RESUMO
OBJECTIVE: We aimed to investigate whether combined physical exercise may affect plasma lipid variables, paraoxonase 1 (PON1) activity, and inflammation parameters in adults with obesity. METHODS: Thirty-six participants were recruited to complete the study protocol. The mean age was 37 ± 1 years, and the baseline body mass index was 33.0 ± 0.4 kg/m2. Participants were allocated to the control group (CG) and the exercise group (EG). The EG performed three weekly sessions of combined physical exercise for 16 weeks. Plasma lipid variables, PON1 activity, and inflammatory profile were determined before and after intervention. RESULTS: Total cholesterol levels decreased in both groups, without intergroup difference (time p = 0.001). Non-high-density lipoprotein cholesterol (HDL-C) levels decreased in both groups (time p = 0.001); however, they were lower in the EG than in the CG (p = 0.038). The EG had increased HDL-C levels, but the CG had decreased HDL-C levels (time*group p = 0.011). PON1 activity was reduced in both groups (time, p = 0.001). The Castelli risk Index I and II reduced in the EG and increased in the CG (time*group, p = 0.008 and p = 0.011, respectively). The inflammatory markers were not modified. CONCLUSION: Adults with obesity may benefit from regular practice of combined physical exercise training in many metabolic aspects that are related to protection against the development of cardiovascular disease.
Assuntos
Arildialquilfosfatase , Obesidade , Adulto , Colesterol , Exercício Físico , Humanos , Inflamação , Obesidade/terapiaRESUMO
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
Aterosclerose/tratamento farmacológico , Lipídeos/administração & dosagem , Lipoproteínas LDL/efeitos dos fármacos , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Moduladores de Tubulina/administração & dosagem , Animais , Quimioterapia Combinada , Masculino , Tamanho da Partícula , CoelhosRESUMO
Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and has no effective treatment. A lipid nanoemulsion (LDE) can carry chemotherapeutic agents in the circulation and concentrates them in the heart graft. The aim of the study was to investigate the effects of methotrexate (MTX) associated to LDE. Rabbits fed a 0.5% cholesterol diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg·kg-1·day-1 orally) and allocated to treatment with intravenous LDE-MTX (4 mg/kg, weekly, n=10) or with weekly intravenous saline solution (control group, n=10), beginning on the day of surgery. Animals were euthanized 6 weeks later. Compared to controls, grafts of LDE-MTX treated rabbits showed 20% reduction of coronary stenosis, with a four-fold increase in vessel lumen and 80% reduction of macrophage staining in grafts. Necrosis was attenuated by LDE-MTX. Native hearts of both LDE-MTX and Control groups were apparently normal. Gene expression of lipoprotein receptors was significantly greater in grafts compared to native hearts. In LDE-MTX group, gene expression of the pro-inflammatory factors tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-18, vascular cell adhesion molecule-1, and matrix metalloproteinase-12 was strongly diminished whereas expression of anti-inflammatory interleukin-10 increased. LDE-MTX promoted improvement of the cardiac allograft vasculopathy and diminished inflammation in heart grafts.
Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Coração/efeitos adversos , Imunossupressores/administração & dosagem , Lipídeos/administração & dosagem , Metotrexato/administração & dosagem , Nanopartículas/administração & dosagem , Aloenxertos , Animais , Imunossupressores/farmacologia , Metotrexato/farmacologia , Nanopartículas/química , CoelhosRESUMO
OBJECTIVE: Investigate the relations of glycemic levels with plasma lipids and in vitro lipid transfers to HDL in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: 143 patients with type 2 diabetes not taking anti-lipidemic drugs were separated into 2 groups: group A included 62 patients with glycated hemoglobin (HbA1c)≤6.5% (48 mmol/mol) and group B 81 patients with HbA1c>6.5%. In vitro transfer of lipids was determined by 1 h incubation of a donor nanoemulsion containing radioactively labeled unesterified and esterified cholesterol, phospholipids and triglycerides with whole plasma followed by chemical precipitation and radioactive counting in the supernatant (HDL). RESULTS: LDL and HDL cholesterol were similar in Group A and B, but group B had higher triglycerides (2.31±1.30 vs. 1.58±0.61 mmol/l, P<0.0001) and total and non-HDL unesterified cholesterol (36.3±7.8 vs. 33.9±5.9 mmol/l, P<0,05; 30.6±7.9 vs. 27.6±6.2 mmol/l, P<0,05; respectively) than group A and a non-significant trend to increased apolipoprotein B (103±20 vs. 97±20 mg/dl, P=0.08). 