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1.
Am J Pathol ; 190(3): 563-576, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31945314

RESUMO

Hyperlipidemia impacts on various diseases, such as atherosclerosis, hypertension, and diabetes mellitus. However, its influence, if any, on ocular tissues is largely unknown. Herein, we developed hyperlipidemic murine models by feeding 4-week-old male wild-type mice with a high-fat diet and apolipoprotein E knockout (ApoE-/-) mice with a high-fat diet or standard diet to investigate the corneal endothelial change under hyperlipidemic conditions. Oil Red O staining showed an accumulation of lipid droplets in corneal endothelial cells (CECs) of hyperlipidemic mice. Other manifestations included a reduced cell density and distorted cell morphology, a disruption of the endothelial cell tight junctions and adhesion junctions, a reduced number of surface microvilli, down-regulation of Na+-K+-ATPase expression and function, activation of oxidative stress, changes in mitochondrial ultrastructure, and increased apoptosis. CEC recovery after injury, moreover, was diminished in hyperlipidemic mice; and high palmitate levels were found in the aqueous humor. In vitro hyperlipemia model, moreover, was found to be associated with dose-dependent CEC cytotoxicity, altered cell morphology, reduced pump function, and an induction of oxidative stress, leading to functional and pathologic changes in the corneal endothelium.


Assuntos
Apolipoproteínas E/genética , Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/complicações , Estresse Oxidativo , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Apoptose , Sobrevivência Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação para Baixo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epitélio Posterior/metabolismo , Epitélio Posterior/patologia , Hiperlipidemias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Mitocôndrias/ultraestrutura , Palmitatos/toxicidade , ATPase Trocadora de Sódio-Potássio/genética , Junções Íntimas/metabolismo , Junções Íntimas/patologia
2.
PLoS One ; 15(1): e0227637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929574

RESUMO

Leptin resistance and co-existing insulin resistance is considered as hallmark of diet-induced obesity. Here, we investigated therapeutic potential of hesperidin to improve leptin and insulin resistance using high fat diet (HFD)-induced obese experimental animal model. We also performed in silico studies to validate therapeutic effectiveness of hesperidin by performing protein-ligand docking and molecular dynamics simulation studies. Group 1 was identified as control group receiving vehicle only. Group 2 was marked as non-treated group receiving 60% HFD. While, other groups were treated daily with orlistat (120 mg/kg/d), hesperidin (55 mg/kg/d), combination of hesperidin (55 mg/kg/d) + orlistat (120 mg/kg/d). Hesperidin alone (P<0.001) and particularly in combination with orlistat (P<0.001), resulted in controlling the levels of HFD-altered biomarkers including random and fasting state of glycemia, leptin and insulin resistance. Similarly, hesperidin also improved the serum and tissue levels of leptin, interleukin-6 and tumor necrosis factor-alpha more significantly (P<0.05) when compared with that of orlistat. These results were found to be in accordance with the results of histopathological examination of pancreas, liver and adipose tissues. In-silico studies also proved that hesperidin binds to leptin receptor with higher affinity as compared to that of orlistat and induces the favorable variations in geometrical conformation of leptin receptor to promote its association with leptin which may lead to the cascades of reactions culminating the lipolysis of fats that may ultimately lead to cure obesity. The results of this study may be a significant expectation among the forthcoming treatment strategies for leptin and insulin resistance.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Fármacos Antiobesidade/farmacologia , Hesperidina/farmacologia , Inflamação/tratamento farmacológico , Resistência à Insulina , Obesidade/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Fármacos Antiobesidade/química , Dieta Hiperlipídica , Modelos Animais de Doenças , Quimioterapia Combinada , Hesperidina/química , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Inflamação/metabolismo , Inflamação/patologia , Leptina/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Obesidade/metabolismo , Obesidade/patologia , Orlistate/química , Orlistate/farmacologia , Ratos Wistar
3.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505754

RESUMO

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%-93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.


