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1.
Plast Reconstr Surg ; 145(2): 433-443, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31985637

RESUMO

BACKGROUND: This study explored the effect of a single local intraosseous application of a small dose of simvastatin on the wound healing process in type 1 diabetic rats and related mechanisms. METHODS: The authors chose the streptozotocin-induced type 1 diabetic rat to establish a full-thickness dermal wound using a 12-mm-diameter sterile disposable punch. The rats (n = 32) were divided randomly into four groups: (1) normal control rats, (2) type 1 diabetic rats with intraosseous injection of hydrogel vehicle, (3) type 1 diabetic rats with intraosseous injection of simvastatin (0.5 mg), and (4) type 1 diabetic rats with intragastric administration of simvastatin (20 mg/kg per day). Wound closure was followed by digital planimetry. Mobilization of endothelial progenitor cells into the circulatory system was studied using fluorescence-activated cell sorting. Neovascularization was analyzed with immunofluorescence histochemical staining. The relative levels of adiponectin and stromal cell-derived factor 1 (SDF-1) in serum, bone, and wound tissues were examined by enzyme-linked immunosorbent assay and Western blot. RESULTS: Diabetic rats exhibited impaired wound healing. Intraosseous administration of simvastatin accelerated wound healing beginning at day 4, and angiogenesis was more obvious than in the control group. Enzyme-linked immunosorbent assay revealed that adiponectin concentrations in the diabetic rats with intraosseous injection of hydrogel vehicle plus simvastatin 0.5-mg group were significantly higher compared with the diabetic rats with intraosseous injection of hydrogel vehicle group beginning at day 4. Intraosseous administration of simvastatin decreased the expression of adiponectin and SDF-1 in bone tissue but enhanced the expression of adiponectin in wounded skin. CONCLUSIONS: A single local intraosseous application of simvastatin promotes wound healing in type 1 diabetic rat. The underlying mechanisms may be attributed to the regulation of the adiponectin/SDF-1 pathway, which plays a pivotal role in endothelial progenitor cell mobilization and angiogenesis.


Assuntos
Indutores da Angiogênese/farmacocinética , Células Progenitoras Endoteliais/efeitos dos fármacos , Sinvastatina/farmacologia , Cicatrização/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Quimiocina CXCL12/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Combinação de Medicamentos , Hidrogéis , Injeções , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Poloxâmero/administração & dosagem , Ratos Sprague-Dawley , Sinvastatina/administração & dosagem , Pele/metabolismo
2.
Zhonghua Nei Ke Za Zhi ; 59(1): 52-57, 2020 Jan 01.
Artigo em Chinês | MEDLINE | ID: mdl-31887837

RESUMO

Objective: To investigate the endothelial protective effects of simvastatin on the coagulation system in septic rats. Methods: A total of 54 SD male rats were divided into 3 groups. Six healthy rats were intraperitoneally injected with normal salineas control group. Twenty-four rats in septic group were intraperitoneally injected with normal saline followed by lipopolysaccharide 2.5 mg. Study group had 24 rats intraperitoneally injected with simvastatin followed by lipopolysaccharide. Plasma von Willebrand factor (vWF), thrombomodulin (TM), platelet activating factor (PAF) and antithrombin-Ⅲ (AT-Ⅲ) were tested at 1 h, 3 h, 6 h and 12 h after treatment. Scanning electron microscopy and transmission electron microscopy were used to observe the morphology and apoptosis of rat aorta endothelial cells. Results: Compared with healthy control group, vWF [(68.3±4.8) ng/ml, (59.2±5.1) ng/ml, (74.2±20.1) ng/ml, (53.5±4.0)ng/ml, respectively], TM [(1.4±0.3) ng/ml, (1.6±0.4) ng/ml, (2.8±0.9) ng/ml, (1.4±0.5) ng/ml, respectively], PAF [(29.1±6.5) pg/ml, (28.6±1.5) pg/ml, (28.7±2.7) pg/ml, (18.2±4.1) pg/ml, respectively] and AT-Ⅲ [(262.2±38.1)µg/ml, (233.0±70.4) µg/ml, (218.7±54.7) µg/ml, (162.2±37.2) µg/ml, respectively] were significantly increased in the sepsis group at 1 h, 3 h, 6 h and 12 h (P<0.05). Compared with the sepsis group, the plasma levels of PAF in simvastatin intervention group at 1 h [(15.6±2.5) pg/ml, 3 h(10.4±5.3) pg/ml, 6 h (9.3±1.4) pg/ml, 12 h(11.0±2.7) pg/ml] were significantly decreased, so were the TM level at 6 h (1.6±0.9) ng/ml, and the AT-Ⅲ levels at 1 h[(190.3±29.2) µg/ml],6 h [(104.4±33.6) µg/ml] and 12 h [(73.6±39.0) µg/ml, P<0.05]. Conclusion: In the condition of sepsis, toxins and over-activated inflammatory factors damage the vascular endothelium. A large amount of circulating vWF, TM, PAF, and AT-Ⅲ cause early hypercoagulability. Simvastatin significantly reduces plasma amount of these procoagulants, suggesting it smodification of coagulopathy and vascular protective effectsin a septic rat model.


