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1.
Braz. J. Pharm. Sci. (Online) ; 58: e191142, 2022. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1394056

RESUMO

A series of N-(benzoylphenyl)-carboxamide derivatives (2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a and 6b) was prepared with good yields by reacting the corresponding carbonyl chlorides with aminobenzophenones at room temperature. This was followed by evaluating the hypotriglyceridemic and hypocholesterolemic effects of 3b, 5a and 5b. Triton WR-1339 (300 mg/kg) was intraperitoneally administered to overnight-fasted rats to induce hyperlipidemia. Rats were divided into six groups: control, hyperlipidemic, hyperlipidemic plus compounds 3b, 5a and 5b and hyperlipidemic plus bezafibrate. Results showed that after 18 h of treatment at a dose of 15 mg/kg body weight of each of the test compounds, the elevated plasma levels of triglycerides (TG) and total cholesterol (TC) were significantly lowered by compounds 5b and 3b (p < 0.001) and by 5a (p < 0.0001), compared to the hyperlipidemic control group. Compounds 3b and 5a significantly increased levels of high-density lipoprotein cholesterol (HDL-C) by 58 and 71%, respectively. In addition, compounds 3b and 5a caused significant reduction (p < 0.0001) of low-density lipoprotein cholesterol (LDL-C) levels compared to the control group. These results suggest a promising potential for compounds 3b, 5a and 5b as lipid-lowering agents, which may contribute to reducing the risk of atherosclerosis and cardiovascular disease


Assuntos
Animais , Masculino , Ratos , Piridinas/farmacologia , Hiperlipidemias/induzido quimicamente , Lipídeos/sangue , Hipolipemiantes/farmacologia , Polietilenoglicóis , Piridinas/síntese química , Triglicerídeos/sangue , Colesterol/sangue , Ratos Wistar , Modelos Animais de Doenças , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas LDL/efeitos dos fármacos , Hipolipemiantes/síntese química
2.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281247

RESUMO

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before-after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.


Assuntos
Hiperlipoproteinemia Tipo II/tratamento farmacológico , Inibidores de PCSK9 , Ativação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/análise , LDL-Colesterol/sangue , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/genética , Itália , Lipoproteínas LDL/análise , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , NADPH Oxidase 2/análise , NADPH Oxidase 2/sangue , Pró-Proteína Convertase 9/genética
3.
Molecules ; 26(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204618

RESUMO

There is scientific evidence of the positive effect of polyphenols from plant foods on inflammation and oxidative status. The aim of the present study was to investigate whether treatment with a high-polyphenolic nutraceutical reduces the plasmatic concentration of certain oxidative and inflammatory biomarkers in a healthy population. One hundred and eight subjects were selected and stratified by sex in the intervention group (n = 53) and the placebo group (n = 55). Ninety-two subjects completed the study after two 16-week treatment periods separated by a four-week washout period. The results revealed statistically significant differences in subjects treated with the polyphenolic extract compared to the placebo: A decrease in homocysteine, oxidized low-density lipoprotein (OxLDL), TNF-α, sTNFR1, and C-reactive protein (CRP). The most significant decrease was observed for OxLDL (from 78.98 ± 24.48 to 69.52 ± 15.64; p < 0.05) and CRP (from 1.50 ± 0.33 to 1.39 ± 0.37; p < 0.05), both showing significant differences compared to the placebo (p < 0.001). Moreover, catecholamines increased after the administration of the product under investigation, especially in the case of dopamine (from 15.43 ± 2.66 to 19.61 ± 5.73; p < 0.05). Therefore, the consumption of a nutraceutical based on fruit and vegetables with a high polyphenol content seems to improve the parameters related to health benefits (oxidative and inflammatory biomarkers), including remarkable changes in the expression of catecholamines.


Assuntos
Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Adulto , Antioxidantes/farmacologia , Biomarcadores/sangue , Catecolaminas/metabolismo , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Frutas/metabolismo , Humanos , Lipoproteínas LDL/efeitos dos fármacos , Masculino , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Placebos , Verduras/metabolismo
4.
Aging (Albany NY) ; 13(1): 910-932, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33290264

RESUMO

Tanshinone IIA (Tan IIA) possesses potent anti-atherogenic function, however, the underlying pharmacological mechanism remains incompletely understood. Previous studies suggest that oxidized LDL (oxLDL)-induced NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome activation in macrophages plays a vital role in atherogenesis. Whether the anti-atherogenic effect of Tan IIA relies on the inhibition of the NLRP3 inflammasome has not been investigated before. In this study, we found that Tan IIA treatment of high-fat diet fed ApoE-/- mice significantly attenuated NLRP3 inflammasome activation in vivo. Consistently, Tan IIA also potently inhibited oxLDL-induced NLRP3 inflammasome activation in mouse macrophages. Mechanically, Tan IIA inhibited NF-κB activation to downregulate pro-interleukin (IL) -1ß and NLRP3 expression, and decreased oxLDL-induced expression of lectin-like oxidized LDL receptor-1 (LOX-1) and cluster of differentiation 36 (CD36), thereby attenuating oxLDL cellular uptake and subsequent induction of mitochondrial and lysosomal damage - events that promote the NLRP3 inflammasome assembly. Through regulating both the inflammasome 'priming' and 'activation' steps, Tan IIA potently inhibited oxLDL-induced NLRP3 inflammasome activation, thereby ameliorating atherogenesis.


