RESUMEN
Vitamin A and provitamin A carotenoids are involved in the regulation of adipose tissue metabolism and inflammation. We examined the effect of dietary supplementation using all-trans and 9-cis ß-carotene-rich Dunaliella bardawil alga as the sole source of vitamin A on obesity-associated comorbidities and adipose tissue dysfunction in a diet-induced obesity mouse model. Three-week-old male mice (C57BL/6) were randomly allocated into two groups and fed a high-fat, vitamin A-deficient diet supplemented with either vitamin A (HFD) or ß-carotene (BC) (HFD-BC). Vitamin A levels in the liver, WATs, and BAT of the HFD-BC group were 1.5-2.4-fold higher than of the HFD group. BC concentrations were 5-6-fold greater in BAT compared to WAT in the HFD-BC group. The eWAT mRNA levels of the Mcp-1 and Cd68 were 1.6- and 2.1-fold lower, respectively, and the plasma cholesterol and triglyceride concentrations were 30% and 28% lower in the HFD-BC group compared with the HFD group. Dietary BC can be the exclusive vitamin A source in mice fed a high-fat diet, as shown by the vitamin A concentration in the plasma and tissues. Feeding BC rather than vitamin A reduces adipose tissue macrophage recruitment markers and plasma lipid concentrations.
Asunto(s)
Chlorophyceae , beta Caroteno , Tejido Adiposo/metabolismo , Animales , Chlorophyceae/metabolismo , Dieta Alta en Grasa/efectos adversos , Expresión Génica , Hígado , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Triglicéridos/metabolismo , Vitamina A/farmacología , beta Caroteno/metabolismo , beta Caroteno/farmacologíaRESUMEN
BACKGROUND: Low tissue concentrations of carotenoids have been suggested to contribute to insulin resistance in obesity. OBJECTIVES: The objectives of the study were to 1) evaluate the relations of adipose tissue and serum carotenoids with body fat, abdominal fat distribution, muscle, adipose tissue and liver insulin resistance, and dietary intake; 2) evaluate the relations and distributions of carotenoids detected in adipose tissue and serum; and 3) compare serum carotenoids and retinol concentrations in subjects with and without obesity. METHODS: Post hoc analysis of serum and adipose tissue carotenoids in individuals [n = 80; 31 men, 49 women; age (mean ± SEM): 51.4 ± 1.1 y] who participated in 2 separate studies conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney) between 2008 and 2013. Retinol, α-carotene, ß-carotene, ζ-carotene, lutein, lycopene, phytoene, and phytofluene were measured using HPLC. Body composition was measured by dual-energy X-ray absorptiometry. Insulin resistance was measured by 2-step hyperinsulinemic-euglycemic clamps with deuterated glucose (n = 64), and subcutaneous and visceral abdominal volume and liver and pancreatic fat by MRI (n = 60). Periumbilical subcutaneous fat biopsy was performed and carotenoids and retinol measured in the tissue (n = 16). RESULTS: We found that ζ-carotene, phytoene, and phytofluene were stored in considerable amounts in adipose tissue (25% of adipose tissue carotenoids). Carotenoid concentrations in adipose tissue and serum correlated significantly, but they followed different distributions: ζ-carotene was 3-fold higher in adipose tissue compared with serum, while lutein and lycopene made up 20% and 21% of serum carotenoids compared with 2% and 12% of adipose tissue carotenoids, respectively. Liver (P ≤ 0.028) and adipose tissue (P = 0.023), but not muscle (P ≥ 0.16), insulin resistance correlated inversely with many of the serum carotenoids. CONCLUSIONS: Multiple serum and adipose tissue carotenoids are associated with favorable metabolic traits, including insulin sensitivity in liver and adipose tissue in humans.
