Effects Of Simvastatin Research Articles

Comparative Study on Effect of Fenofibrate and Simvastatin in Streptozotocin Induced Diabetic Albino Rats

Comparative Study on Effect of Fenofibrate and Simvastatin in Streptozotocin Induced Diabetic Albino Rats

Simvastatin Prevents Liver Microthrombosis and Sepsis Induced Coagulopathy in a Rat Model of Endotoxemia.

Background: Endotoxemia causes endothelial dysfunction and microthrombosis, which are pathogenic mechanisms of coagulopathy and organ failure during sepsis. Simvastatin has potential anti-thrombotic effects on liver endothelial cells. We investigated the hemostatic changes induced by lipopolysaccharide (LPS) and explored the protective effects of simvastatin against liver vascular microthrombosis. Methods and results: We compared male Wistar rats exposed to LPS (5 mg/kg one i.p. dose) or saline in two experimental protocols—placebo (vehicle) and simvastatin (25 mg/kg die, orally, for 3 days before LPS). Morphological studies were performed by light- and electron-microscopy analyses to show intravascular fibrin deposition, vascular endothelial structure and liver damage. Peripheral- and organ-hemostatic profiles were analyzed using whole blood viscoelastometry by ROTEM, liver biopsy and western-blot/immunohistochemistry of thrombomodulin (TM), as well as immunohistochemistry of the von Willebrand factor (VWF). LPS-induced fibrin deposition and liver vascular microthrombosis were combined with a loss of sinusoidal endothelial TM expression and VWF-release. These changes were associated with parenchymal eosinophilia and necrosis. ROTEM analyses displayed hypo-coagulability in the peripheral blood that correlated with the degree of intrahepatic fibrin deposition (p < 0.05). Simvastatin prevented LPS-induced fibrin deposition by preserving TM expression in sinusoidal cells and completely reverted the peripheral hypo-coagulability caused by endotoxemia. These changes were associated with a significant reduction of liver cell necrosis without any effect on eosinophilia. Conclusions: Simvastatin preserves the antithrombotic properties of sinusoidal endothelial cells disrupted by LPS, deserving pharmacological properties to contrast sepsis-associated coagulopathy and hepatic failure elicited by endotoxemia

Simvastatin Inhibits Tumor Growth and Migration by Mediating Caspase-1–Dependent Pyroptosis in Glioblastoma Multiforme

ObjectivesGlioblastoma multiforme (GBM) is the most common and lethal central nervous system cancer and is associated with a poor prognosis. Simvastatin, a kind of widely used hypolipidemic agent, has been investigated for its beneficial effects on various types of cancers. The main purpose of this paper is to investigate the potential inhibitory effects of simvastatin on GBM and the underlying mechanism. MethodsCell viability and cell cycle of simvastatin-treated U87 and U251 cells were determined by CCK8 assay and flow cytometry, respectively. Additionally, we assessed cell migration and invasion abilities using a wound-healing assay and transwell assay. mRNA and protein expression patterns of caspase-1 and its markers nucleotide-binding oligomerization domain-like receptor pyrin domain–containing 3 (NLRP3) and IL-1β in different conditions were detected by real-time polymerase chain reaction, immunofluorescence staining, and Western blot. ResultsSimvastatin decreased the viability of GBM cells and inhibited cell migration and invasion in a dose-dependent manner. Moreover, suppression of pyroptosis, as characterized by decreased expression of caspase-1, NLRP3, and IL-1β, was observed. However, use of an miR-214 inhibitor reversed the simvastatin suppressive effect on GBM cells. ConclusionsSimvastatin inhibits GBM progression by suppressing caspase-1–dependent pyroptosis, regulated by miR-214.

Simvastatin and Muscle: Zebrafish and Chicken Show that the Benefits are not Worth the Damage.

Simvastatin is one of the most common medicines prescribed to treat human hypercholesterolemia. Simvastatin acts through the inhibition of cholesterol synthesis. Unfortunately, simvastatin causes unwanted side effects on muscles, such as soreness, tiredness, or weakness. Therefore, to understand the mechanism of action of simvastatin, it is important to study its physiological and structural impacts on muscle in varied animal models. Here we report on the effects of simvastatin on two biological models: zebrafish embryos and chicken muscle culture. In the last years, our group and others showed that simvastatin treatment in zebrafish embryos reduces fish movements and induces major structural alterations in skeletal muscles. We also showed that simvastatin and membrane cholesterol depletion induce major changes in proliferation and differentiation of muscle cells in chick muscle cultures. Here, we review and discuss these observations considering reported data on the use of simvastatin as a potential therapy for Duchenne muscular dystrophy.