Assuntos
Células Endoteliais/efeitos dos fármacos , Sepse , Sinvastatina/farmacologia , Fator de von Willebrand/metabolismo , Animais , Coagulação Sanguínea , Masculino , Ratos
3.
Life Sci ; 242: 117225, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881229

RESUMO

AIMS: Data concerning the influence of statin lipophilicity on the myotoxic and pleiotropic effects of statins is conflicting, and mechanistic head-to-head comparison studies evaluating this parameter are limited. In order to address the disparity, this mechanistic investigation aimed to assess the effects of two short-acting statins with different lipophilic indices on skeletal, cardiac and vascular smooth muscle physiology. MATERIALS AND METHODS: Young female Wistar rats were randomised to simvastatin (80 mg kg-1 day-1), pravastatin (160 mg kg-1 day-1) or control treatment groups. Changes in functional muscle performance were assessed, as well as mRNA levels of genes relating to atrophy, hypertrophy, mitochondrial function and/or oxidative stress. KEY FINDINGS: There were no significant differences in the mRNA profiles of isolated skeletal muscles amongst the treatment groups. In terms of skeleletal muscle performance, simvastatin reduced functionality but treatment with pravastatin significantly improved force production. Rodents given simvastatin demonstrated comparable myocardial integrity to the control group. Conversely, pravastatin reduced left ventricular action potential duration, diastolic stiffness and Mhc-ß expression. Pravastatin improved endothelium-dependent relaxation, particularly in muscular arteries, but this effect was absent in the simvastatin-treated rats. The responsiveness of isolated blood vessels to noradrenaline also differed between the statin groups. The findings of this study support that the effects of statins on skeletal, cardiac and vascular smooth muscle vary with their lipophilic indices. SIGNIFICANCE: The results of this work have important implications for elucidating the mechanisms responsible for the myotoxic and pleiotropic effects of statins.


Assuntos
Coração/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Músculo Esquelético/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Pravastatina/farmacologia , Sinvastatina/farmacologia , Animais , Feminino , Microeletrodos , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Liso Vascular/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
4.
Bratisl Lek Listy ; 120(10): 744-751, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31663349

RESUMO

OBJECTIVE: This study was conducted to investigate the effects of Simvastatin (SIM), a member of statin family, on the cellular antioxidant system, autophagy and apoptosis in NSCs exposed to hydrogen peroxide. BACKGROUND: Reduction in cellular oxidative stress increases the survival of neural stem cells (NSCs) after transplantation into the damaged area of the affected central nervous system. MATERIAL AND METHODS: NSCs derived from bone marrow stromal cells (BMSCs) were exposed to H2O2 (100 µM) for 48 hours after pretreatment with SIM (2 µM). Next, the expressions of the master antioxidant transcription factor, Nrf2/nuclear factor erythroid 2 (NFE2)-related factor 2, autophagy-related proteins (microtubule-associated proteins 1A/1B light chain 3B known as LC3I and LC3II and also p62/Sequestosome), and apoptosis (Bcl-2/ B-cell lymphoma 2 and Bax/BCL2 associated X protein) were analyzed. RESULTS: SIM caused Nrf2 over-activation (more localizations in the cellular nucleus), reduction in reactive oxygen species (ROS), induction of autophagy (decrease in p62 expression and increase in LC3II/LC3I ratio) and inhibition of apoptosis (decrease in Bax protein and increase in Bcl-2) in NSCs exposed to H2O2-induced oxidative stress, thereby prolonging the cell viability within 48 hours at low concentration (2 µM). CONCLUSION: SIM protects NSCs against H2O2-induced apoptosis in a pleiotropic signaling manner (Fig. 7, Ref. 35).


Assuntos
Apoptose , Autofagia , Células-Tronco Neurais/efeitos dos fármacos , Neuroproteção , Sinvastatina/farmacologia , Antioxidantes/fisiologia , Células Cultivadas , Humanos , Peróxido de Hidrogênio
5.
Int J Nanomedicine ; 14: 7975-7985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632012

RESUMO

Background: Multidrug-resistant bacteria such as extended-spectrum beta-lactamase (ESBL), Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus (MRSA) pose a challenge to the human health care system. MRSA is among the major causes of hospital-acquired and community infections. Methods: Therefore, in the present study, we evaluated the antibacterial activity of silver nanoparticles synthesized by Fusarium oxysporum (AgNPbio) in combination with simvastatin against reference and multidrug-resistant bacterial strains. Results: Simvastatin showed a minimal inhibitory concentration (MIC) ranging from 0.062 to 0.25 mg mL-1 against MRSA. AgNPbio with a size of 77.68± 33.95 nm and zeta potential -34.6 ± 12.7 mV showed an MIC of 0.212 mg mL-1 against S. aureus including MRSA strains. The checkerboard assay and time-kill curves exhibited a synergistic effect of the simvastatin-AgNPbio combination on antibacterial activity against MRSA strains. The combination of simvastatin and AgNPbio demonstrated antibacterial activity against Escherichia coli producing ESBL. Scanning electron microscopy showed the formation of cell surface protrusions after treatment with AgNPbio and the formation of a large amorphous mass after treatment with simvastatin, both in MRSA. Conclusion: Our results indicate that the combination of AgNPbio and simvastatin could be a great future alternative in the control of bacterial infections, where, when combined with simvastatin, smaller doses of AgNPbio are required, with the same antibacterial activity.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Fusarium/metabolismo , Nanopartículas Metálicas/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Prata/farmacologia , Sinvastatina/farmacologia , Morte Celular/efeitos dos fármacos , Sinergismo Farmacológico , Eritrócitos/efeitos dos fármacos , Fusarium/efeitos dos fármacos , Fusarium/ultraestrutura , Humanos , Nanopartículas Metálicas/ultraestrutura , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana
6.
Cardiovasc Intervent Radiol ; 42(12): 1777-1785, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31392490