Assuntos
Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Lorazepam/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/química , Carragenina/farmacologia , Cromanos/química , Cromanos/farmacologia , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Lorazepam/análogos & derivados , Ratos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacologia
4.
Biomed Pharmacother ; 119: 109410, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518877

RESUMO

AIMS: The present study aimed to investigate the effect of metformin on diabetes-accelerated atherosclerosis and whether Nod-like receptor protein 3 (NLRP3) inflammasome is a target for metformin. MATERIALS AND METHODS: ApoE-/- male mice were divided randomly into control, streptozocin-induced diabetes mellitus and metformin groups. Metabolic parameters, atherosclerotic lesion, activation of NLRP3 inflammasomes and related signaling pathways were detected. THP-1-differentiated macrophages were used in in vitro experiments. RESULTS: Compared with control mice, increased plasma lipids and proinflammatory interleukin-1ß, aggravated macrophage infiltration into the atherosclerotic lesion, and accelerated development of atherosclerosis were observed in diabetic mice, which were associated with the activation of NLRP3 inflammasomes and dysregulation of thioredoxin-1 and thioredoxin-interacting protein. Treatment with metformin alleviated diabetes-induced metabolic disorders and atherosclerosis, as well as NLRP3 inflammasomes activation and dysregulation of thioredoxin-1/thioredoxin-interacting protein. In vitro experiments showed that high glucose induced the accumulation of reactive oxygen species and activated NLRP3 inflammasomes, which was significantly suppressed by treatment with metformin or antioxidant N-acetyl-L-cysteine. Moreover, Compound C, an inhibitor of adenosine 5'-monophosphate-activated protein kinase (AMPK), blocked the anti-inflammatory effect of metformin, indicating that metformin inhibited high glucose-induced NLRP3 inflammasomes activation through AMPK activation. Moreover, high glucose decreased thioredoxin-1 expression and increased thioredoxin-interacting protein expression, which was also reversed by metformin. CONCLUSIONS: Metformin inhibited NLRP3 inflammasomes activation and suppressed diabetes-accelerated atherosclerosis in apoE-/- mice, which at least partially through activation of AMPK and regulation of thioredoxin-1/thioredoxin-interacting protein.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Diabetes Mellitus/tratamento farmacológico , Inflamassomos/metabolismo , Metformina/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Adenilato Quinase/metabolismo , Animais , Aorta/patologia , Apolipoproteínas E/metabolismo , Aterosclerose/sangue , Aterosclerose/patologia , Glicemia/metabolismo , Proteínas de Transporte/metabolismo , Ativação Enzimática/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/complicações , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Lipídeos/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Metformina/farmacologia , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxinas/metabolismo
5.
Int J Mol Sci ; 20(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31373312

RESUMO

Diabetic nephropathy is increasingly recognized as a major contributor to kidney failure in patients with obesity and type 2 diabetes. This study was designed to identify the molecular mediators of kidney injury associated with metabolic syndrome with or without hyperglycemia. We compared renal gene expression profiles in Zucker lean (ZL), Zucker obese (ZO), and Zucker diabetic (ZD) rats using cDNA microarray with quantitative verification of selected transcripts by real-time PCR. Compared to the 20-week-old ZL control (glucose: 110 ± 8 mg/dL), both prediabetic ZO (glucose: 157 ± 11 mg/dL) and diabetic ZD (glucose: 481 ± 37 mg/dL) rats displayed hyperlipidemia and kidney injury with a high degree of proteinuria. cDNA microarray identified 25 inflammation and injury-related transcriptomes whose expression levels were similarly increased in ZO and ZD kidneys. Among them, kidney injury molecule-1 (KIM-1) was found to be the most highly upregulated in both ZO and ZD kidneys. Immunofluorescence staining of kidney sections revealed a strong correlation between lipid overload and KIM-1 upregulation in proximal tubules of ZO and ZD rats. In cultured primary renal tubular epithelial cells (TECs), administration of saturated fatty acid palmitate resulted in an upregulation of KIM-1, osteopontin, and CD44, which was greatly attenuated by U0126, an inhibitor of extracellular signal-regulated kinase (ERK)1/2. Moreover, knockdown of KIM-1 by siRNA interference inhibited palmitate-induced cleaved caspase-3, osteopontin, and CD44 proteins in primary TECs. Our results indicate that KIM-1 expression is upregulated in renal lipotoxicity and may play an important role in fatty acid-induced inflammation and tubular cell damage in obesity and diabetic kidney disease.


