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1.
Biomed Res Int ; 2021: 6644630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527740

RESUMO

The object of this study was to prepare binary and ternary solid dispersions of atorvastatin (ATR) by the melting method using PEGs and poloxamer 188 (P188) as the carriers, singly and in combination with each other. Dissolution behavior, solubility studies, X-ray diffractometry, differential scanning calorimetry, and Fourier transform infrared spectroscopy were studied. Furthermore, antihyperlipidemic activities of formulations were compared to each other by serum lipid analyses in hyperlipidemic rats. Based on the results, the highest dissolution efficiency (DE30 = 83%) was obtained by binary systems consisted of ATR and P188. Also, no additional improvement was observed in dissolution properties of ternary solid dispersion formulations. Solubility studies showed enhancement of ATR phase solubility in water and a buffer solution containing P188 or PEG 10000. Furthermore, saturated solubility of ATR in the buffer solution improved more than twofold in the optimized ternary dispersion system. No crystalline changes occurred in PEG-based formulations; meanwhile, partial amorphization happened in the ATR-P188 combination. Finally, the in vivo study in hyperlipidemic rats exhibited a rapid decrease in the lipid profile of all formulations compared to ATR (after 7 days). Moreover, reduction of serum triglycerides and total cholesterol on the 14th day in the ATR group (p value < 0.01) was less than solid dispersion or physical mixing preparations (p value < 0.001). These findings proved the appropriate influence of using PEG and P188 in solid dispersion systems for the improvement of the therapeutic efficiency of ATR.


Assuntos
Atorvastatina/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos/fisiologia , Animais , Atorvastatina/farmacologia , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Masculino , Poloxâmero/química , Polietilenoglicóis/química , Polímeros/química , Ratos , Ratos Wistar , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodos
2.
Mol Med ; 27(1): 105, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503440

RESUMO

BACKGROUND: Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. METHODS: We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and molecular docking analyses, with in vitro tests using a lung organoid model of SARS-CoV-2 entry, to identify drugs with putative multimodal properties against COVID-19. RESULTS: Out of thousands of FDA-approved drugs considered, we observed that atorvastatin was the most promising candidate, as its effects negatively correlated with the transcriptional changes associated with infection. Atorvastatin was further predicted to bind to SARS-CoV-2's main protease and RNA-dependent RNA polymerase, and was shown to inhibit viral entry in our lung organoid model. CONCLUSIONS: Small clinical studies reported that general statin use, and specifically, atorvastatin use, are associated with protective effects against COVID-19. Our study corroborrates these findings and supports the investigation of atorvastatin in larger clinical studies. Ultimately, our framework demonstrates one promising way to fast-track the identification of compounds for COVID-19, which could similarly be applied when tackling future pandemics.


Assuntos
Antivirais/farmacologia , Atorvastatina/farmacologia , COVID-19/tratamento farmacológico , Pulmão/efeitos dos fármacos , Organoides/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Atorvastatina/química , COVID-19/prevenção & controle , Linhagem Celular , Proteases 3C de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/química , Doxiciclina/farmacologia , Aprovação de Drogas , Reposicionamento de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/virologia , Modelos Biológicos , Simulação de Acoplamento Molecular , Organoides/virologia , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacologia , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/genética , Trifluoperazina/química , Trifluoperazina/farmacologia , Estados Unidos , United States Food and Drug Administration , Vesiculovirus/genética , Internalização do Vírus/efeitos dos fármacos
3.
Int J Mol Sci ; 22(16)2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34445462