Asunto(s)
Tejido Adiposo/metabolismo , Carotenoides/sangre , Carotenoides/metabolismo , Resistencia a la Insulina , Obesidad/sangre , Adulto , Citocinas/genética , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica , Glucosa , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: Mediterranean diet has been associated with decreased cardiovascular morbidity and mortality. Both fish and olive oil are key components of this diet. Therefore, we compared their effects on nonalcoholic fatty liver disease (NAFLD) and atherogenesis in a mouse model, fed a high fat diet. METHODS AND RESULTS: Forty nine, female LDL receptor knockout (LDLR KO) mice were allocated into 3 groups and fed an atherogenic high fat (HF) diet for 9 weeks. The HF group was fed a high fat diet alone. A HF + OO group was fed a HF diet with added olive oil (60 ml/kg feed), and the third group (HF + FO) was fed a HF diet with added fish oil (60 ml/kg feed). Both additions of fish and olive oil, significantly decreased plasma cholesterol elevation compared to HF diet. Nevertheless, only fish oil addition reduced significantly atherosclerotic lesion area by 51% compared to HF group. Liver levels of eicosapentenoic (EPA) and docosahexaenoic (DHA) acids were several folds higher in HF + FO group than in HF and HF + OO groups. Liver levels of oleic acid were higher in HF + OO compared to the other groups. Moreover, Fish oil addition significantly decreased NAFLD scores related to steatosis and inflammation and lowered the expression of the inflammatory genes interleukin 6 (IL6) and monocyte chemoattractant protein 1 (MCP1). CONCLUSION: These results suggest that fish oil addition on top of an atherogenic, HF diet, is beneficial, while olive oil is not, in its effect on plaque formation and NAFLD in LDLR KO mice.
Asunto(s)
Aterosclerosis/prevención & control , Dieta Alta en Grasa , Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Aceite de Oliva/administración & dosificación , Animales , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Biomarcadores/sangre , Quimiocina CCL2/metabolismo , Colesterol/sangre , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Femenino , Interleucina-6/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Ácido Oléico/administración & dosificación , Ácido Oléico/metabolismo , Placa Aterosclerótica , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de TiempoRESUMEN
BACKGROUND: Breast cancer is a heterogeneous disease displaying distinct molecular features and clinical outcome. The molecular profile of triple-negative breast cancers (TNBCs) overlaps with that of basal-like breast cancers that in turn show similarities with high-grade serous ovarian and endometrial carcinoma. L1CAM is an established biomarker for the latter cancers and we showed before that approximately 18% of primary breast cancers are positive for L1CAM and have a bad prognosis. Here we analysed the expression of L1CAM breast cancer subtypes. METHODS: We analyzed mRNA and protein expression data from different breast cancer cohorts for L1CAM, estrogen receptor, progesterone receptor, Her-2 and Androgen receptor (AR) and correlated the data. We performed Western blot analysis on tumor cell lysates and carried out chromatin-immuno-precipitation (CHIP) after AR overexpression. RESULTS: We find that L1CAM is expressed preferentially though not exclusively in TNBCs. Using the human cancer genome atlas database and two independent breast cancer cohorts we find that L1CAM is inversely correlated with androgen receptor (AR) expression. We found that L1CAM(high)AR(low) primary breast tumors have the worst clinical outcome. Overexpression of AR in MDA-MB436 breast cancer cells decreased L1CAM expression at the protein and mRNA level and CHIP-analysis revealed binding of AR to the L1CAM promoter region. CONCLUSIONS: These results suggest that L1CAM in breast cancer is under AR control. The data also strongly advocate the use of L1CAM assessment in breast cancer diagnosis. We suggest that L1CAM expression could be causally related to the bad prognosis of TNBCs.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Molécula L1 de Adhesión de Célula Nerviosa/genética , Receptores Androgénicos/genética , Neoplasias de la Mama Triple Negativas/genética , Adulto , Anciano , Anciano de 80 o más Años , Sitios de Unión , Biomarcadores de Tumor , Línea Celular Tumoral , Bases de Datos Genéticas , Femenino , Humanos , Persona de Mediana Edad , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Androgénicos/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/mortalidadRESUMEN
Carotenoids are common and diverse organic compounds with various functional roles in animals. Except for certain aphids, mites, and gall midges, all animals only acquire necessary carotenoids through their diet. The house fly (Musca domestica) is a cosmopolitan pest insect that populates diverse habitats. Its larvae feed on organic substrates that may vary in carotenoid composition according to their specific content. We hypothesized that the carotenoid composition in the adult house fly's body would reflect the carotenoid composition in the larval feed. House fly larvae were reared on diets that differed in carotenoid composition. HPLC analysis of the emerging adult flies indicate that the carotenoid composition of adult house flies is related, but not identical, to the carotenoid composition in its natal substrate. These findings may be developed to help identify potential sources of house fly infestations. Also, it is recommended that rearing substrates of house fly larvae, used for animal feed, should be carefully considered.