Assuntos
Moléculas de Adesão Celular/metabolismo , Nefropatias Diabéticas/patologia , Hiperlipidemias/patologia , Túbulos Renais/patologia , Obesidade/patologia , Animais , Caspase 3/biossíntese , Moléculas de Adesão Celular/genética , Perfilação da Expressão Gênica , Receptores de Hialuronatos/biossíntese , Hiperglicemia/patologia , Hiperlipidemias/sangue , Túbulos Renais/lesões , Síndrome Metabólica/patologia , Osteopontina/biossíntese , Palmitatos/toxicidade , Proteinúria/urina , Interferência de RNA , RNA Interferente Pequeno/genética , Ratos , Ratos Zucker , Transcriptoma/genética
6.
Nutrients ; 11(9)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443409

RESUMO

Oxidative stress is a common condition described in risk factors for cardiovascular disease. Betanin, a bioactive pigment from red beetroot demonstrates anti-inflammatory and antioxidant properties. The main aim of this study was to evaluate the short-term intake of betanin against oxidative stress in a rodent model, a common condition described in several risk factors for cardiovascular disease. Oxidative stress was induced in Wistar rats by a hyperlipidemic diet for 60 days, followed by betanin administration (20 mg·kg-1) through oral gavage for 20 days. Plasma biochemical parameters and antioxidant enzyme activities were evaluated. Lipid peroxidation and histopathological changes were determined in the liver. The hyperlipidemic diet caused hyperglycemia, hyperinsulinemia, insulin resistance, and increases in alanine transaminase and aspartate transaminase levels. Oxidative stress status was confirmed by reduction of antioxidant enzyme activities, increased lipid peroxidation, and liver damage. Purified betanin regulated glucose levels, insulin, and insulin resistance. Hepatic damage was reversed as evidenced by the reduction in alanine transaminase and aspartate transaminase levels and confirmed by histological analyses. Betanin reduced hepatic malondialdehyde and increased superoxide dismutase, catalase, and glutathione peroxidase activities. Short-term betanin intake modulated biochemical parameters, reversed hepatic tissue damage, and attenuated oxidative stress in Wistar rats.


Assuntos
Antioxidantes/administração & dosagem , Betacianinas/administração & dosagem , Hiperlipidemias/prevenção & controle , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Esquema de Medicação , Hiperlipidemias/sangue , Hiperlipidemias/patologia , Insulina/sangue , Resistência à Insulina , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos Wistar , Fatores de Tempo
7.
Int J Mol Sci ; 20(14)2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323736

RESUMO

OBJECTIVE: Familial hypercholesterolemia (FH) is a dominant inherited disease caused mainly by low-density lipoprotein receptor (LDLR) gene mutations. To different extents, both heterozygous and homozygous FH patients develop premature coronary heart disease (CHD). However, most of the experimental animal models with LDLR deficiency could not fully recapitulate FH because they develop hyperlipidemia and atherosclerosis only in homozygous, but not in heterozygous, form. In the current study, we investigated the responsiveness of the LDLR+/- hamster to dietary cholesterol and whether plasma cholesterol levels were positively associated with the severity of atherosclerosis. Approach and Methods: wild type WT and LDLR+/- hamsters were fed a high fat diet with different cholesterol contents (HCHF) for 12 or 16 weeks. Plasma lipids, (apo)lipoproteins, and atherosclerosis in both the aorta and coronary arteries were analyzed. After a HCHF diet challenge, the levels of total cholesterol (TC) in WT and LDLR+/- hamsters were significantly elevated, but the latter showed a more pronounced lipoprotein profile, with higher cholesterol levels that were positively correlated with dietary cholesterol contents. The LDLR+/- hamsters also showed accelerated atherosclerotic lesions in the aorta and coronary arteries, whereas only mild aortic lesions were observed in WT hamsters. CONCLUSIONS: Our findings demonstrate that, unlike other rodent animals, the levels of plasma cholesterol in hamsters can be significantly modulated by the intervention of dietary cholesterol, which were closely associated with severity of atherosclerosis in LDLR+/- hamsters, suggesting that the LDLR+/- hamster is an ideal animal model for FH and has great potential in the study of FH and atherosclerosis-related CHD.


