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1.
J Mol Neurosci ; 72(3): 565-573, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34569007

RESUMO

As one of the main types of secondary craniocerebral injury, the onset, progression, and prognosis of chronic subdural hematoma (CSDH) are closely related to the local inflammation of intracranial hematoma. Atorvastatin is reported to be effective in the conservative treatment of CSDH. This study aimed to clarify whether atorvastatin regulated the inflammatory responses in CSDH by interfering with the function of macrophages. The rat CSDH model was prepared by repeated intracranial blood injection with velocity gradient, and MRI was applied to calculate the intracranial hematoma volume. Changes in rat nerve functions were evaluated by foot-fault and Morris water maze tests. Flow cytometry was applied to detect the number of total macrophages and the percentage of M1 or M2 macrophages. The expression of inflammatory factors was examined by ELISA and western blot. Western bolt was applied to detect the expression of proteins involved in the colony-stimulating factor 1 receptor (CSF-1R) signaling pathway. Our results showed that atorvastatin significantly accelerated the absorption of hematoma and improved the nerve functions of CSDH rats. In addition, atorvastatin treatment effectively suppressed the expression of TNF-α, IL-6, and IL-8 and promoted the expression of IL-10. The total number of macrophages was decreased, and the percentage of M2 macrophages was increased in the intracranial hematoma following atorvastatin treatment. Furthermore, atorvastatin increased the levels of M2-related genes and surface markers in BMDMs stimulated by lipopolysaccharides and IFNγ, and activated the CSF-1R signaling pathway. In conclusion, our study shows that atorvastatin could alleviate the symptoms of CSDH and promote hematoma ablation by polarizing macrophages to M2 type and regulating the inflammatory responses.


Assuntos
Hematoma Subdural Crônico , Animais , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Hematoma Subdural Crônico/diagnóstico , Hematoma Subdural Crônico/tratamento farmacológico , Hematoma Subdural Crônico/etiologia , Inflamação , Macrófagos/metabolismo , Imageamento por Ressonância Magnética , Ratos
2.
Drug Des Devel Ther ; 16: 3805-3816, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36349306

RESUMO

Purpose: The prevalence of hyperlipidemia and related illnesses is on its rise, and atorvastatin is the frequently used hypolipidemic agent. However, there is still uncertainty about the mechanisms, especially the relationship between the lipid-lowering effect, intestinal microbiome, and metabolic profiles. We aim to intensively explain the mechanism of the hypolipidemic effect of atorvastatin through multi-omics perspective of intestinal microbiome and metabolomics. Methods: Multi-omics methods play an increasingly important role in the analysis of intestinal triggers and evaluation of metabolic disorders such as obesity, hyperlipidemia, and diabetes. Therefore, we were prompted to explore intestinal triggers, underlying biomarkers, and potential intervention targets of atorvastatin in the treatment of dyslipidemia through multi-omics. To achieve this, SPF Wistar rats were fed a high-fat diet or normal diet for 8 weeks. Atorvastatin was then administered to high-fat diet-fed rats. Results: By altering intestinal microbiome, a high-fat diet can affect feces and plasma metabolic profiles. Treatment with atorvastatin possibly increases the abundance of Bacteroides, thereby improving "propanoate metabolism" and "glycine, serine and threonine metabolism" in feces and plasma, and contributing to blood lipid reduction. Conclusion: Our study elucidated the intestinal triggers and metabolites of high-fat diet-induced dyslipidemia from the perspective of intestinal microbiome and metabolomics. It equally identified potential intervention targets of atorvastatin. This further explains the mechanism of the hypolipidemic effect of atorvastatin from a multi-omics perspective.


Assuntos
Dieta Hiperlipídica , Hiperlipidemias , Animais , Ratos , Dieta Hiperlipídica/efeitos adversos , Atorvastatina/farmacologia , Bacteroides , Metabolismo dos Lipídeos , Ratos Wistar , Hiperlipidemias/tratamento farmacológico , Lipídeos
3.
Nutrients ; 14(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36297049

