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1.
Phytomedicine ; 130: 155704, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-38759316

RESUMEN

BACKGROUND: Dysregulation of vascular smooth muscle cell (VSMC) function leads to a variety of diseases such as atherosclerosis and hyperplasia after injury. However, antiproliferative drug targeting VSMC exhibits poor specificity. Therefore, there is an urgent to develop highly specific antiproliferative drugs to prevention and treatment VSMC dedifferentiation associated arteriosclerosis. Kanglexin (KLX), a new anthraquinone compound designed by our team, has potential to regulate VSMC phenotype according to the physicochemical properties. PURPOSE: This project aims to evaluate the therapeutic role of KLX in VSMC dedifferentiation and atherosclerosis, neointimal formation and illustrates the underlying molecular mechanism. METHODS: In vivo, the ApoE-/- mice were fed with high-fat diet (HFD) for a duration of 13 weeks to establish the atherosclerotic model. And rat carotid artery injury model was performed to establish the neointimal formation model. In vitro, PDGF-BB was used to induce VSMC dedifferentiation. RESULTS: We found that KLX ameliorated the atherosclerotic progression including atherosclerotic lesion formation, lipid deposition and collagen deposition in aorta and aortic sinus in atherosclerotic mouse model. In addition, The administration of KLX effectively ameliorated neointimal formation in the carotid artery following balloon injury in SD rats. The findings derived from molecular docking and surface plasmon resonance (SPR) experiments unequivocally demonstrate that KLX had potential to bind PDGFR-ß. Mechanism research work proved that KLX prevented VSMC proliferation, migration and dedifferentiation via activating the PDGFR-ß-MEK -ERK-ELK-1/KLF4 signaling pathway. CONCLUSION: Collectively, we demonstrated that KLX effectively attenuated the progression of atherosclerosis in ApoE-/- mice and carotid arterial neointimal formation in SD rats by inhibiting VSMC phenotypic conversion via PDGFR-ß-MEK-ERK-ELK-1/KLF4 signaling. KLX exhibits promising potential as a viable therapeutic agent for the treatment of VSMC phenotype conversion associated arteriosclerosis.


Asunto(s)
Antraquinonas , Desdiferenciación Celular , Factor 4 Similar a Kruppel , Músculo Liso Vascular , Neointima , Animales , Masculino , Ratones , Ratas , Antraquinonas/farmacología , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/prevención & control , Aterosclerosis/tratamiento farmacológico , Becaplermina/farmacología , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Desdiferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Neointima/tratamiento farmacológico , Ratas Sprague-Dawley , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/efectos de los fármacos
2.
Clin Exp Pharmacol Physiol ; 51(6): e13867, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38684457

RESUMEN

Cardiovascular diseases, particularly those involving arterial stenosis and smooth muscle cell proliferation, pose significant health risks. This study aimed to investigate the therapeutic potential of curcumol in inhibiting platelet-derived growth factor-BB (PDGF-BB)-induced human aortic smooth muscle cell (HASMC) proliferation, migration and autophagy. Using cell viability assays, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays and Western Blot analyses, we observed that curcumol effectively attenuated PDGF-BB-induced HASMC proliferation and migration in a concentration-dependent manner. Furthermore, curcumol mitigated PDGF-BB-induced autophagy, as evidenced by the downregulation of LC3-II/LC3-I ratio and upregulation of P62. In vivo experiments using an arteriosclerosis obliterans model demonstrated that curcumol treatment significantly ameliorated arterial morphology and reduced stenosis. Additionally, curcumol inhibited the activity of the KLF5/COX2 axis, a key pathway in vascular diseases. These findings suggest that curcumol has the potential to serve as a multi-target therapeutic agent for vascular diseases.


Asunto(s)
Arteriosclerosis , Proliferación Celular , Músculo Liso Vascular , Miocitos del Músculo Liso , Sesquiterpenos , Animales , Sesquiterpenos/farmacología , Sesquiterpenos/uso terapéutico , Humanos , Ratas , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/patología , Arteriosclerosis/metabolismo , Proliferación Celular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/citología , Masculino , Movimiento Celular/efectos de los fármacos , Extremidad Inferior/irrigación sanguínea , Autofagia/efectos de los fármacos , Ratas Sprague-Dawley , Becaplermina/farmacología
3.
Clin Investig Arterioscler ; 34(6): 303-310, 2022.
Artículo en Inglés, Español | MEDLINE | ID: mdl-35654677

RESUMEN

INTRODUCTION: Clinical studies show that patients with high cardiovascular risk are still far from reaching the therapeutic objectives, especially of the levels of LDL cholesterol. If the management of these patients in specialized units differs from other scenarios is known. PATIENTS AND METHODS: 61 certified Lipid Units were selected in the Registry of Dyslipemias of the Spanish Arteriosclerosis Society for the collection of study data. The study included 3958 subjects >18 years of age who met the criteria for hypercholesterolemia (LDL cholesterol ≥160 mg/dL or non-HDL cholesterol ≥190 mg/dL) without familial hypercholesterolemia. A total 1,665 subjects were studied with a mean follow-up time of 4.2 years. RESULTS AND CONCLUSIONS: A total of 42 subjects had a cardiovascular event since their inclusion in the Registry, which represents 0.6%. There were no differences in the treatment used at follow-up, but 50% of the patients did not reach the therapeutic goals at the visit end of follow-up. An increase in the potency of the lipid-lowering treatment was observed, including PCSK9 inhibitors use in 16.7% of subjects with recurrences.


