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1.
Life Sci ; 289: 120224, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34896343

RESUMO

BACKGROUND: T cell mediates immune response in type 1 diabetes mellitus (T1DM) through its trafficking into pancreatic islets. The role of A Disintigrin And Metalloproteinase 10 (ADAM10) and 17 (ADAM17) in pancreatic T-cells recruitment into the pancreatic islets during T1DM is not known. AIM: Explore the role of ADAM10 and ADAM17 in the processing of CXCL16 in T1DM and possible protective effect of simvastatin (SIM) in streptozotocin (STZ)-induced T1DM. MAIN METHODS: Balb/c mice were classified into 4 groups, 10 each. Control group received buffer while SIM group received 50 mg/kg, i.p daily for 12 days starting from day 4 of the experiment. Diabetic group; received STZ (55 mg/kg, i.p.) for 5 consecutive days starting from day 1 of the experiment. SIM + STZ group; received SIM (50 mg/kg, i.p.) daily for 12 days and STZ (55 mg/kg, i.p.) for 5 consecutive days. Biochemical, inflammatory and apoptotic markers as well as expression of CXCL16, ADAM10, NF-κB and pancreatic T-cells expression were analyzed. KEY FINDINGS: Significant increase in biochemical, inflammatory, apoptotic parameters, expression of ADAM10, ADAM17, CXCL16, NF-κB, and infiltrated T-cells to the pancreatic islets were found in STZ group. SIM treatment in the presence of STZ improved biochemical and inflammatory parameters as well as it reduced the expression of CXCL16, ADAM10, ADAM17, NF-κΒ, T-cells migration and apoptosis in the pancreatic islets. SIGNIFICANCE: SIM mitigated pancreatic ß-cell death induced by STZ through down regulation of ADAM10, ADAM17and CXCL16. Therefore, ADAM10/ADAM17 and CXCL16 may serve as novel therapeutic targets for T1DM.


Assuntos
Proteína ADAM10/biossíntese , Proteína ADAM17/biossíntese , Secretases da Proteína Precursora do Amiloide/biossíntese , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Regulação para Baixo/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteínas de Membrana/biossíntese , Sinvastatina/farmacologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 454-459, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816650

RESUMO

Objective: To investigate the effects of simvastatin (SIM) on pulmonary fibrosis and the expression of VE-cadherin(VE-cad),vimentin(VIM) and alpha-smooth muscle actin(α-SMA)in the pulmonary fibrosis tissue of rats. Methods: Sixty healthy male SD rats were randomly divided into control group(group A), bleomycin group(group B), 5 mg SIM group (group C) and 10 mg SIM group (group D),15 rats in each group. The model of rat pulmonary fibrosis was established by itraperitoneal injection of bleomycin(5 mg/kg). Since the first day of modeling, the rats of group C and D were treated with simvastatin suspension 5 mg/(kg·d) and 10 mg/(kg·d) by intragastric administration everyday, and the rats of group A and B were treated with equal volume of saline 10 ml/(kg·d) everyday. Five rats of each group were sacrificed randomly at the 7th, 14th and 28th day. Masson staining was used to observe the morphological changes of lung tissue in rats. The degree of fibrosis in lung tissues of each group was evaluated by the content of hydroxyproline (HYP) . The microvessel density (MVD) was analyzed by immunohistochemistry,The expressions of protein and mRNA of VE-cad, VIM and α-SMA were determined by immunohistochemistry and RT-PCR. Results: ①Compared with group A, the levels of HYP and MVD, the mRNA and protein expression levels of VIM and α-SMA in lung tissues of groups B, C and D were increased significantly at the 7th, 14th and 28th day(all P<0.05), which reached highest level at the 28th day. However, the mRNA and protein expression levels of VE-CAD were decreased significantly at the corresponding time (P<0.05), which reached lowest level at 28th day. ②Compared with group B, the levels of HYP and MVD, the mRNA and protein expression levels of VIM and α-SMA in groups C and D were decreased at the 7th, 14th and 28th day (all P<0.05), which were decreased more obviously in group D at the 28th day. However, the mRNA and protein expression levels of VE-CAD were increased at the corresponding time (all P<0.05), which were increased more obviously in group D at the 28th day. Conclusion: Simvastatin can reduce the degree of pulmonary fibrosis in rats through inhibiting the process of EnMT, which can enhance the expression of VE-cad and reduce the expression of VIM and α-SMA.