RESUMO

Liver cancer is the sixth most common cancer worldwide with high morbidity and mortality. Programmed death ligand 1 (PD-L1) is a major ligand of programmed death 1 receptor (PD1), and PD1/PD-L1 checkpoint acts as a negative regulator of the immune system. Cancers evade the host's immune defense via PD-L1 expression. This study aimed to investigate the effects of tumor-related cytokines, interferon gamma (IFNγ), and tumor necrosis factor alpha (TNFα) on PD-L1 expression in human hepatocellular carcinoma cells, HepG2. Furthermore, as atorvastatin, a cholesterol-lowering agent, is documented for its immunomodulatory properties, its effect on PD-L1 expression was investigated. In this study, through real-time RT-PCR, Western blot, and immunocytochemistry methods, PD-L1 expression in both mRNA and protein levels was found to be synergistically upregulated in HepG2 by a combination of IFNγ and TNFα, and STAT1 activation was mainly responsible for that synergistic effect. Next, atorvastatin can inhibit the induction of PD-L1 by either IFNγ alone or IFNγ/TNFα combination treatment in HepG2 cells. In conclusion, in HepG2 cells, expression of PD-L1 was augmented by cytokines in the tumor microenvironment, and the effect of atorvastatin on tumor immune response through inhibition of PD-L1 induction should be taken into consideration in cancer patients who have been prescribed atorvastatin.


Assuntos
Atorvastatina/farmacologia , Antígeno B7-H1/imunologia , Carcinoma Hepatocelular/imunologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/imunologia , Proteínas de Neoplasias/imunologia , Antígeno B7-H1/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/genética
4.
Front Immunol ; 12: 618365, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34434187

RESUMO

The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara -/- mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD.


Assuntos
Atorvastatina/farmacologia , Colite/tratamento farmacológico , PPAR alfa/imunologia , Animais , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Sulfato de Dextrana/toxicidade , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Knockout , PPAR alfa/genética , Células Th17/imunologia , Células Th2/imunologia
5.
Biomolecules ; 11(7)2021 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-34356676

RESUMO

Genistein (4,5,7-trihydroxyisoflavone) is abundant in various dietary vegetables, especially soybeans, and is known to have not only an estrogenic effect but also an antiadipogenic effect. Atorvastatin (dihydroxy monocarboxylic acid) is a statin used to prevent heart disease. Although genistein and atorvastatin have been reported to possess antiadipogenic effects, their combined effects are still unclear. The aim of the current study was to explore whether the combination of genistein and atorvastatin at low concentrations significantly suppresses adipogenesis in a murine preadipocyte cell line (3T3-L1) compared to treatment with genistein or atorvastatin alone. Our results showed that cotreatment with 50 µM genistein and 50 nM atorvastatin significantly suppressed preadipocyte differentiation, whereas when each compound was used alone, there was no inhibitory effect. Additionally, cotreatment with genistein and atorvastatin significantly downregulated adipogenic marker proteins, including mitogen-activated protein kinases (MAPKs), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), glucocorticoid receptor (GR), and CCAAT/enhancer-binding protein ß (C/EBPß). This is the first evidence of the combined antiadipogenic effects of genistein and atorvastatin. Although additional experiments are required, combinational treatment with genistein and atorvastatin may be an alternative treatment for menopause-associated lipid metabolic disorders and obesity.


Assuntos
Adipogenia/efeitos dos fármacos , Atorvastatina/farmacologia , Genisteína/farmacologia , Células 3T3-L1 , Adipogenia/fisiologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sinergismo Farmacológico , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , PPAR gama/metabolismo , Receptores de Glucocorticoides/metabolismo
6.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208774

RESUMO

Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high-saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl-coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet-fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.


Assuntos
Atorvastatina/farmacologia , Ácidos e Sais Biliares/metabolismo , Homeostase , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Biomarcadores , Dieta Hiperlipídica , Modelos Animais de Doenças , Fígado/metabolismo , Camundongos , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/biossíntese
7.
Tissue Eng Regen Med ; 18(5): 863-873, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34260048

