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1.
Sci Rep ; 10(1): 17012, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046789

RESUMO

Statins are prescribed to treat hypercholesterolemia and to reduce the risk of cardiovascular disease. However, statin users frequently report myalgia, which can discourage physical activity or cause patients to discontinue statin use, negating the potential benefit of the treatment. Although a proposed mechanism responsible for Statin-Associated Myopathy (SAM) suggests a correlation with impairment of mitochondrial function, the relationship is still poorly understood. Here, we provide evidence that long-term treatment of hypercholesterolemic patients with Simvastatin at a therapeutic dose significantly display increased mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), and platelets compared to untreated controls. Furthermore, the amount of superoxide is higher in mitochondria in PBMCs, and platelets from Simvastatin-treated patients than in untreated controls, and the abundance of mitochondrial superoxide, but not mitochondrial respiration trends with patient-reported myalgia. Ubiquinone (also known as coenzyme Q10) has been suggested as a potential treatment for SAM; however, an 8-week course of oral ubiquinone had no impact on mitochondrial functions or the abundance of superoxide in mitochondria from PBMCs, and platelets. These results demonstrate that long-term treatment with Simvastatin increases respiration and the production of superoxide in mitochondria of PBMCs and platelets.


Assuntos
Plaquetas/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sinvastatina/farmacologia , Plaquetas/metabolismo , Linhagem Celular , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Sinvastatina/uso terapêutico , Superóxidos/metabolismo
2.
Bratisl Lek Listy ; 121(10): 722-726, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32955904

RESUMO

AIM: In this study we tried to determine the possible neuroprotective effects of simvastatin in a rat model of Spinal Cord Injury (SCI) with the help of biochemical and histopathological tests. METHODS: Rats were divided into 5 groups:1) SCI control, 2) Sham operated, 3) SCI with 10 mg/kg intraperitoneal simvastatin, 4) SCI with 10 mg/kg oral simvastatin, 5) SCI with 10 mg/kg subcutaneous simvastatin. After the treatment period, all rats were sacrificed; their blood and spinal cord samples were taken for biochemical and histopathological assessment. RESULTS: When the groups were compared in terms of oedema and inflammation status, the scores of groups receiving simvastatin were better than the control and sham groups (p = 0.001 and p = 0.038 respectively). When the 3 treatment groups (oral, intraperitoneal and subcutaneous simvastatin groups) were compared with each other in terms of inflammation, haemorrhage and oedema, there were no significant differences between groups (p = 0.112, p = 0.797 and p = 0.188, respectively). NSE and S100B levels were significantly lower in the treatment groups compared to the sham group (p = 0.039 and p = 0.004 respectively). CONCLUSION: According to our biochemical and histopathological findings, simvastatin 10 mg/kg has a positive impact in the spinal cord injury model in rats, regardless of route of application (Tab. 1, Fig. 5, Ref. 26).


Assuntos
Fármacos Neuroprotetores , Sinvastatina , Traumatismos da Medula Espinal , Animais , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Sinvastatina/farmacologia , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico
3.
AAPS PharmSciTech ; 21(6): 223, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32749629

RESUMO

This study aimed to enhance the dissolution of simvastatin (SMV) through its formulation in liquisolid tablets (LSTs) to improve its bioavailability and hypolipidemic activity after oral administration. SMV-LSTs were optimized using Box-Behnken design to maximize the rate and extent of SMV dissolution. The optimized SMV-LST was evaluated for pharmacokinetic parameters and potential hypolipidemic activity on induced hyperlipidemic rats. The dissolution parameters revealed a shortening of mean dissolution time from 10.99 to 6.82 min, increasing of dissolution rate during the first 10 min from 1253.15 to 1667.31 µg/min, and enhancing of dissolution efficiency after 60 min from 71.92 to 86.93% for SMV-LSTs versus the commercial SMV tablets. The obtained data reflected an improvement in the relative bioavailability of SMV with 148.232% which was confirmed by the significant reduction of the levels of circulating total cholesterol, triglycerides that reached the normal level after 12 h. In particular, the optimized SMV-LSTs reduced serum low-density lipoproteins (LDL) by 44.6% which was significantly different from the commercial SMV tablets. In contrast, the level of serum high-density lipoprotein (HDL) was significantly augmented after 4 h in rats treated with the optimized SMV-LSTs by 47.6%. Finally, the optimized SMV-LSTs showed a significant lower atherosclerotic index value which could maximize its potential in decreasing the risk of coronary disease and atherosclerosis. Overall enhancement in pharmacokinetics and pharmacodynamics in comparison with the commercial tablets confers the potential of the liquisolid approach as a promising alternative for improved oral bioavailability, hypolipidemic, and cardioprotective effects of SMV. Graphical abstract.