Asunto(s)
Anticolesterolemiantes , Arteriosclerosis , Dislipidemias , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , LDL-Colesterol , Proproteína Convertasa 9 , Prevención Secundaria , Dislipidemias/complicaciones , Dislipidemias/tratamiento farmacológico , Sistema de Registros , Arteriosclerosis/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Anticolesterolemiantes/uso terapéutico
4.
Shanghai Kou Qiang Yi Xue ; 31(6): 597-601, 2022 Dec.
Artículo en Chino | MEDLINE | ID: mdl-36970794

RESUMEN

PURPOSE: To investigate the effect of grape seed extract on pathological changes of aorta in rats with chronic periodontitis and arteriosclerosis, and to analyze the possible mechanism. METHODS: Fifteen SPF male rats with chronic periodontitis and arteriosclerosis were randomly divided into three groups, i.e., model group(n=5), low dose of grape seed extract group (n=5), high dose of grape seed extract group (n=5) , and control group (n=10). The rats in the low and high dose groups were treated with 40 mg·kg-1·d-1 and 80 mg·kg-1·d-1 for 4 weeks respectively, while the rats in the normal control group and the model group were treated with the same amount of normal saline at the same time. The maximal intima-media thickness(IMT) of abdominal aorta was measured by H-E staining, the activity of SOD and the content of MDA in serum were measured by colorimetry, the content of GSH-px in serum and serum levels of inflammatory factor (TNF-α) and interleukin-6(IL-6) were detected by ELISA. p38 mitogen-activated protein kinase/nuclear transcription factor Kappa B p65(p38 MAPK/NF-κB p65) pathway was detected by Western blotting. SPSS 20.0 software package was used for statistical analysis. RESULTS: In the model group, the intima of abdominal aorta was irregularly thickened, with a lot of inflammatory cell infiltration, and arterial lesions appeared. In the low-and high-dose groups of grape seed extract, the plaque of abdominal aorta intima decreased and inflammatory cells reduced significantly, arterial vascular disease was improved, and the improvement was more obvious in high dose group than in low dose group. Compared with the control group, the levels of IMT, serum MDA, TNF-α, IL-6, p-p38MAPK/p38MAPK, NF-κB p65 and serum SOD and GSH-px in the model group were increased, while those in the model group were decreased(P<0.05); the levels of IMT, serum MDA, TNF-α, IL-6, p-p38MAPK/p38MAPK, NF-κB p65 and SOD, GSH-px were decreased in the low and high dose groups(P<0.05). CONCLUSIONS: Grape seed extract can inhibit the oxidative stress level and inflammatory reaction in serum of chronic periodontitis with arteriosclerosis rats, thus improving the intimal lesion of aorta, possibly by inhibiting the activation of p38MAPK/NF-κB p65 pathway.


Asunto(s)
Arteriosclerosis , Periodontitis Crónica , Extracto de Semillas de Uva , Ratas , Masculino , Animales , FN-kappa B , Extracto de Semillas de Uva/farmacología , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Estrés Oxidativo , Arteriosclerosis/tratamiento farmacológico , Aorta/metabolismo , Superóxido Dismutasa/metabolismo
5.
Cardiovasc Drugs Ther ; 36(2): 301-308, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-33555511

RESUMEN

PURPOSE: Low-density lipoprotein (LDL) cholesterol reduction by statin therapy is dose-dependent, varies among different statins, and has wide inter-individual variability. The present study aimed to compare mean LDL cholesterol reduction and its variability achieved with different doses of the three statins most frequently used in monotherapy or combined with ezetimibe in a real clinical setting. METHODS: Of 5620 cases with primary hypercholesterolemia on the Spanish Arteriosclerosis Society Registry, 1004 with non-familial hypercholesterolemia and complete information on drug therapy and lipid profile were included. RESULTS: The lowest mean percentage LDL cholesterol reduction was observed with simvastatin 10 mg (32.5 ± 18.5%), while the highest mean percentage LDL reduction was obtained with rosuvastatin 40 mg (58.7 ± 18.8%). As to combined treatment, the lowest and highest mean percentage LDL cholesterol reductions were obtained with simvastatin 10 mg combined with ezetimibe (50.6 ± 24.6%) and rosuvastatin 40 mg combined with ezetimibe (71.6 ± 11.1%), respectively. Factors associated with a suboptimal response were male sex, lower age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol reduction (OR 0.603, p < 0.001). CONCLUSION: In a real clinical setting, rosuvastatin was superior to the other statins in lowering LDL cholesterol, both as monotherapy or combined with ezetimibe. Factors associated with a suboptimal response in LDL cholesterol decline were male sex, age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol improvement.