RESUMO

PURPOSE: Contrast-induced nephropathy (CIN) is one of the leading causes of hospital-acquired acute kidney injury due to the use of iodinated contrast media in various interventional procedures like endovascular aneurysm repair. Its pathophysiology remains mostly unclear. The purpose of the present study was to comparatively study the possible protective role of direct intra-arterial administration of mannitol and acetylcysteine and per os administration of simvastatin in a histopathological level. MATERIALS AND METHODS: In the present study, we administered iopromide directly in the infrarenal aorta of 24 New Zealand white rabbits after laparotomy. Animals were divided in four groups of six: G1 received iopromide with no protection, G2 iopromide with mannitol, G3 iopromide with acetylcysteine, and G4 iopromide with simvastatin. Renal function blood parameters were assessed prior to the administration, and in 48 h; histopathological evaluation of the kidneys was performed. RESULTS: CIN was evident only in the no protection group G1. Moreover, G1 demonstrated significantly more severe lesions than groups G2, G3, and G4 regarding histopathological findings in glomeruli, vacuolization of tubular epithelial cells, tubular proteinaceous casts, and tubular necrosis. According to our results, intra-arterial administration of mannitol seems to be effective in protection against tubular necrosis. CONCLUSION: In general, all three agents demonstrated a protective role in preventing the development of CIN, although it seems that there are various pathways that remain to be investigated further.


Assuntos
Acetilcisteína/uso terapêutico , Lesão Renal Aguda/tratamento farmacológico , Meios de Contraste/efeitos adversos , Manitol/uso terapêutico , Sinvastatina/farmacologia , Acetilcisteína/administração & dosagem , Lesão Renal Aguda/induzido quimicamente , Administração Oral , Animais , Modelos Animais de Doenças , Diuréticos Osmóticos/administração & dosagem , Diuréticos Osmóticos/uso terapêutico , Humanos , Infusões Intra-Arteriais , Iohexol/efeitos adversos , Iohexol/análogos & derivados , Masculino , Manitol/administração & dosagem , Coelhos
7.
Int J Mol Med ; 44(4): 1289-1298, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432100

RESUMO

Atherosclerosis is a major pathogenic factor in patients with cardiovascular diseases, and endothelial dysfunction (ED) plays a primary role in its occurrence and development. Simvastatin is a lipid­lowering drug, which is commonly used to prevent or treat risk factors of cardiovascular diseases with a significant anti­atherogenic effect. However, its impact on endothelial cells under conditions of oxidative stress and broader mechanisms of action remain unclear. The present study evaluated the effect of simvastatin on human umbilical vein endothelial cells (HUVECs) under oxidative stress with H2O2, and the associated mechanisms. At a high dose (1 µM), simvastatin exacerbated H2O2­induced endothelial cell dysfunction. Moreover, inhibition of the Wnt/ß­catenin pathway by salinomycin significantly suppressed the simvastatin­associated HUVEC dysfunction. Western blot analysis further demonstrated that simvastatin promoted the phosphorylation of low­density lipoprotein receptor­related protein 6 (LRP6) and activated the Wnt/ß­catenin pathway. Simvastatin also activated endoplasmic reticulum (ER) stress, which was reversed by salinomycin treatment. Based on these results, it was hypothesized that simvastatin may promote ER stress by facilitating LRP6 phosphorylation and the subsequent activation of the Wnt/ß­catenin pathway, thereby enhancing H2O2­induced ED. Therefore, high­dose simvastatin treatment could have potential toxic side effects, indicating the need for close clinical management, monitoring and patient selection.


