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OBJECTIVES: Conducting a scoping review (SR) to assess scientific evidence for topical simvastatin's impact on alveolar bone regeneration and determine its level of support for clinical applications. MATERIALS AND METHODS: This SR followed the PRISMA-ScR and OSF registries protocol; systematic searching was conducted on MEDLINE/PubMed, Cochrane, Embase, Scopus, Web of Science, and LILACS, to identify relevant articles until June 2023. Inclusion criteria covered clinical trials, case series, prospective and retrospective studies, along with in vivo investigations, involving participants of any sex and age. RESULTS: Out of 1312 identified studies, 20 (9 in vivo, 11 RCTs) met inclusion criteria. RCTs focused on third molar extraction, in vivo on mandibular incisor surgery. The majority of RCTs employed a collagen sponge and a simvastatin concentration of 10mg; conversely, most in vivo studies favored polylactide-co-glycolide and a 2 mg simvastatin concentration. RCTs had 3-month follow-ups; in vivo, studies extended to 8 weeks. Seven RCTs assessed pain outcomes, simvastatin did not significantly affect pain in six studies. Among four RCTs on postoperative swelling, only two observed a significant increase in the simvastatin group. In general, positive bone formation and the absence of adverse effects directly linked to topical simvastatin were observed across the study models. CONCLUSIONS: Intra-alveolar simvastatin post-tooth extraction has been to be shown to be effective and safe for preserving alveolar bone, with varied concentrations and carriers, with no significant adverse effects. CLINICAL RELEVANCE: This review provides critical insights into the effects of simvastatin on alveolar bone regeneration, informing potential benefits and possible challenges associated with its post-extraction application. OSF REGISTRY PROTOCOL: osf.io/q3bnf.

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Astrocytes have key regulatory roles in central nervous system (CNS), integrating metabolic, inflammatory and synaptic responses. In this regard, type I interferon (IFN) receptor signaling in astrocytes can regulate synaptic plasticity. Simvastatin is a cholesterol-lowering drug that has shown anti-inflammatory properties, but its effects on astrocytes, a main source of cholesterol for neurons, remain to be elucidated. Herein, we investigated the effects of simvastatin in inflammatory and functional parameters of primary cortical and hypothalamic astrocyte cultures obtained from IFNα/ß receptor knockout (IFNα/ßR-/-) mice. Overall, simvastatin decreased extracellular levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), which were related to a downregulation in gene expression in hypothalamic, but not in cortical astrocytes. Moreover, there was an increase in anti-inflammatory interleukin-10 (IL-10) in both structures. Effects of simvastatin in inflammatory signaling also involved a downregulation of cyclooxygenase 2 (COX-2) gene expression as well as an upregulation of nuclear factor κB subunit p65 (NFκB p65). The expression of cytoprotective genes sirtuin 1 (SIRT1) and nuclear factor erythroid derived 2 like 2 (Nrf2) was also increased by simvastatin. In addition, simvastatin increased glutamine synthetase (GS) activity and glutathione (GSH) levels only in cortical astrocytes. Our findings provide evidence that astrocytes from different regions are important cellular targets of simvastatin in the CNS, even in the absence of IFNα/ßR, which was showed by the modulation of cytokine production and release, as well as the expression of cytoprotective genes and functional parameters.

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BACKGROUND: Simvastatin administration to decompensated cirrhosis patients improved Child-Pugh (CP) at the end of a safety trial (EST). AIM: To evaluate whether simvastatin reduces cirrhosis severity through a secondary analysis of the safety trial. METHODS: Thirty patients CP class (CPc) CPc A (n = 6), CPc B (n = 22), and CPc C (n = 2) received simvastatin for one year. PRIMARY ENDPOINT: cirrhosis severity. Secondary endpoints: health-related quality of life (HRQoL) and hospitalizations for cirrhosis complications. RESULTS: Cirrhosis severity decreased baseline versus EST only across CP score (7.3 ± 1.3 versus 6.7 ± 1.7, P = 0.041), and CPc: 12 patients lessened from CPc B to CPc A, and three patients increased from CPc A to CPc B (P = 0.029). Due to cirrhosis severity changes and differences in clinical outcomes, 15 patients completed the trial as CPc AEST and another 15 as CPc B/C. At baseline, CPc AEST showed greater albumin and high-density lipoprotein cholesterol concentrations than CPc B/C (P = 0.036 and P = 0.028, respectively). Comparing EST versus baseline, only in CPc AEST, there was a reduction in white-cell blood (P = 0.012), neutrophils (P = 0.029), monocytes (P = 0.035), and C-reactive protein (P = 0.046); an increase in albumin (P = 0.011); and a recovery in HRQoL (P < 0.030). Finally, admissions for cirrhosis complications decreased in CPc AEST versus CPc B/C (P = 0.017). CONCLUSIONS: Simvastatin would reduce cirrhosis severity only in CPc B at baseline in a suitable protein and lipid milieu, possibly due to its anti-inflammatory effects. Furthermore, only in CPc AEST would improve HRQoL and reduce admissions by cirrhosis complications. However, as these outcomes were not primary endpoints, they require validation.

