RESUMEN
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.
Asunto(s)
Diabetes Mellitus Experimental , Emulsiones , Glucosa Oxidasa , Cicatrización de Heridas , Animales , Emulsiones/química , Cicatrización de Heridas/efectos de los fármacos , Ratas , Diabetes Mellitus Experimental/tratamiento farmacológico , Glucosa Oxidasa/química , Glucosa Oxidasa/metabolismo , Simvastatina/química , Simvastatina/farmacología , Catalasa/química , Catalasa/metabolismo , Oxígeno/química , Glucemia/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
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.
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Apoptosis , Biomarcadores de Tumor , Neoplasias de la Mama , Proliferación Celular , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Apoptosis/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Persona de Mediana Edad , Proliferación Celular/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Anciano , Adulto , Estadificación de Neoplasias , Simvastatina/farmacología , Simvastatina/uso terapéutico , Antígeno Ki-67/metabolismo , Ciclina D1/metabolismo , Caspasa 3/metabolismoRESUMEN
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.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Ratones Endogámicos C57BL , Simvastatina , Linfocitos T Reguladores , Células Th17 , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Células Th17/inmunología , Células Th17/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Simvastatina/farmacología , Simvastatina/administración & dosificación , Ratones , Femenino , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Interleucina-17/metabolismo , Factores de Transcripción Forkhead/metabolismo , Médula Espinal/inmunología , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Humanos , Factor de Crecimiento Transformador beta/metabolismo , Modelos Animales de EnfermedadRESUMEN
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.
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Hemorragia Cerebral , Sistema Glinfático , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Simvastatina , Animales , Masculino , Ratas , Apoptosis/efectos de los fármacos , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/metabolismo , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/tratamiento farmacológico , Modelos Animales de Enfermedad , Sistema Glinfático/efectos de los fármacos , Sistema Glinfático/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Simvastatina/farmacologíaRESUMEN
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.
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Antibacterianos , Quitina , Sistemas de Liberación de Medicamentos , Hidrogeles , Nanopartículas , Impresión Tridimensional , Hidrogeles/química , Hidrogeles/farmacología , Quitina/química , Quitina/farmacología , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Nanopartículas/química , Animales , Periodontitis/tratamiento farmacológico , Periodontitis/terapia , Periodontitis/microbiología , Periodontitis/patología , Simvastatina/farmacología , Simvastatina/química , Simvastatina/administración & dosificación , Células Madre Mesenquimatosas/efectos de los fármacos , Regeneración Ósea/efectos de los fármacos , Porphyromonas gingivalis/efectos de los fármacosRESUMEN
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.
Asunto(s)
Dieta Alta en Grasa , Trampas Extracelulares , Hiperlipidemias , Hígado , Daño por Reperfusión , Simvastatina , Animales , Simvastatina/farmacología , Simvastatina/uso terapéutico , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Ratones , Trampas Extracelulares/efectos de los fármacos , Trampas Extracelulares/metabolismo , Masculino , Dieta Alta en Grasa/efectos adversos , Hígado/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Hiperlipidemias/complicaciones , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Lipoproteínas LDL/metabolismo , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacosRESUMEN
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.
Asunto(s)
Atorvastatina , Encéfalo , Metabolismo Energético , Mitocondrias , Especies Reactivas de Oxígeno , Simvastatina , Animales , Atorvastatina/farmacología , Simvastatina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratas , Metabolismo Energético/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Calcio/metabolismoRESUMEN
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.
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Apoptosis , Autofagia , Estrés del Retículo Endoplásmico , Proteína 2 de la Membrana Asociada a los Lisosomas , Fármacos Neuroprotectores , Ratas Sprague-Dawley , Simvastatina , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratas , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Simvastatina/farmacología , Masculino , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patologíaRESUMEN
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.
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Membrana Celular , Colesterol , Membrana Dobles de Lípidos , Pravastatina , Simvastatina , Simvastatina/farmacología , Simvastatina/química , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Humanos , Pravastatina/farmacología , Pravastatina/química , Colesterol/metabolismo , Colesterol/química , Interacciones Hidrofóbicas e Hidrofílicas/efectos de los fármacos , Viscosidad/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/químicaRESUMEN
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.