RESUMO

BACKGROUND: We previously found that atorvastatin (ATV) enhanced mesenchymal stem cells (MSCs) migration, by a yet unknown mechanism. CXC chemokine receptor 4 (CXCR4) is critical to cell migration and regulated by microRNA-146a (miR-146a). Therefore, this study aimed to assess whether ATV ameliorates MSCs migration through miR-146a/CXCR4 signaling. METHODS: Expression of CXCR4 was evaluated by flow cytometry. Expression of miR-146a was examined by reverse transcription-quantitative polymerase chain reaction. A transwell system was used to assess the migration ability of MSCs. Recruitment of systematically delivered MSCs to the infarcted heart was evaluated in Sprague-Dawley rats with acute myocardial infarction (AMI). Mimics of miR-146a were used in vitro, and miR-146a overexpression lentivirus was used in vivo, to assess the role of miR-146a in the migration ability of MSCs. RESULTS: The results showed that ATV pretreatment in vitro upregulated CXCR4 and induced MSCs migration. In addition, flow cytometry demonstrated that miR-146a mimics suppressed CXCR4, and ATV pretreatment no longer ameliorated MSCs migration because of decreased CXCR4. In the AMI model, miR-146a-overexpressing MSCs increased infarct size and fibrosis. CONCLUSION: The miR-146a/CXCR4 signaling pathway contributes to MSCs migration and homing induced by ATV pretreatment. miR-146a may be a novel therapeutic target for stimulating MSCs migration to the ischemic tissue for improved repair.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Animais , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Movimento Celular , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , Receptores CXCR4/genética , Transdução de Sinais
8.
J Oral Biosci ; 63(3): 253-258, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34280533

RESUMO

OBJECTIVES: Myocardial ischemia-reperfusion injury is a phenomenon that promotes myocardial damage when the blood supply returns to the tissue after a period of ischemia. Anesthetic postconditioning involves myocardial protection against myocardial I/R injury. The effects of atorvastatin (ATV) on sevoflurane postconditioning against myocardial ischemia-reperfusion injury have not been thoroughly studied. The present study aimed to investigate if ATV interacts synergistically with sevoflurane postconditioning against myocardial infarction in rabbit hearts in vivo. METHODS: Twenty-eight male rabbits underwent 30 min of left anterior descending coronary artery occlusion that was followed by reperfusion for 180 min under ketamine/xylazine (K/X) anesthesia. Rabbits were randomly assigned to four groups that included Group K/X (under K/X anesthesia only), Group POST (sevoflurane exposure at initial reperfusion), Group ATV (ATV 5 mg/kg/day administered before ischemia), and Group ATV + POST (POST intervention with atorvastatin administered once daily for 3 days). At the end of reperfusion, the myocardial infarct size and the area at risk were both measured. RESULTS: The mean infarct sizes in the POST, ATV, and ATV + POST groups were significantly smaller compared to those in the K/X group. Furthermore, the mean infarct size in Group ATV + POST was significantly smaller than was that in Group POST and significantly smaller compared to that in Group ATV. CONCLUSION: The combination of sevoflurane postconditioning and pre-administration of ATV further reduced the myocardial infarction size compared to that observed with sevoflurane postconditioning alone or ATV alone. Our data suggest that sevoflurane postconditioning and ATV may function additively to enhance cardioprotection.


Assuntos
Anestésicos Inalatórios , Éteres Metílicos , Animais , Atorvastatina/farmacologia , Masculino , Coelhos , Ratos , Ratos Sprague-Dawley , Sevoflurano
9.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922266

RESUMO

(1) Background and Purpose: Global cerebral ischemia-induced severe hypoxic brain damage is one of the main causes of mortality and long-term neurologic disability even after receiving early blood reperfusion. This study aimed to test the hypothesis that atorvastatin potentially has neuroprotective effects in global cerebral ischemia (GCI). (2) Methods: We performed two sets of experiments, analyzing acute (1-week) and chronic (4-week) treatments. For the vehicle (Veh) and statin treatments, 1 mL of 0.9% saline and 5 mg/kg of atorvastatin (ATOR) were administered orally. For histological analysis, we used the following staining protocols: Fluoro-Jade B and NeuN, 4-hydroxynonenal, CD11b and GFAP, IgG, SMI71, and vWF. Finally, we evaluated the cognitive function with a battery of behavioral tests. (3) Results: The GCI-ATOR group showed significantly reduced neuronal death, oxidative stress, inflammation, and BBB disruption compared with the GCI-Veh group. Moreover, the GCI-ATOR group showed decreased endothelial damage and VV proliferation and had significantly improved cognitive function compared with the GCI-Veh group in both models. (4) Conclusions: ATOR has neuroprotective effects and helps recover the cognitive function after GCI in rats. Therefore, administration of atorvastatin may be a therapeutic option in managing GCI after CA.