Assuntos
Abietanos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Aorta/efeitos dos fármacos , Aterosclerose/metabolismo , Inflamassomos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/patologia , Antígenos CD36/efeitos dos fármacos , Antígenos CD36/metabolismo , Dieta Hiperlipídica , Inflamassomos/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Knockout para ApoE , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Depuradores Classe E/efeitos dos fármacos , Receptores Depuradores Classe E/metabolismo
5.
Food Funct ; 11(6): 4915-4926, 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32432251

RESUMO

Aberrant activation of inflammation and excess accumulation of lipids play pivotal roles in atherosclerosis (AS) progression. Constituents from Citrus aurantium Linn variant amara Engl (CAVA) were effectively investigated for their various bioactivities, especially anti-inflammation. Bergaptol (BER) is particularly abundant in Citrus products. Accumulating studies have confirmed its predominant anti-cancer and antioxidant functions, whereas few studies focused on its antiatherogenic functions. In the current study, BER was isolated from CAVA for the first time. Macrophages were stimulated with lipopolysaccharides (LPSs) or oxidized low-density lipoproteins (ox-LDL) to mimic inflammatory responses and AS development. BER treatment significantly inhibited LPS-induced production of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and gene expression of inducible nitric oxide synthase (iNOS), IL-6, TNF-α, interleukin-1 beta (IL-1ß) and cyclooxygenase-2 (COX-2). BER also potently blocked LPS-induced mitogen-activated protein kinase (MAPK) phosphorylation and nuclear factor-kappa B (NF-κB) activation, as evidenced by the inhibitory effects on c-Jun N-terminal kinase (JNK), P38, P65, IκBα and IκKα/ß phosphorylation, and NF-κB nuclear translocation. Furthermore, BER treatment markedly mitigated ox-LDL-induced foam cell formation by inhibiting scavenger receptor class A type I (SRA1) and cluster of differentiation 36 (CD36)-dependent cholesterol uptake. In conclusion, BER might be a novel therapeutic agent for AS prevention through inhibiting inflammatory responses and cholesterol uptake.


Assuntos
Anti-Inflamatórios/farmacologia , Citrus , Furocumarinas/farmacologia , Lipoproteínas LDL/efeitos dos fármacos , Extratos Vegetais/farmacologia , Flores , Humanos , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Fitoterapia
6.
PLoS One ; 15(5): e0233230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428019

RESUMO

INTRODUCTION: Atorvastatin-80mg/day and Rosuvastatin-40mg/day are the commonest high-dose statin (3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors) regimes for post-PCI (Percutaneous Coronary Interventions) patients to lower (by ≥50%) blood low-density-lipoprotein cholesterol (LDL-C). Dearth of conclusive evidence from developing world, regarding overall safety, tolerability and comparative effectiveness (outcome/safety/tolerability/endothelial inflammation control) of Rosuvastatin over Atorvastatin in high-dose, given its higher cost, called for an overall and comparative assessment among post-PCI patients in a tertiary cardiac-care hospital of Kolkata, India. METHODS: A record-based non-concurrent cohort study was conducted involving 942 post-PCI patients, aged 18-75 years, on high-dose statin for three months and followed up for ≥one year. Those on Atorvastatin-80mg (n = 321) and Rosuvastatin-40mg (n = 621) were compared regarding outcome (death/non-fatal myocardial infarction: MI/repeated hospitalization/target-vessel revascularisation/control of LDL and high-sensitivity C-reactive protein: hsCRP), safety (transaminitis/myopathy/myalgia/myositis/rhabdomyolysis), tolerability (gastroesophageal reflux disease: GERD/gastritis) and inflammation control adjusting for socio-demographics, tobacco-use, medications and comorbidities using SAS-9.4. RESULTS: Groups varied minimally regarding distribution of age/gender/tobacco-use/medication/comorbidity/baseline (pre-PCI) LDL and hs-CRP level. During one-year post-PCI follow up, none died. One acute MI and two target vessel revascularizations occurred per group. Repeated hospitalization for angina/stroke was 2.18% in Atorvastatin group vs. 2.90% in Rosuvastatin group. At three-months follow up, GERD/Gastritis (2.18% vs 4.83%), uncontrolled hs-CRP (22.74% vs 31.08%) and overall non-tolerability (4.67% vs. 8.21%) were lower for Atorvastatin group. Multiple logistic regression did show that compared to Atorvastatin-80mg, Rosuvastatin-40mg regime had poorer control of hs-CRP (A3OR = 1.45,p = 0.0202), higher (A3OR = 2.07) adverse effects, poorer safety profile (A3OR = 1.23), higher GERD/Gastritis (A3OR = 1.50) and poorer overall tolerability (A3OR = 1.50). CONCLUSION: Post-PCI high dose statins were effective, safe and well-tolerated. High dose Rosuvastatin as compared to high dose Atorvastatin were similar in their clinical efficacy. Patients treated with Atrovastatin had significantly lower number of patients with hs-CRP (high-sensitivity C-reactive protein)/C-reactive protein (CRP) level beyond comparable safe limit and relatively better tolerated as opposed to Rosuvastatin-40mg.Thus given the lower price, Atorvastatin 80mg/day appeared to be more cost-effective. A head-to-head cost-effectiveness as well as efficacy trial may be the need of the hour.