Assuntos
Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sinvastatina/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Fosforilação
8.
Curr Pharm Biotechnol ; 20(9): 733-744, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258074

RESUMO

BACKGROUND: Recurrent pharyngotonsillitis due to Streptococcus pyogenes develops regardless of whether infecting strains are resistant or susceptible to first-line antimicrobials. Causation for recurrent infection is associated with the use of first-line antimicrobials that fail to penetrate deep tissue and host cell membranes, enabling intracellular S. pyogenes to survive throughout repeated rounds of antimicrobial therapy. OBJECTIVE: To determine whether simvastatin, a therapeutic approved for use in the treatment of hypercholesterolemia, and ML141, a first-in-class small molecule inhibitor with specificity for human CDC42, limit host cell invasion by S. pyogenes. METHODS: Assays to assess host cell invasion, bactericidal activity, host cell viability, actin depolymerization, and fibronectin binding were performed using the RAW 267.4 macrophage cell line and Human Umbilical Vein Endothelial Cells (HUVEC) infected with S. pyogenes (90-226) and treated with simvastatin, ML141, structural analogs of ML141, or vehicle control. RESULTS: Simvastatin and ML141 decreased intracellular infection by S. pyogenes in a dose-dependent manner. Inhibition by simvastatin persisted following 1 h washout whereas inhibition by ML141 was reversed. During S. pyogenes infection, actin stress fibers depolymerized in vehicle control treated cells, yet remained intact in simvastatin and in ML141 treated cells. Consistent with the previous characterization of ML141, simvastatin decreased host cell binding to fibronectin. Structural analogs of ML141, designated as the RSM series, decreased intracellular infection through non-cytotoxic, nonbactericidal mechanisms. CONCLUSION: Our findings demonstrate the potential of repurposing simvastatin and of developing CDC42-targeted therapeutics for eradicating intracellular S. pyogenes infection to break the cycle of recurrent infection through a host-directed approach.


Assuntos
Antibacterianos/farmacologia , Pirazóis/farmacologia , Sinvastatina/farmacologia , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus pyogenes/efeitos dos fármacos , Sulfonamidas/farmacologia , Proteína cdc42 de Ligação ao GTP/antagonistas & inibidores , Animais , Antibacterianos/química , Células Cultivadas , Fibronectinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/microbiologia , Humanos , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Estrutura Molecular , Pirazóis/química , Células RAW 264.7 , Sinvastatina/química , Sulfonamidas/química
9.
Acta Parasitol ; 64(3): 612-616, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31286354

RESUMO

PURPOSE: Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the metabolism of isoprenoids and other pivotal mediators for the parasite survival. Statins are drugs that inhibit cholesterol synthesis, blocking the conversion of the substrate HMG-CoA to mevalonate, thus preventing the initial processes of the biosynthesis of these precursors, both in humans and parasite. Our goal was to verify whether the Toxoplasma gondii (RH strain) tachyzoites form pretreated with pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations could affect the infection processes, suggesting direct action on protozoa intracellular proliferation through the inhibition of isoprenoids in the parasite's apicoplast. METHODS: To have the adhesion, infection, and parasite proliferation during experimental infection investigated, HeLa cells (105) were subjected to a 24-hour infection by T. gondii tachyzoites forms of RH strain (5 × 105) pretreated for 30 min with pravastatin and/or simvastatin combined or not with pyrimethamine and sulfadiazine. RESULTS: Combined with conventional drugs at low concentrations pravastatin and simvastatin inhibit the adhesion, invasion, and intracellular proliferation of T. gondii in HeLa cells which are similar to the positive control. CONCLUSION: Pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations can be regarded as a promising, effective alternative to toxoplasmosis treatment with reduced side effects.


Assuntos
Antiprotozoários/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Pravastatina/farmacologia , Pirimetamina/farmacologia , Sinvastatina/farmacologia , Sulfadiazina/farmacologia , Toxoplasma/efeitos dos fármacos , Toxoplasmose/parasitologia , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Células HeLa , Humanos , Toxoplasma/crescimento & desenvolvimento , Toxoplasma/fisiologia , Toxoplasmose/tratamento farmacológico
10.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(3): 283-290, 2019 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-31282320

