Study of preventing venous graft restenosis by local application of simvastatin and mechanical preconditioning / 中国胸心血管外科临床杂志

@#Objective    To investigate the effect of simvastatin and mechanical pretreatment on intimal hyperplasia of venous graft and its mechanism. Methods    Twelve New Zealand rabbits were selected and randomly divided into 4 groups: a blank control group, a simvastatin topical treatment group, a mechanical precondition group and a combined group (n=3 in each group). Ultrasound was used to evaluate the changes of graft wall and blood flow velocity in the graft, and pathological section was used to evaluate the intimal hyperplasia. Human umbilical cord endodermal cells were cultured in vitro. A simvastatin group and a solvent control group were set to detect YAP phosphorylation, downstream target gene expression and cell proliferation. Results    Vascular ultrasound showed that except the simvastatin topical treatment group, the flow velocity in vein grafts in the other three groups significantly increased 21 days after surgery compared with 7 days after surgery (P<0.01). Pathological sections showed that the thickness of new intima in the simvastatin topical treatment group, mechanical precondition group, combined group and blank control group were 45.56±4.11 μm, 201.28±16.71 μm, 143.57±7.82 μm, 249.45±13.33 μm, respectively, and there were statistical differences compared with the blank control group (P<0.05). In vitro results showed that compared with the solvent control group, cell death was observed in high concentration simvastatin (5 mmol/L) group, cell proliferation was inhibited in low concentration simvastatin (2.5 mmol/L) group (P<0.05), the expression of YAP protein in the simvastatin group was unchanged, but the expression of phosphorylated YAP protein significantly increased (P<0.05), and the expression of downstream target gene ccn1 was down-regulated (P<0.001). Conclusion    Intravascular local application of simvastatin and mechanical preconditioning alone or in combination can inhibit intimal hyperplasia of venous graft. High concentration of simvastatin has cytotoxicity, while low concentration of simvastatin has inhibitory effect on cell proliferation. Simvastatin can inhibit the formation of new intima by inhibiting the entry of YAP into the nucleus and reducing the transcription of cell proliferation-related target gene ccn1.

Compound Danshen Dripping Pill inhibits hypercholesterolemia/atherosclerosis-induced heart failure in ApoE and LDLR dual deficient mice via multiple mechanisms

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE-/-LDLR-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

A rationally designed cancer vaccine based on NIR-II fluorescence image-guided light-triggered remote control of antigen cross-presentation and autophagy

Cancer vaccines represent a promising immunotherapeutic treatment modality. The promotion of cross-presentation of extracellular tumor-associated antigens on the major histocompatibility complex (MHC) class I molecules and dendritic cell maturation at the appropriate time and place is crucial for cancer vaccines to prime cytolytic T cell response with reduced side effects. Current vaccination strategies, however, are not able to achieve the spatiotemporal control of antigen cross-presentation. Here, we report a liposomal vaccine loading the second near-infrared window (NIR-II, 1000-1700 nm) fluorophore BPBBT with an efficient photothermal conversion effect that offers an NIR-light-triggered endolysosomal escape under the imaging guidance. The NIR-II image-guided vaccination strategy specifically controls the cytosolic delivery of antigens for cross-presentation in the draining lymph nodes (DLNs). Moreover, the photothermally induced endolysosomal rupture initiates autophagy. We also find that the adjuvant simvastatin acts as an autophagy activator through inhibiting the PI3K/AKT/mTOR pathway. The light-induced autophagy in the DLNs together with simvastatin treatment cooperatively increase MHC class II expression by activating autophagy machinery for dendritic cell maturation. This study presents a paradigm of NIR-II image-guided light-triggered vaccination. The approach for remote control of antigen cross-presentation and autophagy represents a new strategy for vaccine development.

Efeito da sinvastatina e do propranolol no desenvolvimento da lesão periapical de ratos submetidos ao estresse / Effect of Simvastatin and Propranolol on the development of periapical lesions in rats subjected to stress

