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1.
J Immunother Cancer ; 11(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36650022

RESUMO

BACKGROUND: Anti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients respond. Statin drugs (HMG-CoA reductase inhibitors) are associated with superior survival in several cancer types, including HNSCC. Emerging data suggest that manipulation of cholesterol may enhance some aspects of antitumor immunity. METHODS: We used syngeneic murine models (mouse oral cancer, MOC1 and TC-1) to investigate our hypothesis that a subset of statin drugs would enhance antitumor immunity and delay tumor growth. RESULTS: Using an ex vivo coculture assay of murine cancer cells and tumor infiltrating lymphocytes, we discovered that all seven statin drugs inhibited tumor cell proliferation. Simvastatin and lovastatin also enhanced T-cell killing of tumor cells. In mice, daily oral simvastatin or lovastatin enhanced tumor control and extended survival when combined with PD-1 blockade, with rejection of MOC1 tumors in 30% of mice treated with lovastatin plus anti-PD-1. Results from flow cytometry of tumors and tumor-draining lymph nodes suggested T cell activation and shifts from M2 to M1 macrophage predominance as potential mechanisms of combination therapy. CONCLUSIONS: These results suggest that statins deserve further study as well-tolerated, inexpensive drugs that may enhance responses to PD-1 checkpoint blockade and other immunotherapies for HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço , Inibidores de Hidroximetilglutaril-CoA Redutases , Animais , Camundongos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Checkpoint Imunológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Lovastatina/farmacologia , Lovastatina/uso terapêutico , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
2.
J Pharmacol Sci ; 151(1): 17-27, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36522119

RESUMO

Hsp90 is a molecular chaperone that contributes to the activation and stabilization of client proteins. In our previous studies, we found that inhibition of Hsp90 delayed cardiac remodeling during the development of chronic heart failure in animal models. Simvastatin, an inhibitor of HMG-CoA reductase, has been shown to inhibit Hsp90. However, it is unclear whether simvastatin can prevent cardiac remodeling by inhibiting Hsp90. Therefore, the effects of simvastatin were examined in a rat model of chronic heart failure following myocardial infarction. The results showed that simvastatin reduced cardiac remodeling by inhibiting cardiac fibrosis. Furthermore, simvastatin decreased the expression of c-Raf and calcineurin, which are involved in intracellular signaling during the development of myocardial remodeling. In vitro, we found that the interaction of Hsp90 with c-Raf and calcineurin was reduced and the expression levels these client proteins were decreased in fibroblasts cultured in the presence of simvastatin. In addition, simvastatin also reduced proliferation, migration, and collagen production of fibroblasts. These results suggest that Hsp90 inhibition is partly responsible for the inhibitory effect of simvastatin on the development of myocardial remodeling.


Assuntos
Insuficiência Cardíaca , Inibidores de Hidroximetilglutaril-CoA Redutases , Ratos , Animais , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Calcineurina , Remodelação Ventricular , Proteínas de Choque Térmico HSP90/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
3.
Biomed Pharmacother ; 158: 114089, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36538862

RESUMO

BACKGROUND: Combining mouse experiments with big data analysis of the Austrian population, we investigated the association between high-dose statin treatment and bone quality. METHODS: The bone microarchitecture of the femur and vertebral body L4 was measured in male and ovariectomized female mice on a high-fat diet containing simvastatin (1.2 g/kg). A sex-specific matched big data analysis of Austrian health insurance claims using multiple logistic regression models was conducted (simvastatin 60-80 mg/day vs. controls; males: n = 138,666; females: n = 155,055). RESULTS: High-dose simvastatin impaired bone quality in male and ovariectomized mice. In the trabecular femur, simvastatin reduced bone volume (µm3: ♂, 213 ± 15 vs. 131 ± 7, p < 0.0001; ♀, 66 ± 7 vs. 44 ± 5, p = 0.02) and trabecular number (1/mm: ♂, 1.88 ± 0.09 vs. 1.27 ± 0.06, p < 0.0001; ♀, 0.60 ± 0.05 vs. 0.43 ± 0.04, p = 0.01). In the cortical femur, bone volume (mm3: ♂, 1.44 ± 0.03 vs. 1.34 ± 0.03, p = 0.009; ♀, 1.33 ± 0.03 vs. 1.12 ± 0.03, p = 0.0002) and cortical thickness were impaired (µm: ♂, 211 ± 4 vs. 189 ± 4, p = 0.0004; ♀, 193 ± 3 vs. 169 ± 3, p < 0.0001). Similar impairments were found in vertebral body L4. Simvastatin-induced changes in weight or glucose metabolism were excluded as mediators of deteriorations in bone quality. Results from mice were supported by a matched cohort analysis showing an association between high-dose simvastatin and increased risk of osteoporosis in patients (♂, OR: 5.91, CI: 3.17-10.99, p < 0.001; ♀, OR: 4.16, CI: 2.92-5.92, p < 0.001). CONCLUSION: High-dose simvastatin dramatically reduces bone quality in obese male and ovariectomized female mice, suggesting that direct drug action accounts for the association between high dosage and increased risk of osteoporosis as observed in comparable human cohorts. The underlying pathophysiological mechanisms behind this relationship are presently unknown and require further investigation.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Osteoporose , Humanos , Masculino , Feminino , Camundongos , Animais , Sinvastatina/farmacologia , Densidade Óssea , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osso e Ossos , Ovariectomia/efeitos adversos
4.
Ultrastruct Pathol ; 47(1): 1-11, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36520527