Assuntos
Aterosclerose/sangue , Aterosclerose/patologia , Colesterol na Dieta , Hiperlipidemias/sangue , Hiperlipidemias/patologia , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/patologia , Animais , Aterosclerose/metabolismo , Colesterol/sangue , Cricetinae , Feminino , Hiperlipidemias/metabolismo , Hiperlipoproteinemia Tipo II/metabolismo , Masculino , Receptores de LDL/deficiência , Receptores de LDL/metabolismo
9.
Oxid Med Cell Longev ; 2019: 5172480, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089408

RESUMO

Baoyuan decoction (BYD), a traditional representative formula, has a long usage history in the treatment of cardiovascular diseases. Since the hyperlipidemia-induced dysfunction of erythrocyte is one of the most important causes of cardiovascular diseases, the improving effects of BYD against high-fat diet (HFD) induced the physiological and physical function of the erythrocytic injury and the potential mechanisms were deeply researched in this study. After 6 weeks of drug treatment, all doses of BYD had significantly decreased the lipid peroxidation in plasma of HFD-induced ApoE-/- mice, even if it had not improved the lipid levels. Then, the erythrocyte-related experimental results showed that BYD had reduced erythrocyte osmotic fragility, stabilized erythrocyte membrane skeleton protein 4.2, and reformed the erythrocyte morphological changes by decreasing erythrocyte membrane lipid peroxidation levels. This study demonstrated that BYD may ameliorate the physiological and physical function of erythrocyte in hyperlipidemic mice through the antioxidant effect on erythrocyte membranes.


Assuntos
Antioxidantes/farmacologia , Apolipoproteínas E/deficiência , Dieta Hiperlipídica , Medicamentos de Ervas Chinesas/farmacologia , Eritrócitos/patologia , Hiperlipidemias/sangue , Hiperlipidemias/patologia , Animais , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Eritrócitos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Fragilidade Osmótica , Oxirredução
10.
PLoS One ; 14(5): e0217112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120956

RESUMO

Ulmus macrocarpa Hance as an oriental medicinal plant has shown enormous potential for the treatment of several metabolic disorders in Korea. Hyperlipidemia, which is characterized by the excess accumulation of lipid contents in the bloodstream, may lead to several cardiovascular diseases. Therefore, in this study, anti-hyperlipidemic potential of U. macrocarpa water extract (UME) was examined in vitro and in vivo using HepG2 cells and experimental rats, respectively. The hyperlipidemia in experimental rats was induced by the high-cholesterol diet (HCD) followed by oral administration of various concentrations (25, 50 and 100 mg/kg) of UME for 6 weeks. As a result, the UME significantly improved the biochemical parameters such as increased the level of triglyceride, total cholesterol, and low-density lipoprotein cholesterol as well as reduced the high-density lipoprotein cholesterol in the HCD-fed rats. In addition, UME also prevented lipid accumulation through regulating AMPK activity and lipid metabolism proteins (ACC, SREBP1 and HMGCR) in the HCD-fed rats as compared to the controls. Moreover, similar pattern of gene expression levels was confirmed in oleic acid (OA)-treated HepG2 cells. Taken together, our results indicate that UME prevents hyperlipidemia via activating the AMPK pathway and regulates lipid metabolism. Thus, based on the above findings, it is estimated that UME could be a potential therapeutic agent for preventing the hyperlipidemia.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ulmus/química , Animais , Células Hep G2 , Humanos , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Masculino , Ratos , Ratos Sprague-Dawley
11.
Indian J Cancer ; 56(2): 180-181, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062741

RESUMO

Severe hyperlipidemia (>1000 mg/dL) at initial presentation of acute lymphoblastic leukemia (ALL) is rare. Cases of hyperlipidemia during therapy for childhood ALL where they were secondary to L-asparaginase or steroids have been described. This is a case report of a one-and-half-year-old boy who presented to us with fever, abdominal distension, severe pallor, and hepatosplenomegaly. Although his investigations were suggestive of ALL, the initial blood samples were found to be grossly lipemic. The lipid profile was abnormal, showing severe hypertriglyceridemia (serum triglycerides 1552 mg/dL). High-density lipoprotein and low-density lipoprotein levels were low, but there were raised very low-density lipoprotein level and serum lactate dehydrogenase (18117 U/L). The patient was started on induction of remission with careful monitoring of biochemical parameters. Abnormal lipid levels declined gradually with normalization of the levels at the end of one week of chemotherapy. No further complications were encountered during the course of induction of remission.