RESUMO

Objective To investigate the effects of simvastatin on diabetic neuropathic pain and systematic inflammation in diabetic rats and explore their molecular mechanisms.Methods Totally 24 rats were equally randomized into the normal+vehicle(NV)group,diabetic+vehicle(DV)group,and diabetic+simvastatin(DS)group using the random number table.Streptozotocin(STZ)was used to establish the rat models of diabetes.Blood glucose,body mass,paw withdrawal mechanical threshold(PWMT),and paw withdrawal thermal latency(PWTL)in each group were observed on days 7,14,21,and 28 after STZ injection.On day 28 after STZ injection,rats were sacrificed,and the lumbar spinal dorsal horn and serum were collected.Western blotting was used to detect the expression of receptor for advanced glycation end products(RAGE)and the phosphorylation levels of protein kinase B(AKT),extracellular signal-regulated kinase(ERK),p38,and c-Jun N-terminal kinase(JNK)in the spinal dorsal horn of rats in each group.Enzyme-linked immunosorbent assay was performed to determine the serum concentrations of oxidized low density lipoprotein(ox-LDL)and interleukin-1ß(IL-1ß).Results On days 14,21 and 28 after STZ injection,the PWMT in DV group were(8.6 ± 0.8),(7.1 ± 1.6),and(7.8 ± 0.8)g respectively,which were significantly lower than (12.0 ± 0.9)(q=8.482,P =0.000),(11.6 ± 1.5)(q=11.309,P =0.000),and(11.7 ± 1.5)g(q=9.801,P =0.000)in NV group.The PWMT in DS group on days 21 and 28 were(9.4 ± 1.4)(q=5.780,P =0.000)and(9.7 ± 0.9)g(q=4.775,P =0.003),respectively,which were significantly improved comparing with those of DV group.On days 7,14,21,and 28,there were no significant differences in PWTL among these three groups (all P<0.05).The expression of RAGE in the spinal dorsal horn of DV group was significantly higher than those of NV group(q=6.299,P =0.000)and DS group(q=2.891,P =0.025).The phosphorylation level of AKT in the spinal dorsal horn of DV group was significantly higher than those of NV group(q=8.915,P=0.000)and DS group(q=4.103,P=0.003).The phosphorylation levels of ERK(q =8.313,P=0.000),p38(q =2.965,P =0.022),and JNK(q=7.459,P =0.000)in the spinal dorsal horn of DV group were significantly higher than those of NV group;the phosphorylation level of JNK in the spinal dorsal horn of DS group was significant lower than that of DV group(q=3.866,P =0.004);however,there were no significant differences in the phosphorylation levels of ERK(q=1.987,P=0.122)and p38(q=1.260,P=0.375)in the spinal dorsal horn between DS group and DV group.The serum concentrations of ox-LDL and IL-1ß in DV group were(41.86 ± 13.40)ng/ml and(108.16 ± 25.88)pg/ml,respectively,which were significantly higher than those in NV group [(24.66 ± 7.87)ng/ml(q=3.606,P=0.003)and(49.32 ± 28.35)pg/ml(q=5.079,P=0.000)] and DS group [(18.81 ± 5.62)ng/ml (q=4.833,P =0.000)and(32.73 ± 11.73)pg/ml(q=6.510,P =0.000)].Conclusions Simvastatin can relieve the mechanical allodynia of diabetic rats possibly by inhibiting the activation of RAGE/AKT and the phosphorylation of JNK in the spinal dorsal horn.Simvastatin can also decrease the serum concentrations of ox-LDL and IL-1ß in diabetic rats,which may contribute to the relief of systematic inflammation.


Assuntos
Diabetes Mellitus Experimental/complicações , Inflamação/tratamento farmacológico , Neuralgia/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Hiperalgesia , Interleucina-1beta/sangue , Lipoproteínas LDL/sangue , Proteínas Proto-Oncogênicas c-akt/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada/metabolismo
11.
Pol J Vet Sci ; 22(2): 263-270, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31269349

RESUMO

The present study was undertaken to highlight the influence of simvastatin administration on hepatocyte morphology, proliferation, and apoptosis. The study included 48 gilts aged 3 months (weighing ca. 30 kg) divided into groups I (control; n=24) and II, receiving 40 mg/animal simvastatin orally (simavastatin; n=24) for 29 days. The animals were euthanized on days subsequent to the experiment. The livers were sampled, fixed, and processed routinely for histopathology, histochemistry, and immunohistochemistry (for proliferating cell nuclear antigen, Bcl-2, and caspase-3). Apoptosis was visualized by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL). Simvastatin administration caused acute hepatocyte swelling, glycogen depletion, hyperaemia, multifocal hepatocyte proliferation with occasional pseudoacinar formation, connective tissue hyperplasia, eosinophil infiltration, and interface hepatitis. The proliferating cell nuclear antigen index, mean diameter of argyrophilic nucleolar organizer regions, and Bcl-2 immunoexpression were lower compared to control, and mean caspase-3 immunoexpression was higher in group II compared to control. On day 25 and 29 single hepatocytes in the simvastatin- treated group were TUNEL-positive. Simvastatin caused morphological alteration which became more intense over time. The results from the present study suggest that simvastatin treatment may cause glycogen, lipid metabolism and cell membrane permeability distortion, fibrosis, interface hepatitis, reduction in hepatocyte proliferation and transcriptional activity, and enhanced vulnerability to apoptosis. Summing up the results, it can be concluded that simvastatin caused liver damage with similar morphological changes seen in autoimmune-like liver injury, which may indicate that simvastatin may induce autoimmune-like drug induced liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Doenças dos Suínos/induzido quimicamente , Animais , Feminino , Imuno-Histoquímica , Distribuição Aleatória , Suínos
12.
Chem Biol Interact ; 310: 108730, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260663

RESUMO

The present study shows the basis for the anti-inflammatory effects of statins in interleukin 1ß (IL-1ß) induced SW1353 chondrosarcoma cell-line. The cells were pre-treated with simvastatin (5 µM, 10 µM, and 50 µM), followed by IL-1ß (5 ng/mL) stimulation. Effects of simvastatin on cell viability and cytotoxicity of chondrocytes were measured with WST-1 and lactate dehydrogenase (LDH) assays, respectively. Under inflammatory conditions, in the absence/presence of simvastatin, the changes in matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression levels were examined. Expression levels of MMP-1, -2, -3, -9, -13, and TIMP-1 and -2 were examined by qPCR. MMP-1, -9, -13, TIMP-1, and -2 levels were also determined by Western blotting. Gelatin zymography was performed to analyze the released and intracellular MMP-2 and MMP-9 activity levels. The results showed that simvastatin downregulated the degradation related genes MMP-3, MMP-13, MMP-2, MMP-9 and TIMP-2 in a dose-dependent manner.