The Effect of Simvastatin and Vitamin D Co-Administration on Rats Brain Function and Behavior: A Behavioral and Biochemical Study

Background &amp; Objective: The simvastatin (Sim) is a lipophilic statin and can cross the blood-brain barrier. The role of vitamin D (Vit D) in brain development and function has been supported over the past decade. This study aimed to evaluate the effect of simvastatin on memory and anxiety levels in healthy male rats.&#x0D; Materials &amp; Methods: In this experimental study, 36 male Wistar rats weighing 250-300 g were randomly divided into six groups (n=6) including control, Vit D (5 µg/kg/day; IP), Simvastatin (1 mg/kg/day; orally) (SimL), Simvastatin (10 mg/kg/day; orally) (SimH), SimL + Vit D and SimH + Vit D. After 28 days, at the end of the treatment, the behavioral anxiety test and memory behavioral test were performed. Then, the rats were euthanized, and oxidative stress markers of the brain, serum low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and cholesterol levels were investigated. Data were analyzed by SPSS 24 software and Tukey’s test.&#x0D; Results: Co-administration of simvastatin and vitamin D significantly increased working memory, catalase activity, total antioxidant capacity, HDL-C, and decreased anxiety levels, malondialdehyde (MDA) concentration, cholesterol, and LDL-C compared to the control group (p&lt;0.05). However, the administration of simvastatin and vitamin D alone did not significantly change the mentioned parameters compared to the control group (p&gt;0.05).&#x0D; Conclusion: Co-administration of simvastatin and vitamin D can improve brain function by reducing oxidative stress and cholesterol levels.

Simvastatin Downregulates Cofilin and Stathmin to Inhibit Skeletal Muscle Cells Migration.

Statins are the most effective therapeutic agents for reducing cholesterol synthesis. Given their widespread use, many adverse effects from statins have been reported; of these, musculoskeletal complications occurred in 15% of patients after receiving statins for 6 months, and simvastatin was the most commonly administered statin among these cases. This study investigated the negative effects of simvastatin on skeletal muscle cells. We performed RNA sequencing analysis to determine gene expression in simvastatin-treated cells. Cell proliferation and migration were examined through cell cycle analysis and the transwell filter migration assay, respectively. Cytoskeleton rearrangement was examined through F-actin and tubulin staining. Western blot analysis was performed to determine the expression of cell cycle-regulated and cytoskeleton-related proteins. Transfection of small interfering RNAs (siRNAs) was performed to validate the role of cofilin and stathmin in the simvastatin-mediated inhibition of cell migration. The results revealed that simvastatin inhibited the proliferation and migration of skeletal muscle cells and affected the rearrangement of F-actin and tubulin. Simvastatin reduced the expression of cofilin and stathmin. The knockdown of both cofilin and stathmin by specific siRNA synergistically impaired cell migration. In conclusion, our results indicated that simvastatin inhibited skeletal muscle cell migration by reducing the expressions of cofilin and stathmin.

Simvastatin is associated with superior lipid and glycaemic control to atorvastatin and reduced levels of incident Type 2 diabetes, in men and women, in the UK Biobank.