Assuntos
Atorvastatina/farmacologia , Isquemia Encefálica/complicações , Transtornos Cognitivos/tratamento farmacológico , Inflamação/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Comportamento Animal , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/etiologia , Inflamação/patologia , Masculino , Neurônios/patologia , Ratos , Ratos Sprague-Dawley
10.
Acta Biochim Biophys Sin (Shanghai) ; 53(5): 528-537, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33674828

RESUMO

In clinic, perioperative neurocognitive disorder is becoming a common complication of surgery in old patients. Neuroinflammation and blood-brain barrier (BBB) disruption are important contributors for cognitive impairment. Atorvastatin, as a strong HMG-CoA reductase inhibitor, has been widely used in clinic. However, it remains unclear whether atorvastatin could prevent anesthesia and surgery-induced BBB disruption and cognitive injury by its anti-inflammatory property. In this study, aged C57BL/6J mice were used to address this question. Initially, the mice were subject to atorvastatin treatment for 7 days (10 mg/kg). After a simple laparotomy under 1.5% isoflurane anesthesia, Morris water maze was performed to assess spatial learning and memory. Western blot analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were used to examine the inflammatory response, BBB integrity, and cell apoptosis. Terminal-deoxynucleotidyl transferase mediated nick end labeling assay was used to assess cell apoptosis. The fluorescein sodium and transmission electron microscopy were used to detect the permeability and structure of BBB. The results showed that anesthesia and surgery significantly injured hippocampal-dependent learning and memory, which was ameliorated by atorvastatin. Atorvastatin could also reverse the surgery-induced increase of systemic and hippocampal cytokines, including IL-1ß, TNF-α, and IL-6, accompanied by inhibiting the nuclear factor kappa-B (NF-κB) pathway and Nucleotide-Binding Oligomerization Domain, or Leucine Rich Repeat and Pyrin Domain Containing 3 (NLRP3) inflammasome activation, as well as hippocampal neuronal apoptosis. In addition, surgery triggered an increase of BBB permeability, paralleled by a decrease of the ZO-1, occludin, and Claudin 5 proteins in the hippocampus. However, atorvastatin treatment could protect the BBB integrity from the impact of surgery, by up-regulating the expressions of ZO-1, occludin, and Claudin 5. These findings suggest that atorvastatin exhibits neuroprotective effects on cognition in aged mice undergoing surgery.


Assuntos
Envelhecimento/metabolismo , Atorvastatina/efeitos adversos , Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/metabolismo , Inflamassomos/metabolismo , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Envelhecimento/patologia , Animais , Atorvastatina/farmacologia , Barreira Hematoencefálica/patologia , Disfunção Cognitiva/etiologia , Camundongos
11.
Korean J Gastroenterol ; 77(3): 123-131, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33686046

RESUMO

Backgrounds/Aims: PPARγ, farnesoid X receptor (FXR) and CYP7A1 are associated with solubility of bile. This study was performed to understand a mechanism and interactions of statin-induced PPARγ, PGC-1α and HNF-4α related to the statin-induced activation of FXR and CYP7A1, and verify whether the mevalonate pathway is involved in the mechanism. Methods: MTT assays were performed using cultured human Hep3B cells to determine the effect of atorvastatin on the cell proliferation. Expression levels of indicated proteins were measured using Western blotting assays by inhibiting the protein expression or not. Results: Atorvastatin increased expression of PPARγ, PGC-1α, HNF-4α, FXR, and CYP7A1 in Hep3B cells. PPARγ ligand of troglitazone upregulated the expression of PGC-1α, HNF-4α, FXR, and CYP7A1 in Hep3B cells. Silencing of PPARγ, PGC1α, and HNF4α using respective siRNA demonstrated that atorvastatin-induced FXR and CYP7A1 activation required sequential action of PPARγ /PGC-1α/HNF-4α. The silencing of PPARγ completely inhibited atorvastatin-induced PGC-1α expression, and the PGC1α silencing partially inhibited atorvastatin-induced PPARγ expression. The inhibition of HNF4α did not affect atorvastatin-induced PPARγ expression, but partially inhibited atorvastatin-induced PGC-1α expression. Besides, mevalonate completely reversed the effect of atorvastatin on PPARγ, PGC-1α, HNF-4α, FXR, and CYP7A1. Conclusions: Atorvastatin induces FXR and CYP7A1 activation as a result of sequential action of PPARγ/PGC-1α/HNF-4α in human hepatocytes. We propose that atorvastatin enhances solubility of cholesterol in bile by simultaneously activating of FXR and CYP7A1.