Assuntos
Fibrose Pulmonar , Sinvastatina , Animais , Bleomicina , Pulmão , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Sinvastatina/farmacologia
3.
J Virol ; 95(23): e0139621, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34549987

RESUMO

Emerging evidence suggests that endothelial activation plays a central role in the pathogenesis of acute respiratory distress syndrome (ARDS) and multiorgan failure in patients with coronavirus disease 2019 (COVID-19). However, the molecular mechanisms underlying endothelial activation in COVID-19 patients remain unclear. In this study, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins that potently activate human endothelial cells were screened to elucidate the molecular mechanisms involved in endothelial activation. It was found that nucleocapsid protein (NP) of SARS-CoV-2 significantly activated human endothelial cells through Toll-like receptor 2 (TLR2)/NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Remarkably, though the protein sequences of N proteins from coronaviruses are highly conserved, only NP from SARS-CoV-2 induced endothelial activation. The NPs from other coronaviruses such as SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), HUB1-CoV, and influenza virus H1N1 did not activate endothelial cells. These findings are consistent with the results from clinical investigations showing broad endotheliitis and organ injury in severe COVID-19 patients. In conclusion, the study provides insights on SARS-CoV-2-induced vasculopathy and coagulopathy and suggests that simvastatin, an FDA-approved lipid-lowering drug, may help prevent the pathogenesis and improve the outcome of COVID-19 patients. IMPORTANCE Coronavirus disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, is a worldwide challenge for health care systems. The leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure from acute respiratory distress syndrome (ARDS). To date, pulmonary endothelial cells (ECs) have been largely overlooked as a therapeutic target in COVID-19, yet emerging evidence suggests that these cells contribute to the initiation and propagation of ARDS by altering vessel barrier integrity, promoting a procoagulative state, inducing vascular inflammation and mediating inflammatory cell infiltration. Therefore, a better mechanistic understanding of the vasculature is of utmost importance. In this study, we screened the SARS-CoV-2 viral proteins that potently activate human endothelial cells and found that nucleocapsid protein (NP) significantly activated human endothelial cells through TLR2/NF-κB and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Our results provide insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients.


Assuntos
Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/virologia , SARS-CoV-2 , Transdução de Sinais , Sinvastatina/farmacologia , COVID-19/virologia , Linhagem Celular , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Receptor 2 Toll-Like/metabolismo
4.
Pulm Pharmacol Ther ; 70: 102075, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34428598

RESUMO

Chronic Obstructive Pulmonary Disease - COPD is characterized by the destruction of alveolar walls associated to a chronic inflammatory response of the airways. There is no clinical therapy for COPD. In this context, cell-based therapies represent a promising therapeutic approach for chronic lung disease. The goal of this work was to evaluate the effect of simvastatin on cell-based therapy in a mice emphysema model. Female FVB mice received intranasal instillation of elastase (three consecutive doses of 50 µL) in order to promote pulmonary emphysema. After 21 days of the first instillation, the animals were treated with Adipose-Derived Mesenchymal Stromal Cells (AD-MSC, 2.6 × 106) via retro-orbital infusion associated or not with simvastatin administrated daily via oral gavage (15 mg/kg/15d). Before and after these treatments, the histological and morphometrical analyses of the lung tissue, as so as lung function (whole body plethysmography) were evaluated. PAI-1 gene expression, an upregulated factor by ischemia that indicate a low survival of transplanted MSC, was also evaluated. The result regarding morphological and functional aspects of both lungs, presented no significant difference among the groups (AD-MSC or AD-MSC + Simvastatin). However, significant anatomical difference was observed in the right lung of the both groups of mice. The results shown a higher deposition of cells in the right lung, with might to be explained by anatomical differences (slightly higher right bronchi). Decreased levels of PAI-1 were observed in the simvastatin treated groups. The pulmonary ventilation was similar between the groups with only a tendency to a lower in the elastase treated animals due to a low respiratory frequency. In conclusion, the results suggest that both AD-MSC and simvastatin treatments could promote an improvement of morphological recovery of pulmonary emphysema, that it was more pronounced in the right lung.


