Effects of Simvastatin-Loaded Nanomicelles on the Early Preservation of Tooth Extraction Sites.

Object: The present study intended to evaluate the effect of simvastatin-loaded nanomicelles (SVNs) on promoting new bone formation and reducing alveolar ridge resorption at the tooth extraction sites at the early healing of the extraction sockets. Methods: SVNs were synthesized using a dialysis method. The rabbit tooth extraction model was established, SVNs and simvastatin (SV) were loaded on gelatin sponge and inserted into the extraction socket. CBCT scans were performed at 0, 2, and 4 weeks postoperatively to evaluate bone formation and alveolar ridge absorption in the extraction sockets. And all the animals were sacrificed and the mandibles were harvested. And HE staining and Masson staining were used for histological evaluation of the bone formation in the extraction sockets. Results: Radiographic evaluation showed that compared with the blank control group, at 2 and 4 weeks after extraction, SVNs increased the new bone density in the extraction sockets by 75.7% and 96.5%, and reduced the absorption rate of alveolar ridge length at the extraction sites by 60.8% and 49.1%, respectively. Histological evaluation showed that SVNs significantly improved the maturation of new bone tissue in the extraction sockets. Conclusion: SVNs can significantly accelerate healing and effectively reduce the absorption of alveolar ridge at the extraction sites in the early stage of tooth extraction socket healing.

Delayed simvastatin treatment improves neurological recovery after cryogenic traumatic brain injury through downregulation of ELOVL1 by inhibiting mTOR signaling.

Statins are well-tolerated and widely available lipid-lowering medications with neuroprotective effects against traumatic brain injury (TBI). However, whether delayed statin therapy starting in the subacute phase promotes recovery after TBI is unknown. Elongation of the very long-chain fatty acid protein 1 (ELOVL1) is involved in astrocyte-mediated neurotoxicity, but its role in TBI and the relationship between ELOVL1 and statins are unclear. We hypothesized that delayed simvastatin treatment promotes neurological functional recovery after TBI by regulating the ELOVL1-mediated production of very long-chain fatty acids (VLCFAs). ICR male mice received daily intragastric administration of 1, 2 or 5 mg/kg simvastatin on Days 1-14, 3-14, 5-14, or 7-14 after cryogenic TBI (cTBI). The results showed that simvastatin promoted motor functional recovery in a dose-dependent manner, with a wide therapeutic window of at least 7 days postinjury. Meanwhile, simvastatin inhibited astrocyte and microglial overactivation and glial scar formation, and increased total dendritic length, neuronal complexity and spine density on day 14 after cTBI. The up-regulation of ELOVL1 expression and saturated VLCFAs concentrations in the cortex surrounding the lesion caused by cTBI was inhibited by simvastatin, which was related to the inhibition of the mTOR signaling. Overexpression of ELOVL1 in astrocytes surrounding the lesion using HBAAV2/9-GFAP-m-ELOVL1-3xFlag-EGFP partially attenuated the benefits of simvastatin. These results showed that delayed simvastatin treatment promoted functional recovery and brain tissue repair after TBI through the downregulation of ELOVL1 expression by inhibiting mTOR signaling. Astrocytic ELOVL1 may be a potential target for rehabilitation after TBI.

Anticancer effects of simvastatin-loaded albumin nanoparticles on monolayer and spheroid models of breast cancer.

Breast cancer is a prominent cause of death among women and is distinguished by a high occurrence of metastasis. From this perspective, apart from conventional therapies, several alternative approaches have been researched and explored in recent years, including the utilization of nano-albumin and statin medications like simvastatin. The objective of this study was to prepare albumin nanoparticles incorporating simvastatin by the self-assembly method and evaluate their impact on breast cancer metastasis and apoptosis. The data showed the prepared nanoparticles have a diameter of 185 ± 24nm and a drug loading capacity of 8.85 %. The findings exhibit improved release in a lysosomal-like environment and under acidic pH conditions. MTT data showed that nanoparticles do not exhibit a dose-dependent effect on cells. Additionally, the results from MTT, flow cytometry, and qPCR analyses demonstrated that nanoparticles have a greater inhibitory and lethal effect on MDA-MB-231 cells compared to normal simvastatin. And cause cells to accumulate in the G0/G1 phase, initiating apoptotic pathways by inhibiting cell cycle progression. Nanoparticles containing simvastatin can prevent cell invasion and migration in both monolayer and spheroid models, as compared to simvastatin alone, at microscopic levels and in gene expression. The obtained data clearly showed that, compared to simvastatin, nanoparticles containing simvastatin demonstrated significant efficacy in suppressing the growth, proliferation, invasion, and migration of cancer cells in monolayer (2D) and spheroid (3D) models.