RESUMO

Type 2 diabetes is a major health burden to the society. Macrophages and liver inflammation emerged as important factors in its development. We investigated ultrastructural changes in the liver, with a special emphasis on macrophages in high fat diet (HFD) fed C57BL/6 J mice treated with metformin or simvastatin, two drugs that are used frequently in diabetes. Both metformin and simvastatin reduced the liver damage in HFD fed animals, manifested as the prevention of nonalcoholic steatohepatitis development and reduced activation and number of macrophages in the liver, as well as the percentage of these cells with lipid droplets in the cytoplasm compared to untreated HFD animals. In contrast with untreated HFD-fed animals, lipid droplets were not observed in lysosomes of macrophages in HFD animals treated with metformin and simvastatin. These findings provide new insight into the effects of metformin and simvastatin on the liver in this experimental model of type 2 diabetes and provide further rationale for implementation of statins in the therapeutic regimens in this disease.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Metformina/farmacologia , Sinvastatina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Fígado , Macrófagos
5.
Cells ; 11(24)2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-36552711

RESUMO

Steroid-induced osteonecrosis of femoral head (SONFH) is one of the most common bone disorders in humans. Statin treatment is beneficial in preventing the development of SONFH through anti-inflammation effects and inhibition of the glucocorticoid receptor (GR). However, potential mechanisms of statin action remain to be determined. In this study, pulse methylprednisolone (MP) treatment was used to induce SONFH in broilers, and then MP-treated birds were administrated with simvastatin simultaneously to investigate the changes in cartilage homeostasis. Meanwhile, chondrocytes were isolated, cultured, and treated with MP, simvastatin, or GR inhibitor in vitro. The changes in serum homeostasis factors, cell viability, and expression of GR were analyzed. The results showed that the morbidity of SONFH in the MP-treated group increased significantly compared with the simvastatin-treated and control group. Furthermore, MP treatment induced apoptosis and high-level catabolism and low-level anabolism in vitro and vivo, while simvastatin significantly decreased catabolism and slightly recovered anabolism via inhibiting GR and the hypoxia-inducible factor (HIF) pathway. The GR inhibitor or its siRNA mainly affected the catabolism of cartilage homeostasis in vitro. In conclusion, the occurrence of SONFH in broilers was related to the activation of GR and HIF pathway, and imbalance of cartilage homeostasis. Simvastatin and GR inhibitor maintained cartilage homeostasis via GR and the HIF pathway.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Osteonecrose , Humanos , Animais , Receptores de Glucocorticoides/metabolismo , Sinvastatina/farmacologia , Cabeça do Fêmur/metabolismo , Galinhas , Osteonecrose/metabolismo , Metilprednisolona/farmacologia , Homeostase , Cartilagem
6.
J Indian Prosthodont Soc ; 22(2): 152-160, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36511026