Assuntos
Hipolipemiantes/farmacologia , Sinvastatina/farmacologia , Animais , Disponibilidade Biológica , Masculino , Poloxâmero/toxicidade , Ratos , Ratos Wistar , Sinvastatina/química , Sinvastatina/farmacocinética , Solubilidade , Comprimidos
4.
Int J Nanomedicine ; 15: 4001-4020, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606661

RESUMO

Background: Simvastatin (SMV), a hypocholesterolemic agent, suffers from very low bioavailability due to its poor aqueous solubility and extensive first-pass metabolism. Methods: Two SMV carrier systems, namely, polymeric drug inclusion complex (IC) and mixed micelles (MM) nanoparticles, were developed and loaded into mucoadhesive buccal films to enhance SMV bioavailability. The two carrier systems were characterized and their permeation across human oral epithelial cells (OEC) was studied. The effect of IC to MM ratio (X1) and the mucoadhesive polymer concentration (X2) on the cumulative percent of drug released, elongation percent and the mucoadhesive strength, from the prepared mucoadhesive films, were optimized. Ex vivo permeation across bovine mucosal tissue was investigated. The permeation parameters for the in vitro and ex vivo release data were calculated. Results: Complexation of SMV with hydroxypropyl beta-cyclodextrin (HP ß-CD) was superior to all other polymers as revealed by the equilibrium saturation solubility, stability constant, complexation efficiency and thermodynamic potential. SMV-HP ß-CD IC was utilized to develop a saturated polymeric drug solution. Both carrier systems showed enhanced permeation across OEC when compared to pure drug. X1 and X2 were significantly affecting the characteristics of the prepared films. The optimized mucoadhesive buccal film formulation loaded with SMV IC and drug MM nanoparticles demonstrated superior ex vivo permeation when compared to the corresponding pure drug buccal film, and the calculated permeation parameters confirmed this finding. Conclusion: Mucoadhesive buccal films containing SMV IC and drug MM can be used to improve drug bioavailability; however, additional pharmacokinetic and pharmacodynamic studies are required.


Assuntos
Portadores de Fármacos/química , Liberação Controlada de Fármacos , Mucosa Bucal/efeitos dos fármacos , Muco/química , Sinvastatina/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina/química , Adesividade , Animais , Varredura Diferencial de Calorimetria , Bovinos , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas/química , Nanopartículas/ultraestrutura , Permeabilidade , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
5.
Invest Ophthalmol Vis Sci ; 61(5): 29, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32421147

RESUMO

Purpose: Matrix metalloproteinases (MMPs) are involved in extracellular matrix (ECM) maintenance and remodeling. The present study aimed to determine whether transforming growth factor (TGF)-ß2 regulates MMP-2 and MMP-9 levels and activities in astrocytes derived from the optic nerve head (ONH) and the role of statins in such modulation. Methods: Primary astrocytes cultured from the lamina cribrosa of human donor ONHs were incubated with three types of statins (5 µg/mL) for 1 hour followed by recombinant TGF-ß2 (5 ng/mL) for various periods to test their effects. Levels and activities of MMP-2 and MMP-9 in astrocytes in vitro were determined by western blotting and zymography, respectively. Levels of phosphorylated myosin phosphatase target subunit 1 (MYPT1) in astrocyte lysates were determined by western blotting, and those of phosphorylated myosin light chain (MLC) were determined by western blotting and immunocytochemistry. Results: MMP-2 and MMP-9 levels were upregulated by TGF-ß2 in human ONH astrocytes. Prior incubation with simvastatin, lovastatin, and atorvastatin inhibited TGF-ß2-mediated MMP-2 and MMP-9 expression and activities. Prior incubation with statins downregulated the TGF-ß2-induced phosphorylation of MYPT1 and MLC, which are downstream substrates of RhoA and ROCKs. Conclusions: Statins inhibited the TGF-ß2-mediated regulation of MMP-2 and MMP-9 by inhibiting the RhoA/ROCK signaling pathway. Considering the role of MMP in ECM remodeling, the present findings support the notion that statins positively impact ECM remodeling within the ONH.