RESUMO

Statin treatment is accepted to prevent adverse cardiovascular events. However, atorvastatin, an HMG-CoA reductase inhibitor, has been reported to exhibit distinct effects on senescent phenotypes. Whether atorvastatin can induce adipose tissue senescence and the mechanisms involved are unknown. The effects of atorvastatin-induced senescence were examined in mouse adipose tissue explants. Here, we showed that statin initiated higher levels of mRNA related to cellular senescence markers and senescence-associated secretory phenotype (SASP), as well as increased accumulation of the senescence-associated ß-galactosidase (SA-ß-gal) stain in adipose tissues. Furthermore, we found that the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ were elevated in adipose tissues treated with atorvastatin, accompanied by a decrease in the expression of glutathione (GSH), and glutathione peroxidase 4 (GPX4), indicating an iron-dependent ferroptosis. Atorvastatin-induced was prevented by a selective ferroptosis inhibitor (Fer-1). Moreover, supplementation with geranylgeranyl pyrophosphate (GGPP), a metabolic intermediate, reversed atorvastatin-induced senescence, SASP, and lipid peroxidation in adipose tissue explants. Atorvastatin depleted GGPP production, but not Fer-1. Atorvastatin was able to induce ferroptosis in adipose tissue, which was due to increased ROS and an increase in cellular senescence. Moreover, this effect could be reversed by the supplement of GGPP. Taken together, our results suggest that the induction of ferroptosis contributed to statin-induced cell senescence in adipose tissue.


Assuntos
Ferroptose , Inibidores de Hidroximetilglutaril-CoA Redutases , Camundongos , Animais , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Atorvastatina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Glutationa , beta-Galactosidase , Ferro/metabolismo , Tecido Adiposo/metabolismo , RNA Mensageiro , Malondialdeído
4.
Redox Rep ; 27(1): 212-220, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36200598

RESUMO

BACKGROUND: Oxidative damage is critical in the pathogenesis of ovarian ischaemia/reperfusion (I/R) injury, and statins have been reported to exert antioxidant activity. However, the role of VCAM-1 and xanthine oxidase (XO)/uric acid (UA) in ovarian I/R injury is not known. Also, whether or not atorvastatin exerts antioxidant activity like other statins is unclear. OBJECTIVES: This study investigated the involvement of VCAM-1 and XO/UA in ovarian I/R injury and the likely protective role of atorvastatin. METHODS: Forty female Wistar rats were randomized into sham-operated, ischaemia, ischaemia/reperfusion (I/R), ischaemia and atorvastatin, and I/R and atorvastatin. RESULTS: In comparison with the sham-operated group, atorvastatin blunted ischaemia and I/R-induced distortion of ovarian histoarchitecture and follicular degeneration. Also, atorvastatin alleviated ischaemia and I/R-induced rise in XO, UA, and malondialdehyde, which was accompanied by inhibition of ischaemia and I/R-induced reductions in reduced glutathione level, enzymatic antioxidant activities and increase in myeloperoxidase activity and TNF-α and IL-6 levels by atorvastatin treatment. Additionally, atorvastatin blocked ischaemia and I/R-induced increase in VCAM-1 expression, caspase 3 activity, 8-hydroxydeoxyguanosine level and ovarian DNA fragmentation index. CONCLUSION: For the first time, this study revealed that atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative injury, inflammation, and apoptosis induced by ovarian ischaemia/reperfusion injury.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Traumatismo por Reperfusão , Animais , Feminino , Ratos , 8-Hidroxi-2'-Desoxiguanosina , Antioxidantes/metabolismo , Apoptose , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Caspase 3/metabolismo , Regulação para Baixo , Glutationa/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Interleucina-6 , Isquemia/complicações , Isquemia/tratamento farmacológico , Malondialdeído/metabolismo , Estresse Oxidativo , Peroxidase/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico , Molécula 1 de Adesão de Célula Vascular/metabolismo , Xantina Oxidase/metabolismo
5.
Analyst ; 147(23): 5372-5385, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36285592

RESUMO

Cardiovascular diseases are still among the leading causes of mortality and morbidity worldwide. The build-up of fatty plaques in the arteries, leading to atherosclerosis, is the most common cause of cardiovascular diseases. The central player in atherosclerotic plaque formation is the foam cell. Foam cells are formed when monocytes infiltrate from the blood stream into the sub-endothelial space, differentiating into macrophages. With the subsequent uptake and storage of lipoprotein, especially low-density lipoprotein (LDL), they change their phenotype to lipid laden cells. Lowering circulating LDL levels, or initiating cholesterol efflux/reverse cholesterol transport in foam cells, is one of the current clinical therapies. Prescription of the pleiotropic drugs, statins, is the most successful therapy for the treatment and prevention of atherosclerosis. In this study, we used a foam cell model from the macrophage cell line, RAW 246.7, and applied the label-free Fourier Transform Infrared Spectroscopy (FTIR) method, i.e. synchrotron-based microFTIR spectroscopy, to study the lipid efflux process initiated by statins in a dose and time dependent manner. We used glass coverslips as substrates for IR analysis. The optical images (visible and fluorescent light) clearly identify the localization and lipid distribution within the foam cells, and the associated changes before and after culturing them with atorvastatin at concentrations of 0.6, 6 and 60 µg mL-1, for a culture duration between 24 to 72 hours. MicroFTIR spectroscopic spectra uniquely displayed the reduction of lipid content, with higher lipid efflux observed at higher doses of, and longer incubation time with, atorvastatin. Principal Component Analysis (PCA) and t-distributed Stochastic Neighbor Embedding (t-SNE) analysis demonstrated defined cluster separation at both lipid (3000-2800 cm-1) and fingerprint (1800-1350 cm-1) regions, with more profound discrimination for the atorvastatin dose treatment than time treatment. The data indicate that combining synchrotron-based microFTIR spectroscopy and using glass substrates for foam cells can offer an alternative tool in atherosclerosis investigation at a molecular level, and through cell morphology.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Placa Aterosclerótica , Humanos , Células Espumosas/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Atorvastatina/farmacologia , Atorvastatina/metabolismo , Atorvastatina/uso terapêutico , Colesterol/metabolismo , Aterosclerose/tratamento farmacológico
6.
Int Immunopharmacol ; 112: 109082, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36108401