Assuntos
Atorvastatina/uso terapêutico , Lipoproteínas LDL/efeitos dos fármacos , Rosuvastatina Cálcica/uso terapêutico , Adulto , Idoso , Proteína C-Reativa/análise , Proteína C-Reativa/efeitos dos fármacos , LDL-Colesterol/sangue , Estudos de Coortes , Feminino , Refluxo Gastroesofágico , Coração , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Intervenção Coronária Percutânea/métodos , Resultado do Tratamento , Triglicerídeos/sangue
7.
Andrologia ; 52(6): e13584, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32293755

RESUMO

In this study, the effect of low-dose curcumin on sperm parameters, reproductive hormones, lipid profile, biochemical antioxidant parameters and the histopathological structure of the testis in diabetic male rats were evaluated. In the study, 28 male Wistar albino rats weighing 300-370 g and aged 8-10 weeks were used. Four groups of equal numbers have been created. Diabetes mellitus was induced with 45 mg/kg streptozotocin (STZ) in seven rats. Curcumin was administered to the rats in curcumin and the diabetes + curcumin group by gavage for 15 days at a dose of 10 mg/kg. Then, the rats were sacrificed. Blood samples and testis tissues were obtained, while the rats were under anaesthesia. Glucose, lipid profile, reproductive hormones, sperm parameters, biochemical antioxidant parameters and histopathological examination of the testis were performed. Abnormal sperm ratio, malondialdehyde, glucose, cholesterol, low-density lipoprotein, and triglyceride levels and caspase-3 expression were increased in diabetic rats, while the sperm motility and intensity and reduced glutathione, catalase and testosterone levels were decreased. When low-dose curcumin (10 mg/kg) was administered to diabetic rats, we found that curcumin significantly increased sperm motility and density, and decreased abnormal sperm rate according to the diabetic group. Moreover, curcumin significantly suppressed the lipid profile and increased follicle-stimulating hormone (FSH) and testosterone levels compared to the diabetic group. On testicular damage and decreased reproductive hormones caused by diabetes, curcumin may have a protective effect with indirect effect of glycaemic control by curcumin.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Curcumina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Catalase/efeitos dos fármacos , Catalase/metabolismo , Colesterol/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Triglicerídeos/metabolismo
8.
World Neurosurg ; 138: 758-763, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004735

RESUMO

OBJECTIVE: We sought to investigate the effects and mechanism of lead and a high-fat diet on cognitive function and the central nervous system in mice. METHODS: Eighty-four healthy male mice were randomly divided into a control group (n = 21) (fed with common diet and free drinking), a lead exposure group (n = 21) (fed with common diet and 300 mg/L lead acetate solution), a high-fat group (n = 21) (fed with high-fat diet and free drinking), and a lead + high-fat group (n = 21) (fed with high-fat diet and 300 mg/L lead acetate solution). In 10 weeks after lead exposure, the mice of all groups were tested for the cognition, learning and memory abilities, body weight, serum triglyceride (TG), low-density lipoprotein, and high-density lipoprotein, as well as for the contents of lead, interleukin 6 (IL-6), interleukin 17 (IL-17), interferon γ, advanced glycation end products (AGEs), glutathione S-transferase (GSH-ST), and hydrogen peroxide in the brain tissues. RESULTS: Compared with the control group and the lead-exposed group, the body weights of mice in the high-fat group and the lead + high-fat group increased significantly from the sixth week of the experiment, of which the difference was statistically significant (P < 0.05). Compared with the control group and the high-fat group, the lead content in brain tissue of the lead exposure group and the lead + high-fat group increased significantly, of which the difference was statistically significant (P < 0.05). Compared with the control group, the escape latent period, triglyceride, low-density lipoprotein, IL-6, IL-17, interferon γ, and AGEs of the remaining 3 groups increased significantly, but the recognition index, passing platform times, high-density lipoprotein, and GSH-ST significantly decreased (P < 0.05); the second and third escape latent periods, IL-6, IL-17, and AGEs of lead + high-fat group, were obviously higher than the remaining 3 groups, but the passing platform times were obviously lower than the remaining 3 groups, of which the difference was statistically significant. The content of hydrogen peroxide in brain tissues had no difference among groups (P > 0.05). CONCLUSIONS: The lead and high-fat diet resulted in lipid metabolism disorders and impaired the cognitive function and central nervous system by promoting the secretion of inflammatory factors in glial cells, inducing the inflammatory reaction of brain tissue, inhibiting GSH-ST expression, and increasing AGEs content.


Assuntos
Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Dieta Hiperlipídica , Intoxicação por Chumbo/psicologia , Chumbo/toxicidade , Animais , Encéfalo/metabolismo , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Produtos Finais de Glicação Avançada/efeitos dos fármacos , Produtos Finais de Glicação Avançada/metabolismo , Peróxido de Hidrogênio/metabolismo , Interferon gama/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Intoxicação por Chumbo/metabolismo , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Distribuição Aleatória , Triglicerídeos/metabolismo
9.
Arterioscler Thromb Vasc Biol ; 39(10): 1902-1910, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31462089

RESUMO

Vascular calcification (VC) is strongly associated with all-cause mortality and is an independent predictor of cardiovascular events. Resulting from its complex, multifaceted nature, targeted treatments for VC have not yet been developed. Lipoproteins are well characterized in the pathogenesis of atherosclerotic plaques, leading to the development of plaque regressing therapeutics. Although their roles in plaque progression are well documented, their roles in VC, and calcification of a plaque, are not well understood. In this review, early in vitro data and clinical correlations suggest an inhibitory role for HDL (high-density lipoproteins) in VC, a stimulatory role for LDL (low-density lipoprotein) and VLDL (very low-density lipoprotein) and a potentially causal role for Lp(a) (lipoprotein [a]). Additionally, after treatment with a statin or PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, plaque calcification is observed to increase. With the notion that differing morphologies of plaque calcification associate with either a more stable or unstable plaque phenotype, uncovering the mechanisms of lipoprotein-artery wall interactions could produce targeted therapeutic options for VC.


