RESUMO
Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and immune activation in the nigro-striatal pathway. Simvastatin regulates cholesterol metabolism and protects from atherosclerosis disease. Simvastatin-tween 80 was administered 7 days before sterotaxic intrastriatal administration of MPP+ (1-methyl-4-phenylpyridine) in rats. Fluorescent lipidic product formation, dopamine levels, and circling behavior were considered damage markers. Twenty-four hours and six days after, the animal group lesioned with MPP+ showed significant damage in relation to the control group. Animals pretreated with simvastatin significantly reduced the MPP+-induced damage compared to the MPP+ treated group. As apoptosis promotes neuroinflammation and neuronal degeneration in Parkinson's disease, and since there is not currently a proteomic map of the nigro-striatum of rats and assuming a high homology among the identified proteins in other rat tissues, we based the search for rat protein homologs related to the establishment of inflammation response. We demonstrate that most proteins related to inflammation decreased in the simvastatin-treated rats. Furthermore, differential expression of antioxidant enzymes in striated tissue of rat brains was found in response to simvastatin. These results suggest that simvastatin could prevent striatal MPP+-induced damage and, for the first time, suggest that the molecular mechanisms involved in this have a protective effect.
Assuntos
Doença de Parkinson , Ratos , Animais , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Sinvastatina/metabolismo , Proteômica , Substância Negra/metabolismo , Dopamina/metabolismo , 1-Metil-4-fenilpiridínio/farmacologia , Corpo Estriado/metabolismo , Modelos Animais de DoençasRESUMO
High cholesterol levels have been linked to a high risk of cardiovascular diseases, and preventative pharmacological care to lower cholesterol levels is critically important. Statins, which are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are drugs used to reduce the endogenous cholesterol synthesis, thus minimizing its pathophysiological effects. Despite the proven benefits, statins therapy is known to cause a number of skeletal muscle disorders, including myalgia, myopathy and myositis. The mechanisms underlying such statin-induced side effects are unknown. Recently, a group of genes and molecular pathways has been described to participate in statin-induced myopathy, caused by either simvastatin or rosuvastatin, although the mechanism by which changes in gene regulation occur was not studied. Transposable Elements (TEs), repetitive elements that move within the genome, are known to play regulatory roles in gene expression; however, their role in statin-induced muscle damage has not been studied. We analyzed the expression of TEs in human skeletal fiber cells treated with either simvastatin or rosuvastatin, as well as their respective controls, and identified TEs that change their expression in response to the treatment. We found that simvastatin resulted in >1000 differentially expressed (DE) TEs, whereas rosuvastatin resulted in only 27 DE TEs. Using network analysis tools, we predicted the impact of the DE TEs on the expression of genes and found that amongst the genes potentially modulated by TEs, there are some previously associated to statin-linked myopathy pathways (e.g., AKT3). Overall, our results indicate that TEs may be a key player in the statin-induced muscle side effects.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Doenças Musculares , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Elementos de DNA Transponíveis , Rosuvastatina Cálcica/efeitos adversos , Sinvastatina/efeitos adversos , Sinvastatina/metabolismo , Fibras Musculares Esqueléticas , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Doenças Musculares/tratamento farmacológico , Colesterol/metabolismo , Músculo Esquelético/metabolismoRESUMO
In this study, in silico approaches are employed to investigate the binding mechanism of peptides derived from cowpea ß-vignin and HMG-CoA reductase. With the obtained information, we designed synthetic peptides to evaluate their in vitro enzyme inhibitory activity. In vitro, the total protein extract and <3 kDa fraction, at 5000 µg, support this hypothesis (95% and 90% inhibition of HMG-CoA reductase, respectively). Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides were predicted to bind to the substrate binding site of HMGCR via HMG-CoAR. In silico, it was established that the mechanism of HMG-CoA reductase inhibition largely entailed mimicking the interactions of the decalin ring of simvastatin and via H-bonding; in vitro studies corroborated the predictions, whereby the HMG-CoA reductase activity was decreased by 69%, 77%, and 78%, respectively. Our results suggest that Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides derived from cowpea ß-vignin have the potential to lower cholesterol synthesis through a statin-like regulation mechanism.