Beneficial adjunctive effects of the 5HT3 receptor antagonist ondansetron on symptoms, function and cognition in early phase schizophrenia in a double-blind, 2 × 2 factorial design, randomised controlled comparison with simvastatin.

BACKGROUND: Variable benefits have been reported from the adjunctive use of simvastatin and the 5HT3 receptor antagonist, ondansetron, in patients with schizophrenia. We investigated their independent efficacy and possible synergy to improve negative symptoms of schizophrenia within a single trial. METHODS: A 6-month, randomised, double-blind, placebo-controlled trial with a 4-arm, 2 × 2 factorial design, in three centres in Pakistan. In total, 303 people with stable treated schizophrenia aged 18-65 were randomly allocated to add-on ondansetron, simvastatin, both or neither. The primary outcome was a Positive and Negative Syndrome Scale (PANSS) negative score at 3 and 6 months. RESULTS: Mixed model analysis and analysis of covariance revealed no main effects of simvastatin or ondansetron but a significant negative interaction between them (p = 0.03); when given alone, both drugs significantly reduced negative symptoms compared to placebo but they were ineffective in combination. Individual treatment effects versus placebo were -1.9 points (95%CIs -3.23, -0.49; p = 0.01) for simvastatin and -1.6 points for ondansetron (95%CIs -3.00, -0.14; p = 0.03). Combined treatment significantly increased depression and side effects. In those with less than the median 5 years of treatment, ondansetron improved all PANSS subscales, global functioning measures and verbal learning and fluency, whereas simvastatin did not. CONCLUSION: Small improvement in negative symptoms on simvastatin and ondansetron individually are not synergistic in combination in treating negative symptoms of schizophrenia. Ondansetron showed broad efficacy in patients on stable antipsychotic treatment within 5 years of illness. The findings suggest that ondansetron should be evaluated in patients at risk of psychosis or early in treatment.

Microsphere-Composite Hydrogel for Recruiting Stem Cells and Promoting Osteogenic Differentiation.

By recruiting stem cells into scaffolds and differentiating them into osteoblasts, stem cells can be mobilized to directly repair bone defects, which avoids a series of disadvantages of exogenous stem cell implantation. In this study, a microsphere-composite hydrogel for the recruitment and osteogenic differentiation of stem cells was constructed. Methacrylic anhydride modified gelatin (GelMA) and heparin (HepMA), as well as nanohydroxyapatite (nHAP), were used to prepare microspheres followed by adsorbing platelet-derived growth factor BB (PDGF-BB) whose loading efficiency was 53.7 ± 2.2%. Then the microspheres were compounded to the GelMA hydrogel encapsulated with simvastatin (SIM) to obtain microsphere-composite hydrogel GHnH-P@GS. GHnH-P@GS hydrogel could slowly release SIM and PDGF-BB, and the extents of release within 7 days were 44.1 ± 2.0% and 32.8 ± 1.1%. The synergistic effect of small molecule drugs and growth factors not only induced the recruitment of rabbit bone marrow-derived mesenchymal stem cells, but also promoted the osteogenic differentiation of stem cells, which was confirmed by experiments of cell migration, alkaline phosphatase, and alizarin red staining. Collectively, the microsphere-composite hydrogel GHnH-P@GS has a certain reference significance for the design of scaffolds for alveolar bone repair and regeneration.

Simvastatin induces ferroptosis and activates anti-tumor immunity to sensitize anti-PD-1 immunotherapy in microsatellite stable gastric cancer.