Uma vez que o estresse crônico pode estimular o sistema nervoso simpático, diminuindo a resposta imune, favorecendo a perda óssea frente a um processo inflamatório, os objetivos deste estudo foram: 1) Avaliar os efeitos de modelos de indução de estresse no desenvolvimento da periodontite apical (P.a) e avaliar o nível de estresse gerado pelos mesmos; 2) A partir do melhor protocolo de estresse obtido foi avaliado o perfil inflamatório da PA induzida em animais sob condições de estresse, utilizando sistemicamente a Sinvastatina, Propranolol e a Sinvastatina associada ao propranolol. Na primeira parte foram utilizados 32 ratos Wistar (N=8) divididos aleatoriamente em: SE: sem estresse, sem periodontite apical (P.a); SE+P.a: sem estresse, com P.A; EP+P.a: Estresse previsível + P.a; EI+P.a: estresse imprevisível + P.a. Os animais foram submetidos ao estresse crônico por 42 dias sendo que no dia 21 foi induzida a P.a. Para comprovação do estresse foram utilizadas análises de peso e comportamentais de campo aberto (CA) e labirinto em y (Y). Foram realizadas análises micro tomográfica e histológica para avaliar o efeito de ambas as metodologias sobre a progressão da P.a. Os dados foram avaliados estatisticamente. Observou-se que não houve diferença no ganho de peso entre os animais SE e SE+P.a. Em relação aos grupos estressados o grupo estresse imprevisível apresentou menor ganho de peso quando comparado ao grupo sem estresse. Nos testes comportamentais, Y e CA observou-se um mesmo padrão de comportamento nos animais do grupo SE e SE+P.a (p>0.05). Verificou-se diferenças entre os grupos SE+P.a e EI +P.a no volume da lesão periapical, mas não houve diferença entre os protocolos de estresse. A Análise histológica mostrou maior área de P.a nos animais do grupo EI+P.a o que também foi observado pela análise microtomográfica. Na segunda etapa foram utilizados 48 animais divididos em 5 grupos (N=8): SE+P.a: sem estresse e com P.a; E+SS: Estresse + Periodontite Apical + soro; E+SN: Estresse + Periodontite Apical + Sinvastatina; E+P: Estresse + Periodontite Apical + Propranolol e S+SN+P: Estresse + Periodontite Apical + Sinvastatina + Propranolol. O protocolo de estresse utilizado foi o estresse crônico imprevisível por 42 dias. Realizou-se análises de peso e comportamentais de labirinto em y e campo aberto. Após a eutanásia foram realizadas as análises microtomográfica e a análise histológica e histomorfométrica. Os valores obtidos foram analisados estatisticamente.Observouse que todos os grupos medicados apresentaram ganho de peso maior do que o grupo solução salina. No grupo Sinvastatina e no grupo Propranolol, os animais apresentaram maior atividade locomotora do que no grupo Solução salina. O volume da P.a foi significativamente menor nos grupos Sinvastatina e Propranolol quando comparado ao grupo solução salina. Na análise histológica observou-se que a área da lesão foi significativamente menor nos animais do grupo Sinvastatina quando comparado ao da solução salina, bem como menor intensidade e extensão do infiltrado inflamatório. Concluindo-se que o estresse crônico imprevisível aumenta a perda óssea periapical em animais com PA induzida. Além disso, concluiu-se que tanto a Sinvastatina quanto o Propranolol reduze o estresse crônico, reduzindo a perda óssea nestes animias (AU)

Since chronic stress can stimulate the sympathetic nervous system, decreasing the immune response, favoring bone loss in the face of an inflammatory process, the objectives of this study were: 1) To evaluate the effects of stress induction models on the development of apical periodontitis (P.a) and assess the level of stress generated by them; 2) Based on the best stress protocol obtained, the inflammatory profile of BP induced in animals under stress conditions was evaluated, systemically using Simvastatin, Propranolol and Simvastatin associated with propranolol. In the first part, 32 Wistar rats (N=8) were randomly divided into: SE: without stress, without apical periodontitis (P.a); SE+P.a: without stress, with P.A; EP+P.a: Predictable stress + P.a; EI+P.a: unpredictable stress + P.a. The animals were subjected to chronic stress for 42 days, and on the 21st, P.a. To prove the stress, weight and behavioral analyzes of open field (CA) and maze in y (Y) were used. Micro tomographic and histological analyzes were performed to evaluate the effect of both methodologies on the progression of P.a. Data were statistically evaluated. It was observed that there was no difference in weight gain between SE and SE+P.a animals. In relation to the stressed groups, the unpredictable stress group showed less weight gain when compared to the non-stress group. In the behavioral tests, Y and CA, the same pattern of behavior was observed in animals from the SE and SE+P.a groups (p>0.05). There were differences between groups SE+P.a and EI +P.a in the volume of the periapical lesion, but there was no difference between the stress protocols. The histological analysis showed a greater area of P.a in the animals from the EI+P.a group, which was also observed by the microtomographic analysis. In the second stage, 48 animals were divided into 5 groups (N=8): SE+P.a: without stress and with P.a; E+SS: Stress + Apical Periodontitis + serum; E+SN: Stress + Apical Periodontitis + Simvastatin; E+P: Stress + Apical Periodontitis + Propranolol and S+SN+P: Stress + Apical Periodontitis + Simvastatin + Propranolol. The stress protocol used was unpredictable chronic stress for 42 days. Weight and behavioral analyzes of y-maze and open field were performed. After euthanasia, microtomographic analysis and histological and histomorphometric analysis were performed. The values obtained were statistically analyzed. It was observed that all medicated groups had greater weight gain than the saline group. In the Simvastatin group and in the Propranolol group, the animals showed greater locomotor activity than in the Saline group. The BP volume was significantly lower in the Simvastatin and Propranolol groups when compared to the saline group. In the histological analysis, it was observed that the area of the lesion was significantly smaller in the animals of the Simvastatin group when compared to the saline solution, as well as lower intensity and extension of the inflammatory infiltrate. Concluding that unpredictable chronic stress increases periapical bone loss in animals with induced AP. In addition, it was concluded that both Simvastatin and Propranolol reduce chronic stress, reducing bone loss in these animals. (AU)