Assuntos
Atorvastatina/farmacologia , Colesterol , Colesterol 7-alfa-Hidroxilase/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , PPAR gama , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Receptores Citoplasmáticos e Nucleares
12.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673196

RESUMO

Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.


Assuntos
Atorvastatina/farmacologia , Raios gama/efeitos adversos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Enteropatias/metabolismo , Monócitos/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Lesões Experimentais por Radiação/metabolismo , Migração Transendotelial e Transepitelial , Animais , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Enteropatias/patologia , Camundongos , Monócitos/patologia , Lesões Experimentais por Radiação/patologia , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Migração Transendotelial e Transepitelial/efeitos da radiação
13.
Mol Cell Biochem ; 476(6): 2307-2316, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33582946

RESUMO

Obesity is a risk factor for Barrett's oesophagus and oesophageal adenocarcinoma. Adipose tissue secretes the hormone leptin. Leptin is a growth factor for several cell types, including Barrett's cells and oesophageal adenocarcinoma cells. Statins are associated with reduced rates of Barrett's oesophagus and oesophageal cancer and exhibit anti-cancer effects in vitro. The mechanisms of these effects are not fully established. We have examined the effects of leptin and the lipid-soluble statin, atorvastatin, on signalling via monomeric GTP-binding proteins and Akt. Proliferation and apoptosis were assessed in OE33 cells. Akt activity was quantified by cell-based ELISA and in vitro kinase assay. Specific small-molecule inhibitors and a dominant-negative construct were used to reduce Akt activity. Small GTPases were inhibited using transfection of dominant-negative plasmids, prenylation inhibitors and pretreatment with atorvastatin. Leptin stimulated Akt activity and cell proliferation and inhibited camptothecin-induced apoptosis in an Akt-sensitive manner. Leptin induced phosphorylation of Bad and FOXO1 in an Akt-sensitive manner. Leptin activated Ras, Rac, RhoA and cdc42. Transfection of dominant-negative plasmids confirmed that leptin-induced Akt activation required Ras, RhoA cdc42 but not Rac. Atorvastatin inhibited leptin-induced activation of Ras, RhoA, cdc42 and Akt. Co-treatment with mevalonate prevented these effects of atorvastatin. The protein kinase Akt is essential to the growth-promoting and anti-apoptotic effects of leptin in oesophageal adenocarcinoma cells. Akt is activated via Ras-, Rho- and cdc42-dependant pathways. Atorvastatin reduces leptin-induced Akt activation by inhibiting prenylation of small GTPases. This may explain the reduced incidence of oesophageal adenocarcinoma in statin-users.


Assuntos
Atorvastatina/farmacologia , Neoplasias Esofágicas/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Leptina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Neoplasias Esofágicas/patologia , Humanos
14.
Life Sci ; 272: 119230, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33600864

RESUMO

The current study was conducted to investigate the therapeutic effects of atorvastatin (ATV) and resveratrol (RVT) in sole and simultaneous forms of administration against the symbiosis between glucose transporters 1 and 3 (GLUT-1 and GLUT-3), monocarboxylate transporters 1 a and 4 (MCT-1 and MCT-4) and neovascularization in ectopic endometrial tissue (EET). For this purpose, the experimental endometriosis was induced in 24 virgin female Wistar rats, and then the rats were divided into non-treated endometriosis-induced (ENDO-sole), AVT-treated (5 mg kg-1), RVT-treated (40 mg kg-1) and AVT +RVT-treated groups (n = 6 rats in each group). Following 28 days from the experimental endometriosis induction, the EETs were collected and the EETs size, neovascularization ratio, and expression levels of GLUT-1, GLUT-3, MCT-1, and MCT-4 were analyzed by qRT-PCR and immunohistochemistry (IHC). The AVT and RVT sole and simultaneous-treated animals exhibited decreased EET sizes and neovascularization. Moreover, the mRNA levels of GLUT-1, GLUT-3, MCT-1, and MCT-4, as well as GLUT-1+, GLUT-3+, and MCT-4+ cells distribution per mm2 of tissue were decreased in AVT and RVT sole and simultaneous-treated groups. Our findings showed that the AVT and RVT, especially in the simultaneous form of administration, could decrease the neovascularization development in the EETs by suppressing the GLUTs (1 and 3) and MCTs (1 and 4) expressions. Therefore, it can be concluded that the simultaneous administration of AVT and RVT can inhibit the EET's establishment and development through suppressing glycolysis and neovascularization.