Assuntos
Enfisema , Células-Tronco Mesenquimais , Enfisema Pulmonar , Animais , Modelos Animais de Doenças , Feminino , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Elastase Pancreática , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/tratamento farmacológico , Sinvastatina/farmacologia
5.
Biomolecules ; 11(8)2021 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-34439919

RESUMO

Methyl CpG binding protein 2 (MeCP2) is the main DNA methyl-binding protein in the brain that binds to 5-methylcytosine and 5-hydroxymethyl cytosine. MECP2 gene mutations are the main origin of Rett Syndrome (RTT), a neurodevelopmental disorder in young females. The disease has no existing cure, however, metabolic drugs such as metformin and statins have recently emerged as potential therapeutic candidates. In addition, induced MECP2-BDNF homeostasis regulation has been suggested as a therapy avenue. Here, we analyzed nascent RNA synthesis versus steady state total cellular RNA to study the transcriptional effects of metformin (an anti-diabetic drug) on MECP2 isoforms (E1 and E2) and BNDF in a human brain cell line. Additionally, we investigated the impact of simvastatin (a cholesterol lowering drug) on transcriptional regulation of MECP2E1/E2-BDNF. Metformin was capable of post-transcriptionally inducing BDNF and/or MECP2E1, while transcriptionally inhibiting MECP2E2. In contrast simvastatin significantly inhibited BDNF transcription without significantly impacting MECP2E2 transcripts. Further analysis of ribosomal RNA transcripts confirmed that the drug neither individually nor in combination affected these fundamentally important transcripts. Experimental analysis was completed in conditions of the presence or absence of serum starvation that showed minimal impact for serum deprival, although significant inhibition of steady state MECP2E1 by simvastatin was only detected in non-serum starved cells. Taken together, our results suggest that metformin controls MECP2E1/E2-BDNF transcriptionally and/or post-transcriptionally, and that simvastatin is a potent transcriptional inhibitor of BDNF. The transcriptional effect of these drugs on MECP2E1/E2-BDNF were not additive under these tested conditions, however, either drug may have potential application for related disorders.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Regulação da Expressão Gênica , Metformina/farmacologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Sinvastatina/farmacologia , Animais , Linhagem Celular , Metilação de DNA , Perfilação da Expressão Gênica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Meduloblastoma/metabolismo , Proteína 2 de Ligação a Metil-CpG/química , Camundongos , Camundongos Transgênicos , Mutação , Isoformas de Proteínas , RNA/biossíntese , Processamento Pós-Transcricional do RNA , RNA Ribossômico/metabolismo , Síndrome de Rett/metabolismo
6.
Carbohydr Polym ; 269: 118255, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34294292

RESUMO

Cellulose is well known as a biocompatible material or natural reducing material. In this study, As an eco-friendly and facile method, we prepared monodispersed silver nanoparticles (AgNPs) in cellulose-framework through photocatalytic reaction. and we fabricated electrospun fiber scaffolds with excellent antibacterial properties and biocompatibility. UV-irradiation causes the electrical change of the cellulose-framework, thereby converting Ag ions into Ag particles. We applied a three-electrode system to confirm the phenomenon. Through STEM and EDS, it was found that the synthesized AgNPs were monodisperse in the nanofibers, and antibacterial activity was confirmed using gram-negative and gram-positive bacteria. In addition, it was suggested that the gradual release of simvastatin contained in the nanofibers and excellent mineralization would be easy to apply to bone regeneration. Therefore, the manufactured composite electrospun fiber mat can be used not only in biomedical fields but also in various applications that need to prevent the accumulation of microorganisms.


Assuntos
Antibacterianos/farmacologia , Conservadores da Densidade Óssea/farmacologia , Celulose/química , Nanopartículas Metálicas/química , Prata/farmacologia , Sinvastatina/farmacologia , Animais , Antibacterianos/química , Conservadores da Densidade Óssea/química , Regeneração Óssea/efeitos dos fármacos , Catálise/efeitos da radiação , Linhagem Celular , Sistemas de Liberação de Medicamentos , Escherichia coli/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Nanofibras/química , Osteogênese/efeitos dos fármacos , Prata/química , Sinvastatina/química , Staphylococcus aureus/efeitos dos fármacos , Tecidos Suporte/química , Raios Ultravioleta
7.
Biomed Pharmacother ; 139: 111494, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243595