Assuntos
Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Peptídeos/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Domínio Catalítico , Meia-Vida , Ligação de Hidrogênio , Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Simulação de Acoplamento Molecular , Peptídeos/química , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Sinvastatina/química , Sinvastatina/metabolismo , Vigna/metabolismoRESUMO
This study aims to produce and characterize alginate bilayer membranes composed of single membranes with varying cross-linking degrees to modulate simvastatin release, with potential to be used for wound-dressing. The single-layer and bilayer membranes were characterized by weight, thickness, surface pH, equilibrium-humidity, swelling degree, solubility, infrared spectroscopy (attenuated total reflectance Fourier-transform infrared), scanning electron microscopy, and water vapor transmission. Simvastatin diffusion and release rates were analyzed using Franz's cells; its indirect cytotoxicity was analyzed using human keratinocyte cells. The difference in the cross-linking degree (bottom and top layers) influenced the morphology of the membrane, and consequently its physical barrier properties. An in vitro release study demonstrated that the bilayer membrane could sustain drug-release for longer time as compared to the single-layer membrane, which could be potentially beneficial for long-term treatment of chronic wounds. A cell viability assay showed that simvastatin-loaded alginate membranes could be characterized as noncytotoxic, demonstrating their potential for use in wound-dressing applications.
Assuntos
Alginatos/química , Bicamadas Lipídicas/química , Sinvastatina/metabolismo , Bandagens , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Bicamadas Lipídicas/farmacologia , Sinvastatina/química , Sinvastatina/farmacologia , Solubilidade , Cicatrização/efeitos dos fármacosRESUMO
OBJECTIVE: Because autonomic dysfunction has been found to lead to cardiometabolic disorders and because studies have reported that simvastatin treatment has neuroprotective effects, the objective of the present study was to investigate the effects of simvastatin treatment on cardiovascular and autonomic changes in fructose-fed female rats. METHODS: Female Wistar rats were divided into three groups: controls (n = 8), fructose (n = 8), and fructose+ simvastatin (n = 8). Fructose overload was induced by supplementing the drinking water with fructose (100 mg/L, 18 wks). Simvastatin treatment (5 mg/kg/day for 2 wks) was performed by gavage. The arterial pressure was recorded using a data acquisition system. Autonomic control was evaluated by pharmacological blockade. RESULTS: Fructose overload induced an increase in the fasting blood glucose and triglyceride levels and insulin resistance. The constant rate of glucose disappearance during the insulin intolerance test was reduced in the fructose group (3.4 ± 0.32%/min) relative to that in the control group (4.4 ± 0.29%/min). Fructose + simvastatin rats exhibited increased insulin sensitivity (5.4 ± 0.66%/min). The fructose and fructose + simvastatin groups demonstrated an increase in the mean arterial pressure compared with controls rats (fructose: 124 ± 2 mmHg and fructose+simvastatin: 126 ± 3 mmHg vs. controls: 112 ± 2 mmHg). The sympathetic effect was enhanced in the fructose group (73 ± 7 bpm) compared with that in the control (48 ± 7 bpm) and fructose+simvastatin groups (31 ± 8 bpm). The vagal effect was increased in fructose + simvastatin animals (84 ± 7 bpm) compared with that in control (49 ± 9 bpm) and fructose animals (46 ± 5 bpm). CONCLUSION: Simvastatin treatment improved insulin sensitivity and cardiac autonomic control in an experimental model of metabolic syndrome in female rats. These effects were independent of the improvements in the classical plasma lipid profile and of reductions in arterial pressure. These results support the hypothesis that statins reduce the cardiometabolic risk in females with metabolic syndrome.