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Supervivencia Celular , Osteoblastos , Especies Reactivas de Oxígeno , Simvastatina , Titanio , Titanio/farmacología , Simvastatina/farmacología , Osteoblastos/efectos de los fármacos , Humanos , Supervivencia Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Osteogénesis/efectos de los fármacos , Técnicas In Vitro , Reacción en Cadena en Tiempo Real de la Polimerasa , Ensayo de Inmunoadsorción Enzimática , Citocinas/metabolismo , Interleucina-1beta/metabolismo , Citometría de Flujo , Factor de Necrosis Tumoral alfa/metabolismo , Osteocalcina/metabolismo , Implantes Dentales , Ligando RANK/metabolismo , Propiedades de Superficie , Línea Celular , Células CultivadasRESUMEN
Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases such as coronary heart disease. Black phosphorus quantum dots (BPQDs) are a novel nanomaterial with good optical properties and biocompatibility, which was applied in the treatment of AS in mice, with good results shown in our previous study. In this study, BPQDs were injected into high-fat diet-fed apolipoprotein E knockout mice as a preventive drug for 12 weeks. Simvastatin, a classic preventive drug for AS, was used as a control to verify the preventive effect of BPQDs. The results showed that after preventive treatment with BPQDs, the plaque area in mice was significantly reduced, the vascular elasticity was increased, and serum lipid levels were significantly lower than those in the model group. To explore the mechanism, macrophages were induced to become foam cells using oxidized low-density lipoprotein. We found that BPQDs treatment could increase cell autophagy, thereby regulating intracellular lipid metabolism. Taken together, these data revealed that BPQDs may serve as a functional drug in preventing the development of AS.
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Aterosclerosis , Dieta Alta en Grasa , Fósforo , Puntos Cuánticos , Animales , Dieta Alta en Grasa/efectos adversos , Aterosclerosis/prevención & control , Ratones , Fósforo/sangre , Ratones Noqueados , Apolipoproteínas E/genética , Masculino , Autofagia/efectos de los fármacos , Ratones Noqueados para ApoE , Metabolismo de los Lípidos/efectos de los fármacos , Modelos Animales de Enfermedad , Placa Aterosclerótica/prevención & control , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/sangre , Simvastatina/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismoRESUMEN
In this in vitro study, for the first time, we evaluate the effects of simvastatin-loaded liposome nanoparticles (SIM-LipoNPs) treatment on fibrosis-induced liver microtissues, as simvastatin (SIM) has shown potential benefits in the non-alcoholic fatty liver disease process. We developed multicellular liver microtissues composed of hepatic stellate cells, hepatoblastoma cells and human umbilical vein endothelial cells. The microtissues were supplemented with a combination of palmitic acid and oleic acid to develop fibrosis models. Subsequently, various groups of microtissues were exposed to SIM and SIM-LipoNPs at doses of 5 and 10 mg/mL. The effectiveness of the treatments was evaluated by analysing cell viability, production of reactive oxygen species (ROS) and nitric oxide (NO), the expression of Kruppel-like factor (KLF) 2, and pro-inflammatory cytokines (interleukin(IL)-1 α, IL-1 ß, IL-6 and tumour necrosis factor-α), and the expression of collagen I. Our results indicated that SIM-LipoNPs application showed promising results. SIM-LipoNPs effectively amplified the SIM-klf2-NO pathway at a lower dosage compatible with a high dosage of free SIM, which also led to reduced oxidative stress by decreasing ROS levels. SIM-LipoNPs administration also resulted in a significant reduction in pro-inflammatory cytokines and Collagen I mRNA levels, as a marker of fibrosis. In conclusion, our study highlights the considerable therapeutic potential of using SIM-LipoNPs to prevent liver fibrosis progress, underscoring the remarkable properties of SIM-LipoNPs in activating the KLF2-NO pathway and anti-oxidative and anti-inflammatory response.
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Células Estrelladas Hepáticas , Factores de Transcripción de Tipo Kruppel , Liposomas , Cirrosis Hepática , Nanopartículas , Especies Reactivas de Oxígeno , Simvastatina , Humanos , Simvastatina/farmacología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Nanopartículas/química , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Óxido Nítrico/metabolismoRESUMEN
Psoriasis, a chronic inflammatory skin disorder, is associated with comorbidities such as acute myocardial infarction (AMI). However, the molecular mechanisms connecting these conditions are unclear. In this study, we conducted bioinformatics analyses using gene expression datasets to identify differentially expressed genes and hub genes associated with both psoriasis and AMI. Our findings emphasize the involvement of immune-related pathways in the pathogenesis of both conditions. Furthermore, we investigated the expression levels of hub genes in AMI patients and myocardial infarction (MI) mice. ELISA measurements revealed significantly higher levels of CXCL8, IL1B, S100A9, and S100A12 in the serum of AMI patients compared to normal individuals. Immunohistochemical staining of heart tissue from MI mice showed a progressive increase in the expression of CXCL8 and IL-1B as MI advanced, while S100A9 exhibited high expression at day 3 post-MI. mRNA expression analysis validated these findings. Additionally, we explored the skin lesions of psoriasis patients and found significantly higher expression of CXCL8, IL-1B, S100A9, and S100A12 in the affected skin areas compared to unaffected regions. These results highlight the consistent upregulation of hub genes in both AMI and psoriasis patients, as well as in myocardial infarction mice, underscoring their potential as reliable markers for disease diagnosis. Moreover, molecular docking simulations revealed potential interactions between simvastatin and key target proteins, suggesting a potential therapeutic avenue. Overall, our study uncovers shared molecular signatures and potential therapeutic targets, providing a foundation for future investigations targeting common pathways in psoriasis and AMI.