Asunto(s)
Anticolesterolemiantes , Arteriosclerosis , Dislipidemias , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Anticolesterolemiantes/efectos adversos , Arteriosclerosis/tratamiento farmacológico , LDL-Colesterol , Quimioterapia Combinada , Dislipidemias/diagnóstico , Dislipidemias/tratamiento farmacológico , Ezetimiba/efectos adversos , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/tratamiento farmacológico , Masculino , Sistema de Registros , Rosuvastatina Cálcica/efectos adversos , Simvastatina/efectos adversos
6.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-34360682

RESUMEN

Fundamental pancreatic ß-cell function is to produce and secrete insulin in response to blood glucose levels. However, when ß-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic ß-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the ß-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of ß-cells. However, GLP-1R expression in ß-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on ß-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of ß-cells against glucose toxicity in routine medical care.


Asunto(s)
Arteriosclerosis/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hiperglucemia/complicaciones , Incretinas/uso terapéutico , Células Secretoras de Insulina/efectos de los fármacos , Arteriosclerosis/etiología , Arteriosclerosis/prevención & control , Humanos , Incretinas/farmacología , Células Secretoras de Insulina/fisiología
8.
Biomed Pharmacother ; 134: 111103, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33338747

RESUMEN

Nanomedicines offer nanoscale drug delivery system. They offer ways of promising drug transportation, and address the issues of lack of targeting and permeability of traditional drugs. The physical and chemical properties in the domain of nanomedicine applications in vivo have not been sufficiently delivered. What's more, the metabolic of nanomedicines is not clear enough. Those factors which mentioned above determine that many nanomedicines have not yet realized clinical application due to their safety problems and in vivo efficacy. For example, they may cause immune response and cytotoxicity, as well as the ability to clear organs in vivo, the penetration ability of them and the lack of targeting ability may also cause poor efficacy of drugs in vivo. In this review, the new progresses of different kinds of nanomedicines (including gold nanoparticles, nanorobots, black phosphorus nanoparticles, brain diseases, gene editing and immunotherapy etc.) in anti-tumor, antibacterial, ocular diseases and arteriosclerosis in recent years were summarized. Their shortcomings were pointed out, and the new methods to improve the biosafety and efficacy were summarized.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Nanomedicina/métodos , Neoplasias/tratamiento farmacológico , Animales , Arteriosclerosis/tratamiento farmacológico , Encefalopatías/tratamiento farmacológico , Oftalmopatías/tratamiento farmacológico , Oro/química , Humanos , Inmunoterapia/métodos , Medicina Tradicional/métodos , Nanopartículas del Metal/química , Nanopartículas/química , Nanotecnología/métodos , Fósforo/química
9.
J Atheroscler Thromb ; 28(2): 169-180, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32493881

RESUMEN

AIMS: The efficacy of antiplatelet therapy may vary among different disease subtypes. Prasugrel is generally a more potent, consistent, and fast-acting platelet inhibitor than clopidogrel. This sub-analysis of the phase III comparison of PRAsugrel and clopidogrel in Japanese patients with ischemic STROke (PRASTRO-I) trial aimed to assess the differences in efficacy of these treatments for each stroke subtype. METHODS: In the PRASTRO-I trial, a total of 3,753 patients with ischemic stroke were recruited from 224 centers throughout Japan and randomized (1:1) to prasugrel (3.75 mg/day) or clopidogrel (75 mg/day) for 96 weeks. For the sub-analysis, strokes were classified as large-artery atherosclerosis, small-artery occlusion (lacunar), stroke of other etiology, and stroke of undetermined etiology. The cumulative incidence of primary events (ischemic stroke, myocardial infarction, and death from other vascular cause) and hazard ratios (HRs) were calculated for each subgroup. RESULTS: For patients with large-artery atherosclerosis, the primary event incidence was 3.8% in the prasugrel group and 4.8% in the clopidogrel group (HR 0.79; 95% confidence interval [CI] 0.45-1.41). For patients with small-artery occlusion, the incidence was 3.3% in the prasugrel group and 3.9% in the clopidogrel group (HR 0.82; 95% CI 0.45-1.50). For patients with stroke of undetermined etiology, the incidence was 4.6% in the prasugrel group and 3.0% in the clopidogrel group (HR 1.56; 95% CI 0.90-2.72). The incidence of bleeding was similar across subtypes. CONCLUSIONS: Although statistical significance was not reached, the efficacy of prasugrel was potentially different between stroke subtypes, warranting further studies.