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Doxorubicin (DOX) is a potent chemotherapeutic drug used as the first line in breast cancer treatment; however, cardiotoxicity is the main drawback of the therapy. Preclinical studies evidenced that the association of simvastatin (SIM) with DOX leads to a better prognosis with reduced side effects and deaths. In this work, a novel pH-sensitive liposomal formulation capable of co-encapsulating DOX and SIM at different molar ratios was investigated for its potential in breast tumor treatment. Studies on physicochemical characterization of the liposomal formulations were carried out. The cytotoxic effects of DOX, SIM, and their combinations at different molar ratios (1:1; 1:2 and 2:1), free or co-encapsulated into pH-sensitive liposomes, were evaluated against three human breast cancer cell lines (MDA-MB-231, MCF-7, and SK-BR-3). Experimental protocols included cell viability, combination index, nuclear morphological changes, and migration capacity. The formulations showed a mean diameter of less than 200 nm, with a polydispersity index lower than 0.3. The encapsulation content was ~100% and ~70% for DOX and SIM, respectively. A more pronounced inhibitory effect on breast cancer cell lines was observed at a DOX:SIM molar ratio of 2:1 in both free and encapsulated drugs. Furthermore, the 2:1 ratio showed synergistic combination rates for all concentrations of cell inhibition analyzed (50, 75, and 90%). The results demonstrated the promising potential of the co-encapsulated liposome for breast tumor treatment.

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Acute lung injury (ALI) is a disease of high prevalence and is characterized by the excessive production of inflammatory mediators in the lungs of people sick. Inflammation is the major characteristic of ALI and studies report that inhibition of inflammatory cytokines could be an alternative treatment. Statins such as Simvastatin (SV) are known to their use for cholesterol reduction but also for inflammatory and immunoregulatory processes. In this study, we evaluated the effects of SV on LPS-induced alveolar macrophages and in ALI mice model. Our study has demonstrated the protective effects of SV on LPS-activated alveolar macrophages RAW 264.7 and LPS-induced ALI in mice. SV treatment significantly inhibited the alveolar macrophages activation by decreasing the iNOS, IL-1ß, and IL-6 gene expression in vitro and in vivo. The treatment also decreased the inflammatory cells migration and the cytokines gene expression. Our findings suggest that SV can act as an anti-inflammatory agent for acute lung injury.

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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)

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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.

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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.

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AIMS: The lung is an important target organ damage in intestinal ischemia/reperfusion (II/R), but mechanisms involved in II/R-induced pulmonary artery (PA) dysfunction, as well as its treatment, are not clear. The present study aimed to investigate the mechanisms involved in the II/R-induced PA dysfunction and a possible protective role of acute simvastatin pretreatment. MAIN METHODS: Male Wistar rats were subjected to occlusion of the superior mesenteric artery for 45 min followed by 2 h reperfusion (II/R) or sham-operated surgery (sham). In some rats, simvastatin (20 mg/kg, oral gavage) was administrated 1 h before II/R. KEY FINDINGS: II/R reduced acetylcholine-induced relaxation and phenylephrine-induced contraction of PA segments, which were prevented by acute simvastatin pretreatment in vivo or restored by inducible nitric oxide synthase (iNOS) inhibition in situ with 1400 W. Elevated reactive oxygen species (ROS) levels and higher nuclear translocation of nuclear factor kappa B (NFκB) subunit p65 were observed in PA of II/R rats and prevented by simvastatin. Moreover, simvastatin increased superoxide dismutase (SOD) activity and endothelial nitric oxide synthase (eNOS) expression in PA of the II/R group as well as prevented the increased levels of interleukin (IL)-1ß and IL-6 in lung explants following II/R. SIGNIFICANCE: The study suggests that pretreatment with a single dose of simvastatin prevents the II/R-induced increase of inflammatory factors and oxidative stress, as well as PA endothelial dysfunction and adrenergic hyporreactivity. Therefore, acute simvastatin administration could be therapeutic for pulmonary vascular disease in patients suffering from intestinal ischemic events.

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Simvastatin is one of the most common medicines prescribed to treat human hypercholesterolemia. Simvastatin acts through the inhibition of cholesterol synthesis. Unfortunately, simvastatin causes unwanted side effects on muscles, such as soreness, tiredness, or weakness. Therefore, to understand the mechanism of action of simvastatin, it is important to study its physiological and structural impacts on muscle in varied animal models. Here we report on the effects of simvastatin on two biological models: zebrafish embryos and chicken muscle culture. In the last years, our group and others showed that simvastatin treatment in zebrafish embryos reduces fish movements and induces major structural alterations in skeletal muscles. We also showed that simvastatin and membrane cholesterol depletion induce major changes in proliferation and differentiation of muscle cells in chick muscle cultures. Here, we review and discuss these observations considering reported data on the use of simvastatin as a potential therapy for Duchenne muscular dystrophy.