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Calgranulina B , Infarto del Miocardio , Psoriasis , Psoriasis/genética , Psoriasis/metabolismo , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Animales , Humanos , Ratones , Calgranulina B/genética , Calgranulina B/metabolismo , Interleucina-8/metabolismo , Interleucina-8/genética , Simulación del Acoplamiento Molecular , Simvastatina/farmacología , Simvastatina/uso terapéutico , Proteína S100A12/genética , Proteína S100A12/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Masculino , Modelos Animales de Enfermedad , Biología Computacional/métodos , Perfilación de la Expresión Génica , Femenino , BiomarcadoresRESUMEN
BACKGROUND: Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained. METHODS: To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335). RESULTS: The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model (p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43 ± 18% and -23 ± 19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335R1092W allele(s) exhibited a significantly blunted LDL statin response. CONCLUSIONS: Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.
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LDL-Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Simvastatina , Animales , Humanos , Ratones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Simvastatina/farmacología , LDL-Colesterol/sangre , Línea Celular , Masculino , Femenino , Perfilación de la Expresión Génica , Transcriptoma , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Colesterol/sangre , Mutación MissenseRESUMEN
Tissue engineering aims to improve or restore damaged tissues by using scaffolds, cells and bioactive agents. In tissue engineering, one of the most important concepts is the scaffold because it has a key role in keeping up and promoting the growth of the cells. It is also desirable to be able to load these scaffolds with drugs that induce tissue regeneration/formation. Based on this, in our study, gelatin cryogel scaffolds were developed for potential bone tissue engineering applications and simvastatin loading and release studies were performed. Simvastatin is lipoliphic in nature and this form is called inactive simvastatin (SV). It is modified to be in hydrophilic form and converted to the active form (SVA). For our study's drug loading and release process, simvastatin was used in both inactive and active forms. The blank cryogels and drug-loaded cryogels were prepared at different glutaraldehyde concentrations (1, 2, and 3%). The effect of the crosslinking agent and the amount of drug loaded were discussed with morphological and physicochemical analysis. As the glutaraldehyde concentration increased gradually, the pores size of the cryogels decreased and the swelling ratio decreased. For the release profile of simvastatin in both forms, we can say that it depended on the form (lipophilic and hydrophilic) of the loaded simvastatin.
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Huesos , Criogeles , Gelatina , Simvastatina , Ingeniería de Tejidos , Andamios del Tejido , Simvastatina/química , Simvastatina/farmacología , Ingeniería de Tejidos/métodos , Gelatina/química , Criogeles/química , Andamios del Tejido/química , Porosidad , Ensayo de Materiales , Regeneración Ósea/efectos de los fármacos , Materiales Biocompatibles/química , Humanos , Reactivos de Enlaces Cruzados/químicaRESUMEN
BACKGROUND: The objective of this research was to elucidate the hypocholesterolemic effects of a bioactive compound extracted from buckwheat, and to delineate its influence on the regulatory mechanisms of cholesterol metabolism. The compound under investigation was identified as quercetin. MATERIAL AND RESULTS: In vitro experiments conducted on HepG2 cells treated with quercetin revealed a significant reduction in intracellular cholesterol accumulation. This phenomenon was rigorously quantified by assessing the transcriptional activity of key genes involved in the biosynthesis and metabolism of cholesterol. A statistically significant reduction in the expression of HMG-CoA reductase (HMGCR) was observed, indicating a decrease in endogenous cholesterol synthesis. Conversely, an upregulation in the expression of cholesterol 7 alpha-hydroxylase (CYP7A1) was also observed, suggesting an enhanced catabolism of cholesterol to bile acids. Furthermore, the study explored the combinatory effects of quercetin and simvastatin, a clinically utilized statin, revealing a synergistic action in modulating cholesterol levels at various dosages. CONCLUSIONS: The findings from this research provide a comprehensive insight into the mechanistic pathways through which quercetin, a phytochemical derived from buckwheat, exerts its hypocholesterolemic effects. Additionally, the observed synergistic interaction between quercetin and simvastatin opens up new avenues for the development of combined therapeutic strategies to manage hyperlipidemia.