Assuntos
Condrócitos/citologia , Condrossarcoma/patologia , Metaloproteinases da Matriz/metabolismo , Sinvastatina/farmacologia , Anti-Inflamatórios/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Citotoxinas/farmacologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/farmacologia , Metaloproteinases da Matriz/efeitos dos fármacos , Inibidores Teciduais de Metaloproteinases/metabolismo
13.
J Mater Sci Mater Med ; 30(8): 87, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31325047

RESUMO

Previous studies have demonstrated the significant roles of simvastatin (SVA) and oxysterols in the osteogenesis process. In this study, we evaluate the effect of a combination of SVA and 20(S)-hydroxycholesterol (20(S)OHC) on the cell viability and osteogenic differentiation of bone marrow stromal cells (BMSCs). After treatment with a control vehicle, SVA (0.025, 0.10, 0.25 or 1.0 µM), 20(S)OHC (5 µM), or a combination of both (0.25 µM SVA + 5 µM 20(S)OHC), the proliferation, apoptosis, ALP activity, mineralization, osteogenesis-related gene expression and Raf/MEK/ERK signaling activity in BMSCs were measured. Our results showed that high concentrations of SVA (0.25 and 1.0 µM) enhanced osteogenesis-related genes expression while attenuating cell viability. The addition of 5 µM 20(S)OHC induced significantly higher proliferative activity, which neutralized the inhibitory effect of SVA on the viability of BMSCs. Moreover, compared to supplementation with only one of the additives, combined supplementation with both SVA and 20(S)OHC induced significantly enhanced ALP activity, calcium sedimentation, osteogenesis-related genes (ALP, OCN and BMP-2) expression and Raf/MEK/ERK signaling activity in BMSCs; these enhancements were attenuated by treatment with the inhibitor U0126, indicating a significant role of Raf/MEK/ERK signaling in mediating the synergistically enhanced osteogenic differentiation of BMSCs by combined SVA and 20(S)OHC treatment. Additionally, histological examination confirmed a synergistic effect of SVA and 20(S)OHC on enhancing bone regeneration in a rabbit calvarial defect model. This newly developed SVA/20(S)OHC formulation may be used as an osteoinductive drug to enhance bone healing.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Hidroxicolesteróis/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Sinvastatina/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Regeneração Óssea/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Sinergismo Farmacológico , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Células-Tronco Mesenquimais/fisiologia , Osteogênese/genética , Coelhos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Quinases raf/metabolismo
14.
Int J Nanomedicine ; 14: 4881-4893, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308664

RESUMO

Purpose: This study was designed to evaluate the in vitro and in vivo biocompatibility and osteointegration of plasma-sprayed hydroxyapatite (HA)-coated polyethylene terephthalate (PET) ligaments encapsulated with a simvastatin (SV)-chitosan (CS) composite. Methods: This study compared the in vitro and in vivo bone responses to three different PET ligaments: SV/CS/PET-HA, CS/PET-HA and PET-HA. A field emission scanning electron microscope was used to characterize the morphology, and the in vitro SV release profile was analyzed. MC3T3 cells were cocultured with SV/CS/PET-HA, CS/PET-HA and PET-HA to test their biocompatibility using CCK-8 tests. Osteogenic differentiation was investigated by the expression of marker genes using qPCR. Osteointegration was performed by implanting the PET ligaments into the proximal tibia bone tunnels of male Sprague-Dawley rats for 3 weeks and 6 weeks. The bone-implant interface was evaluated by micro-computed tomography (micro-CT) and histological analysis. Results: The characteristic nanoporous structures mainly formed on the surface of the plasma-sprayed HA particles in the SV/CS/PET-HA and CS/PET-HA groups. The SV release test showed that the sustained release of simvastatin lasted for 25 days in the SV/CS/PET-HA group. The in vitro studies demonstrated that the SV/CS/PET-HA ligaments induced osteogenic differentiation in the MC3T3 cells, with higher mRNA expression levels of collagen-1, bone morphogenetic protein-2, osteocalcin and alkaline phosphatase than those in the CS/PET-HA and PET-HA ligament groups. The in vivo tests showed that both micro-CT analysis (bone mineral density and bone volume per total volume) and histological analysis (bone implant contact and interface area) revealed significantly higher peri-implant bone formation and less interface area in the SV/CS/PET-HA group than in the other groups. Conclusion: The SV-CS composite nanoporous structure was associated with the improved biocompatibility and osteogenic differentiation in vitro and enhanced osteointegration process in vivo of plasma-sprayed HA-coated PET ligaments.