RESUMO

Aim: The purpose of this study was to compare the effects of autologous platelet-rich fibrin (PRF) alone and PRF loaded with SIM on peri-implant bone changes and implant stability in patients undergoing implant rehabilitation. Settings and Design: This was a nonrandomized controlled split-mouth study. Materials and Methods: The study included 8 males between the ages of 45 and 60 years. Each patient received two implants, one on each side of the arch. One side was treated with PRF alone and the other side with PRF loaded with SIM at the time of osteotomy. A cone-beam computed tomography was used to evaluate bone changes around the insertion of implant sites at 3, 6, and 12 months postoperatively. The secondary outcome included measuring implant stability using Osstell device at baseline and 3 months postinsertion. To compare groups at different time periods, data were examined using a two-way analysis of variance. Statistical Analysis Used: The results were compared between the groups using a two-way analysis of variance, followed by a post hoc Bonferroni test. To examine total bone changes and stability comparisons between the two groups at the end of the trial, an unpaired t-test was utilized. Results: The mean crestal bone-level changes in the SIM/PRF group were significantly lower than the PRF group, with a mean shift of 0.9788 ± 0.04853 versus 1.356 ± 0.0434, respectively (P < 0.0001). There was no significant difference between the two groups in implant stability. Conclusion: Peri-implant application of SIM/PRF resulted in less bone changes than PRF alone, which may prove to be beneficial for the long-term success of implants. SIM showed promising results in limiting peri-implant bone resorption providing new clinical application for SIM in dental implant rehabilitation.


Assuntos
Implantes Dentários , Fibrina Rica em Plaquetas , Masculino , Humanos , Pessoa de Meia-Idade , Implantes Dentários/efeitos adversos , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Implantação Dentária Endóssea , Transplante Ósseo
7.
Int J Pharm ; 629: 122379, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36370997

RESUMO

Anthracyclines such as doxorubicin (Dox) are the preferred chemotherapeutics for several cancers. However, Dox-induced cardiotoxicity limits its therapeutic potential. Liposomal encapsulation of Dox has been used for patients with risk to develop Dox induced cardiotoxicity but does not surpass the efficacy of the unencapsulated drug. Statins are widely used as cholesterol lowering drugs and have also demonstrated cardioprotective activity in cancer patients undergoing Dox therapy. We developed a liposome loaded with Dox and simvastatin (Sim) and investigated their effect on cardiomyocytes and zebrafish larvae. Furthermore, we investigated if the doses required for cardioprotection compromised the cytotoxicity of Dox in mammary and prostate cancer cells. Combination of Sim and Dox reduced ROS generation in cardiomyocytes, both given as free drugs, or co-encapsulated in liposomes. In contrast, Sim potentiated ROS-generation and cytotoxic activity of Dox towards cancer cells also when co-encapsulated in liposomes. In zebrafish larvae, Sim treatment reduced Dox-induced cardiac affection, and the liposomes did not induce any sign of Dox-induced cardiotoxicity. Our results show that liposomal co-encapsulation of Sim and Dox can be an efficient way of further reducing the risk of cardiotoxic events of liposomal Dox, while retaining, or even potentiating the anti-cancer effect of Dox.


Assuntos
Lipossomos , Neoplasias , Masculino , Animais , Peixe-Zebra , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Sinvastatina/farmacologia , Espécies Reativas de Oxigênio , Doxorrubicina/efeitos adversos , Neoplasias/tratamento farmacológico
8.
Redox Biol ; 58: 102539, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36401888

RESUMO

Statins have manifold protective effects on the cardiovascular system. In addition to lowering LDL cholesterol levels, statins also have antioxidant effects on cardiovascular tissues involving intracellular redox pathways that are incompletely understood. Inhibition of HMG-CoA reductase by statins not only modulates cholesterol synthesis, but also blocks the synthesis of lipids necessary for the post-translational modification of signaling proteins, including the GTPase Rac1. Here we studied the mechanisms whereby Rac1 and statins modulate the intracellular oxidant hydrogen peroxide (H2O2) via NADPH oxidase (Nox) isoforms. In live-cell imaging experiments using the H2O2 biosensor HyPer7, we observed robust H2O2 generation in human umbilical vein endothelial cells (HUVEC) following activation of cell surface receptors for histamine or vascular endothelial growth factor (VEGF). Both VEGF- and histamine-stimulated H2O2 responses were abrogated by siRNA-mediated knockdown of Rac1. VEGF responses required the Nox isoforms Nox2 and Nox4, while histamine-stimulated H2O2 signals are independent of Nox4 but still required Nox2. Endothelial H2O2 responses to both histamine and VEGF were completely inhibited by simvastatin. In resting endothelial cells, Rac1 is targeted to the cell membrane and cytoplasm, but simvastatin treatment promotes translocation of Rac1 to the cell nucleus. The effects of simvastatin both on receptor-dependent H2O2 production and Rac1 translocation are rescued by treatment of cells with mevalonic acid, which is the enzymatic product of the HMG-CoA reductase that is inhibited by statins. Taken together, these studies establish that receptor-modulated H2O2 responses to histamine and VEGF involve distinct Nox isoforms, both of which are completely dependent on Rac1 prenylation.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , NADPH Oxidases , Humanos , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Peróxido de Hidrogênio/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Histamina/farmacologia , Sinvastatina/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
9.
Int Immunopharmacol ; 113(Pt A): 109347, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36332451