Assuntos
Hiperlipidemias/sangue , Lipídeos/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/patologia , Lactente , L-Lactato Desidrogenase/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Indução de Remissão , Triglicerídeos/sangue
12.
Lipids Health Dis ; 18(1): 115, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101130

RESUMO

BACKGROUND: Experimental and epidemiological studies show that bergamot polyphenolic fraction (BPF) ameliorates the serum lipemic profile, normalizes blood pressure and improves non alcoholic fatty liver disease in patients suffering from metabolic syndrome. Despite this evidence, the molecular mechanisms responsible for these beneficial effects remain unclear. The aim of our study is to clarify the effects of BPF on the lipoprotein assembly and to identify oxidative stress biomarkers correlating hyperlipidaemia and BPF-induced metabolic changes. METHODS: Male Wistar rats (180-200 g) were randomly assigned to receive a standard diet, a hypercholesterolemic diet or a hypercholesterolemic diet+BPF (20 mg/Kg/rat daily, gavage), respectively, for 90 days. Total cholesterol (tChol), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and fasting plasma glucose were evaluated at the baseline as well as at the end of the treatment. To assess the effect of BPF on the Lipid Transfer Protein System, detection of ACAT, LCAT, CETP, PON1, Apo A1 and Apo B have also been carried out. Finally, the lipid peroxidation biomarker (TBARS) and oxyLDL were also measured. RESULTS: BPF prevented tChol, LDL-C, TG and fasting plasma glucose enhancement and improved HDL-C. Treatment of hyperlipæmic rats with BPF significantly restored altered the serum concentration of lipemic biomarkers and the activity of ACAT, LCAT, CETP and PON1, an effect accompanied by the concomitant normalization of Apo A1 and APO B levels. In addition, TBARS levels were reduced significantly by the treatment with BPF. CONCLUSIONS: BPF prevents diet-induced alteration of the lipid profile in rats, counteracting oxidative stress and improving the dysregulation of the Lipid Transfer Protein System. These data add new insights into the molecular mechanisms underlying the beneficial role of BPF in the therapy of hyperlipidaemia, thus suggesting a novel approach in the prevention of cardiovascular disease.


Assuntos
Proteínas de Transporte/metabolismo , Citrus/química , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/uso terapêutico , Acetil-CoA C-Acetiltransferase/metabolismo , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Hiperlipidemias/sangue , Lipoproteínas LDL/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Polifenóis/farmacologia , Ratos Wistar
13.
Biomed Res Int ; 2019: 2835152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984778

RESUMO

Traditionally, in many countries, various parts of the Adansonia digitata (A. digitata) tree have been used in the treatment of many clinical ailments including diarrhea and dysentery. The phytochemical screening has indicated that the leaf extract of A. digitata contains flavonoids, saponins, mucilage, steroids, and alkaloids. Thus, this paper aims to evaluate the hyperglycaemic and hypolipidaemic effects of methanolic extract of A. digitata leaves (200 mg/kg and 400 mg/kg) in diabetic rats. The extract was administered orally for six weeks in the streptozotocin (STZ)-induced diabetic rats. The treatment with the extract caused a significant reduction in the blood glucose, glycosylated hemoglobin, cholesterol, triglycerides, low-density lipoprotein (LDL), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and malondialdehyde (MDA) levels by 46.7%, 46.15%, 48.91%, 43%, 60%, 66%, 45.45%, and 30.4%, respectively, as compared to the diabetic group after the sixth week of treatment. The leaf extract also mitigated the decline of high-density lipoprotein (HDL) level, RBCs count, hemoglobin level, packed cell volume (PCV %), and erythropoietin concentration in diabetic rats by 31%, 33.25%, 24.72%, 51.42%, and 220.68% with respect to the diabetic group. Also, the extract maintained the level of antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD), and reduced glutathione (GSH) in the diabetic rats. It also reduced the elevation in the white blood corpuscles (WBC) count in the STZ-induced diabetic rats. Our study, therefore, indicates that methanolic extract of A. digitata leaf exerts strong antidiabetic and hypolipidaemic properties in a dose-dependent manner by improving the hematological properties and redox parameters in the experimental diabetic rats.