RESUMO

This study set out to optimize simvastatin (SV) in lipid nanoparticles (SLNs) to improve bioavailability, efficacy and alleviate adverse effects. Simvastatin-loaded solid lipid nanoparticles (SV-SLNs) were prepared by hot-melt ultrasonication method and optimized by box-Behnken experimental design. Sixty Wister albino rats were randomly assigned into six groups and treated daily for 16 weeks: control group, the group fed with 20 g of high-fat diet (HFD), group treated with vehicle (20 mg/kg, P.O.) for last four weeks, group treated with HFD and SV (20 mg/kg, P.O.) / or SV-SLNs (20 mg/kg/day, P.O.) / or SV-SLNs (5 mg/kg, P.O.) at last four weeks. Blood, liver tissues, and quadriceps muscles were collected for biochemical analysis, histological and immunohistochemical assays. The optimized SV-SLNS showed a particle-size 255.2 ± 7.7 nm, PDI 0.31 ± 0.09, Zeta-potential - 19.30 ± 3.25, and EE% 89.81 ± 2.1%. HFD showed severe changes in body weight liver functions, lipid profiles, atherogenic index (AIX), albumin, glucose, insulin level, alkaline phosphatase as well as muscle injury, oxidative stress biomarkers, and protein expression of caspase-3. Simvastatin treatment in animals feed with HFD showed a significant improvement of all tested parameters, but it was associated with hepatotoxicity, myopathy, and histological changes in quadriceps muscles. SV-SLNs exhibited a significant improvement of all biochemical, histological examinations, and immunohistochemical assays. SV-SLNs (5 mg/kg) treatment returns all measured parameters to control itself. These results represent that SV-SLNs is a promising candidate as a drug carrier for delivering SV with maximum efficacy and limited adverse reaction.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Lipídeos/química , Doenças Musculares/tratamento farmacológico , Nanopartículas/química , Sinvastatina/farmacologia , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar
8.
Cells ; 10(7)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209035

RESUMO

Glioblastoma is a high-grade glial neoplasm with a patient survival of 12-18 months. Therefore, the identification of novel therapeutic targets is an urgent need. RAB38 is a GTPase protein implicated in regulating cell proliferation and survival in tumors. The role of RAB38 in glioblastoma is relatively unexplored. Here, we test the hypothesis that RAB38 regulates glioblastoma growth using human glioblastoma cell lines. We found that genetic interference of RAB38 resulted in a decrease in glioblastoma growth through inhibition of proliferation and cell death induction. Transcriptome analysis showed that RAB38 silencing leads to changes in genes related to mitochondrial metabolism and intrinsic apoptosis (e.g., Bcl-xL). Consistently, rescue experiments demonstrated that loss of RAB38 causes a reduction in glioblastoma viability through downregulation of Bcl-xL. Moreover, RAB38 knockdown inhibited both glycolysis and oxidative phosphorylation. Interference with RAB38 enhanced cell death induced by BH3-mimetics. RAB38 antagonists are under development, but not yet clinically available. We found that FDA-approved statins caused a rapid reduction in RAB38 protein levels, increased cell death, and phenocopied some of the molecular changes elicited by loss of RAB38. In summary, our findings suggest that RAB38 is a potential therapeutic target for glioblastoma treatment.


Assuntos
Metabolismo Energético , Glioblastoma/metabolismo , Glioblastoma/patologia , Proteínas rab de Ligação ao GTP/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Biomarcadores Tumorais/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sinvastatina/farmacologia , Proteína bcl-X/metabolismo
9.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299106

RESUMO

Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 µm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.


Assuntos
Anti-Inflamatórios/farmacologia , Anticolesterolemiantes/farmacologia , Dioxanos/química , Sistemas de Liberação de Medicamentos , Inflamação/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Anti-Inflamatórios/química , Anticolesterolemiantes/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Microesferas , Ratos , Ratos Wistar , Sinvastatina/administração & dosagem
10.
J Dent Res ; 100(10): 1118-1126, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34315311