RESUMO

Lymphocytes infiltration is a key mechanism that drives asthma lung inflammation. Our previous results demonstrated a significant increase in the frequency and persistence of central memory T (TCM) cells in inflamed lung tissue. This could be due to an increase in the infiltration of TCM in the lung tissue, or the possible differentiation of lung effector memory T (TEM) cells into TCM during lung inflammation. Thus, targeting the accumulation of memory T cells provides a potential approach for asthma treatment. Simvastatin and other statins were shown to impact both the structural and immune lung cells, presenting a distinct immunomodulatory effect on T lymphocyte activation, infiltration, and function. Therefore, we sought to evaluate the effect of simvastatin on the frequency and function of CD4 and CD8 TEM and TCM cells in an ovalbumin (OVA)-induced mouse model of asthma. Simvastatin treatment significantly attenuated the infiltration of both TEM and TCM memory subtypes, along with their production of IL-4 and IL-13 cytokines in a T helper 2 (Th2) OVA-sensitized mouse model. Furthermore, we detected a reduction in ICAM-1 and VCAM-1 levels in the lung homogenate of OVA-sensitized and challenged mice, as well as in human umbilical vein endothelial cells (HUVECs) following treatment with simvastatin. The reduction in leucocyte homing receptors following simvastatin treatment might have contributed to the observed decrease in infiltrated memory T cell numbers. In conclusion, this study demonstrated how statin drug may attenuate allergic asthma lung inflammation by targeting memory T cells and reducing their numbers, whilst limiting their cytokine production at the site of inflammation. Longer clinical trials are required to assess the effectiveness and safety of statin treatment in different asthma phenotypes.


Assuntos
Asma , Inibidores de Hidroximetilglutaril-CoA Redutases , Camundongos , Humanos , Animais , Ovalbumina/uso terapêutico , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Células Endoteliais , Camundongos Endogâmicos BALB C , Pulmão , Inflamação/tratamento farmacológico , Modelos Animais de Doenças , Células Th2 , Líquido da Lavagem Broncoalveolar
10.
Skelet Muscle ; 12(1): 25, 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36447272

RESUMO

Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Duchenne MD (DMD) are caused by mutations to the Dysferlin and Dystrophin genes, respectively. We have recently demonstrated in typically mild dysferlin- and dystrophin-deficient mouse models that increased plasma cholesterol levels severely exacerbate muscle wasting, and that DMD patients display primary dyslipidemia characterized by elevated plasma cholesterol and triglycerides. Herein, we investigate lipoprotein abnormalities in LGMD2B and if statin therapy protects dysferlin-deficient mice (Dysf) from muscle damage. Herein, lipoproteins and liver enzymes from LGMD2B patients and dysferlin-null (Dysf) mice were analyzed. Simvastatin, which exhibits anti-muscle wasting effects in mouse models of DMD and corrects aberrant expression of key markers of lipid metabolism and endogenous cholesterol synthesis, was tested in Dysf mice. Muscle damage and fibrosis were assessed by immunohistochemistry and cholesterol signalling pathways via Western blot. LGMD2B patients show reduced serum high-density lipoprotein cholesterol (HDL-C) levels compared to healthy controls and exhibit a greater prevalence of abnormal total cholesterol (CHOL)/HDL-C ratios despite an absence of liver dysfunction. While Dysf mice presented with reduced CHOL and associated HDL-C and LDL-C-associated fractions, simvastatin treatment did not prevent muscle wasting in quadriceps and triceps muscle groups or correct aberrant low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) protein expression. LGMD2B patients present with reduced serum concentrations of HDL-C, a major metabolic comorbidity, and as a result, statin therapy is unlikely to prevent muscle wasting in this population. We propose that like DMD, LGMD2B should be considered as a new type of genetic dyslipidemia.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Distrofia Muscular do Cíngulo dos Membros , Camundongos , Animais , Disferlina/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Distrofina , HDL-Colesterol , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Distrofia Muscular do Cíngulo dos Membros/genética , Atrofia Muscular , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
11.
Nutrients ; 14(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36235772