Assuntos
Astrócitos/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Quinases Associadas a rho/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Adulto , Astrócitos/enzimologia , Atorvastatina/farmacologia , Western Blotting , Células Cultivadas , Feminino , Humanos , Imuno-Histoquímica , Lovastatina/farmacologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Disco Óptico/citologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia , Fator de Crescimento Transformador beta2/farmacologia
6.
Am J Obstet Gynecol ; 223(5): 733.e1-733.e14, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32417359

RESUMO

BACKGROUND: Uterine leiomyomas, the most common tumors of the female reproductive system, are characterized by excessive deposition of disordered stiff extracellular matrix and fundamental alteration in the mechanical signaling pathways. Specifically, these alterations affect the normal dynamic state of responsiveness to mechanical cues in the extracellular environment. These mechanical cues are converted through integrins, cell membrane receptors, to biochemical signals including cytoskeletal signaling pathways to maintain mechanical homeostasis. Leiomyoma cells overexpress ß1 integrin and other downstream mechanical signaling proteins. We previously reported that simvastatin, an antihyperlipidemic drug, has antileiomyoma effects through cellular, animal model, and epidemiologic studies. OBJECTIVE: This study aimed to examine the hypothesis that simvastatin might influence altered mechanotransduction in leiomyoma cells. STUDY DESIGN: This is a laboratory-based experimental study. Primary leiomyoma cells were isolated from 5 patients who underwent hysterectomy at the Department of Gynecology and Obstetrics of the Johns Hopkins University Hospital. Primary and immortalized human uterine leiomyoma cells were treated with simvastatin at increasing concentrations (0.001, 0.01, 0.1, and 1 µM, or control) for 48 hours. Protein and mRNA levels of ß1 integrin and extracellular matrix components involved in mechanical signaling were quantified by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. In addition, we examined the effect of simvastatin on the activity of Ras homolog family member A using pull-down assay and gel contraction. RESULTS: We found that simvastatin significantly reduced the protein expression of ß1 integrin by 44% and type I collagen by 60% compared with untreated leiomyoma cells. Simvastatin-treated cells reduced phosphorylation of focal adhesion kinase down to 26%-60% of control, whereas it increased total focal adhesion kinase protein expression. Using a Ras homolog family member A pull-down activation assay, we observed reduced levels of active Ras homolog family member A in simvastatin-treated cells by 45%-85% compared with control. Consistent with impaired Ras homolog family member A activation, simvastatin treatment reduced tumor gel contraction where gel area was 122%-153% larger than control. Furthermore, simvastatin treatment led to reduced levels of mechanical signaling proteins involved in ß1 integrin downstream signaling, such as A-kinase anchor protein 13, Rho-associated protein kinase 1, myosin light-chain kinase, and cyclin D1. CONCLUSION: The results of this study suggest a possible therapeutic role of simvastatin in restoring the altered state of mechanotransduction signaling in leiomyoma. Collectively, these findings are aligned with previous epidemiologic studies and other reports and support the need for clinical trials.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Leiomioma/genética , Mecanotransdução Celular/efeitos dos fármacos , Sinvastatina/farmacologia , Neoplasias Uterinas/genética , Proteínas de Ancoragem à Quinase A/efeitos dos fármacos , Proteínas de Ancoragem à Quinase A/genética , Proteínas de Ancoragem à Quinase A/metabolismo , Colágeno Tipo I/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Ciclina D1/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Proteína-Tirosina Quinases de Adesão Focal/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Integrina beta1/efeitos dos fármacos , Integrina beta1/genética , Integrina beta1/metabolismo , Leiomioma/metabolismo , Mecanotransdução Celular/genética , Antígenos de Histocompatibilidade Menor/efeitos dos fármacos , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Quinase de Cadeia Leve de Miosina/efeitos dos fármacos , Quinase de Cadeia Leve de Miosina/genética , Quinase de Cadeia Leve de Miosina/metabolismo , Fosforilação , Cultura Primária de Células , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Neoplasias Uterinas/metabolismo , Quinases Associadas a rho/efeitos dos fármacos , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
7.
Sao Paulo Med J ; 138(1): 40-46, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32321104

RESUMO

BACKGROUND: Statins are used as cholesterol-lowering drugs and may also have direct antimicrobial effects. OBJECTIVE: To evaluate synergic interactions between simvastatin and both amphotericin B and fluconazole, against environmental strains of Cryptococcus neoformans isolated from captive birds' droppings. DESIGNAND SETTING: Experimental study conducted at Federal University of Piauí, Parnaíba, in collaboration with Federal University of Triângulo Mineiro, Uberaba, Brazil. METHODS: Statin susceptibility tests of Cryptococcus neoformans samples were performed as prescribed in standards. Interactions of simvastatin with amphotericin and fluconazole were evaluated using the checkerboard microdilution method. Presence of these interactions was quantitatively detected through determining the fractional inhibitory concentration index (FICI). RESULTS: Isolates of Cryptococcus neoformans were obtained from 30 of the 206 samples of dry bird excreta (14.5%) that were collected from pet shops and houses. Ten isolates were selected for susceptibility tests. All of them were susceptible to amphotericin and fluconazole. All presented minimum inhibitory concentration (MIC) > 128 µg/ml and, thus, were resistant in vitro to simvastatin. An in vitro synergic effect was shown through combined testing of amphotericin B and simvastatin, such that six isolates (60%) presented FICI < 0.500. Two isolates showed considerable reductions in MIC, from 1 µg/ml to 0.250 µg/ml. No synergic effect was observed through combining fluconazole and simvastatin. CONCLUSION: These results demonstrate that simvastatin should be considered to be a therapeutic alternative, capable of potentiating the action of amphotericin B. However, further studies are necessary to clarify the real effect of simvastatin as an antifungal agent.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Cryptococcus neoformans , Sinvastatina/farmacologia , Brasil , Sinergismo Farmacológico , Fluconazol , Humanos , Testes de Sensibilidade Microbiana , Estudos Prospectivos
8.
Dent Mater ; 36(6): 755-764, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32312480