Assessment of the regenerative potential of macro-porous chitosan-calcium simvastatin scaffolds on bone cells

Abstract This study evaluated the bioactive potential of a macro-porous chitosan scaffold incorporated with calcium hydroxide (CH-Ca) and functionalized with bioactive doses of simvastatin (SV) for bone tissue regeneration. Initially, the bioactive dose of SV in osteoblastic cells (SAOS-2) was determined. For the direct contact experiment, SAOS-2 cells were plated on scaffolds to assess cell viability and osteogenic differentiation. The second assay was performed at a distance using extracts from scaffolds incubated in culture medium to assess the effect of conditioned medium on viability and osteogenic differentiation. The initial screening showed that 1 μM SV presented the best biostimulating effects, and this dose was selected for incorporation into the CH-Ca and pure chitosan (CH) scaffolds. The cells remained viable throughout the direct contact experiment, with the greatest cell density in the CH-Ca and CH-Ca-SV scaffolds because of their higher porosity. The CH-Ca-SV scaffold showed the most intense bio-stimulating effect in assays in the presence and absence of osteogenic medium, leading to an increased deposition of mineralized matrix. There was an increase in the viability of cells exposed to the extracts for CH-Ca, CH-SV, and CH-Ca-SV during the one-day period. There was an increase in ALP activity in the CH-Ca and CH-Ca-SV; however, the CH-Ca-SV scaffold resulted in an intense increase in the deposition of mineralized nodules, approximately 56.4% at 7 days and 117% at 14 days, compared with CH (control). In conclusion, functionalization of the CH-Ca scaffold with SV promoted an increase in bioactivity, presenting a promising option for bone tissue regeneration.

Alopecia Universal após Tratamento com Sinvastatina e Ezetimiba: Impactos na Família / Alopecia Universalis after Treatment with Simvastatin and Ezetimibe: Affects on Family

Resumo A alopecia areata (AA) é uma doença autoimune que se desenvolve no couro cabeludo ou em outras partes do corpo. A alopecia universal, que é uma forma rara de alopecia areata, é caracterizada pela perda de pelos que afeta todo o corpo. Nos dois pacientes apresentados, o tratamento com atorvastatina foi iniciado com o diagnóstico de hipercolesterolemia, mas, quando as metas de valores não foram alcançadas, foi iniciado o tratamento com uma combinação de sinvastatina e ezetimiba. Depois de um período de tratamento com sinvastatina e ezetimiba, o distúrbio de AA, o qual começou com a perda de cabelo no couro cabeludo, espalhou pelo corpo todo e se transformou em alopecia universal. Embora as estatinas possam causar alopecia com reações autoimunes, elas geralmente são utilizadas no tratamento da alopecia, por seus efeitos imunomoduladores.

Abstract Alopecia areata (AA) is an autoimmune disease that grows in the scalp or in other parts of the body. Alopecia universalis, which is a rare form of alopecia areata, is characterized by a loss of hair that affects the entire body. In the two patients presented in this study, atorvastatin treatment was implemented, with the diagnosis of hypercholesterolemia; however, when the target values were not reached, a combination of simvastatin and ezetimibe was implemented. After a period of simvastatin/ezetimibe treatment, the AA disorder, which began with hair loss on the scalp, spread to the entire body and turned into Alopecia Universalis. Although statins can cause alopecia with autoimmune reactions, they are generally used in the treatment of alopecia due to their immunomodulatory effects.