Assuntos
Atorvastatina/farmacologia , Endometriose/tratamento farmacológico , Resveratrol/farmacologia , Animais , Atorvastatina/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Feminino , Glucose/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Neovascularização Patológica/metabolismo , Ratos , Ratos Wistar , Resveratrol/metabolismo , Simportadores/metabolismo
15.
Cochrane Database Syst Rev ; 1: CD013211, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482034

RESUMO

BACKGROUND: Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolaemia and dyslipidaemia. By reducing the level of cholesterol, which is the precursor of the steroidogenesis pathway, atorvastatin may cause a reduction in levels of testosterone and other androgens. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgen levels, caused by atorvastatin might cause negative effects in most settings. In contrast, in the setting of polycystic ovary syndrome (PCOS), reducing excessive levels of androgens with atorvastatin could be beneficial. OBJECTIVES: Primary objective To quantify the magnitude of the effect of atorvastatin on total testosterone in both males and females, compared to placebo or no treatment. Secondary objectives To quantify the magnitude of the effects of atorvastatin on free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulphate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs) in both males and females, compared to placebo or no treatment. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to 9 November 2020: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; ;two international trials registries, and the websites of the US Food and Drug Administration, the European Patent Office and the Pfizer pharmaceutical corporation. These searches had no language restrictions. We also contacted authors of relevant articles regarding further published and unpublished work. SELECTION CRITERIA: RCTs of daily atorvastatin for at least three weeks, compared with placebo or no treatment, and assessing change in testosterone levels in males or females. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the citations, extracted the data and assessed the risk of bias of the included studies. We used the mean difference (MD) with associated 95% confidence intervals (CI) to report the effect size of continuous outcomes,and the risk ratio (RR) to report effect sizes of the sole dichotomous outcome (WDAEs). We used a fixed-effect meta-analytic model to combine effect estimates across studies, and risk ratio to report effect size of the dichotomous outcomes. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included six RCTs involving 265 participants who completed the study and their data was reported. Participants in two of the studies were male with normal lipid profile or mild dyslipidaemia (N = 140); the mean age of participants was 68 years. Participants in four of the studies were female with PCOS (N = 125); the mean age of participants was 32 years. We found no significant difference in testosterone levels in males between atorvastatin and placebo, MD -0.20 nmol/L (95% CI -0.77 to 0.37). In females, atorvastatin may reduce total testosterone by -0.27 nmol/L (95% CI -0.50 to -0.04), FAI by -2.59 nmol/L (95% CI -3.62 to -1.57), androstenedione by -1.37 nmol/L (95% CI -2.26 to -0.49), and DHEAS by -0.63 µmol/l (95% CI -1.12 to -0.15). Furthermore, compared to placebo, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L (95% CI 0.23 to 5.99). We identified no studies in healthy females (i.e. females with normal testosterone levels) or children (under age 18). Importantly, no study reported on free testosterone levels. AUTHORS' CONCLUSIONS: We found no significant difference between atorvastatin and placebo on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.


Assuntos
Atorvastatina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Síndrome do Ovário Policístico/sangue , Testosterona/sangue , Idoso , Androgênios/sangue , Androstenodiona/sangue , Atorvastatina/efeitos adversos , Viés , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Placebos/farmacologia , Síndrome do Ovário Policístico/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores Sexuais , Globulina de Ligação a Hormônio Sexual/análise , Globulina de Ligação a Hormônio Sexual/efeitos dos fármacos
16.
Sci Rep ; 11(1): 2167, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33500513

RESUMO

Statins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD (P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group (P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ.


