MCP-1 via the Suppression of the JNK Pathway in Human Vascular Endothelial Cells.

An alarmin, interleukin (IL)-33 is a danger signal that causes inflammation, inducing chemotactic proteins such as monocyte chemoattractant protein (MCP)-1 in various cells. As statins have pleiotropic actions including anti-inflammatory properties, we investigated the effects of simvastatin on IL-33-induced MCP-1 expression in human umbilical vein endothelial cells (HUVECs). HUVECs were stimulated with IL-33 in the presence or absence of simvastatin. Gene expression and protein secretion of MCP-1, phosphorylation of mitogen-activated protein kinase (MAPK), nuclear translocation of phosphorylated c-Jun, and human monocyte migration were investigated. Immunocytochemical staining and Western immunoblot analysis revealed that IL-33 augmented MCP-1 protein expression in HUVECs. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) showed that IL-33 significantly increased MCP-1 mRNA and protein secretion, which were suppressed by c-jun N-terminal kinase (JNK) inhibitor SP600125 and p38 MAPK inhibitor SB203580. Simvastatin inhibited IL-33-induced MCP-1 mRNA, protein secretion, phosphorylation of JNK and c-Jun. Additionally, the IL-33-induced nuclear translocation of phosphorylated c-Jun and THP-1 monocyte migration were also blocked by simvastatin. This study demonstrated that IL-33 induces MCP-1 expression via the JNK and p38 MAPK pathways in HUVECs, and that simvastatin inhibits MCP-1 production by selectively suppressing JNK. Simvastatin may inhibit the progression of IL-33-induced inflammation via suppressing JNK to prevent MCP-1 production.

Statins suppress cell-to-cell propagation of α-synuclein by lowering cholesterol

Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of this process are not fully understood. Here, we screened a small-molecule library in a search for agents that suppress the propagation of α-synuclein and mutant huntingtin (mHtt). These screens yielded several molecules, some of which were effective against both α-synuclein and mHtt. Among these molecules, we focused on simvastatin and pravastatin. Simvastatin administration in a transgenic model of synucleinopathy effectively ameliorated behavioral deficits and α-synuclein accumulation, whereas pravastatin had no effect. Because only simvastatin enters the brain effectively, these results suggest that inhibition of brain cholesterol synthesis is important in simvastatin effects. In cultured cells, accumulation of intracellular cholesterol, induced by genetic ablation of the NPC1 gene or by pharmacological treatment with U18666A, increased α-synuclein aggregation and secretion. In contrast, lowering cholesterol using methyl-β-cyclodextrin or statins reversed α-synuclein aggregation and secretion in NPC1-knockout cells. Consistent with these observations, feeding a high-fat diet aggravated α-synuclein pathology and behavioral deficits in the preformed fibril-injected mouse model, an effect that was also reversed by simvastatin administration. These results suggest that statins suppress propagation of protein aggregates by lowering cholesterol in the brain.

Effects of Simvastatin on RBL-2H3 Cell Degranulation.

Hypercholesterolemia is a major complication of arteriosclerosis. Mast cells in arteriosclerosis plaques induce inflammatory reactions and promote arterial sclerosis. In this study, we evaluated the pharmacological effects of simvastatin (SV)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors on the degranulation of rat basophilic leukemia (RBL)-2H3 cells, which are commonly used as mast cell models. SV significantly decreased the degranulation induced by three types of stimulation: antigen antibody reaction (Ag-Ab), thapsigargin (Tg) serosal endoplasmic reticulum calcium ATPase (SERCA) inhibitor, and A23187 calcium ionophore. SV had a stronger inhibitory effect on degranulation induced by Ag-Ab stimulation than the other two stimulations. However, SV did not inhibit increase of intracellular Ca2+ concentrations. Mevalonate or geranylgeraniol co-treatment with SV completely prevented the inhibitory effect of SV on the degranulation induced by these stimulations. Immunoblotting results showed that SV inhibited protein kinase C (PKC) delta translocation induced by Ag-Ab but not by Tg or A23187. SV induced a reduction in active Rac1, and actin filament rearrangement. In conclusion, SV inhibits RBL-2H3 cell degranulation by inhibiting downstream signaling pathways, including the sequential degranulation pathway. These inhibitory effects were completely reversed by the addition of geranylgeraniol and might be induced by changes in the translocation of the small guanosine 5'-triphosphatase (GTPase) families Rab and Rho, which are related to vesicular transport PKC delta translocation and actin filament formation, respectively. These changes are caused by the inhibition of HMG-CoA reductase by SV following the synthesis of geranylgeranyl pyrophosphates, which play important roles in the activation of small GTPases, Rab.