Simvastatin and Its Role in Anti - Inflammation and Cancer Therapy: A Review

3 - Hydroxy - 3 - methylglutaryl - coenzyme, a reductase inhibitors (statins) are widely used drugs to reduce lipid levels by inhibiting cholesterol biosynthesis. Simvastatin, a lipophilic statin is one of the most frequently prescribed statin drugs throughout th e world due to profound reductions in LDL - C with excellent tolerability, with very little risk of important adverse effects, to a lower extent. It also reduce triglycerides and increase high - density lipoprotein cholesterol levels. Beside this, studies on simvastatin have shown to exhibit numerous pleiotropic effects, has beneficial effect on endothelial function, smooth muscle cell function, haemostasis, vascular wall function, LDL oxidation, kidney diseases, inflammation and anticarcinogenic effects on ma ny types of cancer including prostate, breast hepatic and colon carcinoma. In this review, we present a

Simvastatin inhibits HIF-1α and VEGF expression in RPE cells under hypoxia conditions / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To investigate the effects of simvastatin(Sim)on human retinal pigment epithelial cells(RPE-19)and the possible mechanisms <i>in vitro</i> under hypoxia. <p>METHODS: RPE-19 cells were divided into three group: control group, hypoxia group(the final concentration of CoCl2 in the medium was 125 μmol/L), and Sim treatment group(3 μmol/L Sim was added in the RPE cells' medium which contain 125 μmol/L CoCl2). After 24h, the morphology of RPE-19 cells were observed, the proliferation of cells were calculated by MTT, the secretion levels and protein expression of hypoxia-inducible factor 1-Alpha(HIF-1α)and vascular endothelial growth factor(VEGF)were detected by enzyme-linked immunosorbent assay(ELISA)and Western blotting. The expression level of autophagy protein was detected by Western blot and apoptosis was detected by TUNEL.<p>RESULTS: The morphology and activity of RPE-19 cells showed an apparent change under hypoxia. The expression of HIF-1α and VEGF protein were increased obviously in the hypoxia group and then significantly decreased after Sim treatment. Beclin1, and LC3B proteins were decreased in the CoCl2+Sim group, and the expression levels were lower than the control and CoCl2 group. Under hypoxia, Sim inhibited RPE cells' proliferation and promoted the apoptosis.<p>CONCLUSION:Sim inhibits RPE cells' proliferation, decreases HIF-1α and VEGF protein, and promotes apoptosis under hypoxia. Our results suggested that the mechanism by which Sim promoted apoptosis in RPE cells may be related to its inhibition of autophagy.

Comparative evaluation of diode laser and simvastatin gel in pulpotomy of primary molars A randomized clinical trial

Background: Pulpotomy is a vital pulp therapy performed in carious pulp exposures in teeth in which the inflamed coronal pulp is removed and medicament is placed to conserve the vital root pulps. Recently, simvastatin which is a cholesterol-lowering drug has been found to be associated with the pulp regenerative potential. Aim: The aim of this parallel two-arm randomized control trial was to evaluate and compare the clinical and radiographic efficacy of diode laser (DL) and simvastatin gel (SG) in pulpotomy of carious primary molars. Methods: Hundred primary molars (in 98 children, 65 males, 33 females with age 4–8 years) requiring pulpotomy were randomized into the DL or SG group. Pulpotomy was performed as per the standardized protocol; thereafter, all teeth were restored with resin modified glass ionomer cement followed by stainless steel crowns. Follow-up evaluations were done at 3 and 12 months using clinical and radiographic criteria. Statistical analysis was done using Chi-square test at a significance level of 0.05. Results: At 12 months, out of 92 teeth available for clinical and radiographic evaluation by blinded evaluators, DL group showed clinical and radiographic success rates of 76.1% and 52.1%, while SG group showed 80.4% and 65.2% success rates, respectively. There was no statistically significant difference between the efficacy of two techniques clinically (P = 0.49) or radiographically (P = 0.30). Conclusions: Both SG and DL had similar efficacy for primary tooth pulpotomy, clinically and radiographically after 12 months. Considering its ease of application and low-cost, SG can be recommended as a potential pulpotomy medicament in primary molars.

Simvastatin Blocks Reinstatement of Cocaine-induced Conditioned Place Preference in Male Mice with Brain Lipidome Remodeling / 神经科学通报·英文版

Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.

Simvastatin Blocks Reinstatement of Cocaine-induced Conditioned Place Preference in Male Mice with Brain Lipidome Remodeling / 神经科学通报·英文版

Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.