RESUMO

BACKGROUND: The dengue is a vector borne viral infection in humans. Bite of mosquito infected with a dengue virus transmits the disease. The neutrophils support more to the innate immune response by switching to infected tissues and triggering immunomodulatory mechanisms including the release of proteases and host defence peptides. METHODS: Cell viability by MTT and trypan blue dye exclusion assay, bright field microscopy for assessment of cell morphology, cytokines measurements by ELISA, estimation of protein by Bradford assay were done. Assessments of matrix metalloproteinase genes mRNA expressions were done using real-time PCR. RESULTS: In the present study, we have for the first time unveiled that, NS1 antigen of dengue type-2 serotype, induce and stimulate the neutrophils cells to express high levels of matrix metalloproteases. NS1 exposure of HL-60 cells differentiated to neutrophils affected cell morphology and in 24 h of exposure. We have demonstrated that, the NS1 antigen has induced MMP-2, MMP-14 and MMP-9 expressions in neutrophils in a 24hrs exposure time. NS1 exposure has also further upregulated MMP-1, MMP-13, and MMP-8 expressions in neutrophils in a 24hrs exposure time. Notably, treatment with atorvastatin concentrations downregulated the expression profile of the all matrix metalloprotease significantly. Importantly, NS1 antigen has significantly increased the IL-6, IL-13 release by the HL,60 cells which was reversed by atorvastatin. On the other hand, NS1 exposure enhanced the mRNA expressions of VEGF-A and VEGF-D which was reversed by atorvastatin. However, we found that, NS1 exposure reduced the mRNA expressions profile of VEGF-C, which was reversed by atorvastatin. CONCLUSION: In conclusion, we report that, neutrophils associated matrix metalloprotease are involved in the pathogenesis of dengue viral disease. VEGF growth factors may also be released by the neutrophils which may subsequently participate in the endothelial dysfunctions leading to dengue shock syndrome.


Assuntos
Vírus da Dengue , Dengue , Proteínas não Estruturais Virais , Humanos , Anticorpos Antivirais , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Atorvastatina/metabolismo , Vírus da Dengue/fisiologia , Células HL-60 , Interleucina-13/metabolismo , Interleucina-6/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neutrófilos/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator D de Crescimento do Endotélio Vascular/metabolismo
7.
Oxid Med Cell Longev ; 2022: 7957255, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36092168

RESUMO

Abdominal or pelvic radiotherapy (RT) often results in small intestinal injury, such as apoptosis of epithelial cells and shortening of the villi. Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has many biological effects including cholesterol reduction, protection from cell damage, and autophagy activation. To reduce the extent of radiotherapy- (RT-) induced enteritis, we investigated the protective effects of atorvastatin against RT-induced damage of the intestinal tract. In this study, C57BL/6 mice were randomly distributed into the following groups (n = 8 per group): (1) control group: mice were fed water only, (2) atorvastatin group (Ator): mice were administered atorvastatin, (3) irradiation group (IR): mice received abdominal RT, (4) Ator+IR group: mice received abdominal RT following atorvastatin administration, and (5) Ator+IR+3-MA group: abdominal RT following atorvastatin and 3-methyladenine (an autophagy inhibitor) administration. Based on the assessment of modified Chiu's injury score and villus/crypt ratio, we found that atorvastatin administration significantly reduced intestinal mucosal damage induced by RT. Atorvastatin treatment reduced apoptosis (cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase), DNA damage (γH2AX and 53BP1), oxidative stress (OS, 4-hydroxynonenal), inflammatory molecules (phospho-NF-κB p65 and TGF-ß), fibrosis (collagen I and collagen III), barrier leakage (claudin-2 and fluorescein isothiocyanate-dextran), disintegrity (fatty acid-binding protein 2), and dysfunction (lipopolysaccharide) caused by RT in small intestinal tissue. In addition, atorvastatin upregulated the expression of autophagy-active molecules (LC3B), antioxidants (heme oxygenase 1 and thioredoxin 1), and tight junction proteins (occludin and zonula occludens 1). However, the biological functions of atorvastatin in decreasing RT-induced enteritis were reversed after the administration of 3-MA; the function of antioxidant molecules and activity of thioredoxin reductase were independent of autophagy activation. Our results indicate that atorvastatin can effectively relieve RT-induced enteritis through autophagy activation and associated biological functions, including maintaining integrity and function and decreasing apoptosis, DNA damage, inflammation, OS, and fibrosis. It also acts via its antioxidative capabilities.