Assuntos
Adansonia/química , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Glicemia/efeitos dos fármacos , Catalase/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Humanos , Hiperglicemia/sangue , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/patologia , Hipoglicemiantes/administração & dosagem , Interleucina-6/sangue , Malondialdeído/sangue , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Ratos , Superóxido Dismutase/sangue , Fator de Necrose Tumoral alfa/sangue
14.
Int Heart J ; 60(3): 746-755, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31019169

RESUMO

To detect the development of monocytes and proliferative macrophages in atherosclerosis of ApoE-/- mice, we randomly assigned 84 ApoE-/- mice fed western diet or chow diet. On weeks 2, 4, 6, 8, 10, and 12 after fed high-fat diet or normal chow diet, animals were euthanized (n = 7 for each group at each time point). Flow cytometry methods were used to analyze the proportions of circulation monocyte subsets. The macrophage and proliferative macrophage accumulation within atherosclerotic plaques was estimated by confocal florescence microscopy. Plasma levels of total cholesterol and triglyceride were measured by ELISA kit. The plaques of aortic sinus were stained with Oil Red O. The percent of Ly6Chi circulation monocyte, the density of proliferation macrophage, the total plasma cholesterol and triglyceride levels, the lesion area of ApoE-/- mice were consistently elevated in chow diet throughout the trial. The total plasma cholesterol and triglyceride levels, the lesion area were elevated in western diet group with age, and they were always higher than the chow diet group. The Ly6Chi monocytes and proliferative macrophages reached a plateau at 8 weeks and 6 weeks; despite continued high-triglyceride high-cholesterol diet the percent did not significantly change. Interestingly, the density of macrophage did not change significantly over age in western and chow diet groups. Our results provide a dynamic view of Ly6Chi monocyte subset, the density of macrophage and proliferation macrophage change during the development and progression of atherosclerosis, which is relevant for designing new treatment strategies targeting mononuclear phagocytes in this model.


Assuntos
Aterosclerose/patologia , Dieta Hiperlipídica/efeitos adversos , Macrófagos/patologia , Monócitos/patologia , Placa Aterosclerótica/patologia , Animais , Apolipoproteínas E/administração & dosagem , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Colesterol/sangue , Modelos Animais de Doenças , Hiperlipidemias/complicações , Hiperlipidemias/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/ultraestrutura , Triglicerídeos/sangue
15.
Drug Dev Ind Pharm ; 45(6): 995-998, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30892088

RESUMO

Novel fatty acid-bile acid conjugates (1a-1k) were designed and synthesized by coupling of the fatty acids to the 3-OH of bile acids using lysine for linkage. In the conjugates, the 24-COOH of the bile acids was kept intact to preserve liver-specific recognition. The ability of the newly synthesized conjugates (at 100 mg/kg dosage) to reduce total cholesterol (TC) and triglyceride (TG) levels in mice fed with high-fat diet (HFD) was evaluated. Conjugates of stearic acid with cholic acid and palmitic acid with ursodeoxycholic acid (at dosages of 50, 100, and 200 mg/kg) were further evaluated to determine their ability to reduce aspartate aminotransferase (AST), alanine aminotransferase (ALT), TC, and TG levels in mice fed with HFD. All conjugates showed potent hypolipidemic activity. Further investigation revealed that compounds 1c and 1 g not only dose-dependently reduced serum levels of TC and TG, but also inhibited the elevation of serum AST and ALT levels in mice fed with HFD. Thus, compounds 1c and 1 g are promising hypolipidemic agents with hepatocyte protective effects against HFD-induced liver damage.


Assuntos
Ácidos e Sais Biliares/administração & dosagem , Ácidos Graxos/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Fígado/efeitos dos fármacos , Animais , Ácidos e Sais Biliares/química , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos/química , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Hiperlipidemias/patologia , Hipolipemiantes/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Lisina/química , Camundongos , Triglicerídeos/sangue
16.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1555-1566, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905786