BACKGROUND: Gastric cancer (GC), especially the case with microsatellite stability (MSS) phenotype, has limited efficacy for immune checkpoint blockade (ICB) therapy. Metabolism reprogramming is newly recognized to affect tumor immune microenvironment (TIME). However, the relationship between metabolism reprogramming and immunotherapy for MSS GC has not been reported. METHODS: A metabolic stratification for GC was developed based on the glycolysis/cholesterol synthesis axis using the R package "ConsensusClusterPlus". The T cell inflamed score was used to define "immune-hot" and "immune-cold" phenotypes in MSS GC. The anti-tumor and immunological effects of simvastatin were explored using in vitro and in vivo experiments. RESULTS: Three metabolic subtypes were identified in GC patients, including cholesterol, glycolysis and quiescent subtypes. The cholesterol subtype was associated with poorer clinical features and higher tumor purity. Correspondingly, we demonstrated that simvastatin, a specific inhibitor of cholesterol synthesis, significantly inhibited the proliferation, migration, and induced ferroptosis in GC cells. Interestingly, simvastatin markedly inhibited tumor growth in immunocompetent mice, while no significant effect in immunodeficient mice. Upregulation of chemokines and increased recruitment of CD8+ T cells were observed after simvastatin treatment. Consistently, the cholesterol subtype exhibited a less inflamed TIME and coincided significantly with the "immune-cold" phenotype of MSS GC. Finally, we confirmed simvastatin enhanced PD-1 blockade efficacy via modulating the TIME and activating anti-tumor immunity in tumor-bearing mice. CONCLUSION: Our data revealed the significance of cholesterol synthesis in GC and demonstrated simvastatin served as a promising sensitizer for ICB therapy by inducing ferroptosis and anti-tumor immunity in MSS GC patients.

Elevated cerebrospinal fluid glial fibrillary acidic protein levels in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a rare, multiple malformation/intellectual disability disorder caused by pathogenic variants of DHCR7. DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol in the final step of cholesterol biosynthesis. This results in accumulation of 7DHC and a cholesterol deficiency. Although the biochemical defect is well delineated and multiple mechanisms underlying developmental defects have been explored, the post developmental neuropathological consequences of altered central nervous system sterol composition have not been studied. Preclinical studies suggest that astroglial activation may occur in SLOS. To determine if astroglial activation is present in individuals with SLOS, we quantified cerebrospinal fluid (CSF) glial fibrillary acidic protein using a Quanterix Simoa® GFAP Discovery Kit for SR-X™. Relative to an age-appropriate comparison group, we found that CSF GFAP levels were elevated 3.9-fold in SLOS (3980 ± 3732 versus 1010 ± 577 pg/ml, p = 0.0184). Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has previously been shown to increase expression of hypomorphic DHCR7 alleles and in a placebo-controlled trial improved serum sterol levels and decreased irritability. Using archived CSF samples from that prior study, we observed a significant decrease (p = 0.0119) in CSF GFAP levels in response to treatment with simvastatin. Although further work needs to be done to understand the potential contribution of neuroinflammation to SLOS neuropathology and cognitive dysfunction, these data confirm astroglial activation in SLOS and suggest that CSF GFAP may be a useful biomarker to monitor therapeutic responses.

Simvastatin-Loaded Polymeric Nanoparticles: Targeting Inflammatory Macrophages for Local Adipose Tissue Browning in Obesity Treatment.

Obesity is defined as chronic, low-grade inflammation within specific tissues. Given the escalating prevalence of obesity among individuals of all ages, obesity has reached epidemic proportions, posing an important public health challenge. Despite significant advancements in treating obesity, conventional approaches remain largely ineffective or involve severe side effects, thus underscoring the pressing need to explore and develop treatment approaches. Targeted and local immunomodulation using nanoparticles (NPs) can influence fat production and utilization processes. Statins, known for their anti-inflammatory properties, show the potential for mitigating obesity-related inflammation. A localized delivery option offers several advantages over oral and parenteral delivery methods. Here, we developed simvastatin (Sim) encapsulated within PLGA NPs (Sim-NP) for localized delivery of Sim to adipose tissues (ATs) for immunomodulation to treat obesity. In vitro experiments revealed the strong anti-inflammatory effects of Sim-NPs, which resulted in enhanced modulation of macrophage (MΦ) polarization and induction of AT browning. We then extended our investigation to an in vivo mouse model of high-fat-diet (HFD)-induced obesity. Sim-NP administration led to the controlled release of Sim within AT, directly impacting MΦ activity and inducing AT browning while inducing weight loss. Our findings demonstrated that Sim-NP administration effectively inhibited the progression of obesity-related inflammation, controlled white fat production, and enhanced AT modulation. These results highlight the potential of Sim-NP as a potent nanotherapy for treating obesity by modulating the immune system.