IntroductionCardiovascular disease (CVD) is the leading cause of mortality in people with Type 2 diabetes mellitus (T2DM). Statins reduce low‐density lipoproteins and positively affect CVD outcomes. Statin type and dose have differential effects on glycaemia and risk of incident T2DM; however, the impact of gender, and of individual drugs within the statin class, remains unclear.AimTo compare effects of simvastatin and atorvastatin on lipid and glycaemic control in men and women with and without T2DM, and their association with incident T2DM.MethodsThe effect of simvastatin and atorvastatin on lipid and glycaemic control was assessed in the T2DM DiaStrat cohort. Prescribed medications, gender, age, BMI, diabetes duration, blood lipid profile and HbA1c were extracted from Electronic Care Record, and compared in men and women prescribed simvastatin and atorvastatin. Analyses were replicated in the UKBiobank in those with and without T2DM. The association of simvastatin and atorvastatin with incident T2DM was also investigated in the UKBiobank. Cohorts where matched for age, BMI and diabetes duration in men and women, in the UKBioBank analysis, where possible.ResultsSimvastatin was associated with better LDL (1.6 ± 0.6 vs 2.1 ± 0.9 mmol/L, p < .01) and total cholesterol (3.6 ± 0.7 vs 4.2 ± 1.0 mmol/L, p < .05), and glycaemic control (62 ± 17 vs 67 ± 19 mmol/mol, p < .059) than atorvastatin specifically in women in the DiaStrat cohort. In the UKBiobank, both men and women prescribed simvastatin had better LDL (Women: 2.6 ± 0.6 vs 2.6 ± 0.7 mmol/L, p < .05; Men: 2.4 ± 0.6 vs 2.4 ± 0.6, p < .01) and glycaemic control (Women:54 ± 14 vs 56 ± 15mmol/mol, p < .05; Men, 54 ± 14 vs 55 ± 15 mmol/mol, p < .01) than those prescribed atorvastatin. Simvastatin was also associated with reduced risk of incident T2DM in both men and women (p < .0001) in the UKBiobank.ConclusionsSimvastatin is associated with superior lipid and glycaemic control to atorvastatin in those with and without T2DM, and with fewer incident T2DM cases. Given the importance of lipid and glycaemic control in preventing secondary complications of T2DM, these findings may help inform prescribing practices.

Neuroendocrine pathways at risk? Simvastatin induces inter and transgenerational disruption in the keystone amphipod Gammarus locusta.

The primary focus of environmental toxicological studies is to address the direct effects of chemicals on exposed organisms (parental generation - F0), mostly overlooking effects on subsequent non-exposed generations (F1 and F2 - intergenerational and F3 transgenerational, respectively). Here, we addressed the effects of simvastatin (SIM), one of the most widely prescribed human pharmaceuticals for the primary treatment of hypercholesterolemia, using the keystone crustacean Gammarus locusta. We demonstrate that SIM, at environmentally relevant concentrations, has significant inter and transgenerational (F1 and F3) effects in key signaling pathways involved in crustaceans' neuroendocrine regulation (Ecdysteroids, Catecholamines, NO/cGMP/PKG, GABAergic and Cholinergic signaling pathways), concomitantly with changes in apical endpoints, such as depressed reproduction and growth. These findings are an essential step to improve hazard and risk assessment of biological active compounds, such as SIM, and highlight the importance of studying the transgenerational effects of environmental chemicals in animals' neuroendocrine regulation.

Evaluation of the effect of Simvastatin Therapy on Bone remodeling in Rats

Objective: The aim of this study was to evaluate the effect of simvastatin on the bone remolding markers in rats (experimental study). Materials and methods: The study involved 18 male Wistar rats, they were divided into three groups: Group I (n=6; control group), Group II (n=6; was administrated 7.5 mg/kg/ dexamethasone intra muscular for 2 months served as a model of osteoporosis [op]), Group III (n=6;was administered 7.5 mg/kg/ dexamethasone intra muscular for 2month and treated orally with 8mg/kg of simvastatin).After 8 weeks, serum acid phosphatase was determined for the three group. Results: The levels of serum acid phosphatase were notably elevated in the [op] group. Administration of simvastatin produced a significant decrease in the levels of serum acid phosphatase. Conclusion: simvastatin was able to decrease the rate of bone resorption in an animal model of osteoporosis induced by dexamethasone.

Amelioration of Endotoxin-Induced Acute Lung Injury and Alveolar Epithelial Cells Apoptosis by Simvastatin Is Associated with Up-Regulation of Survivin/NF-kB/p65 Pathway.