RESUMO

Obesity causes progressive lipid accumulation and insulin resistance within muscle cells and affects skeletal muscle fibres and muscle mass that demonstrates atrophy and dysfunction. This study investigated the effects of naringin on the metabolic processes of skeletal muscle in obese rats. Male Sprague Dawley rats were divided into five groups: the control group with normal diet and the obese groups, which were induced with a high-fat diet (HFD) for the first 4 weeks and then treated with 40 mg/kg of simvastatin and 50 and 100 mg/kg of naringin from week 4 to 8. The naringin-treated group showed reduced body weight, biochemical parameters, and the mRNA expressions of protein degradation. Moreover, increased levels of antioxidant enzymes, glycogen, glucose uptake, the expression of the insulin receptor substrate 1 (IRS-1), the glucose transporter type 4 (GLUT4), and the mRNA expressions of protein synthesis led to improved muscle mass in the naringin-treated groups. The in vitro part showed the inhibitory effects of naringin on digestive enzymes related to lipid and glucose homeostasis. This study demonstrates the potential benefits of naringin as a supplement for treating muscle abnormalities in obese rats by modulating the antioxidative status, regulating protein metabolism, and improved insulin resistance in skeletal muscle of HFD-induced insulin resistance in obese rats.


Assuntos
Dieta Hiperlipídica , Flavanonas , Resistência à Insulina , Atrofia Muscular , Animais , Antioxidantes/metabolismo , Dieta Hiperlipídica/efeitos adversos , Flavanonas/farmacologia , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Glicogênio/metabolismo , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Músculo Esquelético/metabolismo , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/etiologia , Obesidade/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Sinvastatina/farmacologia
12.
Int J Biol Macromol ; 222(Pt B): 2399-2413, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36220413

RESUMO

This study aims at preparing electrospun PVA NFs incorporating simvastatin/chitosan nanoparticles (SIM CS NPs) as a controlled drug eluting scaffold for bone regeneration. Optimization was performed by Design Expert® software through establishing two factor, three level factorial design, where the independent variables were the applied voltage, flow rate and PVA solution/SIM CS NPs ratio. Formulation variables values for the optimized formula were 18KV, 0.5 mL/h, and 3:1 respectively. NFs diameter and mesh pore size were chosen as the dependent variables. The optimized NFs were evaluated morphologically, chemically, and physically. Additionally, in-vitro SIM release from the scaffolds was investigated along 24 days. Optimum NFs possessed 136 nm diameter size and 6.5 nm porosity. Also, they showed sustained SIM release for 24 days to achieve the desired goal in bone regeneration. The optimized NFs were implanted within induced bone defects in rabbits. In-vivo assessments were performed through cone beam computed tomography 3D images, bone density measurements, histological analysis and bone morphogenetic protein 2 (BMP 2) level. The obtained results proved the high potential of the optimized NFs in promoting bone regeneration compared to untreated group, non-medicated NFs group, free SIM group and NFs loaded with SIM group after 6 weeks of implantation.


Assuntos
Quitosana , Nanofibras , Nanopartículas , Animais , Coelhos , Sinvastatina/farmacologia , Regeneração Óssea , Tecidos Suporte
13.
Int J Pharm ; 628: 122270, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36228882

RESUMO

Melanoma is a form of skin cancer that starts in melanocytes. Rampant chemo-resistance, metastasis, and inability to cross the skin barriers and accumulate within the tumor microenvironment render the conventional chemotherapeutic approaches ineffective. Simvastatin (SIM), a cholesterol synthesis inhibitor, has shown tremendous anticancer potential. Due to the lack of therapeutic alternatives, repositioning SIM in melanoma could be beneficial. Incorporating SIM within the nanoparticles promoted increased melanoma cell internalization, apoptosis, and sustained release profile. Further, the incorporation of nanoparticles into the thermogel facilitated depot formation over the upper dermal layers. Sol-to-gel transition at 34 °C was observed with a 14.03-fold increase in viscosity. This could be fruitful in limiting systemic exposure and preventing adverse effects. Entrapment of SIM in the PLGA NPs enhanced the cytotoxicity by 9.38-fold (p less than 0.05). Nuclear staining with DAPI showed blebbing, membrane shrinkage, and apoptosis confirmed by DCFDA and acridine orange/ethidium bromide staining. Ex vivo diffusion studies revealed the accumulation of C-6 loaded nanoparticles incorporated within the thermogel onto the upper dermal layer and depot formation up to 6 h. Thus, we conclude that SIM-loaded nanoparticulate thermogel could be an efficacious therapeutic alternative for melanoma.