RESUMO

The development of biomaterials based on the combination of biopolymers with bioactive compounds to develop delivery systems capable of modulating dentin regeneration mediated by resident cells is the goal of current biology-based strategies for regenerative dentistry. In this article, the bioactive potential of a simvastatin (SV)-releasing chitosan-calcium-hydroxide (CH-Ca) scaffold was assessed. After the incorporation of SV into CH-Ca, characterization of the scaffold was performed. Dental pulp cells (DPCs) were seeded onto scaffolds for the assessment of cytocompatibility, and odontoblastic differentiation was evaluated in a microenvironment surrounded by dentin. Thereafter, the cell-free scaffold was adapted to dentin discs positioned in artificial pulp chambers in direct contact with a 3-dimensional (3D) culture of DPCs, and the system was sealed to simulate internal pressure at 20 cm/H2O. In vivo experiments with cell-free scaffolds were performed in rats' calvaria defects. Fourier-transform infrared spectroscopy spectra proved incorporation of Ca and SV into the scaffold structure. Ca and SV were released upon immersion in a neutral environment. Viable DPCs were able to spread and proliferate on the scaffold over 14 d. Odontoblastic differentiation occurred in the DPC/scaffold constructs in contact with dentin, in which SV supplementation promoted odontoblastic marker overexpression and enhanced mineralized matrix deposition. The chemoattractant potential of the CH-Ca scaffold was improved by SV, with numerous viable and dentin sialoprotein-positive cells from the 3D culture being observed on its surface. Cells at 3D culture featured increased gene expression of odontoblastic markers in contact with the SV-enriched CH-Ca scaffold. CH-Ca-SV led to intense mineralization in vivo, presenting mineralization foci inside its structure. In conclusion, the CH-Ca-SV scaffold induces differentiation of DPCs into a highly mineralizing phenotype in the presence of dentin, creating a microenvironment capable of attracting pulp cells to its surface and inducing the overexpression of odontoblastic markers in a cell-homing strategy.


Assuntos
Quitosana , Animais , Cálcio , Diferenciação Celular , Polpa Dentária , Dentina , Odontoblastos , Ratos , Sinvastatina/farmacologia
11.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066911

RESUMO

Previous studies suggest that statins may disturb skeletal muscle lipid metabolism potentially causing lipotoxicity with insulin resistance. We investigated this possibility in wild-type mice (WT) and mice with skeletal muscle PGC-1α overexpression (PGC-1α OE mice). In WT mice, simvastatin had only minor effects on skeletal muscle lipid metabolism but reduced glucose uptake, indicating impaired insulin sensitivity. Muscle PGC-1α overexpression caused lipid droplet accumulation in skeletal muscle with increased expression of the fatty acid transporter CD36, fatty acid binding protein 4, perilipin 5 and CPT1b but without significant impairment of muscle glucose uptake. Simvastatin further increased the lipid droplet accumulation in PGC-1α OE mice and stimulated muscle glucose uptake. In conclusion, the impaired muscle glucose uptake in WT mice treated with simvastatin cannot be explained by lipotoxicity. PGC-1α OE mice are protected from lipotoxicity of fatty acids and triglycerides by increased the expression of FABP4, formation of lipid droplets and increased expression of CPT1b.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sinvastatina/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Antígenos CD36/genética , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Colesterol/sangue , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Ácidos Graxos/sangue , Glucose/metabolismo , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/ultraestrutura , Tamanho do Órgão/efeitos dos fármacos , Perilipina-5/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/sangue
12.
J Bone Miner Metab ; 39(6): 944-951, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34189660

RESUMO

INTRODUCTION: The objectives of the present study were to determine whether simvastatin (SIM) could reverse the harmful effects on titanium rod osseointegration in ovariectomized rats fed high-fat diet (HFD). MATERIALS AND METHODS: Ovariectomized female Sprague-Dawley rats were randomly allocated to three groups and received SIM treatment plus HFD for 12 weeks. We then evaluated the microstructure parameters, histological parameters, biomechanical parameters, bone turnover, and blood lipid level. RESULTS: After 12 weeks of treatment, SIM can significantly improve bone formation around the titanium rod and osseointegration including higher values of maximum push-out force, bone area ratio (BAR), bone-to-implant contact (BIC), bone mineral density (BMD), bone volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), mean connective density (Conn.D) when compared with the HFD group. In addition, system administration of SIM showed positive effects on collagen type 1 cross-linked C-telopeptide (CTX-1), procollagen I N-terminal propeptide (PINP), total cholesterol (TC), triglycerides (TGL), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol. Compared with the HFD group, lower values of CTX-1, P1NP, TC, TGL and LDL were observed in the SIM+HFD group (P < 0.05). CONCLUSION: Our findings revealed that HFD may have an adverse effect on osseointegration in osteoporotic conditions, and the harmful effect of HFD on osseointegration could be reversed by SIM.