Disruption of the alveolar–endothelial barrier caused by inflammation leads to the progression of septic acute lung injury (ALI). In the present study, we investigated the beneficial effects of simvastatin on the endotoxin lipopolysaccharide (LPS)-induced ALI and its related mechanisms. A model of ALI was induced within experimental sepsis developed by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment (10–40 mg/kg orally). The severity of the lung tissue inflammatory injury was expressed as pulmonary damage scores (PDS). Alveolar epithelial cell apoptosis was confirmed by TUNEL assay (DNA fragmentation) and expressed as an apoptotic index (AI), and immunohistochemically for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL, an inhibitor of apoptosis, survivin, and transcriptional factor, NF-kB/p65. Severe inflammatory injury of pulmonary parenchyma (PDS 3.33 ± 0.48) was developed after the LPS challenge, whereas simvastatin significantly and dose-dependently protected lung histology after LPS (p < 0.01). Simvastatin in a dose of 40 mg/kg showed the most significant effects in amelioration alveolar epithelial cells apoptosis, demonstrating this as a marked decrease of AI (p < 0.01 vs. LPS), cytochrome C, and cleaved caspase-3 expression. Furthermore, simvastatin significantly enhanced the expression of Bcl-xL and survivin. Finally, the expression of survivin and its regulator NF-kB/p65 in the alveolar epithelium was in strong positive correlation across the groups. Simvastatin could play a protective role against LPS-induced ALI and apoptosis of the alveolar–endothelial barrier. Taken together, these effects were seemingly mediated by inhibition of caspase 3 and cytochrome C, a finding that might be associated with the up-regulation of cell-survival survivin/NF-kB/p65 pathway and Bcl-xL.

Pleiotropic Effects of Simvastatin and Losartan in Preclinical Models of Post-Traumatic Elbow Contracture.

Elbow trauma can lead to post-traumatic joint contracture (PTJC), which is characterized by loss of motion associated with capsule/ligament fibrosis and cartilage damage. Unfortunately, current therapies are often unsuccessful or cause complications. This study aimed to determine the effects of prophylactically administered simvastatin (SV) and losartan (LS) in two preclinical models of elbow PTJC: an in vivo elbow-specific rat injury model and an in vitro collagen gel contraction assay. The in vivo elbow rat (n = 3–10/group) injury model evaluated the effects of orally administered SV and LS at two dosing strategies [i.e., low dose/high frequency/short duration (D1) vs. high dose/low frequency/long duration (D2)] on post-mortem elbow range of motion (via biomechanical testing) as well as capsule fibrosis and cartilage damage (via histopathology). The in vitro gel contraction assay coupled with live/dead staining (n = 3–19/group) evaluated the effects of SV and LS at various concentrations (i.e., 1, 10, 100 µM) and durations (i.e., continuous, short, or delayed) on the contractibility and viability of fibroblasts/myofibroblasts [i.e., NIH3T3 fibroblasts with endogenous transforming growth factor-beta 1 (TGFβ1)]. In vivo, no drug strategy prevented elbow contracture biomechanically. Histologically, only SV-D2 modestly reduced capsule fibrosis but maintained elevated cellularity and tissue hypertrophy, and both SV strategies lessened cartilage damage. SV modest benefits were localized to the anterior region, not the posterior, of the joint. Neither LS strategy had meaningful benefits in capsule nor cartilage. In vitro, irrespective of the presence of TGFβ1, SV (≥10 μM) prevented gel contraction partly by decreasing cell viability (100 μM). In contrast, LS did not prevent gel contraction or affect cell viability. This study demonstrates that SV, but not LS, might be suitable prophylactic drug therapy in two preclinical models of elbow PTJC. Results provide initial insight to guide future preclinical studies aimed at preventing or mitigating elbow PTJC.

Simvastatin inhibits stem cell proliferation in human leiomyoma via TGF‐β3 and Wnt/β‐Catenin pathways