Assuntos
Calcinose/patologia , Doenças Cardiovasculares/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Lipoproteínas LDL/metabolismo , Lipoproteínas VLDL/metabolismo , Placa Aterosclerótica/patologia , Calcinose/tratamento farmacológico , Calcinose/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/mortalidade , Progressão da Doença , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas VLDL/efeitos dos fármacos , Placa Aterosclerótica/fisiopatologia , Prognóstico , Medição de Risco , Papel (figurativo) , Análise de Sobrevida
10.
Med Sci Monit ; 25: 4130-4136, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31156213

RESUMO

BACKGROUND The objective of this study was to study the anti-inflammatory effect and possibly involved molecular mechanisms of matrine on oxidized low-density lipoprotein (ox-LDL)-exposed macrophages. MATERIAL AND METHODS Cultured human macrophages (THP-1 cell line) were exposed to ox-LDL at final concentrations of 0, 25, 50, and 100 µg/mL. Several cells were then treated with matrine at serial diluted concentrations. 2,7-Dichlorodi-hydrofluorescein diacetate (DCFH-DA) staining was used to evaluate reactive oxygen species (ROS) production; a colorimetric method was used to determine the cellular antioxidant capacity; production of pro-inflammatory cytokines interleukin (IL)18 and tumor necrosis factor (TNF)alpha were determined by enzyme-linked immunosorbent assay (ELISA); and immunoblot assay was used to assess the relative protein phosphorylation and expression. RESULTS ox-LDL exposure significantly elevated intracellular ROS level and supernatant IL18 and TNFalpha concentrations, but impaired total antioxidant capacity (TAC) of macrophages. The relative phosphorylations of MAPK kinase kinases (MKK)6, MKK3, and p38 mitogen-activated protein kinases (MAPK) were increased by ox-LDL exposure. The expression levels of IL18 and TNFalpha were also increased in ox-LDL-treated macrophages. The matrine treatment reduced intracellular ROS level and supernatant IL18 and TNFalpha concentrations and increased TAC in a concentration- dependent manner. The relative phosphorylations of MKK6, MKK3, and p38 MAPK were reduced after matrine administration. Moreover, the expression levels of IL18 and TNFalpha were also decreased by matrine treatment, in a concentration-dependent manner. CONCLUSIONS ox-LDL increases inflammatory response in macrophages by activating the ROS-mediated MKKs/p38 MAPK-induced inflammatory signaling pathway. Matrine suppresses ox-LDL-induced inflammatory by inhibiting the MKKs/p38 MAPK signaling pathway.


Assuntos
Alcaloides/farmacologia , Lipoproteínas LDL/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Quinolizinas/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , China , Humanos , Interleucina-18/análise , MAP Quinase Quinase 3/metabolismo , MAP Quinase Quinase 6/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Projetos Piloto , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células THP-1/efeitos dos fármacos , Fator de Necrose Tumoral alfa/análise , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Matrinas
11.
Minerva Med ; 110(2): 107-114, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30371044

RESUMO

BACKGROUND: Foam cells are characteristic pathologic cells of atherosclerosis (AS), they are lipid-loaded macrophages present on atherosclerotic lesions. A large number of studies has shown that the pathogenesis of AS is the result of interactions between the lipid metabolism disorders and chronic inflammatory responses in the body. Albiflorin can inhibit the inflammatory response and it has shown a therapeutic effect on certain inflammatory diseases. METHODS: In this study, a human acute monocytic leukemia cell line (THP-1)-derived foam cell model was established via oxidized low-density lipoprotein (ox-LDL) to observe the effects of albiflorin on the AS-characteristic foam cells. RESULTS: Our results showed that, after the treatment with ox-LDL, macrophages induced by propylene glycol methyl ether acetate (PMA), presented large amounts of lipid deposition in their cytoplasm, indicating that the THP-1-derived foam cell model was successfully established. On the other hand, the same cells pretreated with albiflorin presented significantly reduced amounts of lipid deposition, and their contents of total cholesterol and triglyceride were also clearly lower. Besides, the expression levels of low-density lipoprotein receptor-1 (LOX-1) and nuclear factor-κB (NF-κB) were significantly decreased, and the expression levels of downstream factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also obviously decreased in the cells treated with albiflorin but not in the negative control cells. Moreover, after treatment of macrophages with different concentrations of ox-LDL, the expression levels of LOX-1 and NF-κB were up-regulated in an ox-LDL concentration-dependent manner, and so were the expression levels of IL-6 and TNF-α. And, it was found after treatment with LOX-1 neutralizing antibody or NF-κB inhibitor (during the foam cell formation induction via ox-LDL) that the lipid deposition in the cytoplasm of the cells was reduced, as in the cells treated with albiflorin. CONCLUSIONS: Taken together, our findings suggest that albiflorin decreases lipid deposition in the cytoplasm and blocks the foaming process by regulating the LOX-1/NF-κB signaling pathway.