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Frutose/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Animais , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Modelos Animais de Doenças , Jejum/sangue , Feminino , Frutose/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/tratamento farmacológico , Ratos , Ratos Wistar , Sinvastatina/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: Because autonomic dysfunction has been found to lead to cardiometabolic disorders and because studies have reported that simvastatin treatment has neuroprotective effects, the objective of the present study was to investigate the effects of simvastatin treatment on cardiovascular and autonomic changes in fructose-fed female rats. METHODS: Female Wistar rats were divided into three groups: controls (n=8), fructose (n=8), and fructose+ simvastatin (n=8). Fructose overload was induced by supplementing the drinking water with fructose (100 mg/L, 18 wks). Simvastatin treatment (5 mg/kg/day for 2 wks) was performed by gavage. The arterial pressure was recorded using a data acquisition system. Autonomic control was evaluated by pharmacological blockade. RESULTS: Fructose overload induced an increase in the fasting blood glucose and triglyceride levels and insulin resistance. The constant rate of glucose disappearance during the insulin intolerance test was reduced in the fructose group (3.4+ 0.32 percent/min) relative to that in the control group (4.4+ 0.29 percent/min). Fructose+simvastatin rats exhibited increased insulin sensitivity (5.4+0.66 percent/min). The fructose and fructose+simvastatin groups demonstrated an increase in the mean arterial pressure compared with controls rats (fructose: 124+2 mmHg and fructose+simvastatin: 126 + 3 mmHg vs. controls: 112 + 2 mmHg). The sympathetic effect was enhanced in the fructose group (73 + 7 bpm) compared with that in the control (48 + 7 bpm) and fructose+simvastatin groups (31+8 bpm). The vagal effect was increased in fructose+simvastatin animals (84 + 7 bpm) compared with that in control (49 + 9 bpm) and fructose animals (46+5 bpm). CONCLUSION: Simvastatin treatment improved insulin sensitivity and cardiac autonomic control in an experimental model of metabolic syndrome in female rats. These effects were independent of the improvements in the classical plasma lipid profile and of reductions in arterial pressure. These results support the hypothesis that statins reduce the cardiometabolic risk in females with metabolic syndrome.
Assuntos
Animais , Feminino , Ratos , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Frutose/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Modelos Animais de Doenças , Jejum/sangue , Frutose/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/tratamento farmacológico , Ratos Wistar , Sinvastatina/metabolismo , Fatores de TempoRESUMO
Statins are a group of extremely successful drugs that lower cholesterol levels in blood; decreasing the risk of heath attack or stroke. In recent years, statins have also been reported to have other biological activities and numerous potential therapeutic uses. Natural statins are lovastatin and compactin, while pravastatin is derived from the latter by biotransformation. Simvastatin, the second leading statin in the market, is a lovastatin semisynthetic derivative. Lovastatin is mainly produced by Aspergillus terreus strains, and compactin by Penicillium citrinum. Lovastatin and compactin are produced industrially by liquid submerged fermentation, but can also be produced by the emerging technology of solid-state fermentation, that displays some advantages. Advances in the biochemistry and genetics of lovastatin have allowed the development of new methods for the production of simvastatin. This lovastatin derivative can be efficiently synthesized from monacolin J (lovastatin without the side chain) by a process that uses the Aspergillus terreus enzyme acyltransferase LovD. In a different approach, A. terreus was engineered, using combinational biosynthesis on gene lovF, so that the resulting hybrid polyketide synthase is able to in vivo synthesize 2,2-dimethylbutyrate (the side chain of simvastatin). The resulting transformant strains can produce simvastatin (instead of lovastatin) by direct fermentation.