Assuntos
Antioxidantes , Autofagia , Animais , Antioxidantes/farmacologia , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Fibrose , Camundongos , Camundongos Endogâmicos C57BL
8.
Nature ; 608(7922): 413-420, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35922515

RESUMO

High cholesterol is a major risk factor for cardiovascular disease1. Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 (ASGR1) variants associate with low cholesterol and a reduced risk of cardiovascular disease2. ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins3. The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgr1 deficiency decreases lipid levels in serum and liver by stabilizing LXRα. LXRα upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces4, respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation of glycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORC1 and activates AMPK. On one hand, AMPK increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1 that controls lipogenesis. Anti-ASGR1 neutralizing antibody lowers lipid levels by increasing cholesterol excretion, and shows synergistic beneficial effects with atorvastatin or ezetimibe, two widely used hypocholesterolaemic drugs. In summary, this study demonstrates that targeting ASGR1 upregulates LXRα, ABCA1 and ABCG5/G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels.


Assuntos
Receptor de Asialoglicoproteína , Colesterol , Metabolismo dos Lipídeos , Proteínas Quinases Ativadas por AMP/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Receptor de Asialoglicoproteína/antagonistas & inibidores , Receptor de Asialoglicoproteína/deficiência , Receptor de Asialoglicoproteína/genética , Receptor de Asialoglicoproteína/metabolismo , Assialoglicoproteínas/metabolismo , Atorvastatina/farmacologia , Proteína BRCA1 , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Sinergismo Farmacológico , Endocitose , Ezetimiba/farmacologia , Humanos , Lipídeos/análise , Lipídeos/sangue , Fígado/metabolismo , Receptores X do Fígado/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1 , Ubiquitina-Proteína Ligases/metabolismo
9.
Eur Rev Med Pharmacol Sci ; 26(14): 5210-5217, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35916819

RESUMO

OBJECTIVE: Cardiovascular diseases are responsible for the majority of deaths on a global scale. Atherosclerosis is the main risk factor for cardiovascular disorders and represents a complex phenomenon associated with endothelial dysfunction and inflammation. Statins, especially atorvastatin (ATV) and pitavastatin (PTV), are common agents used to control ongoing atherosclerotic events in the body to minimize cardiovascular disease-based deaths. MATERIALS AND METHODS: The present study aimed at comparing the efficacy of ATV and PTV in a cell line model of inflammation. Human saphenous vein cells were treated with TNF-alpha to mimic atherosclerotic conditions, and the cells were divided into 7 groups, including control, DMSO, TNF-alpha (10 ng/mL-6 hours), ATV (50 µM/24 hours), PTV (2 µM/24 hours), ATV (50 µM/24 hours)+TNF-alpha (10 ng/mL-6 hours) and PTV (2 µM/24 hours)+TNF-alpha (10 ng/mL-6 hours). The expression levels of 20 proinflammatory cytokines and chemokines were investigated in these groups using a human atherosclerosis antibody array. RESULTS: Possible pathway interactions were determined by STRING and PANTHER analyses. Comparison with the effect of ATV indicated that PTV reduced the levels of 4 proinflammatory cytokines: CCL11, CSF2, CCL20, and TGFB1 (p<0.05). CONCLUSIONS: Pleiotropic effects of pitavastatin against cardiovascular diseases appeared to be better; however, additional studies are required to compare statins and to identify new drugs that maintain broader protection from the risks of cardiovascular diseases.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Quinolinas , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Atorvastatina/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Citocinas , Células Endoteliais/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Projetos Piloto , Quinolinas/farmacologia , Veia Safena , Fator de Necrose Tumoral alfa/farmacologia
10.
Microvasc Res ; 144: 104421, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35970408