Assuntos
Aterosclerose/patologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Células Espumosas/efeitos dos fármacos , Leucemia Monocítica Aguda/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Linhagem Celular Tumoral , Colesterol/metabolismo , Citoplasma/metabolismo , Células Espumosas/citologia , Células Espumosas/metabolismo , Humanos , Interleucina-6/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , NF-kappa B/metabolismo , Propilenoglicóis , Receptores Depuradores Classe E/metabolismo , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
12.
Arq. bras. cardiol ; 111(6): 764-770, Dec. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-973820

RESUMO

Abstract Background: The use of combined oral contraceptive (COC) has been related to changes in glycemic, lipid metabolism, increased oxidative stress, and systemic blood pressure, which could suggest a higher oxidation of low-density lipoprotein cholesterol (LDL-cholesterol) in women on use of COC. Objective: To test the hypothesis that there is a difference in the plasma values of oxidized LDL among women who use and do not use COC, as well as to evaluate the correlation between it and the lipid profile and high-sensitivity C-reactive protein (hs-CRP). Methods: Forty-two women with ages between 18 and 35 years old, who were eutrophic, irregularly active, with triglycerides < 150 mg/dL, blood glucose < 100 mg/dL, and who used or did not use COC were selected. These women were allocated in the COC group, formed by 21 women on COC use for at least 1 year; and a control group (CG), consisting of 21 women who had not used any type of hormonal contraceptive for at least 1 year. A significance level of 5% was adopted for statistical analyses. Results: It was observed that GCOC showed higher values of oxidized LDL than the CG, respectively 384 mU/mL versus 283 mU/mL (p < 0.01). A positive correlation between oxidized LDL and LDL-cholesterol (r = 0.3, p < 0.05), with total cholesterol (r = 0.47, p < 0.01) and with triglycerides (r = 0.32, p < 0.03) was observed, and there was no correlation with the hs-CRP. In the categorized analysis of oxidized LDL, 71.4% of GCOC women, and 28.6% of the CG remained above the established cutoff point. Conclusion: Women who use COC have higher plasma levels of oxidized LDL, and there is a positive correlation between oxidized LDL and other lipid variables.


Resumo Fundamento: O uso de contraceptivo oral combinado (COC) tem sido relacionado com alterações no metabolismo glicêmico, lipídico, maior estresse oxidativo e pressão arterial sistêmica, o que poderia sugerir maior oxidação da lipoproteína de baixa densidade colesterol (LDL-colesterol) em mulheres que utilizam COC. Objetivo: Testar a hipótese de que existe diferença nos valores plasmáticos da LDL-oxidada entre mulheres que utilizam e não utilizam COC, bem como avaliar a correlação entre ela e o perfil lipídico e proteína C reativa de alta sensibilidade (PCR-as). Métodos: Foram selecionadas 42 mulheres com idade entre 18 e 35 anos, eutróficas, irregularmente ativas, com triglicerídeos < 150 mg/dL, glicemia < 100 mg/dL e que utilizavam ou não COC. Essas foram alocadas no grupo COC, formado por 21 mulheres em uso COC há pelo menos 1 ano; e grupo controle (GC), composto por 21 mulheres que não utilizavam nenhum tipo de contraceptivo hormonal há pelo menos 1 ano. Adotado um nível de significância de 5% para as análises estatísticas. Resultados: Foi observado que o GCOC apresenta valores mais elevados da LDL-oxidada que o GC, respectivamente 384 mU/mL versus 283 mU/mL (p < 0,01). Também foi observado correlação positiva entre a LDL-oxidada e a LDL-colesterol (r = 0,3, p < 0,05), com o colesterol total (r = 0,47, p < 0,01) e com os triglicerídeos (r = 0,32, p < 0,03), não havendo correlação com a PCR-as. Na análise categorizada da LDL-oxidada, 71,4% das mulheres do GCOC e 28,6% do GC mantiveram-se acima do ponto de corte estabelecido. Conclusão: Mulheres que utilizam COC apresentam valores plasmáticos mais elevados da LDL-oxidada, existindo, correlação positiva entre a LDL-oxidada e outras variáveis lipídicas.


Assuntos
Humanos , Feminino , Adulto , Adulto Jovem , Anticoncepcionais Orais Combinados/sangue , Lipoproteínas LDL/sangue , Triglicerídeos/sangue , Proteína C-Reativa/análise , Estudos Transversais , Fatores de Risco , Estresse Oxidativo , Anticoncepcionais Orais Combinados/farmacologia , Lipoproteínas LDL/efeitos dos fármacos , LDL-Colesterol/sangue
13.
J Periodontal Res ; 53(3): 403-413, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29341140