Lipid profile and response to statin therapy in patients with hypopituitarism

ABSTRACT Objective: Dyslipidemia is prevalent among patients with hypopituitarism, especially in those with growth hormone (GH) deficiency. This study aimed to evaluate the response to statin therapy among adult patients with dyslipidemia and hypopituitarism. Subjects and methods: A total of 113 patients with hypopituitarism following up at a neuroendocrinology unit were evaluated for serum lipid levels. Dyslipidemia was diagnosed in 72 (63.7%) of these patients. A control group included 57 patients with dyslipidemia and normal pituitary function. The distribution of gender, age, weight, and dyslipidemia type was well balanced across both groups, and all participants were treated with simvastatin at doses adjusted to obtain normal lipid levels. Results: Patients with hypopituitarism and dyslipidemia presented deficiency of TSH (69%), gonadotropins (69%), ACTH (64%), and GH (55%) and had a similar number of deficient pituitary axes compared with patients with hypopituitarism but without dyslipidemia. All patients with dyslipidemia (with and without hypopituitarism) had lipid levels well controlled with doses of simvastatin ranging from 20-40 mg/day. The mean daily dose of simvastatin was not significantly different between patients with and without hypopituitarism (26.7 versus 23.5 mg, p = 0.10). Similarly, no significant variation in simvastatin dose was observed between patients with different causes of hypopituitarism, presence or absence of GH deficiency, number of deficient pituitary axes, prior pituitary radiation therapy or not, and presence or absence of obesity. Conclusions: Patients with GH deficiency without GH replacement showed good response to simvastatin at a mean dose equivalent to that used in individuals with dyslipidemia and normal pituitary function.

Simvastatin-enriched macro-porous chitosan-calcium-aluminate scaffold for mineralized tissue regeneration

Abstract The present study evaluated the odontogenic potential of human dental pulp cells (HDPCs) exposed to chitosan scaffolds containing calcium aluminate (CHAlCa) associated or not with low doses of simvastatin (SV). Chitosan scaffolds received a suspension of calcium aluminate (AlCa) and were then immersed into solutions containing SV. The following groups were established: chitosan-calcium-aluminate scaffolds (CHAlCa - Control), chitosan calcium-aluminate with 0.5 µM SV (CHAlCa-SV0.5), and chitosan calcium-aluminate with 1.0 µM SV (CHAlCa-SV1.0). The morphology and composition of the scaffolds were evaluated by SEM and EDS, respectively. After 14 days of HDPCs culture on scaffolds, cell viability, adhesion and spread, mineralized matrix deposition as well as gene expression of odontogenic markers were assessed. Calcium aluminate particles were incorporated into the chitosan matrix, which exhibited regular pores homogeneously distributed throughout its structure. The selected SV dosages were biocompatible with HDPCs. Chitosan-calcium-aluminate scaffolds with 1 µM SV induced the odontoblastic phenotype in the HDPCs, which showed enhanced mineralized matrix deposition and up-regulated ALP, Col1A1, and DMP-1 expression. Therefore, one can conclude that the incorporation of calcium aluminate and simvastatin in chitosan scaffolds had a synergistic effect on HDPCs, favoring odontogenic cell differentiation and mineralized matrix deposition.

Resumo O presente estudo avaliou o potencial odontogênico de células da polpa dental humana (HDPCs) em contato com scaffolds de quitosana contendo aluminato de cálcio (CHAlCa) associado ou não à baixas dosagens de sinvastatina (SV). Scaffolds de quitosana receberam uma suspensão de aluminato de cálcio e foram imersos em soluções contendo a droga. Foram estabelecidos três grupos experimentais: scaffolds de quitosana e aluminato de cálcio (CHAlCa - controle), scaffolds de quitosana-aluminato de cálcio com 0.5 µM SV (CHAlCa-SV0.5), e quitosana-aluminato de cálcio com 1.0 µM SV (CHAlCa-SV1.0). A morfologia e composição foram avaliados por MEV e EDS, respectivamente. Após 14 dias do cultivo das HDPCs sobre os scaffolds, foram avaliados a viabilidade celular, adesão e espalhamento, deposição de matriz mineralizada e expressão gênica de marcadores odontogênicos. Observou-se que as partículas de aluminato de cálcio foram incorporadas à matriz de quitosana, a qual exibiu poros regulares distribuídos por toda sua estrutura. As dosagens selecionadas de sinvastatina foram biocompatíveis com as HDPCs. A concentração de 1 µM de SV induziu intensa expressão de fenótipo odontoblástico pelas HDPCs, demonstrando aumento da deposição de matriz mineralizada e maior expressão de ALP, Col1A1 e DMP-1. Portanto, podemos concluir que a incorporação de aluminato de cálcio e sinvastatina em scaffolds de quitosana apresentou um efeito sinérgico nas HDPCs, favorecendo a diferenciação celular e deposição de matriz mineralizada.