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Colesterol 7-alfa-Hidroxilasa , Colesterol , Fagopyrum , Hidroximetilglutaril-CoA Reductasas , Metabolismo de los Lípidos , Fitoquímicos , Quercetina , Humanos , Fagopyrum/química , Fagopyrum/metabolismo , Células Hep G2 , Colesterol/metabolismo , Quercetina/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Fitoquímicos/farmacología , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hidroximetilglutaril-CoA Reductasas/genética , Colesterol 7-alfa-Hidroxilasa/metabolismo , Colesterol 7-alfa-Hidroxilasa/genética , Anticolesterolemiantes/farmacología , Simvastatina/farmacología , Extractos Vegetales/farmacología , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
Atherosclerosis is a chronic multifactorial cardiovascular disease. To combat atherosclerosis effectively, it is necessary to develop precision and targeted therapy in the early stages of plaque formation. In this study, a simvastatin (SV)-containing prodrug micelle SPCPV was developed by incorporating a peroxalate ester bond (PO). SPCPV could specifically target VCAM-1 overexpressed at atherosclerotic lesions. SPCPV contains a carrier (CP) composed of cyclodextrin (CD) and polyethylene glycol (PEG). At the lesions, CP and SV exerted multifaceted anti-atherosclerotic effects. In vitro studies demonstrated that intracellular reactive oxygen species (ROS) could induce the release of SV from SPCPV. The uptake of SPCPV was higher in inflammatory cells than in normal cells. Furthermore, in vitro experiments showed that SPCPV effectively reduced ROS levels, possessed anti-inflammatory properties, inhibited foam cell formation, and promoted cholesterol efflux. In vivo studies using atherosclerotic rats showed that SPCPV reduced the thickness of the vascular wall and low-density lipoprotein (LDL). This study developed a drug delivery strategy that could target atherosclerotic plaques and treat atherosclerosis by integrating the carrier with SV. The findings demonstrated that SPCPV possessed high stability and safety and had great therapeutic potential for treating early-stage atherosclerosis.
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Aterosclerosis , Micelas , Polietilenglicoles , Profármacos , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Simvastatina , Molécula 1 de Adhesión Celular Vascular , Profármacos/farmacología , Profármacos/química , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Masculino , Polietilenglicoles/química , Simvastatina/farmacología , Simvastatina/química , Simvastatina/administración & dosificación , Simvastatina/farmacocinética , Humanos , Ratas , Molécula 1 de Adhesión Celular Vascular/metabolismo , Ciclodextrinas/química , Portadores de Fármacos/química , Ratones , Células RAW 264.7 , Colesterol , Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Lipoproteínas LDL , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/administración & dosificaciónRESUMEN
INTRODUCTION: Adolescents tend to experiment with ethanol which often results in heavy episodic drinking patterns leading to serious health concerns later in life. Chronic ethanol use damages renal tissue, promotes collagen deposition, and induces renal inflammation, thereby causing renal dysfunction. Therefore, an intervention such as simvastatin (a blood cholesterol-lowering drug) that could suppress the effects of ethanol on the kidney may be beneficial. This study explored the impact of simvastatin against the onset of renal morphological damage, fibrosis, and inflammation caused by ethanol exposure in mice. MATERIALS AND METHODS: Ten four-week old C57BL/6J mice (F = 5; M = 5) were assigned to each experimental group: (I) NT; no administration of ethanol or simvastatin; (II) EtOH; 2.5 g/kg/day of 20% ethanol, intraperitoneal injection (i.p.); (III) SIM; 5 mg/kg/day of simvastatin, orally; (IV) EtOH + SIM5; 5 mg/kg/day of simvastatin, orally, followed by 2.5 g/kg/day of 20% ethanol, i.p.; and (V) EtOH + SIM15; 15 mg/kg/day of simvastatin, orally, followed by 2.5 g/kg/day of 20% ethanol, i.p. After the 28-day treatment period, the right kidney was removed and processed for haematoxylin and eosin staining, Masson's trichrome staining, or tumour necrosis factor-alpha (TNF-α) immunohistochemistry. The renal corpuscular area, glomerular area, and urinary space area were measured and the area of collagen or TNF-α expression was quantified using ImageJ software. RESULTS: Ethanol administration significantly increased the renal corpuscular area, the glomerular area, the area of collagen, and the area of tissue with TNF-α immunoreactivity but decreased the area of urinary space. Simvastatin generally suppressed the ethanol effects in both sexes, although to varying degrees. CONCLUSIONS: Simvastatin proved to suppress collagen deposition and the TNF-α production induced by ethanol in the kidney of mice thus indicating its effectiveness in the treatment of ethanol-related renal diseases.