Simvastatin alleviates experimental autoimmune encephalomyelitis through regulating the balance of Th17 and Treg in mice.

The aim of this study was to elucidate the therapeutic effect of simvastatin on experimental autoimmune encephalomyelitis (EAE) by regulating the balance between Th17 and Treg cells in mice. C57BL/6 mice were randomly divided into four groups: normal group, EAE group, simvastatin (2 and 10 mg/kg) group, and AG490 group (with AG490 serving as the positive control). Neurological function scores of mice were assessed daily. The four groups received treatments of normal saline, normal saline, and simvastatin (2 and 10 mg/kg), respectively. In the AG490 group, mice were injected intraperitoneally with AG490 (1 mg) every other day, and treatment was halted after 3 weeks. The spinal cord was stained with hematoxylin and eosin (H&E), and immunohistochemical staining for retinoic acid receptor-related orphan receptor γ(RORγ) and Foxp3 (Foxp3) was performed. Spleen samples were taken for Th17 and Treg analysis using flow cytometry. The levels of interleukin-17 and transforming growth factor-ß (TGF-ß) were detected using enzyme-linked immunosorbent assay (ELISA). In the simvastatin and AG490 groups, recovery from neurological impairment was earlier compared to the EAE group, and the symptoms were notably improved. Both simvastatin and AG490 reduced focal inflammation, decreased RORγ-positive cell infiltration, and significantly increased the number of FOXP3-positive cells. The number of Th17 cells and the level of IL-17 in the spleen were decreased in the simvastatin and AG490 treatment groups, while the number of Treg cells and TGF-ß levels were significantly increased across all treatment groups. Simvastatin exhibits anti-inflammatory and immunomodulatory effects, potentially alleviating symptoms of neurological dysfunction of EAE. Regulating the balance between Th17 and Treg may represent a therapeutic mechanism for simvastatin in treating EAE.

The effects of simvastatin on the bone microstructure and mechanics of ovariectomized mice: a micro-CT and micro-finite element analysis study.

BACKGROUND: Osteoporosis is a major health concern for postmenopausal women, and the effect of simvastatin (Sim) on bone metabolism is controversial. This study aimed to investigate the effect of simvastatin on the bone microstructure and bone mechanical properties in ovariectomized (OVX) mice. METHODS: 24 female C57BL/6J mice (8-week-old) were randomly allocated into three groups including the OVX + Sim group, the OVX group and the control group. At 8 weeks after operation, the L4 vertebral bones were dissected completely for micro-Computed Tomography (micro-CT) scanning and micro-finite element analysis (µFEA). The differences between three groups were compared using ANOVA with a LSD correction, and the relationship between bone microstructure and mechanical properties was analyzed using linear regression. RESULTS: Bone volume fraction, trabecular number, connectivity density and trabecular tissue mineral density in the OVX + Sim group were significantly higher than those in the OVX group (P < 0.05). For the mechanical properties detected via µFEA, the OVX + Sim group had lower total deformation, equivalent elastic strain and equivalent stress compared to the OVX group (P < 0.05). In the three groups, the mechanical parameters were significantly correlated with bone volume fraction and trabecular bone mineral density. CONCLUSIONS: The findings suggested that simvastatin had a potential role in the treatment of osteoporosis. The results of this study could guide future research on simvastatin and support the development of simvastatin-based treatments to improve bone health.

Serum tsncRNAs reveals novel potential therapeutic targets of Salvianolic Acid B on atherosclerosis.

BACKGROUND: Salvianolic Acid B (SalB) has been proven to delay the progression of atherosclerosis. The therapeutic mechanisms of this compound are unclear. A novel class of short non-coding RNAs, pre-transfer RNA and mature transfer RNA (tsncRNAs) may regulate gene expression. TsncRNAs-sequencing revealed novel therapeutic targets for SalB. This is the first study focusing on tsncRNAs to treat atherosclerosis using SalB. PURPOSE: To explore the potential mechanism of SalB treating atherosclerosis through tsncRNAs. METHODS: Five groups of mice were created at random: control group (CON), atherosclerosis model group (MOD), SalB with high dose-treated group (SABH), SalB with low dose-treated group (SABL), and Simvastatin-treated group (ST). Aortic sinus plaque, body weight and inflammatory cytokines were evaluated. The Illumina NextSeq equipment was used to do expression profiling of tsncRNAs from serum. The targets of tsncRNAs were then predicted using tRNAscan and TargetScan. The KEGG pathway and GO analysis were utilized to forecast the bioinformatics analysis. Potential tsncRNAs and associated mRNAs were validated using quantitative real-time PCR. RESULTS: tRF-Glu-CTC-014 and tRF-Gly-GCC-074 were markedly increased by SalB with high dose treatment and validated with quantitative real-time PCR. Two mRNAs SRF and Arrb related to tRF-Glu-CTC-014 changed consistently. GO analysis revealed that the altered target genes of the selected tsncRNAs were most enriched in protein binding and cellular process. Moreover, KEGG pathway analysis demonstrated that altered target genes of tsncRNAs were most enriched in MAPK signaling pathway. CONCLUSION: SalB can promote the expression of tRF-Glu-CTC-014 to treat atherosclerosis.