Assuntos
Osseointegração , Titânio , Animais , Densidade Óssea , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Ovariectomia , Ratos , Ratos Sprague-Dawley , Sinvastatina/farmacologia
13.
Biochem Pharmacol ; 190: 114649, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34111424

RESUMO

Statins reduce cardiovascular complications in patients with high LDL-cholesterol but are associated with myopathy. We compared the toxicity of simvastatin of C2C12 myoblasts and myotubes. Since myoblasts can proliferate and fuse to myotubes, myoblasts can be considered as satellite cells and myotubes as mature muscle fibers. Simvastatin increased plasma membrane permeability and decreased the cellular ATP content in both myoblasts and myotubes, but with a stronger effect on myoblasts. While insulin prevented cytotoxicity up to 8 h after addition of simvastatin to myotubes, prevention in myoblasts required simultaneous addition. Mevalonate and geranylgeraniol prevented simvastatin-associated cytotoxicity in both myoblasts and myotubes. Simvastatin impaired the phosphorylation of the insulin receptor (IR ß), Akt ser473 and S6rp, and increased phosphorylation of AMPK thr172 in both myotubes and myoblasts, which was prevented by insulin and mevalonate. Simvastatin impaired oxygen consumption and increased superoxide production by myoblasts and myotubes and induced apoptosis via cytochrome c release. In addition, simvastatin impaired proliferation and fusion of myoblasts to myotubes by inhibiting the expression of the nuclear transcription factor MyoD and of the metalloprotease ADAM-12. Decreased expression of the proliferation factor Ki-67 and of ADAM-12 were also observed in gastrocnemius of mice treated with simvastatin. In conclusion, myoblasts were more susceptible to the toxic effects of simvastatin and simvastatin impaired myoblast proliferation and myotube formation. Impaired muscle regeneration may represent a new mechanism of statin myotoxicity.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Sinvastatina/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/farmacologia , Masculino , Ácido Mevalônico/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
14.
Biomed Chromatogr ; 35(10): e5180, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34043824

RESUMO

Globally, simvastatin is one of the most commonly used statin drugs. Its antimicrobial properties have been investigated against various pathogens. However, its effect on biological processes in bacteria has been unclear. This study focused on altered biological and metabolic processes at protein and metabolite levels induced by simvastatin. MS-based proteomics and metabolomics were used to investigate the altered proteins and metabolites between experimental groups. Proteomics results showed that simvastatin induced various antimicrobial targets such as chaperon protein DnaK and cell division protein FtsZ. Metabolomics results revealed phenotypic changes in cells under simvastatin stress. Integrated proteomics and metabolomics result indicated that various metabolic processes were altered to adapt to stress conditions. Energy metabolism (glycolysis, tricarboxylic acid cycle, etc.), amino acid synthesis and ribosomal proteins, and purine and pyrimidine synthesis were induced by the effect of simvastatin. This study will contribute to the understanding of antimicrobial properties of statin drugs.


Assuntos
Antibacterianos/farmacologia , Escherichia coli , Metaboloma/efeitos dos fármacos , Proteoma/efeitos dos fármacos , Sinvastatina/farmacologia , Cromatografia Líquida de Alta Pressão , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/análise , Proteínas de Escherichia coli/metabolismo , Metabolômica , Proteoma/análise , Proteômica , Espectrometria de Massas em Tandem
15.
Radiol Oncol ; 55(3): 305-316, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33939900

RESUMO

BACKGROUND: Statins, small molecular 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are widely used to lower cholesterol levels in lipid-metabolism disorders. Recent preclinical and clinical studies have shown that statins exert beneficial effects in the management of breast cancer by increasing recurrence free survival. Unfortunately, the underlying mechanisms remain elusive. MATERIALS AND METHODS: Simvastatin, one of the most widely prescribed lipophilic statins was utilized to investigate potential radiosensitizing effects and an impact on cell survival and migration in radioresistant breast cancer cell lines. RESULTS: Compared to parental cell counterparts, radioresistant MDA-MB-231-RR, T47D-RR andAu565-RR cells were characterized by upregulation of 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR) expression accompanied by epithelial-to-mesenchymal transition (EMT) activation. Radioresistant breast cancer cells can be killed by simvastatin via mobilizing of a variety of pathways involved in apoptosis and autophagy. In the presence of simvastatin migratory abilities and vimentin expression is diminished while E-cadherin expression is increased. CONCLUSIONS: The present study suggests that simvastatin may effectively eradicate radioresistant breast carcinoma cells and diminish their mesenchymal phenotypes.