36 patients with the highest, ≥8.0% (64 mmol/mol), HbA1c also showed non-significant trend of elevated non-esterified fatty acids (NEFA) compared to 37 with lowest, ≤6.0% (42 mmol/mol), HbA1c (P=0.08). Patients with higher NEFA had higher triglycerides than those with lower NEFA levels (P<0.01).Transfers of all lipids from nanoemulsion to HDL and lipid composition of HDL were equal in both groups. CONCLUSIONS: For the first time it was shown that in addition to triglycerides, unesterified cholesterol is also a marker of poor glycemic control. In vitro HDL lipid transfers, an important aspect of HDL metabolism, were not related with the glycemic control.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metabolismo dos Lipídeos/fisiologia , Lipídeos/sangue , Idoso , Glicemia/metabolismo , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A lipid nanoemulsion (LDE) resembling low-density lipoprotein can target malignant tumours. In in vivo and clinical studies, association of chemotherapeutic agents to LDE decreased their toxicity and increased pharmacological action. Here, safety of LDE as carmustine carrier (50 mg m(-2) , intravenous) combined with vincristine and prednisone for the treatment of dogs with lymphoma was tested and compared with commercial carmustine with vincristine and prednisone. In five dogs from LDE-carmustine and six from commercial carmustine, complete remission was achieved (P > 0.05). Partial remission occurred in two dogs from each group. In both groups, the median progression-free intervals (119 and 199 days) and overall survival times (207 and 247 days) were equal. Neutropenia was observed in both groups, but no other major toxicities occurred. Therefore, no difference was observed between the treatments. LDE-carmustine was shown to be safe and effective in a drug combination protocol, which encourages larger studies to investigate the use of this novel formulation to treat canine lymphomas.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carmustina/administração & dosagem , Doenças do Cão/tratamento farmacológico , Linfoma de Células B/veterinária , Linfoma de Células T/veterinária , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brasil , Carmustina/efeitos adversos , Intervalo Livre de Doença , Doenças do Cão/diagnóstico , Cães , Emulsões Gordurosas Intravenosas/administração & dosagem , Feminino , Estimativa de Kaplan-Meier , Linfoma de Células B/diagnóstico , Linfoma de Células B/tratamento farmacológico , Linfoma de Células T/diagnóstico , Linfoma de Células T/tratamento farmacológico , Masculino , Projetos Piloto , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
BACKGROUND AND AIMS: Vegan diet excludes all foodstuffs of animal origin and leads to cholesterol lowering and possibly reduction of cardiovascular disease risk. The aim was to investigate whether vegan diet improves the metabolic pathway of triglyceride-rich lipoproteins, consisting in lipoprotein lipolysis and removal from circulation of the resulting remnants and to verify whether the diet alters HDL metabolism by changing lipid transfers to this lipoprotein. METHODS AND RESULTS: 21 vegan and 29 omnivores eutrophic and normolipidemic subjects were intravenously injected triglyceride-rich emulsions labeled with (14)C-cholesterol oleate and (3)H-triolein: fractional clearance rates (FCR, in min(-1)) were calculated from samples collected during 60 min for radioactive counting. Lipid transfer to HDL was assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids; % lipids transferred to HDL were quantified in supernatant after chemical precipitation of non-HDL fractions and nanoemulsion. Serum LDL cholesterol was lower in vegans than in omnivores (2.1 ± 0.8, 2.7 ± 0.7 mmol/L, respectively, p < 0,05), but HDL cholesterol and triglycerides were equal. Cholesteryl ester FCR was greater in vegans than in omnivores (0.016 ± 0.012, 0.003 ± 0.003, p < 0.01), whereas triglyceride FCR was equal (0.024 ± 0.014, 0.030 ± 0.016, N.S.). Cholesteryl ester transfer to HDL was lower in vegans than in omnivores (2.7 ± 0.6, 3.5 ± 1.5%, p < 0,05). Free-cholesterol, triglyceride and phospholipid transfer were equal, as well as HDL size. CONCLUSION: Remnant removal from circulation, estimated by cholesteryl oleate FCR was faster in vegans, but the lipolysis process, estimated by triglyceride FCR was equal. Increased removal of atherogenic remnants and diminution of cholesteryl ester transfer may favor atherosclerosis prevention by vegan diet.
Assuntos
Dieta Vegetariana , Lipoproteínas HDL/metabolismo , Lipoproteínas/farmacocinética , Triglicerídeos/farmacocinética , Adulto , Radioisótopos de Carbono , Ésteres do Colesterol/sangue , LDL-Colesterol/sangue , Emulsões/administração & dosagem , Emulsões/farmacocinética , Feminino , Humanos , Lipólise , Lipoproteínas/administração & dosagem , Lipoproteínas HDL/química , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Tamanho da Partícula , Triglicerídeos/administração & dosagem , Trioleína/análise , TrítioRESUMO
Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.