RESUMO

INTRODUCTION: Endometriosis is associated with systemic inflammation and increased risk of cardiovascular disease (CVD). Endothelial dysfunction is one of the first manifestations of CVD but is unexplored in women with endometriosis. HMG-CoA-reductase inhibitors (statins) exert potent anti-inflammatory effects, and have been proposed as an adjunctive therapy in women with endometriosis. We hypothesized that microvascular endothelial function would be impaired in otherwise healthy women with endometriosis mediated by reduced nitric oxide (NO)-dependent dilation and that short term statin administration would improve endothelial function. METHODS: In 8 healthy control (HC: 33 ± 9 yr) and 8 women with endometriosis (EN: 34 ± 9 yr), laser-Doppler flux (LDF) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (Ach: 10-10-10-1 M) alone and in combination with the NO synthase inhibitor (L-NAME: 0.015 M). 6 EN repeated the microdialysis experiment following 7 days of oral atorvastatin treatment (10 mg). Cutaneous vascular conductance was calculated (CVC = LDF*mmHg-1) and normalized to site-specific maximum (28 mM sodium nitroprusside, 43 °C). The NO-dependent dilation was calculated as the difference between the areas under the dose response curves. RESULTS: Ach-induced vasodilation was blunted in women with endometriosis (main effect p < 0.01), indicating impaired endothelial function. NO-dependent vasodilation was also reduced in women with endometriosis (HC: 217 ± 120.3 AUC vs. EN: 88 ± 97 AUC, p = 0.03). Oral atorvastatin improved Ach-induced (main effect p < 0.01) and NO-dependent (295 ± 153 AUC; p = 0.05) vasodilation in women with endometriosis. CONCLUSION: Microcirculatory endothelium-dependent vasodilation is impaired in women with endometriosis, mediated in part by reductions in NO. Short-term oral atorvastatin improved endothelium-dependent vasodilation, suggesting that statin therapy may be a viable intervention strategy to mitigate accelerated CVD risk in women with endometriosis.


Assuntos
Doenças Cardiovasculares , Endometriose , Inibidores de Hidroximetilglutaril-CoA Redutases , Atorvastatina/farmacologia , Endometriose/tratamento farmacológico , Endotélio Vascular , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Microcirculação , Óxido Nítrico , Fluxo Sanguíneo Regional , Pele/irrigação sanguínea , Vasodilatação
11.
J Med Life ; 15(6): 751-756, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35928361

RESUMO

Inflammatory cytokines, cell adhesion molecules, and toll-like receptors (TLRs) play an important role in atherosclerosis. The aim of this study was to further evaluate the role of inflammatory cytokines, cell adhesion molecules, and toll-like receptors in atherosclerosis. Forty local breed domestic male rabbits were divided randomly into 4 groups, 10 rabbits each. Group I was the control group, group II received a high cholesterol diet, group III received the drug solvent dimethyl sulfoxide (DMSO), and group IV received Atorvastatin (3.5 mg/kg/day). Blood samples were collected at 0 times, 5 weeks, and at the end of 10 weeks. TLRs expression on monocyte was measured by flow cytometry, IL-10, IL-17, IL-1ß, intracellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) were measured by ELISA. In group II, a high cholesterol diet led to a statistically significant elevation of lipids profile (TC, TG, and LDL) at both 5 weeks and 10 weeks compared to the control. The expression of TLRs was also increased compared to the control (13.53±2.5 to 25.79±6.5). The intimal thickness increased from 103.46±13.85 to 248.43±11.11. IL-17 increased significantly from 3.4±0.4 to 7.7±1.00, and IL-1ß increased from 1.04±0.19 to 9.66±1.4 (P 0.05) at 10 weeks. ICAM and VCAM increased from 1.7±0.16 to 8.2±0.74 and from 0.89±0.07 to 5.2±0.45, respectively. Atorvastatin significantly reduced TLRs at 10 weeks to 21.98±3.4 and intimal thickness to 191.6±15.59. IL-17, IL-1ß, ICAM, and VCAM were significantly reduced by Atorvastatin. Cytokines, cellular adhesion molecules, and probably TLRs have a role in the pathogenesis of hyperlipidemia and atherosclerosis.


Assuntos
Aterosclerose , Citocinas , Animais , Aterosclerose/tratamento farmacológico , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Moléculas de Adesão Celular , Colesterol , Interleucina-17 , Masculino , Coelhos , Receptores Toll-Like , Molécula 1 de Adesão de Célula Vascular
12.
Environ Sci Technol ; 56(16): 11504-11515, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35926083

RESUMO

In the environmental risk assessment of substances, toxicity to aquatic plants is evaluated using, among other methods, the 7 dayLemna sp. growth inhibition test following the OECD TG 221. So far, the test is not applicable for short-term screening of toxicity, nor does it allow evaluation of toxic modes of action (MoA). The latter is also complicated by the lack of knowledge of gene functions in the test species. Using ecotoxicogenomics, we developed a time-shortened 3 day assay inLemna minor which allows discrimination of ecotoxic MoA. By examining the changes in gene expression induced by low effect concentrations of the pharmaceutical atorvastatin and the herbicide bentazon at the transcriptome and proteome levels, we were able to identify candidate biomarkers for the respective MoA. We developed a homology-based functional annotation pipeline for the reference genome ofL. minor, which allowed overrepresentation analysis of the gene ontologies affected by both test compounds. Genes affected by atorvastatin mainly influenced lipid synthesis and metabolism, whereas the bentazon-responsive genes were mainly involved in light response. Our approach is therefore less time-consuming but sensitive and allows assessment of MoA in L. minor. Using this shortened assay, investigation of expression changes of the identified candidate biomarkers may allow the development of MoA-specific screening approaches in the future.