Assuntos
Melanoma , Nanopartículas , Humanos , Sinvastatina/farmacologia , Melanoma/tratamento farmacológico , Microambiente Tumoral
14.
Biomolecules ; 12(10)2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36291627

RESUMO

BACKGROUND: Because statins were found to decrease the oxygen consumption rate (OCR) of a variety of normal cells, our hypothesis was that statins may also decrease the OCR of cancer cells, alleviate tumor hypoxia and radiosensitize tumors. METHODS: OCR was assessed using the Seahorse XF96 technology and EPR respirometry in PC-3 prostate cancer cells. Mitochondrial superoxide production was measured by EPR with mitoTEMPO-H as a sensing probe. Tumor pO2 was measured in vivo using low-frequency EPR oximetry to define the optimal window of reoxygenation, the time at which tumors were irradiated with a single 6 Gy dose with a Cesium-137 irradiator. RESULTS: 24-h exposure to simvastatin and fluvastatin significantly decreased the OCR of PC-3 cancer cells. An increase in mitochondrial superoxide levels was also observed after fluvastatin exposure. The PC-3 prostate cancer model was found highly hypoxic at the basal level. When mice were treated with simvastatin or fluvastatin (daily injection of 20 mg/kg), tumor oxygenation increased 48 and 72 h after initiation of the treatment. However, despite reoxygenation, simvastatin did not sensitize the PC-3 tumor model to RT. CONCLUSIONS: exposure to statins affect tumor metabolism and tumor oxygenation, however, with limited impact on tumor growth with or without irradiation.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias da Próstata , Humanos , Masculino , Camundongos , Animais , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipóxia Tumoral , Fluvastatina/farmacologia , Superóxidos , Consumo de Oxigênio , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Oxigênio/metabolismo
15.
Atherosclerosis ; 361: 18-29, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36306655

RESUMO

BACKGROUND AND AIMS: ApoEb is a zebrafish homologous to mammalian ApoE, whose deficiency would lead to lipid metabolism disorders (LMDs) like atherosclerosis. We attempted to knock out the zebrafish ApoEb, then establish a zebrafish model with LMD. METHODS: ApoEb was knocked out using the CRISPR/Cas9 system, and the accumulation of lipids was confirmed by Oil Red O staining, confocal imaging, and lipid measurements. The lipid-lowering effects of simvastatin (SIM), ezetimibe (EZE) and Xuezhikang (XZK), an extract derived from red yeast rice, were evaluated through in vivo imaging in zebrafish larvae. RESULTS: In the ApoEb mutant, significant vascular lipid deposition occurred, and lipid measurement performed in the whole-body homogenate of larvae and adult plasma showed significantly increased lipid levels. SIM, EZE and XZK apparently relieved hyperlipidemia in ApoEb mutants, and XZK had a significant inhibitory effect on the recruitment of neutrophils and macrophages. CONCLUSIONS: In this study, an LMD model has been established in ApoEb mutant zebrafish. We suggest that this versatile model could be applied in studying hypercholesterolemia and related vascular pathology in the context of early atherosclerosis, as well as the physiological function of ApoE.


Assuntos
Aterosclerose , Hipercolesterolemia , Hiperlipidemias , Animais , Peixe-Zebra/metabolismo , Metabolismo dos Lipídeos , Hipercolesterolemia/metabolismo , Ezetimiba , Aterosclerose/patologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Sinvastatina/farmacologia , Mamíferos/metabolismo
16.
Biochem Biophys Res Commun ; 634: 168-174, 2022 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-36244115

RESUMO

Classical histological methods such as hematoxylin-eosin staining, have been, and in some areas still are, an important benchmark for the evaluation of biological tissues. However, the current method of assessment is primarily a qualitative assessment of the tissue under investigation. The aim of this paper is to contribute to the improvement of classical histological methods, by applying physical techniques that allow objective, quantitative data to be added to qualitative assessments, especially in areas where conflicting results are available. To this end, the effect of hypolipidemic medication on the callus formation process of normal bone and pathological osteoporotic bone was investigated. The study allowed us to associate UV-VIS spectroscopy wave number with specific hematoxylin-eosin staining of different types of bone tissue structures, the evolving structures in the callus formation process. This association allowed the quantitative assessment of the callusing process in ovariectomized (associated with pathological, osteoporotic bone) and non-ovariectomized (associated with normal bone) rats, with three groups - the control group, simvastatin-treated group, and fenofibrate-treated group. The study showed that in the non-ovariectomized groups both treatments delayed callus formation. In the ovariectomized groups, simvastatin delayed and fenofibrate promoted callus formation.