Assuntos
Quitosana/química , Durapatita/farmacologia , Ligamentos/efeitos dos fármacos , Nanoporos , Osseointegração/efeitos dos fármacos , Polietilenotereftalatos/farmacologia , Sinvastatina/farmacologia , Animais , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Liberação Controlada de Fármacos , Masculino , Nanoporos/ultraestrutura , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Microtomografia por Raio-X
15.
Int J Mol Sci ; 20(14)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31330953

RESUMO

A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia. Since amyloid beta (Aß42) is the protein that is most associated with Alzheimer's disease, this study has focused on how simvastatin influences the turnover of native Aß42 and Aß42 fused with green fluorescent protein (GFP), in the simplest eukaryotic model organism, Saccharomyces cerevisiae. Previous studies have established that yeast constitutively producing Aß42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aß42. Young cells clear the GFP fusion protein and do not have green fluorescence while the older population of cells retains the fusion protein and exhibits green fluorescence, offering a fast and convenient means of studying factors that affect Aß42 turnover. In this study the proportion of cells having GFP fused to Aß after exposure to simvastatin, atorvastatin and lovastatin was analyzed by flow cytometry. Simvastatin effectively reduced levels of the cellular Aß42 protein in a dose-dependent manner. Simvastatin promoted the greatest reduction as compared to the other two statins. A comparison with fluconazole, which targets that same pathway of ergosterol synthesis, suggests that effects on ergosterol synthesis do not account for the reduced amounts of Aß42 fused to GFP. The levels of native Aß42 following treated with simvastatin were also examined using a more laborious approach, quantitative MALDI TOF mass spectrometry. Simvastatin efficiently reduced levels of native Aß42 from the population. This work indicates a novel action of simvastatin in reducing levels of Aß42 providing new insights into how simvastatin exerts its neuroprotective role. We hypothesize that this reduction may be due to protein clearance.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Leveduras/efeitos dos fármacos , Leveduras/metabolismo , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Senescência Celular/genética , Ergosterol/biossíntese , Expressão Gênica , Ordem dos Genes , Genes Reporter , Humanos , Plasmídeos/genética , Proteólise , Proteínas Recombinantes de Fusão , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Leveduras/genética
16.
Transplant Proc ; 51(8): 2798-2807, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351770

RESUMO

PURPOSE: The objective of this research was to survey the therapeutic action of simvastatin (Sim) on intestinal ischemia/reperfusion injury (II/RI) by modulating Omi/HtrA2 signaling pathways. METHODS: Sprague Dawley rats were pretreated with 40 mg/kg Sim and then subjected to 1 hour of ischemia and 3 hours of reperfusion. The blood and intestinal tissues were collected, pathologic injury was observed, the contents of serum tumor necrosis factor-α and interleukin-6 (IL-6) were estimated, and superoxide dismutase, methane dicarboxylic aldehyde, and cysteinyl aspartate specific proteinase-3 (caspase-3) levels, as well as the expressions of Omi/HtrA2 and caspase-3, were measured in the intestinal tissues. RESULTS: Sim preconditioning mitigated the damnification of intestinal tissues by decreasing oxidative stress, inflammatory damage, and apoptosis and downregulating the expression of Omi/HtrA2 compared to the ischemia/reperfusion group, while Sim+Ucf-101 significantly augmented this effect. CONCLUSION: These results suggest that Sim may alleviate intestinal ischemia/reperfusion injury by modulating Omi/HtrA2 signaling pathways.


Assuntos
Anticolesterolemiantes/farmacologia , Serina Peptidase 2 de Requerimento de Alta Temperatura A/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/análise , Caspase 3/metabolismo , Masculino , Proteínas Mitocondriais/metabolismo , Pirimidinonas , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Tionas
17.
Int J Mol Sci ; 20(12)2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31212751

RESUMO

Endothelial dysfunction (ED) is an important contributor to atherosclerotic cardiovascular disease. Our previous study demonstrated that sphingomyelin synthase 2 (SMS2) promotes ED. Moreover, endoplasmic reticulum (ER) stress can lead to ED. However, whether there is a correlation between SMS2 and ER stress is unclear. To examine their correlation and determine the detailed mechanism of this process, we constructed a human umbilical vein endothelial cell (HUVEC) model with SMS2 overexpression. These cells were treated with 4-PBA or simvastatin and with LiCl and salinomycin alone. The results showed that SMS2 can promote the phosphorylation of lipoprotein receptor-related protein 6 (LRP6) and activate the Wnt/ß-catenin pathway and that activation or inhibition of the Wnt/ß-catenin pathway can induce or block ER stress, respectively. However, inhibition of ER stress by 4-PBA can decrease ER stress and ED. Furthermore, when the biosynthesis of cholesterol is inhibited by simvastatin, the reduction in intracellular cholesterol coincides with a decrease in ER stress and ED. Collectively, our results demonstrate that SMS2 can activate the Wnt/ß-catenin pathway and promote intracellular cholesterol accumulation, both of which can contribute to the induction of ER stress and finally lead to ED.