RESUMEN
A significant progressive decline in beta-carotene (ßC) levels in the brain is associated with cognitive impairment and a higher prevalence of Alzheimer's disease (AD). In this study, we investigated whether the administration of 9-cis beta-carotene (9CBC)-rich powder of the alga Dunaliella bardawil, the best-known source of ßC in nature, inhibits the development of AD-like neuropathology and cognitive deficits. We demonstrated that in 3 AD mouse models, Tg2576, 5xFAD, and apoE4, 9CBC treatment improved long- and short-term memory, decreased neuroinflammation, and reduced the prevalence of ß-amyloid plaques and tau hyperphosphorylation. These findings suggest that 9CBC has the potential to be an effective preventive and symptomatic AD therapy.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neuroinflamatorias , Animales , Ratones , beta Caroteno/farmacología , beta Caroteno/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Dieta , Cognición , Modelos Animales de Enfermedad , Placa AmiloideRESUMEN
BACKGROUND: Synthetic retinoids are one of the mainstay treatments of psoriasis. However, their use is occasionally limited by adverse effects, especially mucocutaneous, hepatic, and lipid profile toxicity. Thus, a search for retinoid metabolites that are both safe and active is essential. The alga Dunaliella bardawil is a natural source of the retinoid precursor 9-cis ß-carotene that has a good adverse effect profile. OBJECTIVE: To test the effect of the alga Dunaliella bardawil on psoriasis. METHODS: Thirty-four adult patients with mild, chronic, plaque-type psoriasis were included in this monocentric, prospective, randomized, double-blinded pilot study. Patients received either capsules of the alga D. bardawil or starch powder capsules, as the placebo, for 12 weeks. The response to treatment was evaluated by changes in Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores. Safety of the treatment was evaluated. RESULTS: At the end of 6 weeks, the reduction in the mean PASI score was significantly higher in the Dunaliella group than in the placebo group (61.3% vs 34%, respectively, p = 0.002). The DLQI change did not reach significance (8.5% and 5.9% in the Dunaliella and in the control group, respectively, p = 0.9). We observed no significant change in the liver function tests or in the lipid profile. CONCLUSIONS: 9-cis ß-carotene, in the form of D. bardawil, is an effective and safe treatment for patients with mild, chronic, plaque-type psoriasis. A larger study is warranted.
Asunto(s)
Chlorophyta/química , Psoriasis/tratamiento farmacológico , beta Caroteno/uso terapéutico , Adulto , Anciano , Enfermedad Crónica , Método Doble Ciego , Evaluación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Polvos , Estudios Prospectivos , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , beta Caroteno/sangreRESUMEN
Maternal docosahexaenoic acid (DHA) is required during pregnancy to supply for normal fetal growth and development. This pilot study aimed to assess the unknown fatty acid (FA) composition in a cohort of non-pregnant and pregnant Israeli women at term and their offspring on a normal diet without n-3 FA supplementation. The fatty acid profile, analyzed using gas chromatography, showed significantly higher plasma monounsaturated (MUFA) and lower n-6 FA percent distribution with similar n-3 index, in pregnant compared to non-pregnant women. RBC exhibited significantly higher MUFA with similar n-3 index, in pregnant compared to non-pregnant women. N-3 FA significantly correlated between neonates' plasma, with higher n-3 index, and pregnant women's DHA. Conclusion: DHA levels in non-pregnant and pregnant Israeli women at term were comparable and the DHA in pregnant women's plasma positively correlated with their neonate's level, suggesting an efficient mother-fetus FA transfer and/or fetal fatty acid metabolism to longer FA products.