Prevalence of Side Effects, Drug Interaction among Patients Taking Statin in Turaif, Saudi Arabia

Background:Statins perceived to have favorable safety profile. Although many people on statin therapy do well but no drug is without potential for side effects. Awareness about risks as well as benefits of drugs is needed particularly drugs which are used on wide scale like statins because even uncommon side effects can have significant health impact. Objectives of the Study: To determine side effects occurrence among Saudi patients taking statins and to evaluate drug-drug interactions in Saudi patients taking statins.Methodology:Self administered cross sectional study conducted during a period of four months from October 2018 to January 2019 in Turaif general hospital, Saudi Arabia on random sample of 500 Saudi patients out of which 330 participants were included in the study which were taking different types of statins medication using self-administered questionnaire in Arabic language specially designed for the research purpose after obtaining verbal consent and the data analyzed by SPSS program.Results:A total of 330 patients; 128 (39%) females and 202 (61%) males—participated in the study. The majority 165 (50%) were in the age-group of 50 –59 years. Simvastatin was the most commonly used statin among study participants 136 (41%) followed by rosuvastatin114 (35%). Among the participants, there were some patients who take drugs which have drug interactions with statins; there were 64 (19%) take Amlodipine with simvastatin, 13 (4%) and 6 (2%) take esomeprazole and ompeprazole respectively with statins. Only 9 (3%) reported that they were advised by pharmacist to avoid grape fruit. Majority of participants 309 (94%) reported neck pain, difficulty in walking, frequently fatigue after starting on statin. Also majority of participants 320 (97%) suffer from muscle pain after starting statins medications. Conclusion:The percentage of statin related side effects in this study population is high especially myopathy. Also some patients in this study taking medications that have drug interaction with statins, Counseling to patient regarding statin therapy appear to be insufficient. So, this study indicate that there's a need for more efforts from the physicians and pharmacist to avoid prescribing or dispensing medication that have drug-drug interaction with statins and provide counseling to patients regarding their statin therapy

Calcium phosphate carrying simvastatin enhances bone regeneration: a systematic review

Abstract Several studies have aimed to develop alternative therapeutic biomaterials for bone repair. The purpose of this systematic review was to evaluate how statins carried by calcium phosphate affect the formation and regeneration of bone tissue in animal models when compared to other biomaterials or spontaneous healing. This systematic review followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, the PRISMA guidelines, and the Preclinical Systematic Review & Meta-analysis Facility (SyRF). The protocol of this systematic review was registered in PROSPERO (CRD42018091112) and in CAMARADES. In addition, ARRIVE checklists were followed in order to increase the quality and transparency of the search. An electronic search was performed using the MEDLINE/PubMed, Scopus, SciELO, and PROSPERO library databases. The authors used a specific search strategy for each database, and they also conducted a search in the grey literature and cross-references. The eligibility criteria were animal studies, which evaluated bone repair treated with calcium phosphate as a simvastatin carrier. The selection process yielded 8 studies from the 657 retrieved. All manuscripts concluded that locally applied simvastatin carried by calcium phosphate is biocompatible, enhanced bone repair and induced statistically greater bone formation than cloth or calcium phosphate alone. In conclusion, the pertinent pre-clinical studies evidenced the calcium phosphate biocompatibility and its effectiveness in delivering SIM to improve the repair of bone defects. So, clinical trials are encouraged to investigate the impact of SIM associated with calcium phosphate bone graft in repairing bone defect in humans.

Resumo Muitos estudos objetivaram desenvolver biomateriais terapêuticos alternativos para o reparo ósseo. O objetivo desta revisão sistemática foi avaliar o efeito da estatina carreada por fosfato de cálcio na formação e regeneração de tecido ósseo em modelos animais quando comparado com outros biomateriais ou coágulo. Esta revisão sistemática seguiu as recomendações do Cochrane Handbook for Systematic Reviews of Interventions, PRISMA guidelines, e o Preclinical Systematic Review & Meta-analysis Facility (SyRF). O protocolo desta revisão sistemática foi registrado no PROSPERO (CRD42018091112) e no CAMARADES. Além disso, o guia ARRIVE foi utilizado com o objetivo de aumentar a qualidade e transparência do estudo. Uma pesquisa eletrônica foi realizada através do MEDLINE/PubMed, Scopus, SciELO, e biblioteca do PROSPERO. Os autores utilizaram uma estratégia de busca específica para cada base de dados, e uma busca foi conduzida na literatura cinza e nas referências dos artigos selecionados. Os critérios de elegibilidade foram estudos em animais, os quais avaliaram o repara do ósseo tratado com fosfato de cálcio como carreador de estatina. O processo de seleção obteve 8 estudos dos 657 encontrados. Todos os estudos concluíram que a aplicação local da sinvastatina carreada pelo fosfato de cálcio é biocompatível, melhora o reparo ósseo e induz uma formação óssea significantemente maior que coágulo ou fosfato de cálcio sozinho. Em conclusão, os estudos pré-clínicos pertinentes evidenciaram a biocompatibilidade do fosfato de cálcio e sua eficácia na entrega do SIM para melhorar o reparo de defeitos ósseos. Assim, estudos clínicos são encorajados a investigar o impacto do SIM associado ao enxerto ósseo de fosfato de cálcio na reparação de defeito ósseo em humanos.