Assuntos
Atorvastatina/farmacologia , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Hepáticas/patologia , Mitocôndrias Musculares/metabolismo , Obesidade/patologia , Animais , Biomarcadores/metabolismo , Respiração Celular , Citrato (si)-Sintase/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Metaboloma , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Suínos , Porco Miniatura , Ubiquinona/análogos & derivados , Ubiquinona/metabolismo
17.
Br J Pharmacol ; 178(7): 1705-1721, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33502755

RESUMO

BACKGROUND AND PURPOSES: Cerebral microhaemorrhages (CMHs) are associated with cognitive decline in humans. In rodents, CMHs induces cognitive impairment in male mice along with sex-specific cortical and hippocampal changes affecting neural, glial and vascular functions. Statins, have been proposed to prevent cognitive decline. We tested here the action of atorvastatin on CMH-induced cognitive impairment in a murine model of CMH. EXPERIMENTAL APPROACH: Using a multimodal approach combining behavioural tests, in vivo imaging, biochemistry and molecular biology, the effects of oral administration of atorvastatin on the sex-specific changes induced by a cortical CMH were studied in male and female mice (C57BL/6J) at 6-week post-induction using a collagenase-induced model. KEY RESULTS: Atorvastatin caused specific effects according to the sex-specific CMH-induced changes. In males, atorvastatin improved the visuospatial memory, induced a local modulation of microglial response and enhanced brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (trkB) and vascular endothelial growth factor (VEGF) expression in the cortex. In the hippocampus, atorvastatin increased glucose metabolism and modulated astrocytes morphology. In females, atorvastatin did not modulate visuospatial memory despite the increased expression of cortical BDNF and the decrease in the number of hippocampal astrocytes. Atorvastatin also induced a decrease in the expression of cortical oestrogen receptors but did not modify body weight nor serum cholesterol levels in both sexes. CONCLUSION AND IMPLICATIONS: Atorvastatin modulated the sex-specific cognitive impairment induced by the CMH with a pathophysiological impact mainly within the cortical area. It could represent a promising candidate for future sex-stratified clinical trials in patients with CMH.


Assuntos
Disfunção Cognitiva , Fator A de Crescimento do Endotélio Vascular , Animais , Atorvastatina/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Memória , Camundongos , Camundongos Endogâmicos C57BL
18.
J Nutr Biochem ; 90: 108577, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33388349

RESUMO

Diet quality and statin therapy are established modulators of coronary artery disease (CAD) progression, but their effect on the gastrointestinal tract and subsequent sequelae that could affect CAD progression are relatively unexplored. To address this gap, Ossabaw pigs (N = 32) were randomly assigned to receive isocaloric amounts of a Western-type diet (WD; high in saturated fat, refined carbohydrate, and cholesterol, and low in fiber) or a heart healthy-type diet (HHD; high in unsaturated fat, whole grains, fruits and vegetables, supplemented with fish oil, and low in cholesterol), with or without atorvastatin, for 6 months. At the end of the study, RNA sequencing with 100 base pair single end reads on NextSeq 500 platform was conducted in isolated pig jejunal mucosa. A two-factor edgeR analysis revealed that the dietary patterns resulted in three differentially expressed genes related to lipid metabolism (SCD, FADS1, and SQLE). The expression of these genes was associated with cardiometabolic risk factors and atherosclerotic lesion severity. Subsequent gene enrichment analysis indicated the WD, compared to the HHD, resulted in higher interferon signaling and inflammation, with some of these genes being significantly associated with serum TNF-α and/or hsCRP concentrations, but not atherosclerotic lesion severity. No significant effect of atorvastatin therapy on gene expression, nor its interaction with dietary patterns, was identified. In conclusion, Western and heart healthy-type dietary patterns differentially affect the expression of genes associated with lipid metabolism, interferon signaling, and inflammation in the jejunum of Ossabaw pigs.