Assuntos
Araceae , Herbicidas , Poluentes Químicos da Água , Araceae/metabolismo , Atorvastatina/metabolismo , Atorvastatina/farmacologia , Biomarcadores , Herbicidas/metabolismo , Herbicidas/toxicidade , Toxicogenética , Poluentes Químicos da Água/metabolismo
13.
J Cardiovasc Pharmacol ; 80(5): 732-738, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35856902

RESUMO

ABSTRACT: Doxorubicin is a widely used anticancer drug in clinical practice, and its myocardial toxicity is the main concern in oncotherapy. Statins are commonly used as hypolipidemic drugs. Recent studies have also focused on the effects of statins on autophagy. Autophagy is a process in which cells consume their own cytoplasm or organelles after stimulation and finally degrade the phagosome in the lysosome. Transcription factor EB (TFEB) is the main factor regulating lysosomal gene transcription and function. We found that atorvastatin (ATO) increased TFEB protein levels and the ratio of lysosomal-associated membrane protein 2/LC3B in the myocardial tissue of mice with doxorubicin-induced cardiomyopathy (DIC). Therefore, we speculated that ATO may improve cardiac function in mice with DIC by increasing the expression of TFEB to enhance lysosomal function and autophagy. This study explored the role of TFEB in DIC and the possible mechanism of ATO in improving DIC and used statins to prevent and treat DIC; various dilated cardiomyopathy and heart failure diseases provide more experimental evidence. All relevant data are within the article and its supporting information files.


Assuntos
Cardiomiopatias , Inibidores de Hidroximetilglutaril-CoA Redutases , Camundongos , Animais , Atorvastatina/farmacologia , Atorvastatina/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Lisossomos/genética , Lisossomos/metabolismo , Autofagia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/prevenção & controle , Cardiomiopatias/metabolismo , Doxorrubicina , Dacarbazina/metabolismo , Dacarbazina/farmacologia
14.
J Am Heart Assoc ; 11(14): e025408, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35861833

RESUMO

Background Damage to the coronary arteries during the acute phase of Kawasaki disease (KD) is linked to inflammatory cell infiltration, myointimal proliferation, and endothelial cell (EC) dysfunction. To understand the response of ECs to KD treatment, we studied the genome-wide transcriptional changes in cultured ECs incubated with KD sera before and after treatment with or without atorvastatin. Methods and Results RNA sequencing of human umbilical vein ECs incubated with pooled sera from patients with acute KD before or after treatment with intravenous immunoglobulin and infliximab revealed differentially expressed genes in interleukin-1, tumor necrosis factor-α, and inflammatory cell recruitment pathways. Subacute sera pooled from patients treated with intravenous immunoglobulin, infliximab, and atorvastatin uniquely induced expression of NOS3, Kruppel like factor (KLF2, and KLF4 (promotes EC homeostasis and angiogenesis) and ZFP36 ring finger protein (ZFP36) and suppressor of cytokine signaling 3 (SOCS3) (suppresses inflammation), and suppressed expression of TGFB2 and DKK1 (induces endothelial-mesenchymal transition) and sphingosine kinase 1 (SPHK1) and C-X-C motif chemokine ligand 8 (CXCL8) (induces inflammation). Conclusions These results suggest that atorvastatin treatment of patients with acute KD may improve EC health, reduce mediators of inflammation produced by ECs, and block KD-induced myofibroblast proliferation.


Assuntos
Células Endoteliais , Síndrome de Linfonodos Mucocutâneos , Atorvastatina/farmacologia , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imunoglobulinas Intravenosas , Inflamação/metabolismo , Infliximab/metabolismo , Infliximab/farmacologia , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/metabolismo , Análise de Sequência de RNA
15.
Comput Math Methods Med ; 2022: 7416572, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35872950