Asunto(s)
Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-6/sangre , Intercambio Materno-Fetal , Adulto , Proteínas de Arabidopsis/sangre , Ligasas de Carbono-Oxígeno/sangre , Estudios de Casos y Controles , Ácidos Docosahexaenoicos/sangre , Ácidos Grasos Esenciales/sangre , Ácidos Grasos Insaturados/sangre , Femenino , Humanos , Recién Nacido , Israel , Fenómenos Fisiologicos Nutricionales Maternos , Proyectos Piloto , Embarazo , Triglicéridos/sangre , Ácido alfa-Linolénico/sangre , Ácido gammalinolénico/sangreRESUMEN
Vitamin A deficiency (VAD) is a major health problem, especially in developing countries. In this study, we investigated the effect of VAD from weaning to adulthood in apoE-/- mice. Three-week-old male mice were allocated into four diet groups: I. VAD II. VAD+vitamin A (VA), 1500 IU retinyl-palmitate; III. VAD+ß-carotene (BC), 6 g/kg feed, containing 50% all-trans and 50% 9-cis BC. IV. VAD with BC and VA (BC+VA). After 13 weeks, we assessed the size of atherosclerotic plaques and measured VA in tissues and BC in plasma and tissues. VAD resulted in diminished hepatic VA levels and undetectable brain VA levels compared to the other groups. BC completely replenished VA levels in the liver, and BC+VA led to a two-fold elevation of hepatic VA accumulation. In adipose tissue, mice fed BC+VA accumulated only 13% BC compared to mice fed BC alone. Atherosclerotic lesion area of BC group was 73% lower compared to VAD group (p < 0.05). These results suggest that BC can be a sole source for VA and inhibits atherogenesis.
Asunto(s)
Apolipoproteínas E/deficiencia , Aterosclerosis/etiología , Aterosclerosis/prevención & control , Suplementos Dietéticos , Fitoterapia , Deficiencia de Vitamina A/tratamiento farmacológico , beta Caroteno/administración & dosificación , Animales , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Objective: While extensive research revealed that interleukin (IL)-1ß contributes to insulin resistance (IR) development, the role of IL-1α in obesity and IR was scarcely studied. Using control, whole body IL-1α knockout (KO) or myeloid-cell-specific IL-1α-deficient mice, we tested the hypothesis that IL-1α deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences. Research design and methods: To induce obesity and IR, control and IL-1α KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1α for 24 hours and subjected to gene expression analysis. Results: Although total body weight gain was similar, IL-1α KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1α KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1α KO mice. Treatment with recombinant IL-1α elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1α did not show reduced adiposity and improved glucose tolerance. Conclusions: We demonstrate a novel role of IL-1α in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1α blockade could be used for treatment of obesity and its metabolic consequences.
Asunto(s)
Adiposidad , Dieta Alta en Grasa/efectos adversos , Intolerancia a la Glucosa/prevención & control , Interleucina-1alfa/fisiología , Lipogénesis , Hígado/patología , Obesidad/patología , Animales , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/prevención & control , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Obesos , Obesidad/etiología , Obesidad/metabolismoRESUMEN
Our aim was to study the effect of 9-cis beta-carotene-rich powder of the alga Dunaliella bardawil on lipid profile, atherogenesis, and liver steatosis in high-fat diet-fed LDL receptor knockout mice. In 4 sets of experiments, mice were distributed into the following groups: control, fed an unfortified diet; Dunaliella 50, fed a diet composed of 50% 9-cis and 50% all-trans beta-carotene; Dunaliella 25, fed a diet containing 25% 9-cis and 75% all-trans beta-carotene; beta-carotene-deficient Dunaliella, fed beta-carotene-deficient Dunaliella powder; and all-trans beta-carotene, fed a synthetic all-trans beta-carotene. All fortified diets contained 0.6% total beta-carotene. Algal 9-cis beta-carotene was absorbed by the mice and accumulated in the liver. Synthetic all-trans beta-carotene was not converted to 9-cis beta-carotene. Dunaliella 50 inhibited high-fat diet-induced plasma cholesterol elevation by 40-63% and reduced cholesterol concentrations in the atherogenic VLDL and LDL. Atherosclerotic lesion area in mice treated with Dunaliella 50 was 60-83% lower compared with mice fed the high-fat diet alone. beta-Carotene-deficient Dunaliella did not influence plasma cholesterol and atherogenesis, suggesting that beta-carotene is essential for a Dunaliella protective effect. Moreover, by administrating Dunaliella powder containing different levels of 9-cis and all-trans beta-carotene isomers, we found that the effect on plasma cholesterol concentration and atherogenesis is 9-cis-dependent. Dunaliella 50 also inhibited fat accumulation and inflammation in the livers of mice fed a high-fat diet, which was accompanied by reduced mRNA levels of inflammatory genes. These results in mice suggest that 9-cis beta-carotene may have the potential to inhibit atherogenesis in humans.