Asunto(s)
Arterias/patología , Arteriosclerosis , Aterosclerosis , Clopidogrel , Accidente Cerebrovascular Isquémico , Clorhidrato de Prasugrel , Arteriosclerosis/sangre , Arteriosclerosis/diagnóstico , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/etiología , Aterosclerosis/complicaciones , Aterosclerosis/diagnóstico , Clopidogrel/administración & dosificación , Clopidogrel/efectos adversos , Monitoreo de Drogas/métodos , Monitoreo de Drogas/estadística & datos numéricos , Femenino , Hemorragia/inducido químicamente , Hemorragia/diagnóstico , Humanos , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/etiología , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Evaluación de Procesos y Resultados en Atención de Salud , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Clorhidrato de Prasugrel/administración & dosificación , Clorhidrato de Prasugrel/efectos adversos , Resultado del Tratamiento
10.
Revista Brasileira de Hipertensão ; 27(1): 7-12, 20200310.
Artículo en Portugués | LILACS | ID: biblio-1373180

RESUMEN

A caracterização de rigidez arterial é realizada a partir da análise de alterações nas propriedades físicas da parede arterial, entre elas, distensibilidade, complacência e elasticidade. O aumento da rigidez arterial leva a arteriosclerose que está associada ao envelhecimento e a presença dos fatores de risco cardiovasculares tradicionais determinando alterações no padrão de fluxo nas artérias elevando o risco de progressão da aterosclerose. A aterosclerose promove uma solução de continuidade no endotélio que ao final leva a degeneração elástica na parede arterial e o enrijecimento da parede vascular. Essa é a condição determinante para a perda do mecanismo de adaptação ao volume ejetado na sístole ventricular e à onda de retorno na fase de diástole, fato observado principalmente nas grandes artérias elásticas como a aorta e as carótidas. Os principais fatores envolvidos neste processo são a hiperatividade simpática, o estado inflamatório crônico do vaso e a redução da biodisponibilidade do oxido nítrico. Vários métodos estão disponíveis para avaliar a pressão central e parâmetros de rigidez arterial. O método direto seria o de maior precisão, no entanto, é um método invasivo, e claramente inadequado para uso na avaliação clínica de rotina. Atualmente dispomos de métodos indiretos com adequada aplicação na determinação de índices de enrijecimento das grandes artérias. Um desses métodos permite a avaliação da pressão arterial central (PAc), velocidade da onda de pulso (VOP), e medidas do índice de aumentação (AIx) que são marcadores bem estabelecidos da hemodinâmica central e da rigidez arterial, e nos oferece uma visão importante da vitalidade arterial. Entre esses índices, a VOP se apresenta como um marcador de dano vascular, com elevada importância na determinação do risco cardiovascular global dos pacientes, assim como o AIx, outro parâmetro de envelhecimento vascular, ambos preditores de mortalidade por todas as causas e por causas cardiovasculares. As diferentes classes de anti-hipertensivos têm efeitos diversos sobre a hemodinâmica central e a correta interpretação dos achados obtidos nos exames de avaliação dos parâmetros centrais pode nortear mais adequadamente a estratégia do tratamento da hipertensão arterial.


The characterization of arterial stiffness is performed by analyzing changes in the physical properties of the arterial wall, including distensibility, complacency and elasticity. The increase in arterial stiffness leads to arteriosclerosis that is associated with aging and the presence of traditional cardiovascular risk factors and causes changes in the flow pattern in the arteries, increasing the risk of atherosclerosis progression. Atherosclerosis causes an endothelium injury that ultimately leads to elastic degeneration in the arterial wall and the stiffening of the vascular wall, a determining condition for the loss of the ability to adapt to the volume ejected in the ventricular systole and the return wave in the diastole phase, a fact observed mainly in large elastic arteries such as the aorta and carotids. The main factors involved in this process are sympathetic hyperactivity, the chronic inflammatory state of the vessel and the reduction of nitric oxide bioavailability. Several methods are available to assess central pressure and arterial stiffness parameters. The direct method is the most accurate. However, it is an invasive method, and clearly unsuitable for use in routine clinical evaluation. Currently we have indirect methods which are perfectly applicable for the determination of stiffening indexes of the great arteries. One of these methods allows the assessment of central arterial pressure (PAc), pulse wave velocity (PWV), and measures of the augmentation index (AIx), which are well-established markers of central hemodynamics and arterial stiffness, and provides an important assessment of arterial vitality. Among these indices, PWV consists of a marker of vascular damage, highly important in determining the overall cardiovascular risk of patients, as well as AIx, another parameter for assessing vascular aging, both of them functioning as predictors of risk of mortality from all causes and from cardiovascular causes. The different classes of antihypertensive drugs have different effects on central hemodynamics and the correct interpretation of the findings obtained in the assessment tests of the Central Parameters can more adequately guide the strategy for the treatment of arterial hypertension


Asunto(s)
Humanos , Arteriosclerosis/tratamiento farmacológico , Envejecimiento , Factores de Riesgo , Rigidez Vascular , Antihipertensivos/uso terapéutico
11.
J Toxicol Sci ; 45(1): 25-35, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31932555

RESUMEN

In this study, we found that nuclear receptors FXR and LXR (originally characterized as regulatory factors involved in cholesterol/bile acid homeostasis) regulate the expression of Oct3/4, a marker for cell differentiation, in both normal renal-derived cell line HK-2 and renal adenocarcinoma cell line ACHN. Down-regulation of Oct3/4 expression by activating FXR and LXR occurs only in normal renal cell-derived HK-2 cells. We also found that the RNA-binding protein, ELAVL2, oppositely regulates Oct3/4 expressions in HK-2 and ACHN cells. Moreover, we revealed that LXR-alpha and LXR-beta regulate each other's expression. Although an LXR-beta-specific agonist is assumed to be the basis for an anti-arteriosclerotic drug that only stimulates reverse cholesterol transport, our findings show that the development of such an anti-arteriosclerotic drug would require further elucidation of the complex mechanism of LXR-alpha and LXR-beta regulation.