Assuntos
Doença da Artéria Coronariana/terapia , Dieta Saudável/métodos , Dieta Ocidental , Inflamação/genética , Interferons/genética , Metabolismo dos Lipídeos/genética , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Atorvastatina/farmacologia , Fatores de Risco Cardiometabólico , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Comportamento Alimentar , Feminino , Expressão Gênica , Coração , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/metabolismo , Interferons/metabolismo , Mucosa Intestinal/metabolismo , Jejuno/metabolismo , Masculino , Suínos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
J Nutr Biochem ; 90: 108570, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33429036

RESUMO

Optimizing diet quality in conjunction with statin therapy is currently the most common approach for coronary artery disease (CAD) risk management. Although effects on the cardiovascular system have been extensively investigated, little is known about the effect of these interventions in the colon and subsequent associations with CAD progression. To address this gap, Ossabaw pigs were randomly allocated to receive, for a six-month period, isocaloric amounts of either a heart healthy-type diet (HHD; high in unrefined carbohydrate, unsaturated fat, fiber, supplemented with fish oil, and low in cholesterol) or a Western-type diet (WD; high in refined carbohydrate, saturated fat and cholesterol, and low in fiber), without or with atorvastatin therapy. At the end of the intervention period, colon samples were harvested, mucosa fraction isolated, and RNA sequenced. Gene differential expression and enrichment analyses indicated that dietary patterns and atorvastatin therapy differentially altered gene expression, with diet-statin interactions. Atorvastatin had a more profound effect on differential gene expression than diet. In pigs not receiving atorvastatin, the WD upregulated "LXR/RXR Activation" pathway compared to pigs fed the HHD. Enrichment analysis indicated that atorvastatin therapy lowered inflammatory status in the HHD-fed pigs, whereas it induced a colitis-like gene expression phenotype in the WD-fed pigs. No significant association was identified between gene expression phenotypes and severity of atherosclerotic lesions in the left anterior descending-left circumflex bifurcation artery. These data suggested diet quality modulated the response to atorvastatin therapy in colonic mucosa, and these effects were unrelated to atherosclerotic lesion development.


Assuntos
Atorvastatina/farmacologia , Colo/metabolismo , Doença da Artéria Coronariana/tratamento farmacológico , Dieta/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Colesterol na Dieta/farmacologia , Colo/efeitos dos fármacos , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Dieta Saudável/métodos , Dieta Hiperlipídica/métodos , Dieta Ocidental , Gorduras na Dieta/farmacologia , Comportamento Alimentar , Feminino , Expressão Gênica , Humanos , Masculino , Suínos
20.
AAPS PharmSciTech ; 22(2): 59, 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33517486

RESUMO

Development of fixed dose combinations is growing and many of these drug combinations are being legally marketed. However, the development of these requires careful investigation of possible physicochemical changes during co-processing. This requires investigation of the effect of co-processing of drug combination in absence of excipients to maximize the chance of interaction (if any). Accordingly, the aim was to investigate the effect of co-processing of ezetimibe and atorvastatin on drugs dissolution rate. The objective was extended to in vitro in vivo correlation. Drugs were subjected to wet co-processing in presence of ethanol after being mixed at different ratios. The prepared formulations were characterized using FTIR spectroscopy, X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and in vitro dissolution testing. These investigations proved the possibility of eutectic system formation after drugs co-processing. This was reflected on drugs dissolution rate which was significantly enhanced at dose ratio and 2:1 atorvastatin:ezetimibe molar ratio compared to the corresponding pure drugs. In vivo antihyperlipidemic effects of the co-processed drugs were monitored in albino mice which were subjected to hyperlipidemia induction using poloxamer 407. The results showed significant enhancement in pharmacological activity as revealed from pronounced reduction in cholesterol level in mice administering the co-processed form of both drugs. Besides, histopathological examinations of the liver showed marked decrease in hepatic vacuolation. In conclusion, co-processing of atorvastatin with ezetimibe resulted in beneficial eutexia which hastened the dissolution rate and pharmacological effects of both drugs.Graphical abstract.


Assuntos
Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Ezetimiba/administração & dosagem , Animais , Anticolesterolemiantes/farmacologia , Atorvastatina/química , Atorvastatina/farmacologia , Combinação de Medicamentos , Liberação Controlada de Fármacos , Ezetimiba/química , Ezetimiba/farmacologia , Masculino , Camundongos
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