The Potential Therapeutic Application of Simvastatin for Brain Complications and Mechanisms of Action.

Statins are common drugs that are clinically used to reduce elevated plasma cholesterol levels. Based on their solubility, statins are considered to be either hydrophilic or lipophilic. Amongst them, simvastatin has the highest lipophilicity to facilitate its ability to cross the blood-brain barrier. Recent studies have suggested that simvastatin could be a promising therapeutic option for different brain complications and diseases ranging from brain tumors (i.e., medulloblastoma and glioblastoma) to neurological disorders (i.e., Alzheimer's disease, Parkinson's disease, and Huntington's disease). Specific mechanisms of disease amelioration, however, are still unclear. Independent studies suggest that simvastatin may reduce the risk of developing certain neurodegenerative disorders. Meanwhile, other studies point towards inducing cell death in brain tumor cell lines. In this review, we outline the potential therapeutic effects of simvastatin on brain complications and review the clinically relevant molecular mechanisms in different cases.

Cardioprotective effects of simvastatin‑loaded nano‑niosomes on cardiomyocytes in cardiac ischemia

Background. Cardiac ischemia is the major cause of morbidity and mortality which can be increased by Statins. This study aimed to increase the effectiveness of simvastatin in the form of niosomes. Methods. In this study, 25 male Wistar rats were divided into 5 groups: control, ischemia (induced by closed LAD), ischemia receiving nano-niosomes, ischemia receiving simvastatin, and ischemia receiving simvastatin-loaded nano-niosomes. One month after the drug injection, RNA was extracted from the heart tissue of the studied groups, cDNA was synthesized, and a real-time PCR test was performed using specific primers. SPSS 21.0 software was used for statistical analysis. Analysis of variance was used to investigate the effect of the interventions, and Tukey's post hoc test was used to investigate a significant difference (P&lt;0.05) between the control groups and other groups as well as between intervention groups. Results. Apoptosis and autophagy increased significantly in the ischemia group compared to the control group (P&lt;0.05). In the simvastatin-loaded nano-niosomes group, compared to the simvastatin group, apoptosis and autophagy showed a significant decrease (P&lt;0.05), and also in both simvastatin-loaded nano-niosomes and simvastatin group, compared to the control group, apoptosis and autophagy showed a significant decrease. (P&lt;0.05). Conclusion. Simvastatin is an effective drug in the recovery of cardiac ischemia, but the main problem in using simvastatin is its instability and degradability, and the use of its niosomes form solves this problem properly. Practical Implications. Simvastatin‑loaded nano‑niosomes is more effective in reducing heart ischemia damage compared to simvastatin.

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model

Purpose: To study the effect of simvastatin on behavioral performance in a rat model of autism, and its effect on hippocampal brain-derived BDNF-TrkB pathway.&#x0D; Methods: Twelve rats with valproic acid (VPA)-induced autism were randomly divided into model group and simvastatin group, while six healthy rats served as normal control group. Rats in the simvastatin group received the drug (5 mg/kg) via i.p. route, while rats in model group and normal control group were injected with equivalent volume of normal saline in place of simvastatin. Capacity for interaction and repetitive stereotyped behavior, as well as results of Morris water maze test were determined for each group. The expressions of BDNF-TrkB proteins were assayed with immunoblotting.&#x0D; Results: The frequencies of sniffing normal saline, alcohol and rat urine were significantly higher in model and simvastatin rats than in normal rats, but they were significantly lower in simvastatin-treated rats than in model rats (p &lt; 0.05). There was higher duration of turning, jumping and grooming in the model group and simvastatin group than in the normal rats, but the duration was significantly reduced in simvastatin rats, relative to model rats. Escape latency times was significantly longer in model and simvastatin rats than in controls, but number of target quadrant crossings was significantly reduced. However, escape latency time was lower in simvastatin rats than in model rats, but number of target quadrant crossings was significantly higher. The model and simvastatin rats had down-regulated levels of BDNF and TrkB protein, relative to control rats, but there were markedly higher levels of these proteins in simvastatin-treated rats than in model rats.&#x0D; Conclusion: Simvastatin improves the behavioral performance of autistic rats by regulating BDNF/TrkB signal axis. This finding may be useful in the development of new drugs for treating autism.