Asunto(s)
Adenocarcinoma , Regulación de la Expresión Génica , Neoplasias Renales , Riñón/citología , Receptores X del Hígado/genética , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Arteriosclerosis/tratamiento farmacológico , Línea Celular , Colesterol/metabolismo , Regulación hacia Abajo , Descubrimiento de Drogas , Proteína 2 Similar a ELAV/genética , Humanos
12.
Future Med Chem ; 12(2): 95-110, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31769316

RESUMEN

Aim: To evaluate new chemical entities, based on ferulic acid scaffolds, as reversible myeloperoxidase inhibitors (MPOI). Methodology & results:In silico docking studies are performed with MPO protein as a target for several ferulic acid analogs followed by multiple in vitro assays to validate this approach. Two lead compounds 2a and 3 are identified with optimum docking and IC50 values: -7.95 kcal/mol, 0.9 µM and -8.35 kcal/mol, 8.5 µM, respectively. These MPOIs are able to inhibit oxidation of high-density lipoprotein and further promoted functionality of high-density lipoprotein. Conclusion: Lead analogs are potent MPOIs that exert specific effects on MPO-mediated oxidation as well as inflammatory pathways. It also acts as promoters of cholesterol efflux that sheds light on pharmacological approach in atherosclerosis treatment.


Asunto(s)
Arteriosclerosis/tratamiento farmacológico , Ácidos Cumáricos/farmacología , Inhibidores Enzimáticos/farmacología , Peroxidasa/antagonistas & inhibidores , Fenoles/farmacología , Arteriosclerosis/metabolismo , Ácidos Cumáricos/síntesis química , Ácidos Cumáricos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxidación-Reducción , Peroxidasa/metabolismo , Fenoles/síntesis química , Fenoles/química
13.
Life Sci ; 241: 117141, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31811853

RESUMEN

AIMS: Glibenclamide, a diabetes mellitus type 2 medication, has anti-inflammatory and autoimmune properties. This study investigated the effects of glibenclamide on transplant-induced arteriosclerosis as well as the underlying molecular events. METHODS: Male C57Bl/6 (H-2b) and BALB/c (H-2d) mice were used for aorta transplantation. We used hematoxylin and eosin (HE) and Elastic Van Gieson (EVG) staining for histological assessment, and qRT-PCR and ELISA to measure mRNA and protein levels. Mouse peritoneal macrophages were isolated for lipopolysaccharide (LPS) stimulation and glibenclamide treatment followed by ELISA, Western blot, and Transwell assays. RESULTS: Glibenclamide inhibited transplant-induced arteriosclerosis in vivo. Morphologically, glibenclamide reduced inflammatory cell accumulation and collagen deposition in the aortas. At the gene level, glibenclamide suppressed aortic cytokine mRNA levels, including interleukin-1ß (IL-1ß; 10.64 ± 3.19 vs. 23.77 ± 5.72; P < .05), tumor necrosis factor-α (TNF-α; 4.59 ± 0.78 vs. 13.89 ± 5.42; P < .05), and monocyte chemoattractant protein-1 (MCP-1; 202.66 ± 23.44 vs. 1172.73 ± 208.80; P < .01), while IL-1ß, TNF-α, and MCP-1 levels were also reduced in the mouse sera two weeks after glibenclamide treatment (IL-1ß, 39.40 ± 13.56 ng/ml vs. 78.96 ± 9.39 ng/ml; P < .01; TNF-α, 52.60 ± 13.00 ng/ml vs. 159.73 ± 6.76 ng/ml; P < .01; and MCP-1, 56.60 ± 9.07 ng/ml vs. 223.07 ± 36.28 ng/ml; P < .001). Furthermore, glibenclamide inhibited macrophage expression and secretion of inflammatory factors in vitro through suppressing activation of the nuclear factor-κB (NF-κB) pathway and MCP-1 production. CONCLUSION: Glibenclamide protected against aorta transplantation-induced arteriosclerosis by reducing inflammatory factors in vivo and inhibited macrophage migration and MCP-1 production in vitro.