Uterine leiomyoma (UL) is the most common gynaecologic tumour, affecting an estimated 70 to 80% of women. Leiomyomas develop from the transformation of myometrial stem cells into leiomyoma stem (or tumour‐initiating) cells. These cells undergo self‐renewal and differentiation to mature cells, both are necessary for the maintenance of tumour stem cell niche and tumour growth, respectively. Wnt/β‐catenin and TGF‐β/SMAD pathways, both overactive in UL, promote stem cell self‐renewal, crosstalk between stem and mature cells, cellular proliferation, extracellular matrix (ECM) accumulation and drive overall UL growth. Recent evidence suggests that simvastatin, an antihyperlipidemic drug, may have anti‐leiomyoma properties. Herein, we investigated the effects of simvastatin on UL stem cells. We isolated leiomyoma stem cells by flow cytometry using DyeCycle Violet staining and Stro‐1/CD44 surface markers. We found that simvastatin inhibits proliferation and induces apoptosis in UL stem cells. In addition, it also suppressed the expression of the stemness markers Nanog, Oct4 and Sox2. Simvastatin significantly decreased the production of the key ECM proteins, collagen 1 and fibronectin. Finally, it inhibited genes and/or proteins expression of TGF‐β1, 2 and 3, SMAD2, SMAD4, Wnt4, β‐Catenin, LRP6, AXIN2 and Cyclin D1 in UL stem cells, all are key drivers of the TGF‐β3/SMAD2 and Wnt4/β‐Catenin pathways. Thus, we have identified a novel stem cell‐targeting anti‐leiomyoma simvastatin effect. Further studies are needed to replicate these findings in vivo.

The Effect of Simvastatin on Acute Phase Functional Outcome of Ischemic Stroke

Introduction: Stroke is one of the leading causes of death and disability worldwide, and especially in Indonesia. Several studies showed the pleiotropic and neuroprotective effect of simvastatin in addition to lowering blood cholesterol levels. Objective: This trial was conducted to investigate if the administration of simvastatin in acute ischemic stroke management can improve functional outcomes. Methods: This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in patients with acute ischemic stroke with an NIHSS score of 4-14. Participants were randomly assigned to receive 40 mg of simvastatin or placebo for seven days. The NIHSS scale was compared on admission day, 4th and 8th day after administration of simvastatin between the two groups. Results: 52 individuals were randomized: 28 to simvastatin and 24 to placebo. There was no significant improvement of functional outcome between the two groups (p &gt; 0.05). Conclusion: Administration of simvastatin had no significant effect on outcome (measured by NIHSS) in patients with acute ischemic stroke.

DIABETIC CARDIAC AUTONOMIC NEUROPATHY: SIMVASTATIN, INSULIN RESISTANCE AND LIPIDS

Treatment of diabetic cardiac autonomic neuropathy (CAN) is a complex process, that includes: lifestyle modification; reducing of insulin resistance (IR); optimal glycemic control; management of diabetic dyslipidemia; antioxidants; vitamins; treatment of myocardial metabolic abnormalities; thrombosis and others. The aim of study was to investigate the effects of simvastatin on insulin resistance and blood lipid profile parameters in patients with type 2 diabetes mellitus (T2DM) and the definite stage of cardiac autonomic neuropathy. The study involved 107 patients with T2DM among them 16 patients without CAN, 19 with subclinical stage of CAN and 72 with definite CAN. Median age of patients was 53.6 ± 0.41 yrs, disease duration - 4.12 ± 0.24 yrs and median glycated hemoglobin (HbA1c) - 7.01% ± 0.09%. The control group included 14 almost healthy people without DM. Patients with definite CAN were allocated into two treatment groups: 1st group - 22 patients received standard hypoglycemic therapy and simvastatin 20 mg/day; 2nd group - control (n = 15). The duration of the study was 3 mos. The concentrations of glucose, HbA1c, immunoreactive insulin (IRI) in the blood were determined. Lipid metabolism was assessed by the concentration of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) measurements. The IR index (HOMA-IR), atherogenic coefficient (AC), TG/HDL-C parameters, and TG-glucose (TyG) index were calculated. It was established that in patients with T2DM with subclinical stage of CAN there was statistically significant increase in the parameters of HbA1c, IRI, TC, TG and HOMA-IR, AC, TyG indices and decrease of TG/HDL-C and HDL-C compared to control; increase of IRI, TG, TG/HDL-C and TyG indices compared to patients with T2DM without CAN. The definite stage of CAN is characterized by an increase of HbA1c, IRI, TC, LDL-C levels and HOMA-IR, AC indices and a significant decrease in the concentration of HDL-C (compared to patients with subclinical CAN). As a result of our study, we found out that prescription of simvastatin to patients with definite stage of CAN was accompanied by a statistically significant decrease in the concentration of TC, LDL-C, TG and an increase in the content of HDL-C (compared to 2nd, control group). Obtained results justify the appropriateness of statins prescription to patients with T2DM and the definite stage of CAN.

Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial.