Assuntos
Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Terapia Neoadjuvante/métodos , Receptores de LDL/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , Proteínas de Transporte/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Emulsões , Imuno-Histoquímica , Estadiamento de Neoplasias , Triglicerídeos/sangueRESUMO
Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Terapia Neoadjuvante/métodos , Receptores de LDL/metabolismo , Adulto , Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , Proteínas de Transporte/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Emulsões , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Triglicerídeos/sangueRESUMO
OBJECTIVE: Our purpose was to examine the effects of daily servings of butter, no-trans-fat margarine and plant sterol margarine, within recommended amounts, on plasma lipids, apolipoproteins (Apos), biomarkers of inflammation and endothelial dysfunction, and on the transfer of lipids to HDL particles in free-living subjects with the metabolic syndrome. METHODS: This was a randomized, single-blind study where 53 metabolic syndrome subjects (62% women, mean age 54 years) received isocaloric servings of butter, no-trans-fat margarine or plant sterol margarine in addition to their usual diets for 5 weeks. The main outcome measures were plasma lipids, Apo, inflammatory and endothelial dysfunction markers (CRP, IL-6, CD40L or E-selectin), small dense LDL cholesterol concentrations and in vitro radioactive lipid transfer from cholesterol-rich emulsions to HDL. Difference among groups was evaluated by analysis of variance. RESULTS: There was a significant reduction in Apo-B (-10.4 %, P=0.043) and in the Apo-B/Apo-A-1 ratio (-11.1%, P=0.034) with plant sterol margarine. No changes in plasma lipids were noticed with butter and no-trans-fat margarine. Transfer rates of lipids to HDL were reduced in the no-trans-fat margarine group: triglycerides -42.0%, (P<0.001 vs butter and sterol margarine) and free cholesterol -16.2% (P=0.006 vs sterol margarine). No significant effects were noted on the concentrations of inflammatory and endothelial dysfunction markers among the groups. CONCLUSIONS: In free-living subjects with the metabolic syndrome consumption of plant sterol and no-trans-fat margarines within recommended amounts reduced, respectively, Apo-B concentrations and the ability of HDL to accept lipids.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Gorduras na Dieta/administração & dosagem , Mediadores da Inflamação/sangue , Lipídeos/sangue , Lipoproteínas HDL/metabolismo , Síndrome Metabólica/sangue , Síndrome Metabólica/dietoterapia , Adulto , Apolipoproteínas/sangue , Biomarcadores/sangue , Manteiga/efeitos adversos , Doenças Cardiovasculares/complicações , Gorduras na Dieta/efeitos adversos , Selectina E/sangue , Endotélio Vascular/fisiopatologia , Substitutos da Gordura/administração & dosagem , Substitutos da Gordura/efeitos adversos , Feminino , Humanos , Lipoproteínas HDL/sangue , Masculino , Margarina/efeitos adversos , Margarina/análise , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Fitosteróis/administração & dosagem , Fitosteróis/efeitos adversos , Fatores de Risco , Método Simples-CegoRESUMO
We have shown that the free cholesterol (FC) and the cholesteryl ester (CE) moieties of a nanoemulsion with lipidic structure resembling low-density lipoproteins show distinct metabolic fate in subjects and that this may be related to the presence of dyslipidemia and atherosclerosis. The question was raised whether induction of hyperlipidemia and atherosclerosis in rabbits would affect the metabolic behavior of the two cholesterol forms. Male New Zealand rabbits aged 4-5 months were allocated to a control group (N = 17) fed regular chow and to a 1% cholesterol-fed group (N = 13) during a 2-month period. Subsequently, the nanoemulsion labeled with 3H-FC and 14C-CE was injected intravenously for the determination of plasma kinetics and tissue uptake of the radioactive labels. In controls, FC and CE had similar plasma kinetics (fractional clearance rate, FCR = 0.234 +/- 0.056 and 0.170 +/- 0.038 h-1, respectively; P = 0.065). In cholesterol-fed rabbits, the clearance of both labels was delayed and, as a remarkable feature, FC-FCR (0.089 +/- 0.033 h-1) was considerably greater than CE-FCR (0.046 +/- 0.010 h-1; P = 0.026). In the liver, the major nanoemulsion uptake site, uptake of the labels was similar in control animals (FC = 0.2256 +/- 0.1475 and CE = 0.2135 +/- 0.1580%/g) but in cholesterol-fed animals FC uptake (0.0890 +/- 0.0319%/g) was greater than CE uptake (0.0595 +/- 0.0207%/g; P < 0.05). Therefore, whereas in controls, FC and CE have similar metabolism, the induction of dyslipidemia and atherosclerosis resulted in dissociation of the two forms of cholesterol.