Assembly of Emulsion-Based Cascade Vehicles for Combination Oxygen-Chemotherapy in Diabetic Wound Healing.

High blood glucose and insufficient angiogenesis in diabetic wounds prevent healing, often leading to amputation or death. To address this, a multifunctional emulsion loaded with simvastatin and stabilized by enzymes was synthesized using ultrasound-assisted emulsification. This emulsion promotes angiogenesis and reduces blood glucose levels. Glucose oxidase and catalase at the emulsion interface catalyze a glucose cascading response, lowering the glucose concentration at the diabetic wound site and improving the wound microenvironment. Simvastatin in the emulsion further promotes angiogenesis. The emulsion significantly accelerated wound healing in diabetic rats, offering a promising approach to diabetic wound management.

The Effect of Statins on Markers of Breast Cancer Proliferation and Apoptosis in Women with In Situ or Early-Stage Invasive Breast Cancer.

Statins, inhibitors of HMG-CoA reductase, have been shown to have potential anti-carcinogenic effects through the inhibition of the mevalonate pathway and their impact on Ras and RhoGTAases. Prior studies have demonstrated a reduction in breast tumor proliferation, as well as increased apoptosis, among women with early-stage breast cancer who received statins between the time of diagnosis and the time of surgery. The aim of this study was to evaluate the impact of short-term oral high-potency statin therapy on the expression of markers of breast tumor proliferation, apoptosis, and cell cycle arrest in a window-of-opportunity trial. This single-arm study enrolled 24 women with stage 0-II invasive breast cancer who were administered daily simvastatin (20 mg) for 2-4 weeks between diagnosis and surgical resection. Pre- and post-treatment tumor samples were analyzed for fold changes in Ki-67, cyclin D1, p27, and cleaved caspase-3 (CC3) expression. Out of 24 enrolled participants, 18 received statin treatment and 17 were evaluable for changes in marker expression. There was no significant change in Ki-67 expression (fold change = 1.4, p = 0.597). There were, however, significant increases in the expression of cyclin D1 (fold change = 2.8, p = 0.0003), p27 cytoplasmic (fold change = 3.2, p = 0.025), and CC3 (fold change = 2.1, p = 0.016). Statin treatment was well tolerated, with two reported grade-1 adverse events. These results align with previous window-of-opportunity studies suggesting a pro-apoptotic role of statins in breast cancer. The increased expression of markers of cell cycle arrest and apoptosis seen in this window-of-opportunity study supports further investigation into the anti-cancer properties of statins in larger-scale clinical trials.

Hierarchical Chitin Nanocrystal-Based 3D Printed Dual-Layer Membranes Hydrogels: A Dual Drug Delivery Nano-Platform for Periodontal Tissue Regeneration.

Periodontitis, a prevalent chronic inflammatory disease caused by bacteria, poses a significant challenge to current treatments by merely slowing their progression. Herein, we propose an innovative solution in the form of hierarchical nanostructured 3D printed bilayer membranes that serve as dual-drug delivery nanoplatforms and provide scaffold function for the regeneration of periodontal tissue. Nanocomposite hydrogels were prepared by combining lipid nanoparticle-loaded grape seed extract and simvastatin, as well as chitin nanocrystals, which were then 3D printed into a bilayer membrane that possesses antimicrobial properties and multiscale porosity for periodontal tissue regeneration. The constructs exhibited excellent mechanical properties by adding chitin nanocrystals and provided a sustained release of distinct drugs over 24 days. We demonstrated that the bilayer membranes are cytocompatible and have the ability to induce bone-forming markers in human mesenchymal stem cells, while showing potent antibacterial activity against pathogens associated with periodontitis. In vivo studies further confirmed the efficacy of bilayer membranes in enhancing alveolar bone regeneration and reducing inflammation in a periodontal defect model. This approach suggests promising avenues for the development of implantable constructs that not only combat infections, but also promote the regeneration of periodontal tissue, providing valuable insights into advanced periodontitis treatment strategies.