RESUMO

OBJECTIVE: In vital pulp therapy (VPT), a barrier is created with appropriate capping to protect the remaining pulp and thus maintain pulp vitality. Here, we evaluated the feasibility of a biphasic calcium phosphate cement (CPC)-calcium sulfate hemihydrate (CSH) biomaterial containing simvastatin (Sim) and collagenase (Col) for VPT. METHODS: Combinations of varying CPC and CSH concentrations were analyzed for their handling properties and setting times, with their structures observed through scanning electron microscopy-energy dispersive X-ray spectrometry (SEM-EDS). Drug release patterns of simvastatin and collagenase combined with CPC-CSH (CPC-CSH-Sim-Col) were also analyzed, followed by biocompatibility and bioactivity tests on human dental pulp stem cells (hDPSCs) and in vivo animal study in canine models; the in vivo results were obtained through microcomputed tomography and histological analysis. RESULTS: The results revealed that 70 wt% CPC (CPC7) with 30 wt% CSH (CSH3) exhibited optimal setting time and porous structure for clinical use. The cell viability and cytotoxicity analysis demonstrated that CPC7-CSH3 with or without simvastatin or collagenase did not injure hDPSCs. In vivo, the CPC7-CSH3-Sim-Col induced dentin bridge formation. SIGNIFICANCE: CPC7-CSH3-Sim-Col in this study has great potential as a VPT biomaterial to enhance the dentin bridge formation.


Assuntos
Materiais Biocompatíveis , Sulfato de Cálcio , Animais , Fosfatos de Cálcio , Colagenases , Polpa Dentária , Humanos , Ácido Hialurônico , Fosfatos , Sinvastatina/farmacologia , Microtomografia por Raio-X
9.
Mar Drugs ; 18(4)2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32344610

RESUMO

This work aimed at improving the targeting and cytotoxicity of simvastatin (SMV) against colon cancer cells. SMV was encapsulated in chitosan polymers, followed by eudragit S100 microparticles. The release of SMV double coated microparticles was dependent on time and pH. At pH 7.4 maximum release was observed for 6 h. The efficiency of the double coat to target colonic tissues was confirmed using real-time X-ray radiography of iohexol dye. Entrapment efficiency and particle size were used in the characterization of the formula. Cytotoxicity of SMV microparticles against HCT-116 colon cancer cells was significantly improved as compared to raw SMV. Cell cycle analysis by flow cytomeric technique indicated enhanced accumulation of colon cancer cells in the G2/M phase. Additionally, a significantly higher cell fraction was observed in the pre-G phase, which highlighted enhancement of the proapoptotic activity of SMV prepared in the double coat formula. Assessment of annexin V staining was used for confirmation. Cell fraction in early, late and total cell death were significantly elevated. This was accompanied by a significant elevation of cellular caspase 3 activity. In conclusion, SMV-loaded chitosan coated with eudragit S100 formula exhibited improved colon targeting and enhanced cytotoxicity and proapoptotic activity against HCT-116 colon cancer cells.


Assuntos
Antineoplásicos/administração & dosagem , Quitosana/química , Neoplasias do Colo/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Sinvastatina/administração & dosagem , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Portadores de Fármacos/química , Células HCT116 , Humanos , Concentração de Íons de Hidrogênio , Masculino , Microesferas , Tamanho da Partícula , Ácidos Polimetacrílicos/química , Coelhos , Sinvastatina/farmacologia
10.
Mater Sci Eng C Mater Biol Appl ; 111: 110861, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32279793