Assuntos
Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Sinvastatina/farmacologia , Morte Celular Autofágica/efeitos dos fármacos , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Transição Epitelial-Mesenquimal , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Regulação para Cima
16.
Int J Nanomedicine ; 16: 2533-2553, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33824590

RESUMO

Purpose: The present study was intended to fabricate chitosan (Ch)-tamarind gum polysaccharide (TGP) polyelectrolyte complex stabilized cubic nanoparticles of simvastatin and evaluate their potential against human breast cancer cell lines. Materials and Methods: The antisolvent precipitation method was used for formulation of nanoparticles. Factorial design (32) was utilized as a tool to analyze the effect of Ch and TGP concentration on particle size and entrapment efficiency of nanoparticles. Results: Formulated nanoparticles showed high entrapment efficiency (67.19±0.42-83.36±0.23%) and small size (53.3-383.1 nm). The present investigation involved utilization of two biological membranes (egg and tomato) as biological barriers for drug release. The study revealed that drug release from tomato membranes was retarded (as compared to egg membranes) but the release pattern matched that of egg membranes. All formulations followed the Baker-Lansdale model of drug release irrespective of the two different biological barriers. Stability studies were carried out for 45 days and exhibited less variation in particle size as well as a reduction in entrapment efficiency. Simvastatin loaded PEC stabilized nanoparticles exhibited better control on growth of human breast cancer cell lines than simple simvastatin. An unusual anticancer effect of simvastatin nanoparticles is also supported by several other research studies. Conclusion: The present study involves first-time synthesis of Ch-TGP polyelectrolyte complex stabilized nanoparticles of simvastatin against MCF-7 cells. It recommends that, in future, theoretical modeling and IVIVC should be carried out for perfect designing of delivery systems.


Assuntos
Quitosana/química , Nanopartículas/química , Gomas Vegetais/química , Polieletrólitos/química , Polissacarídeos/química , Sinvastatina/farmacologia , Tamarindus/química , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Células MCF-7 , Nanopartículas/ultraestrutura , Tamanho da Partícula , Espectrofotometria Infravermelho , Eletricidade Estática
17.
J Periodontal Res ; 56(5): 877-884, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33830521

RESUMO

BACKGROUND AND OBJECTIVE: Electrospun chitosan membranes (ESCM) modified with short-chain fatty acids have the ability to control the release of simvastatin (SMV), an anti-cholesterol drug with osteogenic potential, for guided bone regeneration (GBR) applications. This study evaluated in vivo osteogenic effects of rapid short release of SMV (4 weeks) vs long sustained release (8 weeks) from acetic anhydride (AA)-and hexanoic anhydride (HA)-modified ESCMs, respectively. METHODS: AA ESCMs loaded with 10 or 50 µg SMV and HA ESCMs loaded with 50 µg SMV were evaluated for biocompatibility and bone formation at 4 and 8 weeks, in 5 mm critical size rat calvarial defects, using histological evaluation and micro-CT analysis. RESULTS: No severe inflammatory response was noticed around the ESCMs. Less hydrophobic AA membranes showed signs of resorption by week 4 and were almost completely resorbed by week 8 whereas the more hydrophobic HA membranes resorbed slowly, remaining intact over 8 weeks. In micro-CT analysis, 10 µg SMV-loaded AA membranes did not show significant bone formation as compared to non-loaded AA membranes at either evaluation time points. 50 µg SMV-loaded AA membranes stimulated significantly more bone formation than non-loaded AA membranes by week 4 (%bone = 31.0 ± 5.9% (AA50) vs 18.5 ± 13.7% (AA0)) but showed no difference at week 8. HA membranes with 50 µg SMV showed significantly more bone formation as compared to corresponding non-loaded membranes by week 8 (%bone = 61.7 ± 8.9% (HA50) vs 33.9 ± 29.7% (HA0)), though such an effect was not significant at week 4. CONCLUSION: These results indicate that modified ESCMs may be used to control the release of SMV and promote bone healing in GBR applications.


Assuntos
Quitosana , Animais , Regeneração Óssea , Membranas Artificiais , Osteogênese , Ratos , Sinvastatina/farmacologia
18.
Cell Death Dis ; 12(4): 392, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846297