Assuntos
Estresse do Retículo Endoplasmático , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Biomarcadores , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/fisiopatologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Fosforilação , Sinvastatina/farmacologia , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Via de Sinalização Wnt , beta Catenina/metabolismo
18.
Gynecol Oncol ; 154(2): 432-440, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31178149

RESUMO

OBJECTIVE: Recent data show that simvastatin (SIM) and metformin (MET) have anti-proliferative effects in endometrial cancer cells. The combination (MET+SIM) inhibits tumor growth and metastasis in prostate cancer cells which possess similar molecular alterations to many early endometrial cancers. We tested the hypothesis that the anti-proliferative effects of MET+SIM in endometrial cancer cells would be greater than the effects of each agent alone. METHODS: RL95-2, HEC1B, and Ishikawa endometrial cancer cell lines were treated with MET and/or SIM. Growth inhibition was measured by MTS cell proliferation assays. Apoptosis was evaluated by caspase-3, Annexin V, and TUNEL assays and by apoptosis markers (BAX, Bcl-2, Bim) using western blot. Bim was silenced using Bim siRNA to confirm this apoptotic pathway. Treatment effects on the mTOR pathway were investigated by western blot using antibodies to phosphorylated (phospho)-AMPK and phospho-S6. RESULTS: MET+SIM synergistically inhibited growth in all three cell lines. The combination induced apoptosis as measured by TUNEL, Annexin V, and caspase-3 assays. Bim siRNA transfection abrogated this effect-silencing Bim in MET+SIM-treated RL95-2 cells rescued cell viability in MTS assays and reduced caspase-3 activity compared with control siRNA-transfected cells. Combination treatment upregulated phosphorylated AMPK and downregulated downstream phosphorylated S6, suggesting mTOR inhibition as a mechanism for these anti-proliferative effects. CONCLUSIONS: MET+SIM treatment synergistically inhibits endometrial cancer cell viability. This may be mediated by apoptosis and mTOR pathway inhibition. Our results provide preclinical evidence that the combination of these well-tolerated drugs may warrant further clinical investigation for endometrial cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Endométrio/tratamento farmacológico , Metformina/farmacologia , Sinvastatina/farmacologia , Western Blotting , Caspase 3/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Quimioterapia Combinada , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Serina-Treonina Quinases TOR/metabolismo
19.
Med Sci Sports Exerc ; 51(7): 1429-1437, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31210648

RESUMO

INTRODUCTION: Statins are widely used in both primary and secondary prevention of cardiovascular disease. The treatment increases the risk of muscle pain (myalgia) which can affect muscle function and levels of physical activity. We investigated whether statin-associated myalgia is coupled to impaired aerobic exercise performance including fat oxidation as well as impaired muscle strength. METHODS: A population-based survey (6000 people) was performed to assess the prevalence of statin-associated myalgia in the Danish population. In addition, 64 statin users in primary prevention with myalgia (M; n = 25; 61 ± 1 yr) or without myalgia (NM; n = 37; 63 ± 1 yr) as well as a control group not taking statins (C; n = 20; 60 ± 2 yr) were enrolled in a cross-sectional study where they performed aerobic exercise and muscle strength tests. RESULTS: The response rate for the survey was 51% and data showed a prevalence of statin-associated myalgia in 19% of responders using statins. The experimental study showed no difference between the groups in aerobic capacity (C, 29 ± 1 mL O2·min·kg; M, 27 ± 1 mL O2·min·kg; NM, 28 ± 1 mL O2·min·kg) or maximal fat oxidation (C, 247 ± 26 mg·min; M, 295 ± 24 mg·min; NM, 279 ± 17 mg·min). Measurements of strength were similar in all three groups including rate of force development (C, 795 ± 56 N·m·s; M, 930 ± 93 N·m·s; NM, 971 ± 57 N·m·s) and leg extension power (C: 2.6 ± 0.2; M: 2.3 ± 0.1; NM: 2.4 ± 0.1 W·kg). All results are mean ± SEM. CONCLUSION: Statin users in primary prevention experiencing myalgia do not have impaired aerobic exercise performance or muscle strength compared to nonmyalgic statin users or control subjects.


Assuntos
Tolerância ao Exercício/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Força Muscular/efeitos dos fármacos , Sinvastatina/farmacologia , Doenças Cardiovasculares/prevenção & controle , Estudos Transversais , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Mialgia/induzido quimicamente , Cadeias Pesadas de Miosina/metabolismo , Prevenção Primária , Sinvastatina/efeitos adversos
20.
Eur J Clin Pharmacol ; 75(10): 1387-1392, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201436

RESUMO

PURPOSE: Some data indicate that simvastatin may increase the anticoagulative effect in patients treated with warfarin, but the evidence is scarce. The aim of the present study was to investigate how the anticoagulative effect of warfarin is affected by the initiation of simvastatin in a very large patient sample. METHODS: In a retrospective cohort study, we included 5637 individuals on warfarin treatment initiating simvastatin. INR values and warfarin doses were calculated week-by-week during co-treatment. Data were obtained from two large Swedish warfarin registers and from the Swedish Prescribed Drug Register. RESULTS: INR increased from 2.43 at baseline to 2.58, 4 weeks after simvastatin initiation, and did not stabilize until the last quarter of the year studied. Consequently, the proportion of patients with an INR above 3 increased from around 8 to 15%. CONCLUSIONS: In conclusion, initiation of simvastatin resulted in moderately increased INR values and subsequent dose decreases in patients already on warfarin. In order to avoid the increased risk of bleeding, the initiation of simvastatin may be accompanied by closer INR monitoring.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Varfarina/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Interações de Medicamentos , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Suécia , Adulto Jovem
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