Synergistic effects of Cortex Mori alkaloids combined with Simvastatin in rats with hyperlipidaemia / 中国临床药理学与治疗学

AIM: To explore the lipid lowering effect of Cortex Mori alkaloids combined with simvastatin on hyperlipidemia rats. METHODS: Hyperlipidemia model was established by feeding golden hamsters with high-fat diet for 6 weeks, and 40 golden hamsters were randomly divided into normal group, model group, Cortex Mori alkaloids group (CMA, 25 mg•kg-1•d-1),simvastatin group (15 mg•kg-1•d-1) and combination group (Cortex Mori alkaloids, 25 mg•kg-1•d-1, simvastatin 15 mg•kg-1•d-1). 2 weeks after the intragastric administration, cardiac blood sampling was used to determine the blood biochemical indexes such as TG,TC,LDL-C,HDL-C, as well as the levels of ALT,AST,CRP, NO,Lp-PLA2.Liver HE staining was used to observe pathological changes, and liver cell lipid deposition was observed by oil red O staining. RESULTS:Compared with the model group, TC levels in combination group were significantly reduced (P<0.05), LDL-C levels in simvastatin group and the combination group were significantly reduced (P<0.05).The level of NO in the combined group was significantly increased (P<0.05), and the difference was statistically significant compared with that in Cortex Mori alkaloids group and simvastatin group (P<0.05).The levels of CRP were significantly decreased in Cortex Mori alkaloids group, simvastatin group and the combination group (P<0.05).The level of Lp-PLA2 in combination group was significantly reduced (P<0.05). The results of liver HE staining and oil red O staining showed that both of them could improve the hepatic lesion and lipid deposition after drug treatment, and the improvement of the combination group was better than that of the two groups alone. CONCLUSION: Simvastatin combined with Cortex Mori alkaloids can effectively decrease lipid level and inflammatory level of golden hamstrel with hyperlipidemia.Cortex Mori alkaloids can be used as the auxiliary drug of simvastatin, which is expected to provide a new choice for clinical treatment of hyperlipidemia.

Effect of simvastatin pretreatment on human metapneumovirus infection and its mechanism / 解放军医学杂志

Objective: To investigate the effect of simvastatin pretreatment on human metapneumovirus (hMPV) infection and the related mechanism. Methods: Human bronchial epithelial cells (16HBE) were used in vitro experiments and BALB/c mice were used in vivo experiments. They were randomly divided into control group, simvastatin group, hMPV group, hMPV+simvastatin group. After corresponding treatment, the fluorescence of hMPV was observed with microscopy; virus titer and the expressions of autophagy-related gene recombinant human autophagy-related protein 5 (ATG5), Beclin1, and microtubule-associated protein 1 light chain 3 (LC3) were detected by Fluorescence Quantitative Real-time PCR; Western blotting was performed to detect autophagy-related protein ATG5, Beclin1, LC3 and serine/threonine kinase/mammalian rapamycin target protein (AKT/mTOR) pathway proteins. Results: In vitro experiment, the direct and indirect fluorescence expressions of hMPV and the virus titer were lower in hMPV+simvastatin group (0.260 ± 0.018) than those in hMPV group (1.241 ± 0.030), while the mRNA expression levels of autophagy-related gene ATG5, Beclin1 and LC3 were higher in hMPV+simvastatin group [(7.31±0.15), (8.67±0.88) and (6.55±0.30), respectively] than those in control group [(1.00±0.06), (1.00±0.05) and (1.10±0.06), respectively]; the mRNA and protein levels of autophagy-genes were the highest in hMPV+simvastatin group and the differences were statistically significant (P<0.05). The AKT/mTOR pathway was inhibited in hMPV group and hMPV+simvastatin group. In vivo experiment, the virus titer of the lung tissue and of the lung tissue supernatant inoculated in Vero E6 were lower in hMPV+simvastatin group (0.75±0.26 and 0.42±0.17, respectively) than those in hMPV group (2.46±0.53 and 1.80±0.40, respectively). The mRNA and protein expression levels of autophagy-related genes ATG5, Beclin1 and LC3 were the highest in hMPV+simvastatin group (3.89±0.42, 3.13±0.26 and 3.56±0.22, respectively), higher than those in control group and hMPV group, the differences were statistically significant (P<0.05), and the AKT/mTOR pathway was inhibited in this group; HE staining of lung tissue showed an inflammatory response in the hMPV group, and pre-treatment with simvastatin could reduce the inflammation. Conclusion: Pretreatment with simvastatin may reduce human metapneumovirus infection, which is associated with autophagy and the AKT/mTOR pathway.