RESUMO

Objective: To probe into the impact of atorvastatin on RANKL expression in rats during the retention stage after orthodontic tooth movement and its associated molecular mechanisms. Methods: After establishing an orthodontic tooth movement model, the left teeth of the retention-stage rats were the maintained side, and the right teeth were the nonmaintained side, which were given physiological saline or atorvastatin dosing at 7d, 14d, and 21d, respectively, by tube feeding, in order to keep the rats as a control group at the beginning of the retention stage. A model of the rat's upper jaw gypsum in each group was made at various time points to measure the distance at which the teeth relapsed. The pathological slices of the upper jaw arch were taken separately for TRAP staining observation. Results: Compared to the physiological saline group, the recurrence distance of rats in the atorvastatin group was visually lower (p < 0.05), and the number of bone-breaking cells was signally lower (p < 0.05); P-5b, PTH, VitD3, GC, IL-1, and IL-17 expressions (p < 0.05) were visually decreased, while IL-11 expression was elevated (p < 0.05). Conclusion: The atorvastatin given to rats during the retention stage after orthodontic tooth movement inhibits RANKL expression and may function through OPG/RANKL/RANK system.


Assuntos
Técnicas de Movimentação Dentária , Dente , Animais , Atorvastatina/farmacologia , Maxila , Osteoprotegerina/metabolismo , Ratos , Dente/metabolismo
16.
Arch Razi Inst ; 77(1): 285-291, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35891762

RESUMO

It has been approved that atrovastatin is a preferred treatment for hyperlipidemia. One of the atrovastatin drawbacks would be the detrimental effects on skeletal muscles. Therefore, the current study was designed to evaluate all the skeletal muscles alteration in rats' after administration of atrovastatin and identification the mechanisms involved in these structural alterations in the skeletal muscles. A total of 12 healthy adult male rats (Rattus norvegicus) were randomly divided into two groups (n=6). The control group (G1) included rats that received distilled water as the placebo, and the treatment group (G2) included animals that were treated with atorvastatin (80 mg/kg/day) dissolved in distilled water and administrated by a gastric tube for eight weeks. At the end of the experiment, trapezius and vastus medialis muscle tissues were sampled and fixed with 10% formalin for histopathological studies. Atorvastatin administration gave rise to morphological changes in the skeletal muscle fibers and the nerve fibers, including atrophied myofibers, infarction, irregular arrangement of myonuclei, disappearance of nuclei from their normal peripheral position with acute skeletal muscular infarction, and infiltration of accumulated inflammatory cells. Atorvastatin has been revealed to have several adverse effects on the skeletal muscle and the nerve supply. Based on the data in the current study, it is evident that atorvastatin administration for less than two months resulted in some sorts of myotoxic structural changes and apoptosis as evident by deformity and lack of striation degeneration of nuclei, as well as splitting of the muscle fibers in the adult male rats' skeletal muscle.


Assuntos
Músculo Esquelético , Doenças dos Roedores , Animais , Apoptose , Atorvastatina/farmacologia , Infarto/patologia , Infarto/veterinária , Masculino , Músculo Esquelético/patologia , Ratos , Doenças dos Roedores/patologia , Água/farmacologia
17.
J Cell Biochem ; 123(8): 1285-1297, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35894149

RESUMO

Osteoarthritis (OA) is a progressive joint disease. The etiology of OA is considered to be multifactorial. Currently, there is no definitive treatment for OA, and the existing treatments are not very effective. Hypercholesterolemia is considered a novel risk factor for the development of OA. Statins act as a competitive inhibitor of the ß-hydroxy ß-methylglutaryl-CoA (HMG-CoA) reductase and are widely used to manage hypercholesterolemia. Inhibition of HMG-CoA reductase results in reduced synthesis of a metabolite named mevalonate, thereby reducing cholesterol biosynthesis in subsequent steps. By this mechanism, statins such as atorvastatin and simvastatin could potentially have a preventive impact on joint cartilage experiencing osteoarthritic deterioration by reducing serum cholesterol levels. Atorvastatin can protect cartilage degradation following interleukin-1ß-stimulation. Atorvastatin stimulates the STAT1-caspase-3 signaling pathway that was shown to be responsible for its anti-inflammatory effects on the knee joint. Simvastatin had chondroprotective effects on OA in vitro by reducing matrix metalloproteinases expression patterns. In this study, we tried to review the therapeutic effects of statins on OA.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Osteoartrite , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Colesterol , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Osteoartrite/tratamento farmacológico , Oxirredutases , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
18.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(6): 899-904, 2022 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-35790441