Simvastatin Inhibits the Formation of NETs by the Mac-1 Pathway to Reduce Hepatic Ischemia-Reperfusion Injury under High-Fat Conditions.

BACKGROUND: Hyperlipidemia is one of the main causes of aggravated hepatic ischemia-reperfusion injury (IRI). Simvastatin (SIM), a lipid-lowering drug, has been shown to effectively alleviate IRI caused by hyperlipidemia. However, the regulatory mechanism by which SIM alleviates hyperlipidemia-induced hepatic IRI is still not clear. This study aims to explore the potential mechanisms of SIM in inhibiting hyperlipidemia-induced hepatic IRI, providing new therapeutic strategies for the alleviation of hepatic IRI. METHODS: An animal model of hyperlipidemia was induced by feeding mice a high-fat diet for 8 weeks. Subsequently, a hepatic IRI animal model of hyperlipidemia was established by occluding the hepatic artery and portal vein for one hour, followed by reperfusion for 6 or 12 h. Enzyme linked immunosorbent assay, Western blotting, hematoxylin-eosin (H&E) staining, immunohistochemistry, immunofluorescence, and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling assay, were used to evaluate liver injury, neutrophil extracellular traps (NETs) formation, and related molecular mechanisms. RESULTS: Hepatic IRI was accelerated by hyperlipidemia, which enhanced the expression of oxidized low-density lipoprotein (oxLDL) and Macrophage-1antigen (Mac-1), leading to the promotion of NETs formation and apoptosis of liver cells. The administration of simvastatin reduced the levels of oxLDL and Mac-1, decreased the formation of NETs, and alleviated hepatic IRI induced by hyperlipidemia. CONCLUSIONS: Simvastatin reduced hyperlipidemia-induced hepatic IRI by inhibiting the formation of NETs through the regulation of the oxLDL/Mac-1 pathway.

Simvastatin exerts neuroprotective effects post-stroke by ameliorating endoplasmic reticulum stress and regulating autophagy/apoptosis balance through pAMPK/LC3B/ LAMP2 axis.

Statins have evident neuroprotective role in acute ischemic stroke(AIS). The pleiotropic effect by which statin exerts neuroprotective effects, needs to be explored for considering it as one of the future adjunctive therapies in AIS. Endoplasmic reticulum(ER) assists cellular survival by reducing protein aggregates during ischemic conditions. ER-stress mediated apoptosis and autophagy are predominant reasons for neuronal death in AIS. Statin exerts both anti-apoptotic and anti-autophagic effect in neurons under ischemic stress. Although the influence of statin on autophagic neuroprotection has been reported with contradictory results. Thus, in our study we have attempted to understand its influence on autophagic protection while inhibiting upregulation of autophagic death(autosis). Previously we reported, statin can alleviate apoptosis via modulating cardiolipin mediated mitochondrial dysfunction. However, the clearance of damaged mitochondria is essential for prolonged cell survival. In our study, we tried to decipher the mechanism by which statin leads to neuronal survival by the mitophagy mediated cellular clearance. Simvastatin was administered to Sprague Dawley(SD) rats both as prophylaxis and treatment. The safety and efficacy of the statin was validated by assessment of infarct size and functional outcome. A reduction in oxidative and ER-stress were observed in both the prophylactic and treatment groups. The influence of statin on autophagy/apoptosis balance was evaluated by molecular assessment of mitophagy and cellular apoptosis. Statin reduces the post-stroke ER-stress and predominantly upregulated autophagolysosome mediated mitophagy than apoptotic cell death by modulating pAMPK/LC3B/LAMP2 axis. Based on the above findings statin could be explored as an adjunctive therapy for AIS in future.

Simvastatin alleviates glymphatic system damage via the VEGF-C/VEGFR3/PI3K-Akt pathway after experimental intracerebral hemorrhage.