Assuntos
Fraturas do Fêmur , Fenofibrato , Osteoporose , Feminino , Humanos , Ratos , Animais , Ratos Wistar , Consolidação da Fratura , Fenofibrato/farmacologia , Amarelo de Eosina-(YS)/farmacologia , Amarelo de Eosina-(YS)/uso terapêutico , Hematoxilina/farmacologia , Hematoxilina/uso terapêutico , Ratos Sprague-Dawley , Ovariectomia , Calo Ósseo/patologia , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/patologia , Osteoporose/tratamento farmacológico , Osteoporose/patologia , Fêmur/patologia , Análise Espectral , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
17.
Mol Biol Rep ; 49(11): 10377-10385, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36097124

RESUMO

BACKGROUND: Simvastatin can potentially mitigate acute inflammatory phase of myocardial ischemia-reperfusion injury. However, these effects negatively influenced by its poor bioavailability, low water solubility and high metabolism. Here, we investigated the effects of SIM-loaded nano-niosomes on a rat model of MI/R injury to find a drug delivery method to tackle the barriers. METHODS: Nano-niosomes' characteristics were identified using dynamic light scattering and transmission electron microscopy. Fifty male Wistar rats were divided into five groups: Sham; MI/R; MI/R + nano-niosome; MI/R + SIM; MI/R + SIM-loaded nano-niosomes. Left anterior descending artery was ligated for 45 min, and 3 mg/kg SIM, nano-niosomes, or SIM-loaded nano-niosomes was intramyocardially injected ten min before the onset of reperfusion. ELISA assay was used to assess cardiac injury markers (cTnI, CK-MB) and inflammatory cytokines (TNF-α, IL-6, TGF-ß, MPC-1). Expression level of MAPK-NF-κB and histopathological changes were evaluated by western blot and hematoxylin & eosin staining, respectively. RESULTS: the size of nano-niosome was 137 nm, reached to 163 nm when simvastatin was loaded. To achieve optimized niosomes span 80, a drug/cholesterol ratio of 0.4 and seven min of sonication time was applied. Optimized entrapment efficiency of SIM-loaded nano-niosomes was 98.21%. Inflammatory cytokines and the expression level of MAPK and NF-κB were reduced in rats receiving SIM-loaded nano-niosomes compared to MI/R + SIM and MI/R + SIM-loaded nano-niosomes. CONCLUSION: Our results showed that SIM-loaded nano-niosomes could act more efficiently than SIM in alleviating the acute inflammatory response of reperfusion injury via downregulating the activation of MAPK-NF-κB.


Assuntos
Traumatismo por Reperfusão Miocárdica , Masculino , Ratos , Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , NF-kappa B/metabolismo , Sinvastatina/farmacologia , Lipossomos , Ratos Wistar , Ratos Sprague-Dawley , Citocinas
18.
Biomolecules ; 12(9)2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36139129

RESUMO

The present study investigated whether Rho-associated protein kinase (RhoA/ROCK) signaling pathway inhibitor simvastatin inhibits matrix metalloproteinase 2 (MMP-2) activity in a rat ischemia-reperfusion injury (I/Ri) model by inhibiting the RhoA/ROCK pathway and reducing MMP-2 mRNA levels. Isolated rat hearts were subjected to aerobic perfusion or I/Ri control. The effect of simvastatin was assessed in hearts subjected to I/Ri. We determined cardiac mechanical function, the content of RhoA, phosphorylated myosin light chain subunit 1 (phospho-MYL9), troponin I, MMP-2, and MMP-2 mRNA in the heart homogenates, as well as MMP-2 activity in heart tissue. We showed that treatment with simvastatin caused improvement in the contractile function of the heart subjected to I/Ri which was accompanied by a decrease of MMP-2 activity in heart tissue along with inhibition of RhoA pathway, expressed in a reduction in both RhoA and its downstream product-phosphorylated myosin light chain (phospho-MYL9) in hearts treated with simvastatin. MMP-2 inactivation is not due to inhibition of MMP-2 m-RNA synthesis caused by inhibition of RhoA/ROCK pathway and is due, at least in part, to the direct drug action. The protective effect of simvastatin on systolic function in the acute ischemia-reperfusion model does not appear to be related to reduced MMP-2 activation, but other mechanisms related with the inhibition RhoA/ROCK pathway.