RESUMO

The risk of non-alcoholic fatty liver disease increases with obesity. Vulnerability to oxidative stress and/or inflammation represents a crucial step in non-alcoholic fatty liver disease progression through abnormal metabolic responses. In this study, we investigated the role of CCL2 gene ablation in mice that were double deficient in low density lipoprotein receptor and in paraoxonase-1. Mass spectrometry methods were used to assess the liver metabolic response in mice fed either regular chow or a high-fat diet. Dietary fat caused liver steatosis, oxidative stress and the accumulation of pro-inflammatory macrophages in the livers of double deficient mice. We observed alterations in energy metabolism-related pathways and in metabolites associated with the methionine cycle and the glutathione reduction pathway. This metabolic response was associated with impaired autophagy. Conversely, when we established CCL2 deficiency, histologic features of fatty liver disease were abrogated, hepatic liver oxidative stress decreased, and anti-inflammatory macrophage marker expression levels increased. These changes were associated with the normalization of metabolic disturbances and increased lysosome-associated membrane protein 2, expression, which suggests enhanced chaperone-mediated autophagy. This study demonstrates that CCL2 is a key molecule for the development of metabolic and histological alterations in the liver of mice sensitive to the development of hyperlipidemia and hepatic steatosis, a finding with potential to identify new therapeutic targets in liver diseases.


Assuntos
Arildialquilfosfatase/genética , Quimiocina CCL2/genética , Hiperlipidemias/genética , Lipoproteínas LDL/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Receptores de LDL/genética , Animais , Arildialquilfosfatase/deficiência , Autofagia/genética , Quimiocina CCL2/deficiência , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Regulação da Expressão Gênica , Glutationa/metabolismo , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Fígado/metabolismo , Fígado/patologia , Proteína 2 de Membrana Associada ao Lisossomo/genética , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Metaboloma/genética , Metionina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Receptores de LDL/deficiência , Transdução de Sinais
17.
Klin Lab Diagn ; 64(2): 68-77, 2019.
Artigo em Russo | MEDLINE | ID: mdl-30917246

RESUMO

Although the biochemistry of the positive effects of medium-chain fatty acids (FA) and triglycerides (TG) of the same name in vivo is not fully understood, food enriched with medium-chain LC and the same TG is effective in patients with type I diabetes, insulin resistance syndrome and in neurodegenerative pathology. Lauric C12 LC is half the FA in coconut oil. Residents of southeast Asia with constant use of coconut oil, have a low level of diseases of the cardiovascular system in the population. With a regulatory intake with food C12:0 laurin FA formed moderate ketosis and neuroprotective effect. Unlike long-chain LC, medium-chain TG cells are not deposited either in visceral fat cells, or in insulin-dependent adipocytes. Medium-chain fatty acids rapidly oxidize mitochondria; the formation of acetyl-CoA cells is used to form ketone bodies, activating thermogenesis in orange and brown adipocytes. Experiments with animals and observations in the clinic showed that taking medium-chain TG with food is more physiological than long-chain oils. This significantly increases the level of cholesterol in high-density lipoproteins. Food enriched with medium chain TG is optimal for increasing the ketone content in blood plasma, cerebrospinal fluid without limiting the carbohydrate content in food. The formation of excess ketone bodies by cells can be achieved by activating the metabolic transformations of medium-chain FAs, without fasting and preserving carbohydrates in food. Coconut oil has a positive effect on the cardiovascular system, preventing the formation of atherosclerosis and atheromatosis. Effective in the prevention of the pathology of the cardiovascular system is a decrease in food amounts of palmitic acid, an increase in oleic acid, polyene FA with a simultaneous increase in the proportion of medium-chain FA.


Assuntos
Aterosclerose/prevenção & controle , Ácidos Graxos/metabolismo , Hiperlipidemias/patologia , Resistência à Insulina , Triglicerídeos/metabolismo , Animais , Dieta , Humanos
18.
Med Sci Monit ; 25: 2179-2185, 2019 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-30904921