Current clinical practice primarily relies on surgical intervention to remove hematomas in patients with intracerebral hemorrhage (ICH), given the lack of effective drug therapies. Previous research indicates that simvastatin (SIM) may enhance hematoma absorption and resolution in the acute phase of ICH, though the precise mechanisms remain unclear. Recent findings have highlighted the glymphatic system (GS) as a crucial component in intracranial cerebrospinal fluid circulation, playing a significant role in hematoma clearance post-ICH. This study investigates the link between SIM efficacy in hematoma resolution and the GS. Our experimental results show that SIM alleviates GS damage in ICH-induced rats, resulting in improved outcomes such as reduced brain edema, neuronal apoptosis, and degeneration. Further analysis reveals that SIM's effects are mediated through the VEGF-C/VEGFR3/PI3K-Akt pathway. This study advances our understanding of SIM's mechanism in promoting intracranial hematoma clearance and underscores the potential of targeting the GS for ICH treatment.

Influence of Simvastatin and Pravastatin on the Biophysical Properties of Model Lipid Bilayers and Plasma Membranes of Live Cells.

Statins are among the most widely used drugs for the inhibition of cholesterol biosynthesis, prevention of cardiovascular diseases, and treatment of hypercholesterolemia. Additionally, statins also exhibit cholesterol-independent benefits in various diseases, including neuroprotective properties in Alzheimer's disease, anti-inflammatory effects in coronary artery disease, and antiproliferative activities in cancer, which likely result from the statins' interaction and alteration of lipid bilayers. However, the membrane-modulatory effects of statins and the mechanisms by which statins alter lipid bilayers remain poorly understood. In this work, we explore the membrane-modulating effects of statins on model lipid bilayers and live cells. Through the use of fluorescence lifetime imaging microscopy (FLIM) combined with viscosity-sensitive environmental probes, we demonstrate that hydrophobic, but not hydrophilic, statins are capable of changing the microviscosity and lipid order in model and live cell membranes. Furthermore, we show that hydrophobic simvastatin is capable of forming nanoscale cholesterol-rich domains and homogenizing the cholesterol concentrations in lipid bilayers. Our results provide a mechanistic framework for understanding the bimodal effects of simvastatin on the lipid order and the lateral organization of cholesterol in lipid bilayers. Finally, we demonstrate that simvastatin temporarily decreases the microviscosity of live cell plasma membranes, making them more permeable and increasing the level of intracellular chemotherapeutic drug accumulation.

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.

The influence of simvastatin on osteoblast functionality in the presence of titanium dioxide particles In-vitro.

OBJECTIVE: Leaching of particles from dental titanium implant surfaces into preimplant microenvironment causes detrimental effects on bone cells. The current study investigated influence of simvastatin in mitigating adverse pro-inflammatory effects of titanium dioxide (TiO2) micro (MP) and nano (NP) particles on hFOB 1.19 cells in vitro. DESIGN: Viability of hFOB 1.19 cells following exposure to varying concentrations of TiO2 MPs and NPs and simvastatin were measured by XTT assay. hFOB 1.19 cells were treated with 100 µg/mL of TiO2 MPs, 100 µg/mL of TiO2 NPs, 0.1 µM simvastatin, 100 µg/mL of TiO2 MPs+ 0.1 µM simvastatin and 100 µg/mL of TiO2 NPs+ 0.1 µM simvastatin. After 24 h, ROS was measured by flow cytometry. On day 14, real-time PCR analysis for pro-inflammatory cytokines and bone formation markers was done for TNFα, IL1ß, osteocalcin, ALP, and Col1 markers; while ALP and RANKL/OPG ratio were determined by colorimetric and ELISA assays respectively. Further, mineralization study using Alizarin Red S staining (ARS) and calcium quantification were performed. RESULTS: Exposure of hFOB to TiO2 MPs and NPs generated ROS and reduced cell viability significantly, with upregulation of pro-inflammatory markers TNFα and IL1ß and downregulation of bone formation markers OC and increased RANKL/OPG ratio and lowered degree of mineralization. Treatment with 0.1 µM of simvastatin treatment reversed the effects by mitigating oxidative stress, dampening pro-inflammatory markers, upregulation of bone formation markers, lowering RANKL/OPG ratio and increasing degree of mineralization. CONCLUSION: Simvastatin possesses antioxidant, anti-inflammatory, and pro-osteogenic properties that may support bone healing around titanium implants.