RESUMO

BACKGROUND: Fracture healing complications are associated with significant healthcare and economic burden. In this study, we aimed to investigate how the combined administration of local simvastatin and ezetimibe into the femoral defect of the animal model affects the bone-healing process in comparison with their monotherapy. METHODS: A total of 32 four-month-old adult male Wistar rats were randomized into the four study groups: simvastatin + ezetimibe-loaded nanofibers (group 1), simvastatin-loaded nanofibers (group 2), ezetimibe-loaded nanofibers (group 3), and non-loaded nanofibers (group 4). After the generation of femoral defects, the predesigned nanofibers were locally administered into the defect site. The healing measures were serum and bone osteoprotegerin (OPG) expression, pathologic evaluation of union (Allen's fracture healing scores), and radiographic evaluation of bone density (Hounsfield scale) at weeks 2 and 4. RESULTS: The improvement of all evaluated healing measures was remarkably superior in rats that were treated with loaded nanofibers in comparison with the control group. Also, the improvement of all evaluated healing measures was considerably more in the simvastatin-ezetimibe combination therapy group compared to their monotherapy. All the evaluated measures were superior in the ezetimibe monotherapy group compared to the simvastatin monotherapy group. CONCLUSION: The cumulative effect of simvastatin and ezetimibe on the induction of bone healing is more significant than the individual effect of these drugs. Therefore, local administration of nanofibers loaded with simvastatin and ezetimibe could be regarded as a promising osteoinductive compound for the acceleration of bone repair.


Assuntos
Ezetimiba/farmacologia , Fêmur/patologia , Consolidação da Fratura/efeitos dos fármacos , Nanofibras/química , Sinvastatina/farmacologia , Animais , Densidade Óssea/efeitos dos fármacos , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Fêmur/cirurgia , Masculino , Nanofibras/ultraestrutura , Osteoprotegerina/sangue , Ratos Wistar
11.
World J Microbiol Biotechnol ; 36(4): 54, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32172435

RESUMO

Enterococcus faecalis (E. faecalis) is a Gram-positive bacterium closely related to many refractory infections of human and shows the resistant ability against the antibacterial effects of silver. Simvastatin is a semisynthetic compound derived from lovastatin and a hydroxymethyl glutaryl coenzyme A(HMG-COA) reductase inhibitor showing certain inhibitive effects on bacteria. The main purpose of this study was to establish and characterize the Ag+/silver nanoparticles (AgNPs)-resistant E. faecalis, and further evaluate the function of extracellular polymeric substances (EPS) in the silver resistance and the effect of simvastatin on the silver-resistance of E. faecalis. The results showed that the established silver-resistant E. faecalis had strong resistance against both Ag+ and AgNPs and simvastatin could decrease the silver-resistance of both original and Ag+/AgNPs-resistant E. faecalis. The Transmission electron microscopy (TEM), High-angle annular dark-field (HAADF) and mapping images showed that the silver ions or particles aggregated and confined in the EPS on surface areas of the cell membrane when the silver-resistant E. faecalis were incubated with Ag+ or AgNPs. When the simvastatin was added, the silver element was not confined in the EPS and entered the bacteria. These findings may indicate that the silver resistance of E. faecalis was derived from the entrapping function of EPS, but simvastatin could compromise the function of EPS to decrease the silver resistant ability of E. faecalis.


Assuntos
Enterococcus faecalis/efeitos dos fármacos , Prata/farmacologia , Sinvastatina/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterococcus faecalis/fisiologia , Matriz Extracelular de Substâncias Poliméricas/efeitos dos fármacos , Nanopartículas Metálicas , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Transmissão , Sinvastatina/química
12.
Ann Vasc Surg ; 67: 490-496, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32173476

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a progressive dilation of the aortic wall, determined by the unbalanced activity of matrix metalloproteinase (MMPs). In vitro and in vivo studies support the pivotal role of MMP-9 to AAA pathogenesis. In our experience, we elucidated the expression of MMP-9 in an ex vivo model of human mesenchymal stem cells isolated from AAA specimen (AAA-MSCs). Thus, MMP-9 inhibition could be an attractive therapeutic strategy for inhibiting AAA degeneration and rupture. Our study was aimed at testing the effect of 3 different drugs (pioglitazone, doxycycline, simvastatin) on MMP-9 and peroxisome proliferator-activated receptor (PPAR)-γ expression in AAA-MSCs. METHODS: Aneurysmal aortic wall segments were taken from AAA patients after the open surgical treatment. MSCs were isolated from AAA (n = 20) tissues through enzymatic digestion. AAA-MSCs were exposed to different doses of pioglitazone (5-10-25 µM), doxycycline (10-25 µM), and simvastatin (10 µM) for 24 h. The effect of each drug was evaluated in terms of cell survival, by crystal violet stain. MMP-9 and PPAR-γ mRNA were analyzed using real-time PCR. RESULTS: AAA-MSCs were not affected by the exposure to the selected drugs, as shown by the analysis of cell viability. Interestingly, MMP-9 mRNA resulted significantly decreased after each treatment, recording a downregulation of 50% in presence of pioglitazone, 90% with doxycycline, and 40% with exposed to simvastatin, in comparison to untreated cells. We further analyzed the expression of PPAR-γ, target of pioglitazone, observing an upregulation in exposed AAA-MSCs to controls. CONCLUSIONS: Our data support the potential therapeutic effect of pioglitazone, doxycycline, and simvastatin on AAA by reducing the MMP-9 expression in a patient-specific model (AAA-MSCs). In addition, pioglitazone drives the increase of PPAR-G, another promising target for AAA therapy. Further studies are necessary to elucidate the mechanism driving this inhibitory pathway, which can reduces the mortality risk associated with AAA rupture.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/tratamento farmacológico , Doxiciclina/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Pioglitazona/farmacologia , Sinvastatina/farmacologia , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais
13.
Int J Nanomedicine ; 15: 1797-1807, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214812