RESUMO

BACKGROUND AND OBJECTIVE: Several studies have shown an association between periodontitis and cardiovascular disease (CVD). Atherosclerosis is the major cause of CVD, and a key event in the development of atherosclerosis is accumulation of lipoproteins within the arterial wall. Bacteria are the primary etiologic agents in periodontitis and Porphyromonas gingivalis is the major pathogen in the disease. Several studies support a role of modified low-density lipoprotein (LDL) in atherogenesis; however, the pathogenic stimuli that induce the changes and the mechanisms by which this occur are unknown. This study aims to identify alterations in plasma lipoproteins induced by the periodontopathic species of bacterium, P. gingivalis, in vitro. MATERIAL AND METHODS: Plasma lipoproteins were isolated from whole blood treated with wild-type and gingipain-mutant (lacking either the Rgp- or Kgp gingipains) P. gingivalis by density/gradient-ultracentrifugation and were studied using 2-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization mass spectrometry. Porphyromonas gingivalis-induced lipid peroxidation and antioxidant levels were measured by thiobarbituric acid-reactive substances and antioxidant assay kits, respectively, and lumiaggregometry was used for measurement of reactive oxygen species (ROS) and aggregation. RESULTS: Porphyromonas gingivalis exerted substantial proteolytic effects on the lipoproteins. The Rgp gingipains were responsible for producing 2 apoE fragments, as well as 2 apoB-100 fragments, in LDL, and the Kgp gingipain produced an unidentified fragment in high-density lipoproteins. Porphyromonas gingivalis and its different gingipain variants induced ROS and consumed antioxidants. Both the Rgp and Kgp gingipains were involved in inducing lipid peroxidation. CONCLUSION: Porphyromonas gingivalis has the potential to change the expression of lipoproteins in blood, which may represent a crucial link between periodontitis and CVD.


Assuntos
Adesinas Bacterianas/metabolismo , Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/farmacocinética , Lipoproteínas/efeitos dos fármacos , Lipoproteínas/metabolismo , Periodontite/metabolismo , Porphyromonas gingivalis/metabolismo , Adesinas Bacterianas/sangue , Adesinas Bacterianas/genética , Antioxidantes/análise , Apolipoproteína A-I/metabolismo , Apolipoproteína B-100/metabolismo , Cisteína Endopeptidases/sangue , Cisteína Endopeptidases/genética , Cisteína Endopeptidases Gingipaínas , Humanos , Peroxidação de Lipídeos , Lipoproteínas/sangue , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/sangue , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Metionina/metabolismo , Periodontite/microbiologia , Porphyromonas gingivalis/patogenicidade , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
14.
Braz. j. med. biol. res ; 51(3): 7090, 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-889042

RESUMO

Particles are usually polydispersed and size is an important feature for lipid-based drug delivery systems in order to optimize cell-particle interactions as to pharmacologic action and toxicity. Lipid nanoparticles (LDE) with composition similar to that of low-density lipoprotein carrying paclitaxel were shown to markedly reduce atherosclerosis lesions induced in rabbits by cholesterol feeding. The aim of this study was to test whether two LDE fractions, one with small (20-60 nm) and the other with large (60-100 nm) particles, had different actions on the atherosclerotic lesions. The two LDE-paclitaxel fractions, prepared by microfluidization, were separated by density gradient ultracentrifugation and injected (4 mg/body weight, intravenously once a week) into two groups of rabbits previously fed cholesterol for 4 weeks. A group of cholesterol-fed animals injected with saline solution was used as control to assess lesion reduction with treatment. After the treatment period, the animals were euthanized for analysis. After treatment, both the small and large nanoparticle preparations of LDE-paclitaxel had equally strong anti-atherosclerosis action. Both reduced lesion extension in the aorta by roughly 50%, decreased the intima width by 75% and the macrophage presence in the intima by 50%. The two preparations also showed similar toxicity profile. In conclusion, within the 20-100 nm range, size is apparently not an important feature regarding the LDE nanoparticle system and perhaps other solid lipid-based systems.


Assuntos
Animais , Masculino , Coelhos , Paclitaxel/administração & dosagem , Aterosclerose/tratamento farmacológico , Moduladores de Tubulina/administração & dosagem , Nanopartículas/administração & dosagem , Lipídeos/administração & dosagem , Lipoproteínas LDL/efeitos dos fármacos , Tamanho da Partícula , Quimioterapia Combinada
15.
Nutrition ; 41: 107-112, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28760419