Asunto(s)
Arteriosclerosis/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/antagonistas & inhibidores , Regulación de la Expresión Génica/efectos de los fármacos , Gliburida/farmacología , Macrófagos Peritoneales/efectos de los fármacos , Trasplante de Órganos/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Arteriosclerosis/etiología , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Femenino , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
14.
Nanoscale ; 11(42): 20324-20332, 2019 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-31641707

RESUMEN

Janus heterostructural materials as photothermal agents with enhanced optical conversion capability are promising for artery inflammation treatment by the hyperthermia of macrophages, a primordial part in the artery inflammation response that can deteriorate into atherosclerosis and even break the vessels. Herein, a synthesis route of Janus Ag/Ag2S beads with hydrophilic ligands has been developed with a precise control over concentration, time and surface functionalization. These Ag/Ag2S heterodimers show desirable sizes of around 90 nm in diameter, in which Ag nanocrystals have a diameter of around 25 nm, and they exhibit a photothermal conversion efficiency of up to 50.0% as well as relatively low biotoxicity and good biocompatibility. Importantly, the as-prepared Janus Ag/Ag2S beads with a high biological safety can be effectively swallowed by macrophages and have a remarkable benefit of eliminating these cells from the original state of artery inflammation through the excellent photothermal effect of this material, without causing any further damage to the arteries and major organs in vivo. This study further promotes the development of treatment for vascular inflammation by the photothermal melting of macrophage cells in intima environments.


Asunto(s)
Arteriosclerosis , Macrófagos , Nanopartículas , Compuestos de Plata , Plata , Animales , Arteriosclerosis/diagnóstico por imagen , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/metabolismo , Inflamación/diagnóstico por imagen , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Noqueados para ApoE , Nanopartículas/química , Nanopartículas/uso terapéutico , Células RAW 264.7 , Plata/química , Plata/farmacología , Compuestos de Plata/química , Compuestos de Plata/farmacología
15.
Lipids Health Dis ; 18(1): 129, 2019 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-31153375

RESUMEN

BACKGROUND: Apolipoprotein E (ApoE) plays an important role in lipid metabolism and clearance. Statins are the most common drugs used to modulate the lipid profile in the clinic therapy; the associations between ApoE polymorphisms and statin response to lipids were inconsistent in previous studies among different ethnicities. Our study aimed to demonstrate the relationships among the statins response and the ApoE gene common polymorphisms and lifestyle risk factors in Chinese arteriosclerotic cardiovascular disease (ASCVD) patients with dyslipidemia. METHODS: A total of 1002 dyslipidemia ASCVD patients were recruited in this study, including 311 patients with a history of type 2 diabetes mellitus (T2DM). These patients were all treated with drugs atorvastatin (10 mg/d) or rosuvastatin (5 mg/d) for at least 4 weeks and genotyped for ApoE e2/e3/e4 alleles, using Kompetitive Allele Specific PCR (KASP) and Sanger sequencing. The plasma lipids levels were determined before and after statins treatment. RESULTS: The results of ApoE genotyping with KASP method were consistent with the sequencing analysis. In the total 1002 patients, the E2 phenotypes (e2/e3, e2/e2) had significant lower low-density lipoprotein cholesterol (LDL-C) baseline levels than subjects with E3 (e3/e3, e2/e4) and E4 (e3/e4, e4/e4) phenotypes (P = 0.007, 0.005, respectively), and E2 phenotypes had the highest triglyceride (TG) baseline levels. To statins treatment, E2 phenotypes had a better response in TG, Total cholesterol (TC) and LDL-C reduction percentage compared with other phenotypes, and smoking/alcohol drinking status also had a significant influence on statins response of LDL-C lowering. No significant difference was found in the effects of lipids decreasing between atorvastatin and rosuvastatin drugs in all patients. CONCLUSIONS: We developed the KASP technique for the ApoE genotyping, and demonstrated ApoE polymorphisms interacted with smoking/drinking to influence the declining extent of TG, TC and LDL-C levels after statins therapy in Chinese dyslipidemia ASCVD patients. These discoveries developed our cognition with the genetic polymorphisms effects on statin response, which should be taken more seriously in smoking/drinking E4 amino acid isoform carriers.


Asunto(s)
Apolipoproteínas E/genética , Arteriosclerosis/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Adolescente , Adulto , Anciano , Alelos , Aminoácidos/administración & dosificación , Aminoácidos/efectos adversos , Arteriosclerosis/sangre , Arteriosclerosis/epidemiología , Arteriosclerosis/genética , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , China/epidemiología , HDL-Colesterol/sangre , Dislipidemias/sangre , Dislipidemias/epidemiología , Dislipidemias/genética , Femenino , Genotipo , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Rosuvastatina Cálcica/administración & dosificación , Rosuvastatina Cálcica/efectos adversos , Triglicéridos/sangre
16.
Am J Med Genet A ; 179(7): 1246-1252, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31039288

RESUMEN

Schimke immunoosseous dysplasia (SIOD) is a multisystemic condition characterized by early arteriosclerosis and progressive renal insufficiency, among other features. Many SIOD patients have severe, migraine-like headaches, transient neurologic attacks, or cerebral ischemic events. Cerebral events could be exacerbated or precipitated by hypertension, and it is unclear how these are related to arteriosclerotic changes as dyslipidemia is also a feature of SIOD. The correlation between hypercholesterolemia and cardiovascular risk in SIOD is unclear. Also, the etiology and management of headaches is not well characterized. Here we report our clinical observations in the management of SIOD in a patient who was diagnosed in school age despite early signs and symptoms. We describe biallelic variants, including a previously unreported c.1931G>A (p.Arg644Gln) variant in SMARCAL1. We specifically investigated whether migraine-like headaches and progressive nephropathy may be related to blood pressure dysregulation. We found a correlation between tighter blood pressure regulation using ambulatory blood pressure monitoring and a subjective decrease in headache symptoms. We discuss blood pressure medication management in SIOD. We also characterize dyslipidemia relative to atherosclerosis risks and provide new management strategies to consider for optimizing care.