RESUMO

Purpose: Enhancing osteointegration of implants in osteoporosis patients is a necessity since implantations frequently fail in these patients. The aim of this work is to study how simvastatin-strontium-hydroxyapatite coated implants perform in rabbits with osteoporosis. Materials and Methods: Crystalline HA and Sr-HA oxide film were prepared through micro-arc oxidation. Surface characterization including morphology, roughness, element composition, phase composition, hydrophilicity were then evaluated. Simvastatin loaded on porous films through immersion, and the effects of coatings on osteointegration in osteoporotic rabbits were investigated. All samples were obtained after 4, 8 and 12 weeks of healing. Some of them were subjected to biomechanical tests and others were subjected to histological and histomorphometric analysis. Results: Coatings exhibited a microporous network structure with appropriate roughness and high hydrophilicity. Compared to control HA and machined surface implants, simvastatin-Sr-HA coated implants exhibited marked improvements in osteointegration, which is characterized by a quicker mineralization deposition rate, good bone formation mode (large amount of contact osteogenesis and a small amount of distance osteogenesis) and increased bone-to-implant contact and pull-out strength. Conclusion: These biological parameters demonstrate the excellent osteoconductivity of simvastatin-Sr-HA coatings in the osteoporotic state. Overall, this suggests that simvastatin-Sr-HA coatings would be applicable in poor-quality bones of patients experiencing osteoporosis.


Assuntos
Osseointegração/efeitos dos fármacos , Osteoporose/patologia , Próteses e Implantes , Sinvastatina/farmacologia , Animais , Interface Osso-Implante , Materiais Revestidos Biocompatíveis/química , Feminino , Hidroxiapatitas/química , Osteogênese/efeitos dos fármacos , Oxirredução , Coelhos , Sinvastatina/química , Estrôncio/química , Tíbia/fisiopatologia
14.
Acta Cir Bras ; 35(1): e202000102, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215463

RESUMO

PURPOSE: To evaluate the local effect of simvastatin (SVT) combined with deproteinized bovine bone (DBB) with hydroxyapatite/ß-tricalcium phosphate biphasic ceramics (HA/TCP) and with collagen sponge (CS) on bone repair in critical size defects (CSDs) in rat calvaria. METHODS: Forty-two 5-mm diameter CSDs were made bilaterally in the calvaria of 18 rats. The animals were allocated according to the type of biomaterial and associations used to fill the CSD. After 8 weeks, the animals were euthanized, and their calvaria were evaluated for repaired tissue composition using histologic and histometric analyses. RESULTS: In the histometric analysis, the use of SVT showed to increase bone formation in the CSDs when combined with all the bone substitutes tested in this study (p<0.05). Greater bone formation was observed in the groups with SVT compared to the groups without SVT. CONCLUSIONS: The use of SVT without the need for a vehicle and combined with a commercially available biomaterial may be a cheaper way to potentiate the formation of bone tissue without the need to produce new biomaterials. Therefore, SVT combined with DBB induced significantly greater new bone formation than did the other treatments.


Assuntos
Materiais Biocompatíveis/farmacologia , Substitutos Ósseos/farmacologia , Colágeno/farmacologia , Osteogênese/efeitos dos fármacos , Sinvastatina/farmacologia , Crânio/efeitos dos fármacos , Animais , Anticolesterolemiantes/farmacologia , Regeneração Óssea/efeitos dos fármacos , Transplante Ósseo/métodos , Bovinos , Modelos Animais de Doenças , Feminino , Ratos , Ratos Wistar , Crânio/cirurgia
15.
Pregnancy Hypertens ; 20: 83-91, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32199147