RESUMO

OBJECTIVE: To explore the effect of atorvastatin (AVT) on biological behaviors and the miR-146a/PI3K/Akt signaling pathway in human glioma cells. METHODS: Human glioma U251 cells were treated with 8.0 µmol/L AVT or transfected with a miR-146a inhibitor or a negative control fragment (miR-146a NC) prior to AVT treatment. RT-PCR was used to detect miR-146a expression in the cells, and the changes in cell proliferation rate, apoptosis, cell invasion and migration were detected using MTT assay, flow cytometry, and Transwell assay. Western blotting was performed to detect the changes in cellular expressions of proteins in the PI3K/Akt signaling pathway. RESULTS: AVT treatment for 48 h resulted in significantly increased miR-146a expression and cell apoptosis (P < 0.01) and obviously lowered the cell proliferation rate, invasion index, migration index, and expressions of p-PI3K and p-Akt protein in U251 cells (P < 0.01). Compared with AVT treatment alone, transfection with miR-146a inhibitor prior to AVT treatment significantly reduced miR-146a expression and cell apoptosis (P < 0.01), increased the cell proliferation rate, promoted cell invasion and migration, and enhanced the expressions of p-PI3K and p-Akt proteins in the cells (P < 0.01); these effects were not observed following transfection with miR-146a NC group (P>0.05). CONCLUSION: AVT can inhibit the proliferation, invasion and migration and promote apoptosis of human glioma cells possibly by up-regulating miR-146a expression and inhibiting the PI3K/Akt signaling pathway.


Assuntos
Glioma , MicroRNAs , Apoptose , Atorvastatina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Glioma/patologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
19.
Pathol Res Pract ; 235: 153951, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35644046

RESUMO

Endometriosis is a common gynecological hurting disorder in which tissue is similar to the tissue that normally lines the inner layer of the uterus. It often causes fertility problems. Unfortunately, effective treatments are limited. Therefore it's important to explore an imperative and easily accessible treatment to alleviate the probable pathologies and preserve fertility in endometriosis. Consequently, we aimed to investigate the effects of metformin, letrozole, and atorvastatin on inflammation and apoptosis in experimentally induced ovarian and peritoneal endometriosis in rat models. In the present study, 35 rats were randomly divided into five groups. Group 1: sham-operated control group. Group 2: untreated endometriosis group. Group 3: given 100 mg/kg/day of oral metformin. Group 4: given 0.1 mg/kg/day of oral letrozole. Group 5: given 2.5 mg/kg/day of oral atorvastatin. At the end of the 28 days, we examined Ki67, Bax and Bcl-2 immunoexpressions in ovarian and peritoneal tissues, and IL-6, IL-8, and TNF-α levels were evaluated from the peritoneal fluid. All medical treatment groups showed a significant decrease in Ki67 expression. A significant increase in Bax expression was also observed in all samples from all medical treatment groups (other than the untreated endometriosis groups). Further, a significant decrease in Bcl-2 expression was found in all medical treatment groups. IL-6, IL-8, and TNF-α levels were significantly lower in all medical treatment groups than in the endometriosis groups. In conclusion; Metformin, letrozole, and atorvastatin showed apoptosis induction and anti-inflammatory effects on both ovarian and peritoneal endometriosis in experimental models.


Assuntos
Endometriose , Metformina , Animais , Apoptose , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Endometriose/patologia , Feminino , Humanos , Inflamação/tratamento farmacológico , Interleucina-6 , Interleucina-8 , Antígeno Ki-67 , Letrozol , Metformina/farmacologia , Metformina/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2
20.
Hepatol Commun ; 6(9): 2581-2593, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35712812

RESUMO

Lipophilic but not hydrophilic statins have been shown to be associated with reduced risk for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. We investigated differential actions of lipophilic and hydrophilic statins and their ability to modulate a clinical prognostic liver signature (PLS) predicting HCC risk in patients with liver disease. Hepatitis C virus (HCV)-infected Huh7.5.1 cells, recently developed as a model to screen HCC chemopreventive agents, were treated with lipophilic statins (atorvastatin and simvastatin) and hydrophilic statins (rosuvastatin and pravastatin), and then analyzed by RNA sequencing and PLS. Lipophilic statins, particularly atorvastatin, more significantly suppressed the HCV-induced high-risk pattern of PLS and genes in YAP and AKT pathway implicated in fibrogenesis and carcinogenesis, compared with the hydrophilic statins. While atorvastatin inhibited YAP activation through the mevalonate pathway, the distinctive AKT inhibition of atorvastatin was mediated by stabilizing truncated retinoid X receptor alpha, which has been known to enhance AKT activation, representing a target for HCC chemoprevention. In addition, atorvastatin modulated the high-risk PLS in an in vitro model of nonalcoholic fatty liver disease (NAFLD). Conclusion: Atorvastatin distinctively inhibits YAP and AKT activation, which are biologically implicated in HCC development, and attenuates a high-risk PLS in an in vitro model of HCV infection and NAFLD. These findings suggest that atorvastatin is the most potent statin to reduce HCC risk in patients with viral and metabolic liver diseases.


Assuntos
Carcinoma Hepatocelular , Hepatite C , Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Atorvastatina/farmacologia , Carcinoma Hepatocelular/genética , Hepatite C/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Proteínas Proto-Oncogênicas c-akt/genética
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