Assuntos
Metaloproteinase 2 da Matriz , Traumatismo por Reperfusão , Sinvastatina , Quinases Associadas a rho , Animais , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Cadeias Leves de Miosina/metabolismo , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Sinvastatina/farmacologia , Troponina I/metabolismo , Proteínas rho de Ligação ao GTP , Quinases Associadas a rho/metabolismo
19.
Int J Mol Sci ; 23(18)2022 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-36142447

RESUMO

Simvastatin (SIM) is a lipid-lowering drug that also promotes bone formation, but its high liver specificity may cause muscle damage, and the low solubility of lipophilic drugs limits the systemic administration of SIM, especially in osteoporosis (OP) studies. In this study, we utilized the bone-targeting moiety of dendritic oligopeptides consisting of three aspartic acid moieties (dAsp3) and amphiphilic polymers (poly(ethylene glycol)-block-poly(lactic-co-glycolic acid); PEG-PLGA) to create dAsp3-PEG-PLGA (APP) nanoparticles (NPs), which can carry SIM to treat OP. An in vivo imaging system showed that gold nanocluster (GNC)-PLGA/APP NPs had a significantly higher accumulation rate in representative bone tissues. In vivo experiments comparing low-dose SIM treatment (0.25 mg/kg per time, 2 times per week) showed that bone-targeting SIM/APP NPs could increase the bone formation effect compared with non-bone-targeting SIM/PP NPs in a local bone loss of hindlimb suspension (disuse) model, but did not demonstrate good bone formation in a postmenopausal (ovariectomized) model of systemic bone loss. The APP NPs could effectively target high mineral levels in bone tissue and were expected to reduce side effects in other organs affected by SIM. However, in vivo OP model testing showed that the same lower dose could not be used to treat different types of OP.


Assuntos
Nanopartículas , Osteoporose , Animais , Ácido Aspártico , Biopolímeros , Osso e Ossos , Ouro/uso terapêutico , Lipídeos/uso terapêutico , Minerais/uso terapêutico , Osteoporose/tratamento farmacológico , Poliésteres , Polietilenoglicóis/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
20.
An Acad Bras Cienc ; 94(4): e20201909, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36102390

RESUMO

Hederagenin, a natural compound distributed in many medicinal plants, has a variety of pharmacological properties including anti-bacteria, anti-inflammation, anti-oxidation, and anti- apoptosis.. The aim of this study was to evaluate the effects of hederagenin on decreasing blood lipid and anti-oxidative stress in oleic acid-induced HepG2 cells and hyperlipidemic rats, and explore underlying mechanisms. In vitro, TG was used as the index to verify the lipid-lowering effect of hederagenin in oleic acid-induced HepG2 cells. In vivo, TC, TG, LDL-C, and HDL-C were used as direct indicators to study the antilipemic effect of hederagenin in hyperlipidemic rats. MDA, SOD, and GSH-PX were measured to analyze the anti-oxidative effect of hederagenin. The signaling pathways of anti-oxidation were evaluated using Western blot. Our results showed that hederagenin (250µmol/L) increased significantly TG clearance rate. In addition, treatment with hederagenin, XZK and simvastatin reduced effectively TC, TG, LDL-C and MDA content, and increased HDL-C, SOD and GSH-PX in HFD rats. Moreover, the phosphorylation level of p38 MAPK was inhibited after administration of hederagenin, XZK and simvastatin. Our results revealed that hederagenin possessed beneficial potentials for hypolipidemic effects, especially in TG clearance. The mechanism might be associated with inhibition of lipid absorption, reduction of lipid oxidation, and down-regulation of p38MAPK phosphorylation.


Assuntos
Hipolipemiantes , Ácido Oleico , Animais , LDL-Colesterol , Células Hep G2 , Humanos , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Ácido Oleanólico/análogos & derivados , Ratos , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Superóxido Dismutase , Proteínas Quinases p38 Ativadas por Mitógeno
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