Assuntos
Aspergillus/metabolismo , Lovastatina/biossíntese , Aciltransferases/genética , Aciltransferases/metabolismo , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/uso terapêutico , Aspergillus/enzimologia , Aspergillus/genética , Biotecnologia , Fermentação , Lovastatina/análogos & derivados , Lovastatina/uso terapêutico , Pravastatina/biossíntese , Sinvastatina/metabolismoRESUMO
AIM: Statin disposition and response are greatly determined by the activities of drug metabolizing enzymes and efflux/ uptake transporters. There is little information on the regulation of these proteins in human cells after statin therapy. In this study, the effects of atorvastatin and simvastatin on mRNA expression of efflux (ABCB1, ABCG2 and ABCC2) and uptake (SLCO1B1, SLCO2B1 and SLC22A1) drug transporters in Caco-2 and HepG2 cells were investigated. METHODS: Quantitative real-time PCR was used to measure mRNA levels after exposure of HepG2 and Caco-2 cells to statins. RESULTS: Differences in mRNA basal levels of the transporters were as follows: ABCC2>ABCG2>ABCB1>SLCO1B1>>>SLC22A1>SLC O2B1 for HepG2 cells, and SLCO2B1>>ABCC2>ABCB1>ABCG2>>>SLC22A1 for Caco-2 cells. While for HepG2 cells, ABCC2, ABCG2 and SLCO2B1 mRNA levels were significantly up-regulated at 1, 10 and 20 micromol/L after 12 or 24 h treatment, in Caco-2 cells, only the efflux transporter ABCB1 was significantly down-regulated by two-fold following a 12 h treatment with atorvastatin. Interestingly, whereas treatment with simvastatin had no effect on mRNA levels of the transporters in HepG2 cells, in Caco-2 cells the statin significantly down-regulated ABCB1, ABCC2, SLC22A1, and SLCO2B1 mRNA levels after 12 or 24 h treatment. CONCLUSION: These findings reveal that statins exhibits differential effects on mRNA expression of drug transporters, and this effect depends on the cell type. Furthermore, alterations in the expression levels of drug transporters in the liver and/or intestine may contribute to the variability in oral disposition of statins.Acta Pharmacologica Sinica (2009) 30: 956-964; doi: 10.1038/aps.2009.85; published online 22 June 2009.
Assuntos
Células CACO-2/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Pirróis/farmacologia , Animais , Atorvastatina , Células CACO-2/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Ácidos Heptanoicos/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteína 2 Associada à Farmacorresistência Múltipla , Pirróis/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sinvastatina/metabolismo , Sinvastatina/farmacologiaRESUMO
A combinação de estatinas com niacina se apresenta como uma atraente associação, na presença de dislipidemia mista com níveis de HDL baixo, quando monoterapia é insuficiente para o alcance das metas lipídicas. Benefícios clínicos foram observados com a combinação de estatinas com niacina nos estudos FATS, HATS e ARBITER 2, mostrando atenuação no desenvolvimento da aterosclerose e/ou redução de eventos coronários, acompanhados de alterações lipídicas favoráveis. Em geral, esta combinação é bem tolerada. Recomenda-se monitoração adequada das enzimas hepáticas e muscular e, ainda, titulação cuidadosa de cada uma das drogas combinadas.
Assuntos
Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Niacina/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/metabolismo , Distribuição por Idade , Fatores Sexuais , Interações Medicamentosas , Niacina/efeitos adversos , Niacina/metabolismo , Pirróis/efeitos adversos , Pirróis/metabolismo , Pirróis/uso terapêutico , Quimioterapia Combinada , Sinvastatina/efeitos adversos , Sinvastatina/metabolismo , Sinvastatina/uso terapêutico , Ácidos Heptanoicos/efeitos adversos , Ácidos Heptanoicos/metabolismo , Ácidos Heptanoicos/uso terapêuticoRESUMO
Combination of statins with niacin appears to be an attractive association, in the presence of mixed dyslipidemia with low HDL-c levels, when monotherapy is insufficient to achieve target lipid levels. Clinical benefits were observed by the combination of statins with niacin in the FATS, HATS and ARBITER 2 trials, showing attenuation of atherosclerosis development and/or reduction in coronary events following favorable lipid changes. In general, this combination can be well-tolerated. Recommendations for appropriate monitoring of liver and muscle enzymes are important to reduce the rate of side effects. In addition, careful titration of each drug is recommended.