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Etanol , Riñón , Ratones Endogámicos C57BL , Simvastatina , Animales , Simvastatina/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratones , Masculino , Femenino , Factor de Necrosis Tumoral alfa/metabolismo , FibrosisRESUMEN
Hyaluronic acid (HA) hydrogels have arisen as candidate materials to simulate the extracellular matrix and restore the functions of both cartilage and hard bones. However, integration of bone tissue adhesion and long-term osteogenic properties in one hydrogel is often ignored. Herein, a strategy to construct nanocomposite hydrogel with host tissue adhesive properties, enhanced mechanical strength, improved stability and osteogenic effects was developed. Simvastatin (SIM) was firstly incorporated into zeolitic imidazolate framework-8 (ZIF-8) and surface decoration with hydroxyapatite was realized to obtain SIM loaded and hydroxyapatite modified ZIF-8 particles (SP). As the inorganic strengthening component, SP could further cross-link the mixture of dopamine-hyaluronic acid (dHA) and tannic (TA) via coordination interaction to fabricate the hybrid adhesive hydrogel (dHA/TA/SP). Sufficient phenolic groups endowed dHA/TA/SP with excellent tissue adhesion and antibacterial properties, while incorporation of SP significantly improved the mechanical strength and stability of hydrogel. Further, due to the multiple protective effects of ZIF-8 and hydrogel, SIM was sustainably released from dHA/TA/SP. Together with the active Zn2+ and Ca2+, the expressions of ALP, OCN and RUNX2 were upregulated, and the mineralization was also promoted. With significant osteogenic effect in vitro and in vivo, this nanocomposite adhesive hydrogel holds great potential for bone defects repair.
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Regeneración Ósea , Liberación de Fármacos , Ácido Hialurónico , Hidrogeles , Nanocompuestos , Osteogénesis , Simvastatina , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Regeneración Ósea/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Nanocompuestos/química , Animales , Simvastatina/química , Simvastatina/farmacología , Osteogénesis/efectos de los fármacos , Durapatita/química , Ratones , Preparaciones de Acción Retardada/farmacología , Humanos , Adhesivos/química , Adhesivos/farmacologíaRESUMEN
Statins are used to treat hypercholesterolemia and function by inhibiting the production of the rate-limiting metabolite mevalonate. As such, statin treatment not only inhibits de novo synthesis of cholesterol but also isoprenoids that are involved in prenylation, the posttranslational lipid modification of proteins. The immunomodulatory effects of statins are broad and often conflicting. Previous work demonstrated that statins increased survival and inhibited myeloid cell trafficking in a murine model of sepsis, but the exact mechanisms underlying this phenomenon were unclear. Herein, we investigated the role of prenylation in chemoattractant responses. We found that simvastatin treatment abolished chemoattractant responses induced by stimulation by C5a and FMLP. The inhibitory effect of simvastatin treatment was unaffected by the addition of either farnesyl pyrophosphate (FPP) or squalene but was reversed by restoring geranylgeranyl pyrophosphate (GGPP). Treatment with prenyltransferase inhibitors showed that the chemoattractant response to both chemoattractants was dependent on geranylgeranylation. Proteomic analysis of C15AlkOPP-prenylated proteins identified several geranylgeranylated proteins involved in chemoattractant responses, including RHOA, RAC1, CDC42, and GNG2. Chemoattractant responses in THP-1 human macrophages were also geranylgeranylation dependent. These studies provide data that help clarify paradoxical findings on the immunomodulatory effects of statins. Furthermore, they establish the role of geranylgeranylation in mediating the morphological response to chemoattractant C5a.NEW & NOTEWORTHY The immunomodulatory effect of prenylation is ill-defined. We investigated the role of prenylation on the chemoattractant response to C5a. Simvastatin treatment inhibits the cytoskeletal remodeling associated with a chemotactic response. We showed that the chemoattractant response to C5a was dependent on geranylgeranylation, and proteomic analysis identified several geranylgeranylated proteins that are involved in C5a receptor signaling and cytoskeletal remodeling. Furthermore, they establish the role of geranylgeranylation in mediating the response to chemoattractant C5a.