RESUMO

BACKGROUND Cerebral hemorrhage has been increasingly reported in patients with nephrotic syndrome (NS). However, the clinical features and pathogenesis of NS patients with cerebral hemorrhage remain unclear. MATERIAL AND METHODS From January 2007 to August 2017, continuous NS patients with cerebral hemorrhage at the First Affiliated Hospital of Guangxi Medical University were selected. The clinical manifestations, laboratory measurements, and neurological images of these patients were collected and analyzed. RESULTS Acute cerebral hemorrhage was recorded in 15 of 10 461 NS patients. The average age of these 15 patients (9 males and 6 females) was 50.87±23.27 years old. Among these 15 patients, conventional vascular risk factors were identified in 8 patients, hypoalbuminemia and proteinuria were recorded in all 15 patients, coagulopathy was observed in 9 patients, increased D-dimer level was recorded in 13 patients, hyperlipidemia was recorded in 11 patients, and impaired renal function was recorded in 9 patients. The hemorrhage developed in the lobe (n=9), basal ganglia (n=3), cerebellum (n=2), and cerebral hemisphere (n=1). Eight patients were in a coma on the day the cerebral hemorrhage occurred, while 12 patients had a poor prognosis after 30 days of hemorrhage onset. CONCLUSIONS Poor prognosis was recorded in NS patients with cerebral hemorrhage. Although conventional vascular risk factors have only been identified in 8 patients, biochemical abnormalities (hypoalbuminemia, proteinuria, elevated D-dimer, and hyperlipidemia) were recorded in the majority of these 15 patients. Furthermore, most of the hemorrhages developed in the lobes. Coagulopathy might be the potential pathogenesis of cerebral hemorrhage in NS patients.


Assuntos
Hemorragia Cerebral/complicações , Síndrome Nefrótica/complicações , Adulto , Idoso , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipoalbuminemia/metabolismo , Hipoalbuminemia/patologia , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Prognóstico , Proteinúria/patologia , Fatores de Risco
19.
Mol Cell Biochem ; 458(1-2): 39-47, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30905023

RESUMO

The development of new antihyperlipidemic agents with higher potency and lower side effects is of high priority. In this study, 1,3,4 thiadiazole Schiff base derivatives were synthesized as potential peroxisome proliferation-activated receptor-α (PPARα) agonists and characterized using elemental analysis, FTIR, 1H-NMR, 13C-NMR and mass spectroscopy and then tested for their hypolipidemic activity in Triton WR-1339-induced acute hyperlipidemic rat model in comparison with bezafibrate. The compounds showed significant hypolipidemic activity. Induced fit docking showed that the compounds are potential activators of PPARα with binding scores - 8.00 Kcal/mol for 2,5-bis(4-hydroxybenzylidenamino)-1,3,4-thiadiazole. PCR array analysis showed an increase in the expression of several genes involved in lipid metabolism through mitochondrial fatty acid ß oxidation and are part of PPARα signaling pathway including Acsm3, Fabp4 and Hmgcs1. Gene expression of Lrp12 and Lrp1b involved in LDL uptake by liver cells and Cyp7a1 involved in cholesterol catabolism were also found to be upregulated.


Assuntos
Hiperlipidemias/tratamento farmacológico , Hipolipemiantes , PPAR alfa/agonistas , Tiadiazóis , Doença Aguda , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Masculino , PPAR alfa/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tiadiazóis/química , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia
20.
Colloids Surf B Biointerfaces ; 177: 541-549, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30825846

RESUMO

The present work entails development of novel phospholipid-based self-nanoemulsifying systems (SNES) of rosuvastatin calcium for improving the oral biopharmaceutical performance via intestinal lymphatic pathways. The phospholipid complex-loaded SNES exhibited emulsification time of 142 s, particle size of 182.5 nm, polydispersity index of 0.35, zeta potential of -22.5 mV and complete in vitro drug release within 3 h. Cell line study on Caco-2 indicated absence of cytotoxicity and excellent cellular uptake of PL-SNES vis-à-vis plain SNES. Permeability study revealed >85% enhancement in the permeation, while intestinal perfusion study showed 2.9 and 3.5-fold increase in the permeation and absorption of the drug from the optimized PL-SNES over the pure drug suspension. Nearly 2.2 and 7.2-folds improvement in AUC0-t and Cmax, and 0.33-fold reduction in the Tmax of drug was observed for PL-SNES vis-à-vis the pure drug suspension during pharmacokinetic study. Moreover, PL-SNES also showed superior antihyperlipidemic activity over the pure drug suspension during pharmacodynamic study. Overall, the developed nanoformulation yielded significant improvement in the oral deliverability of the explored drug candidate.


Assuntos
Quilomícrons/química , Hiperlipidemias/tratamento farmacológico , Nanopartículas/química , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/uso terapêutico , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Coloides/química , Portadores de Fármacos/química , Humanos , Hiperlipidemias/patologia , Masculino , Ratos , Ratos Wistar , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacologia
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