Background and ObjectivesImproved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.MethodsThe MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.ResultsA total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.DiscussionWe found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.Trial Registration InformationMS-STAT: NCT00647348.Classification of EvidenceThis study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

The evaluation of cytotoxicity and cytokine IL-6 production of root canal sealers with and without the incorporation of simvastatin: an invitro study

BackgroundFreshly mixed root canal sealers when proximate the periapical tissues, trigger varying degrees of cytotoxicity/inflammatory reactions. Simvastatin, a class of the drug statin, is a widely used cholesterol-lowering agent with additional anti-inflammatory activities. This study assessed the effects of simvastatin on cytotoxicity and the release of IL-6 (Interleukin-6) production when incorporated in zinc oxide eugenol and methacrylate resin-based sealers.MethodsExperimental groups consisted of conventional zinc oxide eugenol and methacrylate based-EndoREZ sealers (ZE & ER respectively) and 0.5 mg/mL simvastatin incorporated sealers (ZES & ERS). L929 mouse fibroblast cells were exposed to freshly mixed experimental sealers and evaluated for cytotoxicity (MTT assay) and inflammation levels (inflammatory marker IL-6 for ELISA) at various time intervals (0h, 24h and 7th day). The values were compared to the cell control (CC; L929 cells alone) and solvent control (SC; L929 cells + DMSO) groups. All the experiments were conducted in triplicates and subjected to statistical analysis using IBM SPSS Statistics software. Non parametric tests were conducted using Kruskal-Wallis and Friedman tests for inter-group and intra-group comparisons respectively. Pairwise comparison was conducted by post hoc Dunn test followed by Bonferroni correction. P values < 0.05 were considered statistically significant.ResultsAll the experimental groups (ZE, ER, ZES, ERS) exhibited varying degree of cytotoxicity and IL-6 expression compared to the control groups CC and SC. The cell viability for ZE and ER decreased on day 7 as compared to 24 h. ZES and ERS had higher viable cells (75.93% & 79.90%) compared to ZE and ER (54.39% & 57.84%) at all time periods. Increased expression of IL-6 was observed in ZE & ER (25.49 pg/mL & 23.14 pg/mL) when compared to simvastatin incorporated ZE & ER (ZES-12.70 pg/mL & ERS-14.68 pg/mL) at all time periods. Highest level of cytotoxicity and inflammation was observed in ZE compared to all the other groups on day 7.ConclusionsAddition of 0.5 mg/mL of simvastatin to the sealers (ZES and ERS) decreased the cytotoxicity in the freshly mixed state and reduces their inflammatory effect.

Simvastatin Improves Myocardial Ischemia Reperfusion Injury through KLF-Regulated Alleviation of Inflammation.

Objective To clarify the protective effect of simvastatin on myocardial ischemia reperfusion injury (MIRI) and the underlying mechanism. Materials and Methods The MIRI model in rats was firstly constructed. Twenty-four male rats were randomly assigned into the sham group, ischemia-reperfusion (I/R) group, and simvastatin group, with 8 rats in each group. Contents of superoxide dismutase (SOD) and malondialdehyde (MDA), as well as serum levels of CK and inflammatory factors, in rats were determined by the enzyme-linked immunosorbent assay (ELISA). Lactate dehydrogenase (LDH) activity in the three groups was examined. Through flow cytometry and Cell Counting Kit-8 (CCK-8) assay, apoptosis and viability in each group were detected, respectively. Relative levels of HMGB1, Kruppel-like factor 2 (KLF2), eNOS, and thrombomodulin (TM) were finally determined. Results Simvastatin treatment markedly enhanced SOD activity and reduced contents of MDA, LDH, and creatine kinase (CK) in MIRI rats. The increased apoptosis and decreased viability following MIRI were partially reversed by simvastatin treatment. Besides, MIRI resulted in the upregulation of inflammatory factors and chemokines. Their elevations were abolished by simvastatin. In MIRI rats, simvastatin upregulated KLF2 and p-eNOS. Conclusions Simvastatin protects inflammatory response at post-MIRI through upregulating KLF2, thus improving cardiac function.