Knockdown of VAMP8 attenuates atherosclerosis and enhances the effect of simvastatin in APOE-deficient mice

Purpose: To investigate the regulatory effects of vesicle-associated membrane protein 8 (VAMP8) in atherosclerosis (AS).&#x0D; Methods: VAMP8 expression was assessed using quantitative real time-polymerase chain reaction (qRT-PCR) and western blot, while H&amp;E staining was used to examine the morphology of arterial glandular tissues in AS mice. Lipid accumulation in mice was determined with the aid of Oil Red O staining, whereas the apoptosis of aortic cells was evaluated by TUNEL assay.&#x0D; Results: VAMP8 was highly expressed in the advanced-stage AS samples, and was also elevated in AS mice (p &lt; 0.01). VAMP8 protein level rose in AS mice (p &lt; 0.01). Moreover, the aorta showed atherosclerotic lesions with intima thickening and atherosclerotic plaques in AS group (p &lt; 0.01). However, these changes were alleviated in VAMP8-silenced group (p &lt; 0.01). VAMP8 silencing decreased lipid accumulation and alleviated inflammation and oxidative stress in AS mice (p &lt; 0.01). It was observed that depletion of VAMP8 reduced aortic cell apoptosis in AS mice (p &lt; 0.05). Furthermore, VAMP8 knockdown enhanced the effect of simvastatin on atherosclerosis (p &lt; 0.01). &#x0D; Conclusion: Knockdown of VAMP8 alleviates AS in ApoE-deficient mice. This finding suggests that this might be a potential strategy for the prevention and treatment of AS.

Baseline Severity and Inflammation Would Influence the Effect of Simvastatin on Clinical Outcomes in Cirrhosis Patients.

Simvastatin administration to decompensated cirrhosis patients improved Child-Pugh (CP) at the end of a safety trial (EST). To evaluate whether simvastatin reduces cirrhosis severity through a secondary analysis of the safety trial. Thirty patients CP class (CPc) CPc A (n = 6), CPc B (n = 22), and CPc C (n = 2) received simvastatin for one year. cirrhosis severity. Secondary endpoints: health-related quality of life (HRQoL) and hospitalizations for cirrhosis complications. Cirrhosis severity decreased baseline versus EST only across CP score (7.3 ± 1.3 versus 6.7 ± 1.7, P = 0.041), and CPc: 12 patients lessened from CPc B to CPc A, and three patients increased from CPc A to CPc B (P = 0.029). Due to cirrhosis severity changes and differences in clinical outcomes, 15 patients completed the trial as CPc AEST and another 15 as CPc B/C. At baseline, CPc AEST showed greater albumin and high-density lipoprotein cholesterol concentrations than CPc B/C (P = 0.036 and P = 0.028, respectively). Comparing EST versus baseline, only in CPc AEST, there was a reduction in white-cell blood (P = 0.012), neutrophils (P = 0.029), monocytes (P = 0.035), and C-reactive protein (P = 0.046); an increase in albumin (P = 0.011); and a recovery in HRQoL (P < 0.030). Finally, admissions for cirrhosis complications decreased in CPc AEST versus CPc B/C (P = 0.017). Simvastatin would reduce cirrhosis severity only in CPc B at baseline in a suitable protein and lipid milieu, possibly due to its anti-inflammatory effects. Furthermore, only in CPc AEST would improve HRQoL and reduce admissions by cirrhosis complications. However, as these outcomes were not primary endpoints, they require validation.

The Effect of Simvastatin on the Dynamics of NF-κB-Regulated Neurodegenerative and Neuroprotective Processes in the Acute Phase of Ischemic Stroke

Statins are lipid-lowering drugs that act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-limiting enzyme in cholesterol biosynthesis. Animal studies have shown neuroprotective effects of statins in cerebral stroke. However, the underlying mechanisms are not fully understood. The nuclear factor-kappa B (NF-κB) transcription factor is involved in the regulation of apoptosis in stroke. Different dimers of NF-κB regulate the gene expression of proteins involved in both neurodegeneration and neuroprotection. We aimed to determine whether simvastatin improves stroke outcome via inhibition of the RelA/p65-containing subunit and downregulation of stroke-induced pro-apoptotic genes or via activation of NF-κB dimers containing the c-Rel subunit and upregulation of anti-apoptotic genes during the acute stroke phase. Eighteen-month-old Wistar rats, subjected to permanent MCAO or sham surgery, were administered simvastatin (20 mg/kg b.w.) or saline for 5 days before the procedure. Stroke outcome was determined by measuring cerebral infarct and assessing motor functions. The expression of NF-κB subunits in various cell populations was investigated using immunofluorescence/confocal microscopy. RelA and c-Rel were detected by WB. The NF-κB-DNA binding activity was investigated using EMSA, and expression of Noxa, Puma, Bcl-2, and Bcl-x genes was analyzed by qRT-PCR. Results showed a 50% infarct size reduction and significant motor function improvement in the simvastatin-treated animals which correlated with a decrease in RelA and a transient increase in the c-Rel level in the nucleus, normalization of the NF-κB-DNA binding activity, and downregulation of the NF-κB-regulated genes. Our results provide new insights into the statin-mediated neuroprotective action against stroke based on NF-κB pathway inhibition.