RESUMO

OBJECTIVES: The aim of this study was to examine the hypoglycemic and hypolipidemic effects of Vaccinium myrtillus L. leaf (VLE) and Phaseolus vulgaris L. seed coat (PCE) plant extracts, containing polyphenolic compounds, on carbohydrate and lipid metabolism in Wistar rats with streptozotocin (STZ) and high-fructose diet (HFD)-induced diabetes. METHODS: Male Wistar rats with STZ and HFD-induced diabetes were fed with or without VLE or PCE for 50 d. At different intervals, blood glucose and body weight were recorded. Blood samples were used to determine glycated hemoglobin (HbA) and parameters of lipid profile in serum. Additionally, the levels of serum diene conjugates and malondialdehyde were assessed. RESULTS: Results of HbA and blood glucose level analysis showed the ameliorative effect of VLE on carbohydrate metabolism in diabetic rats. Of the eight diabetic animals treated with bilberry leaf extract, four had normal HbA levels. A significant reduction was observed in VLE group in blood glucose level compared with control diabetic rats (level of hyperglycemia decreased to normal values in 50% of animals versus 0% in the control diabetic group). VLE treatment normalized parameters of lipid metabolism. There was no significant difference from the same parameters in the intact control group. Administration of PCE significantly (P < 0.05) decreased the levels of plasma triacylglycerol (0.81 ± 0.06 mmol/L) and low-density lipoprotein (0.74 ± 0.10 mmol/L) in blood serum compared with the diabetic control group (1.36 ± 0.13 and 1.85 ± 0.30, respectively). Moreover, VLE and PLE showed an antioxidant effect on diene compounds in the blood serum of rats. A significant decrease was found in the plasma diene conjugate levels in PLE group (1.16 ± 0.11 nmol/mL) compared with control diabetic rats (2.09 ± 0.21 nmol/mL; P < 0.05). There was no significant difference from the same parameter in the VLE and intact control groups. CONCLUSIONS: The set of results that was obtained in the present study reveals lipid-lowering and antioxidant action related to the administration of VLE and PCE in Wistar rats with diabetes, induced by STZ, in combination with a high-carbohydrate diet. VLE to a certain extent also reduced hyperglycemia in diabetic animals.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Phaseolus , Fitoterapia/métodos , Vaccinium myrtillus , Animais , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/sangue , Modelos Animais de Doenças , Hipoglicemiantes/sangue , Hipolipemiantes/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/sangue , Lipoproteínas LDL/efeitos dos fármacos , Masculino , Folhas de Planta , Ratos , Ratos Wistar , Sementes , Triglicerídeos/sangue
16.
Wiad Lek ; 69(3 pt 2): 475-479, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27717928

RESUMO

INTRODUCTION: endothelial dysfunction (ED) is one of the most important links in the pathogenesis of atherosclerosis (ASVD) - morphological basis of coronary artery disease (CAD). OBJECTIVE: to study the effect of polyphenolic antioxidants, resveratrol and quercetin, on endothelial degeneration factors in CAD patients. MATERIALS AND METHODS: the study involved 93 patients with coronary artery disease: stable angina pectoris, FC II. The cytofluorometric technique was applied to define the level of circulating endothelial microparticles (EMP) CD32+CD40+ in peripheral blood in order to identify ED. The content of tumor necrosis factor α (TNF-α), fibrinogen, hemocoagulation and lipid profile parameters were being determined in the blood, as well. Patients were divided into 3 groups. Basic therapy (ß-blockers, statins, aspirin) was prescribed to 33 persons of the comparison group, patients of the study group 1 (30 persons) additionally received resveratrol at a dose of 100 mg daily, patients of the study group 2 (30 persons) got quercetin at a dose of 3 g per day. In 2 months, the second examination of the patients was performed in the amount indicated. RESULTS: under the influence of resveratrol a significant reduction of the level of TNF-α and the number of EMP in peripheral blood was shown, in contrast to the results of other study groups. All groups showed a decrease in total cholesterol and low-density lipoprotein cholesterol, statistical differences between data of groups were not found. Indicators of coagulogramma in all study groups did not change significantly, however, there was a statistically significant reduction of fibrinogen in the blood. CONCLUSIONS: resveratrol, unlike quercetin, has a positive effect on the endothelial function and systemic inflammation, which may be the result of its influence on intracellular molecular cascades associated with the nuclear transcription factor of NF-kB.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Quercetina/farmacologia , Estilbenos/farmacologia , Idoso , Antioxidantes/farmacologia , Aterosclerose , Doença da Artéria Coronariana/patologia , Endotélio Vascular/patologia , Feminino , Fibrinogênio/efeitos dos fármacos , Humanos , Inflamação , Lipoproteínas LDL/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Quercetina/uso terapêutico , Resveratrol , Estilbenos/uso terapêutico , Fator de Necrose Tumoral alfa/efeitos dos fármacos
17.
Food Funct ; 7(5): 2169-78, 2016 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-27043127

RESUMO

Platelet dysfunction, oxidative stress and dyslipidemia are important contributors to pro-thrombotic progression particularly in obese and hyper-cholesterolemic populations. Becoming an increasingly widespread endemic, obesity causes a dysfunction in the metabolic system by initiating endothelial dysfunction; increasing free radical production; lipid peroxidation; platelet hyperactivity and aggregation; thereby accelerating thrombogenesis. In the event of increased free radical generation under pro-thrombotic conditions, antioxidants act as scavengers in reducing physiological oxidative stress; free radical-mediated thrombosis and hemostatic function. Anthocyanin, a subclass of the polyphenol family flavonoids has been shown to exhibit anti-dyslipidemic and anti-thrombotic properties by virtue of its antioxidant activity. Current anti-platelet/coagulant therapeutics target specific receptor pathways to relieve the extent of dysfunction and plaque acceleration in pro-thrombotic individuals. Though effective, they have been associated with high bleeding risk and increased response variability. The following review focuses on the potential role of natural dietary anthocyanins in targeting simultaneous mechanistic pathways in alleviating platelet activation, dyslipidemia, and oxidative stress-associated thrombus acceleration in obese pro-thrombotic populations.