Oral simvastatin for 3 continuous months improves learning and memory ability of chronic cerebral hypoperfusion rats / 中国组织工程研究

BACKGROUND: Chronic cerebral hypoperfusion is significantly associated with cognitive decline. Our previous studies have found that mitochondrial aging, increased silent synapses and α-synuclein are important pathological changes of chronic cerebral hypoperfusion. Simvastatin is a traditional lipid regulation agent that can traverse the blood brain barrier, and exerts anti-atherosclerosis, anti-thrombosis and anti-inflammatory effects to improve cognitive function. OBJECTIVE: To observe the effect of continuous oral simvastatin for 3 months on cognitive function of chronic cerebral hypoperfusion male Sprague-Dawley rats, and explore the clinical significance of simvastatin in preventing and treating vascular cognitive impairment and dementia. METHODS: Sprague-Dawley rats were randomly divided into model group, sham group, solvent group and simvastatin group. In the model group, rats were subjected to bilateral common carotid artery occlusion. In the sham group, the bilateral common carotid arteries were not ligated. In the solvent group, the model rats were intragastrically treated with 0.5% carboxymethyl cellulose sodium. In the simvastatin group, the model rats were intragastrically treated with simvastatin suspension. Interventions in each group lasted for 3 months. Behavioral tests were then used to evaluate the learning and memory ability of rats in each group. The expressions of synaptophysin and post-synaptic density 95, key proteins of presynaptic and postsynaptic membrane, were detected by western blot. Ethical approval was obtained from the Animal Experimental Ethics Committee of the General Hospital of Western Theater Command with approval No. 2019ky79. RESULTS AND CONCLUSION: Compared with the sham group, the learning and memory functions of the rats in the model group were significantly impaired. In the open-field test, the moving distance within 5 minutes was significantly reduced in the model group compared with the sham group (P < 0.05), suggesting that autonomous exploration behavior was impaired. In the place navigation test, escape latency was significantly shortened in the model group, implicating the reference memory was damaged. In the spatial probe test, the frequency of passing through the platform and the time for passing through target quadrant were reduced, indicating that the space exploration ability was reduced. In the simvastatin group, however, these indexes were all improved. Western blot results showed that the protein expression of synaptophysin and post-synaptic density 95 decreased significantly in the model group (P < 0.05), but increased in the simvastatin group as compared with the solvent group. Therefore, chronic cerebral hypoperfusion can significantly impair learning and memory function and reduce cognitive level in rats. Continuous oral simvastatin for 3 months can improve cognitive function in chronic cerebral hypoperfusion rats, which indicates that simvastatin may be used as an adjunctive drug to improve the prognosis of patients with vascular cognitive impairment and dementia.

Endothelial protective effect of simvastatin on coagulation system in septic rats / 中华内科杂志

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.

Novel Eudragit® -based polymeric nanoparticles for sustained release of simvastatin

This paper reports on the development of nanoparticles aiming at the in vitro controlled release of simvastatin (SVT). The nanoparticles were prepared by the nanoprecipitation method with polymers Eudragit® FS30D (EDGFS) or Eudragit® NE30D (EDGNE). EDGFS+SVT nanoparticles showed mean size of 148.8 nm and entrapment efficiency of 76.4%, whereas EDGNE+SVT nanoparticles showed mean size of 105.0 nm and entrapment efficiency of 103.2%. Infrared absorption spectra demonstrated that SVT incorporated into the polymer matrix, especially EDGNE. Similarly, the differential scanning calorimeter (DSC) curve presented no endothermic peak of fusion, indicating that the system is amorphous and the drug is not in the crystalline state. The maintenance of SVT in the amorphous state may favors its solubilization in the target release sites. In the in vitro dissolution assay, the SVT incorporated into the EDGFS+SVT nanoparticles showed a rapid initial release, which may be related to the pH of the dissolution medium used. Regarding the EDGNE+SVT nanoparticles, the in vitro release occurred in a bimodal behavior, i.e., an initial "burst" followed by a sustained delivery, with the kinetics of drug release following Baker-Lonsdale's mathematical model. All these features suggest the nanoparticulate system's potential to modulate SVT delivery and enhance its bioavailability.