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by motoneuron loss, for which there is currently no effective treatment. Statins, as inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are used as drugs for treatment for a variety of disease such as ischemic diseases, neurodegenerative diseases, cancer, and inflammation. However, our previous evidence has demonstrated that simvastatin leads to cytotoxicity in NSC34-hSOD1G93A cells by aggravating the impairment of autophagic flux, but the role of simvastatin in ALS model remains elusive. In present study, we reported that after simvastatin treatment, SOD1G93A mice showed early onset of the disease phenotype and shortened life span, with aggravated autophagic flux impairment and increased aggregation of SOD1 protein in spinal cord motoneurons (MNs) of SOD1G93A mice. In addition, simvastatin repressed the ability of Rab7 localization on the membrane by inhibiting isoprenoid synthesis, leading to impaired late stage of autophagic flux rather than initiation. This study suggested that simvastatin significantly worsened impairment of late autophagic flux, resulting in massive MNs death in spinal cord and accelerated disease progression of SOD1G93A mice. Together, these findings might imply a potential risk of clinic application of statins in ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Neurônios Motores/metabolismo , Sinvastatina/farmacologia , Superóxido Dismutase-1/genética , Proteínas rab de Ligação ao GTP/metabolismo , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Animais , Autofagia/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Superóxido Dismutase-1/metabolismo , Vacúolos/metabolismo
19.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923431

RESUMO

Human atherosclerotic plaque contains smooth muscle cells (SMCs) negative for the contractile phenotype (α-smooth muscle actin) but positive for proprotein convertase subtilisin/kexin type 9 (PCSK9). Thus, we generated rat SMCs which overexpressed human PCSK9 (SMCsPCSK9) with the aim of investigating the role of PCSK9 in the phenotype of SMCs. PCSK9 overexpression in SMCsPCSK9 led to a significant downregulation of the low-density lipoprotein receptor (Ldlr) as well as transgelin (Sm22α), a marker of the contractile phenotype. The cell proliferation rate of SMCsPCSK9 was significantly faster than that of the control SMCs (SMCspuro). Interestingly, overexpression of PCSK9 did not impact the migratory capacity of SMCs in response to 10% FCS, as determined by Boyden's chamber assay. Expression and activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) was significantly increased in the presence of PCSK9, both in SMCPCSK9 and after treatment with recombinant PCSK9. The transcriptional activity of sterol regulatory element-binding protein (SREBP) was also increased in the presence of PSCK9, suggesting a direct role of PCSK9 in the control of SRE-responsive genes, like HMGCR. We also observed that cholesterol biosynthesis is elevated in SMCPCSK9, potentially explaining the increased proliferation observed in these cells. Finally, concentration-dependent experiments with simvastatin demonstrated that SMCsPCSK9 were partially resistant to the antiproliferative and antimigratory effect of this drug. Taken together, these data further support a direct role of PCSK9 in proliferation, migration, and phenotypic changes in SMCs-pivotal features of atherosclerotic plaque development. We also provide new evidence on the role of PCSK9 in the pharmacological response to statins-gold standard lipid-lowering drugs with pleiotropic action.


Assuntos
Anticolesterolemiantes/farmacologia , Proliferação de Células , Miócitos de Músculo Liso/metabolismo , Pró-Proteína Convertase 9/metabolismo , Sinvastatina/farmacologia , Animais , Movimento Celular , Células Cultivadas , Colesterol/metabolismo , Feminino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Pró-Proteína Convertase 9/genética , Ratos , Receptores de LDL
20.
J Mater Chem B ; 9(16): 3573-3583, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33909742

RESUMO

The regenerative repair of large bone defects is a major problem in orthopedics and clinical medicine. The key problem is the lack of ability of existing bone graft materials to promote osteogenesis and angiogenesis. Previous studies have shown that the osteogenic or angiogenic abilities of these materials could be significantly improved by adding miRNA or small-molecule drugs to bone graft materials; however, the synergistic effect arising from this combination is not clear. Therefore, we proposed to construct a dual drug delivery system that could simultaneously achieve the co-encapsulation and co-delivery of miRNA and small-molecule drugs to explore the effect of a dual drug delivery system on bone repair. In this study, we constructed dual-sized pore structure calcium-silicon nanospheres (DPNPs) and achieved the co-encapsulation of miR-210, angiogenic gene drugs, and simvastatin (Siv), a small-molecule osteogenic drug, through metal-ion coordination and physical adsorption. In vitro and in vivo osteogenic and angiogenic experiments showed that the dual drug delivery system (Siv/DPNP/miR-210) exhibited better properties than those of the individual unloaded and single drug-loaded systems and could significantly accelerate the process of bone repair, which provides a novel strategy for the regeneration and repair of bone defects.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , MicroRNAs/metabolismo , Sinvastatina/farmacologia , Tecidos Suporte/química , Animais , Cálcio/química , Células Cultivadas , Humanos , Camundongos , MicroRNAs/genética , Nanopartículas/química , Osteogênese/efeitos dos fármacos , Tamanho da Partícula , Porosidade , Silício/química , Sinvastatina/química , Propriedades de Superfície
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