Effect of Simvastatin Treatment on Mitochondrial Function and Inflammatory Status of Human White Adipose Tissue.

Statin therapy has shown pleiotropic effects affecting both mitochondrial function and inflammatory status. However, few studies have investigated the concurrent effects of statin exposure on mitochondrial function and inflammatory status in human subcutaneous white adipose tissue. In a cross-sectional study, we investigated the effects of simvastatin on mitochondrial function and inflammatory status in subcutaneous white adipose tissue of 55 human participants: 38 patients (19 females/19 males) in primary prevention with simvastatin (> 40 mg/d, > 3 mo) and 17 controls (9 females/8 males) with elevated plasma cholesterol. The 2 groups were matched on age, body mass index, and maximal oxygen consumption. Anthropometrics and fasting biochemical characteristics were measured. Mitochondrial respiratory capacity was assessed in white adipose tissue by high-resolution respirometry. Subcutaneous white adipose tissue expression of the inflammatory markers IL-6, chemokine (C-C motif) ligand 2 (CCL2), CCL-5, tumor necrosis factor-α, IL-10, and IL-4 was analyzed by quantitative PCR. Simvastatin-treated patients showed lower plasma cholesterol (P < .0001), low-density lipoprotein (P < .0001), and triglyceride levels (P = .0116) than controls. Simvastatin-treated patients had a lower oxidative phosphorylation capacity of mitochondrial complex II (P = .0001 when normalized to wet weight, P < .0001 when normalized to citrate synthase activity [intrinsic]), and a lower intrinsic mitochondrial electron transport system capacity (P = .0004). Simvastatin-treated patients showed higher IL-6 expression than controls (P = .0202). Simvastatin treatment was linked to mitochondrial respiratory capacity in human subcutaneous white adipose tissue, but no clear link was found between statin exposure, respiratory changes, and inflammatory status of adipose tissue.

Size-optimized simvastatin-loaded TPGS modified lipid nanocapsules for targeting epithelial-to-mesenchymal transition in hepatocellular carcinoma: Role of PTEN/AKT signaling

ABSTRACT Objectives Novel D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) modified lipid nanocapsules (LNC) were prepared with the aim of improving the effectiveness of simvastatin (SIM) in hepatocellular carcinoma (HCC). The present study, therefore, sought to investigate the effect of size-optimized SIM-loaded LNC on epithelial-to-mesenchymal transition (EMT) in HCC, providing insights on the implication of phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) axis. Methods Two optimized SIM-loaded LNCs with particle sizes 25 nm (SIM-LNC25) and 50 nm (SIM-LNC50) were prepared and biodistribution studies were performed. The anticancer effect of the prepared LNC was evaluated both in vitro and in vivo. The anti-migratory potential and EMT suppression through PTEN/AKT axis modulation were also explored. Results SIM-LNC50 was superior to SIM-LNC25 in both in vitro and in vivo experiments, as evidenced by cytotoxicity assays, tumor histopathology, and enhanced apoptosis. SIM-LNC50 also alleviated the migratory potential of HCC cells. Moreover, EMT markers implied a transition of tumor cells toward the epithelial rather than the mesenchymal phenotype both in vitro and in vivo. PTEN/AKT axis modulation was also evident with SIM-LNC50. Conclusion The present study, therefore, suggests the efficacy of the 50 nm particles in SIM-loaded LNC in HCC by targeting EMT via modulating the PTEN/AKT signaling axis.

ТРЕКРЕВИТ: АНГИОПРОТЕКТОРНОЕ И АНТИАТЕРОСКЛЕРОТИЧЕСКОЕ ДЕЙСТВИЕ

The problem of cardiovascular diseases, for example, atherosclerosis, justifies any attempts to identify the mechanisms of not only their formation, but also prevention and treatment, in particular with the use of drugs. In this regard, the purpose of the work was to study the possibility of using the dietary supplement Trekrevit during the treatment of patients with atherosclerosis with simvastatin. 45 men aged 22 to 35 years with signs of carotid artery sclerosis were examined. Patients of the main group, in addition to simvastatin, received Trekrevit for 10 months. It has been established that the addition of basic therapy with the dietary supplement trekrevit causes significant improvements in the characteristics of the walls of the carotid arteries in patients. It is also important that a previously unknown property of trekrevit has been established - to enhance and prolong the effect of simvastatin. This indicates the high effectiveness of combined treatment of patients with atherosclerosis.