Investigation of the inhibitory effects of simvastatin in RPMI 2650: An in-vitro study

Objective: The present study was carried out to investigate the antiproliferative effects of simvastatin involving Human Squamous Nasal Cell Carcinoma (RPMI 2650 cell line), which is one of the most common head and neck cancers with the highest incidence and mortality rates in Asian countries. The anti-cancer effects of simvastatin in NPC have not yet been investigated in depth, hence it will be illustrated in the present study. Materials and methods: The cells were treated with various concentrations of Simvastatin in a dose dependent (0, 0.1, 0. 4, 3.0 mg/ml) and time dependent (24, 48 and 72 hours) manner. The cancer cell viability was then assessed by using MTT assay at absorbance of 590 nm. Results: Simvastatin induced reduction in cell viability number and induced apoptosis in RPMI 2650 cell line. Simvastatin for 72 h significantly reduced cell growth as compared to 48 and 24 h pre-incubation with simvastatin treatment. After 72 h incubation with 0.1 mg/ml, 0.4 mg/ml and 3.0 mg/ml simvastatin, the cell viability decreased from 100% in treated control cells to 23%, 21% and 14% respectively. Conclusions: This finding demonstrate the potential of simvastatin and probably may have therapeutic benefit for NPC cell growth.

Nano delivery of simvastatin targets liver sinusoidal endothelial cells to remodel tumor microenvironment for hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) developed in fibrotic liver does not respond well to immunotherapy, mainly due to the stromal microenvironment and the fibrosis-related immunosuppressive factors. The characteristic of liver sinusoidal endothelial cells (LSECs) in contributing to fibrosis and orchestrating immune response is responsible for the refractory to targeted therapy or immunotherapy of HCC. We aim to seek a new strategy for HCC treatment based on an old drug simvastatin which shows protecting effect on LSEC.MethodThe features of LSECs in mouse fibrotic HCC model and human HCC patients were identified by immunofluorescence and scanning electron microscopy. The effect of simvastatin on LSECs and hepatic stellate cells (HSCs) was examined by immunoblotting, quantitative RT-PCR and RNA-seq. LSEC-targeted delivery of simvastatin was designed using nanotechnology. The anti-HCC effect and toxicity of the nano-drug was evaluated in both intra-hepatic and hemi-splenic inoculated mouse fibrotic HCC model.ResultsLSEC capillarization is associated with fibrotic HCC progression and poor survival in both murine HCC model and HCC patients. We further found simvastatin restores the quiescence of activated hepatic stellate cells (aHSCs) via stimulation of KLF2-NO signaling in LSECs, and up-regulates the expression of CXCL16 in LSECs. In intrahepatic inoculated fibrotic HCC mouse model, LSEC-targeted nano-delivery of simvastatin not only alleviates LSEC capillarization to regress the stromal microenvironment, but also recruits natural killer T (NKT) cells through CXCL16 to suppress tumor progression. Together with anti-programmed death-1-ligand-1 (anti-PD-L1) antibody, targeted-delivery of simvastatin achieves an improved therapeutic effect in hemi-splenic inoculated advanced-stage HCC model.ConclusionsThese findings reveal an immune-based therapeutic mechanism of simvastatin for remodeling immunosuppressive tumor microenvironment, therefore providing a novel strategy in treating HCC.Graphical

Beneficial effect of simvastatin on human umbilical vein endothelial cells gap junctions induced by TNF-α

ABSTRACT Although simvastatin has been shown to inhibit vascular permeability, which might be amplified via gap junction intercellular communication (GJIC), the underlying mechanism of action remains unclear. In the present study, we investigated the effects and mechanisms of simvastatin on endothelial cells GJIC. Specifically, human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-α (10 ng/mL) alone or in combination with simvastatin (5 µM), and their effects on vascular endothelial cell GJIC tested via the scrape loading/dye transfer (SL/DT) assay. Next, we performed immunofluorescence, real-time PCR and western blot assays to analyze expression of Cx37, Cx40 and Cx43 in HUVECs. Results showed that GJIC activity in HUVECs was markedly elevated in HUVECs treated with TNF-α in combination with simvastatin. In addition, simvastatin treatment significantly upregulated expression of Cx37 and Cx40 but downregulated Cx43 mRNAs and proteins. Taken together, these marked changes indicated that simvastatin exerts its regulatory effects on gap junction function by upregulating Cx37 and Cx40 and downregulating Cx43 expression.