Asunto(s)
Arteriosclerosis/tratamiento farmacológico , ADN Helicasas/genética , Dislipidemias/tratamiento farmacológico , Cefalea/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Mutación , Síndrome Nefrótico/tratamiento farmacológico , Osteocondrodisplasias/tratamiento farmacológico , Enfermedades de Inmunodeficiencia Primaria/tratamiento farmacológico , Embolia Pulmonar/tratamiento farmacológico , Anticolesterolemiantes/uso terapéutico , Antihipertensivos/uso terapéutico , Arteriosclerosis/complicaciones , Arteriosclerosis/diagnóstico , Arteriosclerosis/genética , Atorvastatina/uso terapéutico , Benzazepinas/uso terapéutico , Presión Sanguínea , Monitoreo Ambulatorio de la Presión Arterial , Niño , Manejo de la Enfermedad , Dislipidemias/complicaciones , Dislipidemias/diagnóstico , Dislipidemias/genética , Femenino , Expresión Génica , Cefalea/complicaciones , Cefalea/diagnóstico , Cefalea/genética , Humanos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Hipertensión/genética , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/genética , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Propranolol/uso terapéutico , Embolia Pulmonar/complicaciones , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/genética
17.
J Clin Lipidol ; 13(1): 163-169, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30594444

RESUMEN

BACKGROUND: Rural patients with atherosclerotic cardiovascular disease (ASCVD) experience greater cardiovascular morbidity and mortality than their urban counterparts. Statin therapy is a key component of ASCVD treatment. The extent to which there may be regional differences in long-term adherence to statins is unknown. OBJECTIVE: To assess long-term rates of adherence to statins in a high-risk ASCVD cohort, and whether regional differences exist between rural and urban patients. METHODS: Follow-up was conducted in patients who underwent coronary angiography at a single tertiary center between 2009 and 2013. Adherence was defined as consumption of prescribed statin ≥6 days per week. Patients were divided into remoteness areas (RAs), classified as RA1 (major city), RA2 (inner regional), and RA3 (outer regional) based on the Australian Standard Geographical Classification. RESULTS: Five hundred twenty-five patients (69% male, mean age 64 ± 11 years) were followed-up after a median of 5.3 years. Baseline characteristics were similar between RAs. Overall adherence was 83%; however, rural patients were significantly more adherent to their statin therapy (80% in RA1, 83% in RA2, and 93% in RA3, P = .04). Living in RA3 independently predicted greater statin adherence than living in RA1 (odds ratio: 2.75, 95% CI: 1.1-7.8, P = .03). All-cause mortality was significantly higher in RA3 than other regional areas (6% RA1, 12% RA2, and 18% RA3, P = .01). CONCLUSIONS: Despite higher all-cause mortality, rural patients with ASCVD demonstrate significantly greater long-term adherence to statins than urban patients. Other factors, such as reduced access to health care and delayed diagnosis may explain the gap in outcomes between rural and urban patients.


Asunto(s)
Arteriosclerosis/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Población Rural , Arteriosclerosis/epidemiología , Arteriosclerosis/mortalidad , Australia/epidemiología , Angiografía Coronaria , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Riesgo , Análisis de Supervivencia , Centros de Atención Terciaria
18.
J Clin Lipidol ; 13(1): 156-162.e1, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30446321

RESUMEN

BACKGROUND: Statins comprise a key strategy for the prevention and treatment of arteriosclerotic cardiovascular disease, but prescribing remains suboptimal. OBJECTIVES: The objective of this study was to characterize the predictors of statin use among adults aged ≥65 years. METHODS: A cross-sectional study using Pharmaceutical Benefits Scheme (PBS) data on reimbursed prescriptions for a 10% random sample of the Australian population in 2016 was performed. Predictors of statin use were identified via multivariable logistic regression. Analyses were performed separately for people who were concessional beneficiaries (with a low, capped copayment) and other ("general") people. RESULTS: Among 351,471 (concessional = 295,875 and general = 55,596) older adults, 44.2% were dispensed statins (concessional = 46.4% and general = 32.2%). Among the concessional beneficiaries, people aged 75 to 84 years were more likely to use statins (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.06-1.10), whereas those aged ≥85 years were less likely to use statins (OR 0.71, 95% CI 0.69-0.72), compared with people aged 65 to 74 years. Men were more likely to use statins than women (OR 1.14, 95% CI 1.12-1.16). Diabetes was associated with over 2-fold (OR 2.48, 95% CI 2.43-2.53) increased likelihood of statin use. People with cardiovascular-related conditions including hypertension, angina, and congestive heart failure experienced increased likelihood of statin use as was being dispensed anticoagulant or antiplatelet medication. Having malignancy, psychotic illness, or pain were associated with lower likelihood of statin use. Similar predictors of statin use were noted for the general population. CONCLUSION: More than 40% of older adults in Australia used statins in 2016 with uptake dependent on individual-level factors such as demographics and comorbidities. Future research should examine the extent to which provider and/or health system-level factors contribute to the variable uptake of statin therapy.