Simvastatin Reduces Doxorubicin-Induced Cardiotoxicity: Effects beyond Its Antioxidant Activity.

This study aimed to evaluate if Simvastatin can reduce, and/or prevent, Doxorubicin (Doxo)-induced cardiotoxicity. H9c2 cells were treated with Simvastatin (10 µM) for 4 h and then Doxo (1 µM) was added, and the effects on oxidative stress, calcium homeostasis, and apoptosis were evaluated after 20 h. Furthermore, we evaluated the effects of Simvastatin and Doxo co-treatment on Connexin 43 (Cx43) expression and localization, since this transmembrane protein forming gap junctions is widely involved in cardioprotection. Cytofluorimetric analysis showed that Simvastatin co-treatment significantly reduced Doxo-induced cytosolic and mitochondrial ROS overproduction, apoptosis, and cytochrome c release. Spectrofluorimetric analysis performed by means of Fura2 showed that Simvastatin co-treatment reduced calcium levels stored in mitochondria and restored cytosolic calcium storage. Western blot, immunofluorescence, and cytofluorimetric analyses showed that Simvastatin co-treatment significantly reduced Doxo-induced mitochondrial Cx43 over-expression and significantly increased the membrane levels of Cx43 phosphorylated on Ser368. We hypothesized that the reduced expression of mitochondrial Cx43 could justify the reduced levels of calcium stored in mitochondria and the consequent induction of apoptosis observed in Simvastatin co-treated cells. Moreover, the increased membrane levels of Cx43 phosphorylated on Ser368, which is responsible for the closed conformational state of the gap junction, let us to hypothesize that Simvastatin leads to cell-to-cell communication interruption to block the propagation of Doxo-induced harmful stimuli. Based on these results, we can conclude that Simvastatin could be a good adjuvant in Doxo anticancer therapy. Indeed, we confirmed its antioxidant and antiapoptotic activity, and, above all, we highlighted that Simvastatin interferes with expression and cellular localization of Cx43 that is widely involved in cardioprotection.

Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy

BackgroundKRAS mutations are fraught with the progression of colorectal cancer and resistance to chemotherapy. There are pathways such as extracellular regulated protein kinase 1/2 (ERK1/2) and Akt downstream and farnesylation and geranylgeranylation upstream that are activated upon mutated KRAS. Previous studies have shown that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are effective to treat KRAS mutated colorectal cancer cells. Increased doses of oxaliplatin (L-OHP), a well-known alkylating chemotherapeutic drug, causes side effects such as peripheral neuropathy due to ERK1/2 activation in spinal cords. Hence, we examined the combinatorial therapeutic efficacy of statins and L-OHP to reduce colorectal cancer cell growth and abrogate neuropathy in mice.MethodsCell survival and confirmed apoptosis was assessed using WST-8 assay and Annexin V detection kit. Detection of phosphorylated and total proteins was analyzed the western blotting. Combined effect of simvastatin and L-OHP was examined the allograft mouse model and L-OHP-induced neuropathy was assessed using cold plate and von Frey filament test.ResultsIn this study, we examined the effect of combining statins with L-OHP on induction of cell death in colorectal cancer cell lines and improvement of L-OHP-induced neuropathy in vivo. We demonstrated that combined administration with statins and L-OHP significantly induced apoptosis and elevated the sensitivity of KRAS-mutated colorectal cancer cells to L-OHP. In addition, simvastatin suppressed KRAS prenylation, thereby enhancing antitumor effect of L-OHP through downregulation of survivin, XIAP, Bcl-xL, and Bcl-2, and upregulation of p53 and PUMA via inhibition of nuclear factor of κB (NF-κB) and Akt activation, and induction of c-Jun N-terminal kinase (JNK) activation in KRAS-mutated colorectal cancer cells. Moreover, simvastatin enhanced the antitumor effects of L-OHP and suppressed L-OHP-induced neuropathy via ERK1/2 activation in vivo.ConclusionTherefore, statins may be therapeutically useful as adjuvants to L-OHP in KRAS-mutated colorectal cancer and may also be useful in the treatment of L-OHP-induced neuropathy.