Assuntos
Antocianinas/metabolismo , Antocianinas/farmacologia , Obesidade/tratamento farmacológico , Trombose/tratamento farmacológico , Antocianinas/química , Antioxidantes/farmacologia , Aterosclerose/tratamento farmacológico , Disponibilidade Biológica , Plaquetas/efeitos dos fármacos , Dieta , Dislipidemias/tratamento farmacológico , Flavonoides , Radicais Livres , Hemorragia , Hemostáticos , Humanos , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos , Lipoproteínas LDL/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária , Polifenóis , Virtudes
18.
J Cardiovasc Pharmacol ; 67(6): 510-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26859197

RESUMO

Saikosaponins-a (Ssa) is a major bioactive extract of Radix Bupleuri which is a traditional Chinese medicine. The roles of inflammatory response and lipid transportation in the process of atherosclerosis have drawn increasing attention. We explored the regulation of lipid transportation and immune-inflammatory role of Ssa in early atherosclerosis. The antiatherogenic actions and possible molecular mechanisms of Ssa were texted in THP-1 cells. We examined the effect of Ssa on oxidized low-density lipoprotein (ox-LDL)-induced lipid uptake, cholesterol efflux, immune-inflammatory response. THP-1 macrophages were treated with Ssa followed by ox-LDL for 24 hours. Results from western blot showed that Ssa obviously reduced lipoprotein uptake to block foam cell formation and the expression of Density Lipoprotein Receptor-1 and CD36. Ssa also significantly boosted cholesterol efflux and the expression of ATP binding cassettetransporter A1 and peroxisome proliferator-activated receptor γ. The results also indicated that Ssa inhibited ox-LDL-induced activation of AKT and nuclear factor-κB, assembly of NLRP3 inflammasome and production of proinflammatory cytokines. It is suggested that the ability against immune inflammatory response of Ssa is due to modulation of the PI3K/AKT/NF-κB/NLRP3 pathway. In conclusion, this study provides new insight into Ssa's molecular mechanism and its therapeutic potential in the treatment of atherosclerosis.


Assuntos
Aterosclerose/fisiopatologia , Colesterol/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Transportador 1 de Cassete de Ligação de ATP/biossíntese , Antígenos CD36/metabolismo , Técnicas de Cultura de Células , Citocinas/metabolismo , Humanos , Lipoproteínas/metabolismo , NF-kappa B/biossíntese , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Oleanólico/farmacologia , PPAR gama/biossíntese , Receptores de Lipoproteínas/metabolismo
19.
Biomed Pharmacother ; 77: 59-64, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26796266

RESUMO

The aim of this study was to evaluate the effect of polyamines putrescine, spermidine and spermine on human LDL oxidation and to assess the ability of macrophages derived from type 2 diabetic patients to uptake oxLDL. Polyamine effect was compared with α-tocopherol. Four healthy subjects and eight type 2 diabetic patients were included in this study. To characterize type 2 diabetic patients and non-diabetic subjects, laboratory test were carried out. Glucose, glycated haemoglobin (HbA1C), triglycerides, low (LDL) and high density lipoproteins (HDL) and serum lipid peroxidation were measured in blood. The study was performed in three stages. For each stage, ten experimental conditions comparing the effect of polyamines with α-tocopherol (10µM solutions) on LDL oxidation and the uptake of oxLDL by macrophages were analyzed. MDA concentration was found to be significantly higher in type 2 diabetic patients compared to healthy subjects (5.6±0.58 vs. 2.66±0.31µM MDA, respectively, (P<0.05)). Percent of macrophages containing oxLDL was determined by means of red oil staining. The uptake of oxLDL by macrophages derived from diabetic patients was clear. The uptake of oxLDL was inhibited when the oxidation was prevented by polyamines or α-tocopherol. Spermine showed high antioxidant capacity (96.67±1.53% vs. 25.67±2.30%) compared to α-tocopherol (96.67±1.53% vs. 47.00±7.20%) at the concentration tested. In conclusion, polyamines especially spermine, has a potent antioxidant effect compared to α-tocopherol on human LDL oxidation, followed by spermidine and putrescine. The results have clinical relevance in the diabetic complications and add knowledge on the role of polyamines as natural antioxidants. This research is not a clinical evaluation rather a functional analysis utilizing clinical samples.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Poliaminas/farmacologia , Glicemia , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas , Humanos , Peroxidação de Lipídeos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Putrescina/farmacologia , Espermidina/farmacologia , Espermina/farmacologia , alfa-Tocoferol/farmacologia
20.
J Steroid Biochem Mol Biol ; 154: 142-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26255276

RESUMO

Many known estrogens, both natural and synthetic, may act as antioxidants. We designed and synthesized 22 novel estrogen analogues with different ring junctions or substitutions, such as fluorine. We studied the antioxidant capacity in vitro of 35 synthetic estrogen analogues in aqueous lipoprotein solution by monitoring the formation of conjugated dienes. In addition to a free C-3 hydroxyl group, the two most active antioxidants had either a methyl group at C-4 and a six-carbon D-ring, or a fluorine atom at C-2 and an unsaturated B-ring. Extension of the D-ring increased the antioxidant capacity of 6-oxa estrogens. Compounds with a fluorine atom at C-2 were similar or more potent antioxidants compared with the principal endogenous estrogen, 17ß-estradiol. In compounds with a substituted C-3 hydroxyl group, the antioxidant capacity could be significantly increased by additional double bonds in the C- or D-rings. In conclusion, we show that the antioxidant capacity of estrogen analogues could be increased by structural changes.


Assuntos
Antioxidantes/farmacologia , Estrogênios/farmacologia , Lipoproteínas LDL/efeitos dos fármacos , Antioxidantes/química , Estrogênios/química , Humanos , Lipoproteínas LDL/sangue , Masculino , Estrutura Molecular
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