Asunto(s)
Arteriosclerosis/tratamiento farmacológico , Prescripciones de Medicamentos/estadística & datos numéricos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Arteriosclerosis/economía , Arteriosclerosis/epidemiología , Australia/epidemiología , Comorbilidad , Costos y Análisis de Costo , Estudios Transversales , Femenino , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Pronóstico , Factores Sexuales
19.
Circ J ; 82(12): 3058-3063, 2018 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-30282881

RESUMEN

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder and shows globotriosylceramide (Gb3) accumulation in multiple organs, resulting from a deficiency of α-galactosidase. In patients with Fabry disease, cardiovascular disease occurs at an early age. Previous studies have shown that serum levels of high-density lipoprotein-cholesterol (HDL-C) increase in this disease, yet its clinical significance for cardiovascular disease remains unclear. Methods and Results: In order to determine why the serum HDL-cholesterol is high in various cardiovascular diseases of Fabry disease patients, we evaluated the serum lipid profiles, ocular vascular lesions, and levels of serum vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 in 69 patients with Fabry disease diagnosed by genetic examination. The serum HDL-C/total cholesterol (T-Chol) ratio was significantly high, especially in male patients (41.5±1.7%) regardless of body mass index. Ocular vascular lesions were more likely to occur in female patients with a high HDL-C/T-Chol ratio compared with most male patients. Female patients with a high HDL-C/T-Chol ratio also presented a high serum VEGF level, suggesting that vascular endothelium dysfunction and arteriosclerotic changes progress more severely than in patients with a normal HDL-C/T-Chol ratio. In most patients, enzyme replacement therapy improved serum Gb3 and lyso-Gb3 levels, but these Gb3 and lyso-Gb3 still remained higher than in healthy controls, which appears to result in continuous vascular arteriosclerotic changes. CONCLUSIONS: We concluded that increased low-density lipoprotein-cholesterol uptake to the vascular wall caused by endothelial dysfunction is likely to contribute to the high HDL-C/T-Chol ratio observed in Fabry disease patients.


Asunto(s)
Arteriosclerosis/sangre , HDL-Colesterol/sangre , Endotelio Vascular/metabolismo , Enfermedad de Fabry/sangre , Adolescente , Adulto , Arteriosclerosis/tratamiento farmacológico , Niño , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Femenino , Glucolípidos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Esfingolípidos/uso terapéutico
20.
Eur J Med Chem ; 159: 178-186, 2018 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-30292895

RESUMEN

We have previously shown the antioxidant and anti-inflammatory properties of several para-substituted arylnitroalkenes. Since oxidative stress and inflammation are key processes that drive the initiation and progression of atherosclerosis, in the present work the antioxidant, anti-inflammatory and anti-atherogenic properties of an extended library of aryl-nitroaliphatic derivatives, including several newly designed nitroalkanes, was explored. The antioxidant capacity of the nitroaliphatic compounds, measured using the oxygen radical absorbance capacity assay (ORAC) showed that the p-methylthiophenyl-derivatives were about three times more effective than Trolox to prevent fluorescein oxidation, independently of the presence or the absence of the double bond next to the nitro group. The peroxyl radical scavenger capacity of the p-dimethylaminophenyl-derivatives was even higher, being the reduced form of these compounds even more active. In fact, while the antioxidant capacity of 1-dimethylamino-4-(2-nitro-1Z-ethenyl)benzene and 1-dimethylamino-4-(2-nitro-1Z-propenyl)benzene was 4.2 ±â€¯0.1 and 5.4 ±â€¯0.1 Trolox Eq/mol, respectively; ORAC values obtained with the ethyl and the propyl derivatives were 10 ±â€¯1 and 13 ±â€¯2 Trolox Eq/mol, respectively. The p-dimethylamino-derivatives, especially the nitroalkanes, were also able to prevent LDL oxidation mediated by peroxyl radicals. Oxygen consumption due to the oxidation of fatty acids was delayed in the presence of the dimethylamino substituted compounds, only the alkanes interrupted the chain of lipid oxidations decreasing the rate of oxygen consumption. Although the formation of foam cells in the presence of oxidized-LDL (oxLDL) remained unaffected, the molecules containing the dimethylamino moiety were able to decrease the expression of IL-1ß in LPS/INF-γ challenged macrophages.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Arteriosclerosis/tratamiento farmacológico , Inflamasomas/efectos de los fármacos , Lipoproteínas LDL/antagonistas & inhibidores , Nitrocompuestos/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Lipoproteínas LDL/metabolismo , Ratones , Estructura Molecular , Nitrocompuestos/química , Relación Estructura-Actividad
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