RESUMO

OBJECTIVES: There is avid interest in pravastatin as a therapeutic intervention for pre-eclampsia, however little is known on statin action on endothelial dysfunction. This study aimed to evaluate the ability of pravastatin, simvastatin and rosuvastatin to reduce pre-eclampsia-associated markers of endothelial dysfunction in human endothelial cells. STUDY DESIGN: Primary human umbilical vein endothelial cells (HUVECs) and uterine microvascular cells (UtMVs) were isolated and treated with 0.2, 2, 20 and 200 µM pravastatin, simvastatin and rosuvastatin for 24 h, either with or without pre-treatment with TNF-α to induce endothelial dysfunction. MAIN OUTCOME MEASURES: Cell viability (MTS) assays were performed and cells were visually inspected. Expression of endothelial dysfunction markers, endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed by qPCR (n=3). Intracellular VCAM-1 protein was examined by Western Blotting (n=5). ET-1 and soluble fms-like tyrosine kinase-1 (sFLT-1) protein secretion was assessed by ELISA in HUVEC conditioned media (n=3). RESULTS: High doses of simvastatin and rosuvastatin significantly compromised HUVEC survival. 200 µM simvastatin significantly reduced UtMV survival. Abnormal cell structure was observed with these doses and thus were excluded from further analysis. The statins did not mitigate TNF-α induced ET-1 or VCAM-1 expression in either HUVECs or UtMVs, nor VCAM-1 protein expression in HUVECs. 0.2 µM pravastatin and simvastatin significantly reduced ET-1 and sFLT-1 protein secretion. CONCLUSIONS: Pravastatin significantly reduced secretion of both ET-1 and sFLT-1, key mediators of endothelial dysfunction. Importantly, pravastatin had no toxic effects, in contrast to rosuvastatin and simvastatin. This further supports selection of pravastatin for clinical applications to combat pre-eclampsia.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Pravastatina/farmacologia , Pré-Eclâmpsia/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Endotelina-1/genética , Endotelina-1/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Pravastatina/toxicidade , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Rosuvastatina Cálcica/farmacologia , Sinvastatina/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
16.
Food Funct ; 11(3): 2588-2602, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32154540

RESUMO

Sarcodon aspratus is a popular edible fungus that has commonly been used as a functional food in China and other Asian countries. This study is conducted to examine the potential health benefits of Sarcodon aspratus polysaccharides (SATPs), on obesity and related metabolism disorders. C57BL/6J mice were fed with a high-fat diet (HFD) and supplemented with SATPs (100-400 mg kg-1) for 14 weeks. The results indicated that SATP treatment markedly reduced HFD-induced body weight gain and fat accumulation in a dose-dependent manner. SATPs could improve lipid homeostasis and glucose tolerance in HFD-fed mice. Furthermore, SATP intervention significantly attenuated hepatic steatosis, liver oxidative stress and inflammation. Additionally, we detected the macrophage and mRNA levels of lipogenesis markers in epididymal adipose tissues, and the results revealed that SATPs exerted inhibitory effects on the activation of immune cells and adipocyte differentiation in adipose tissues. High-throughput pyrosequencing of 16S rRNA suggested that SATP intervention was able to down-regulate the Firmicutes-to-Bacteroidetes ratio, and also increase the relative abundance of Lactobacillus, Bacteroides and Akkermansia in mice with HFD challenge. Taken together, SATPs showed ameliorative effects on hepatic steatosis, inflammation and adipocyte differentiation in HFD-fed mice. Notably, SATPs could modulate HFD-induced dysbiosis of gut microbiota. Thus, they might be a potential health supplement or prebiotic in the prevention of obesity and related metabolic disorders.


Assuntos
Basidiomycota/química , Dieta Hiperlipídica/efeitos adversos , Doenças Metabólicas/prevenção & controle , Obesidade/induzido quimicamente , Polissacarídeos/química , Polissacarídeos/farmacologia , Tecido Adiposo/efeitos dos fármacos , Animais , Suplementos Nutricionais , Microbioma Gastrointestinal/efeitos dos fármacos , Intolerância à Glucose , Hipolipemiantes/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Doenças Metabólicas/complicações , Camundongos , Obesidade/complicações , Estresse Oxidativo/efeitos dos fármacos , Sinvastatina/farmacologia , Ganho de Peso/efeitos dos fármacos
17.
Fluids Barriers CNS ; 17(1): 5, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32036791

RESUMO

BACKGROUND: Excitotoxicity is a central pathological pathway in many neurological diseases with blood-brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied in detail. Our aim was to examine the direct effects of kainate on cultured cells of the BBB and to test three anti-inflammatory and antioxidant drugs used in clinical practice, simvastatin, edaravone and dexamethasone, to protect against kainate-induced changes. METHODS: Primary rat brain endothelial cell, pericyte and astroglia cultures were used to study cell viability by impedance measurement. BBB permeability was measured on a model made from the co-culture of the three cell types. The production of nitrogen monoxide and reactive oxygen species was followed by fluorescent probes. The mRNA expression of kainate receptors and nitric oxide synthases were studied by PCR. RESULTS: Kainate damaged brain endothelial cells and made the immunostaining of junctional proteins claudin-5 and zonula occludens-1 discontinuous at the cell border indicating the opening of the barrier. The permeability of the BBB model for marker molecules fluorescein and albumin and the production of nitric oxide in brain endothelial cells were increased by kainate. Simvastatin, edaravone and dexamethasone protected against the reduced cell viability, increased permeability and the morphological changes in cellular junctions caused by kainate. Dexamethasone attenuated the elevated nitric oxide production and decreased the inducible nitric oxide synthase (NOS2/iNOS) mRNA expression increased by kainate treatment. CONCLUSION: Kainate directly damaged cultured brain endothelial cells. Simvastatin, edaravone and dexamethasone protected the BBB model against kainate-induced changes. Our results confirmed the potential clinical usefulness of these drugs to attenuate BBB damage.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Edaravone/farmacologia , Células Endoteliais/efeitos dos fármacos , Sinvastatina/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/metabolismo , Óxido Nítrico/metabolismo , Permeabilidade/efeitos dos fármacos , Ratos
18.
Sci Rep ; 10(1): 2158, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034223

RESUMO

Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Statins reduce plasma cholesterol levels and can prevent secondary cardiovascular diseases. Although statin-induced muscle damage has been studied, preventive or curative therapies are yet to be reported. We exposed primary human muscle cell populations (n = 22) to a lipophilic (simvastatin) and a hydrophilic (rosuvastatin) statin and analyzed their expressome. Data and pathway analyses included GOrilla, Reactome and DAVID. We measured mevalonate intracellularly and analyzed eicosanoid profiles secreted by human muscle cells. Functional assays included proliferation and differentiation quantification. More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Cultured human muscle cells secreted ω-3 and ω-6 derived eicosanoids and prostaglandins. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Eicosanoids rescued muscle cell differentiation. Our data suggest a new aspect on the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-n fatty acids might be suitable to prevent or treat statin-myopathy.


Assuntos
Anticolesterolemiantes/farmacologia , Dinoprosta/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Rosuvastatina Cálcica/farmacologia , Sinvastatina/farmacologia , Transcriptoma , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Dinoprosta/farmacologia , Humanos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo
19.
J Exp Clin Cancer Res ; 39(1): 24, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000827

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. METHODS: The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections. RESULTS: Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis. CONCLUSIONS: Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Transporte/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Sinvastatina/farmacologia , Sorafenibe/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Glicólise/efeitos dos fármacos , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , PPAR gama/metabolismo , Hormônios Tireóideos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Clin Ther ; 42(2): e13-e31, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31955966

RESUMO

PURPOSE: Chronic inflammation increases the risks for cardiovascular disease, type 2 diabetes, and cancer. Recently, the antiinflammatory effects of statins, as cholesterol-lowering medications, have been considered. This study systematically reviewed and summarized earlier findings from randomized clinical trials about the effects of statins on serum concentrations of C-reactive protein (CRP) and interleukin (IL)-6 in patients with abnormal glucose homeostasis. METHODS: Relevant articles published through October 2019 were searched using suitable key words on the PubMed/MEDLINE, SCOPUS, EMBASE, and Google Scholar databases. RCTs were included if they compared the effects of statins on serum concentrations of CRP and IL-6 in adults with abnormal glucose homeostasis. The effect sizes were represented as weighted mean differences (WMDs) and 95% CI s using a random-effects model. Subgroup analysis was performed to find possible sources of heterogeneity. FINDINGS: Overall, 17 publications with 21 effect sizes and which enrolled 3766 subjects (1895 participants in intervention and 1871 in control groups) were included. Combining 13 effect sizes from 10 studies, a significant reduction in serum CRP concentration following the administration of atorvastatin was found (WMD, -0.35; 95% CI, -0.54 to -0.17; I2 = 90.6%). Based on 5 effect sizes from 4 studies, we found a statistically significant reduction in serum IL-6 concentration after atorvastatin therapy (WMD, -0.44; 95% CI, -0.65 to -0.22; I2 = 93.9%). Pooling 6 effect sizes from 5 studies revealed a significantly reduced serum concentration of CRP after simvastatin therapy (WMD, -0.66; 95% CI, -0.79 to -0.54; I2 = 97.6%). IMPLICATIONS: The administration of atorvastatin or simvastatin in patients with abnormal glucose hemostasis was associated with a reduced serum CRP concentration. Atorvastatin therapy might also help to decrease serum IL-6 concentration in these patients.


Assuntos
Atorvastatina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Glicemia/efeitos dos fármacos , Proteína C-Reativa/análise , Citocinas/sangue , Glucose/metabolismo , Homeostase , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
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