Asunto(s)
Aterosclerosis/prevención & control , Dieta , Hígado Graso/prevención & control , Receptores de LDL/deficiencia , beta Caroteno/uso terapéutico , Animales , Colesterol/sangre , Eucariontes , Hipercolesterolemia/prevención & control , Absorción Intestinal , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Retinoides/metabolismo , beta Caroteno/administración & dosificación , beta Caroteno/farmacocinéticaRESUMEN
The metabolic syndrome (MS) is a common risk factor for cardiovascular disease and type-2 diabetes. Recently, telmisartan, an angiotensin II receptor antagonist that has an antihypertensive effect, has been reported to be a partial peroxisome proliferator-activated receptor gamma (PPARgamma) agonist. The anti-diabetic hormone adiponectin has been recognized as a marker of in vivo PPARgamma activation. Therefore, we studied telmisartan's effect on the metabolic profile and adiponectin levels in a fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rat model. Twenty-four male Sprague-Dawley rats were divided into three groups (eight in each). One group of control rats was fed standard chow for 5 weeks while a second was fed a fructose-enriched diet. A third group was fed a fructose-enriched diet for 5 weeks and treated with telmisartan 5 mg/kg/day during the last 2 weeks. Fructose feeding increased systolic blood pressure (mean+/-SEM), from 130+/-1 to 148+/-2 mmHg, insulin from 0.26+/-0.03 to 0.68+/-0.08 ng/mL, and triglycerides from 102+/-6 to 285+/-23 mg/dL (p<0.05 for all variables). Telmisartan treatment reversed these effects and reduced blood pressure to 125+/-2 mmHg, insulin levels to 0.41+/-0.07 ng/mL, and triglycerides to 146+/-18 mg/dL (p<0.05 for all variables), while attenuating the increase in body weight during weeks 3 to 5. In contrast, telmisartan did not affect plasma adiponectin levels. In conclusion, although telmisartan is considered a partial PPARgamma agonist, its beneficial effect in the fructose-induced hypertension, hypertriglyceridemia, and hyperinsulinemia rat model is apparently not mediated by adiponectin elevation but rather by direct inhibition of AT1 receptor.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bencimidazoles/farmacología , Benzoatos/farmacología , Fructosa , Hiperinsulinismo/inducido químicamente , Hiperinsulinismo/metabolismo , Hiperlipidemias/inducido químicamente , Hiperlipidemias/metabolismo , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Adiponectina/biosíntesis , Animales , Dieta , Insulina/sangre , Masculino , Síndrome Metabólico/inducido químicamente , Síndrome Metabólico/metabolismo , Ratas , Ratas Sprague-Dawley , Telmisartán , Triglicéridos/sangreRESUMEN
The effect of fibrates on high density lipoprotein (HDL)-cholesterol levels is suggested to be mediated by its binding to peroxisome proliferator-activated receptor-alpha (PPARalpha). Upon ligand binding, PPARalpha heterodimerizes with the 9-cis retinoic acid receptor (RXR) and it is this heterodimer which regulates gene expression. We assessed the hypothesis that a combined treatment with fibrate plus 9-cis beta-carotene-rich powder of the alga Dunaliella bardawil, as a source of 9-cis retinoic acid, would improve the drug's effect on HDL-cholesterol levels. In an open-labeled first trial, 20 fibrate-treated men with plasma HDL-cholesterol levels below 40 mg/dl were given Dunaliella capsules, providing 60 mg beta-carotene/day, containing all-trans and 9-cis beta-carotene (1:1 ratio, w/w). Twenty-two fibrate-treated patients participated in a double-blind placebo-controlled second trial. Eleven patients were treated with Dunaliella capsules, and 11 patients were treated with beta-carotene-deficient Dunaliella capsules. Following 6 weeks of the dual treatment plasma HDL-cholesterol increased by 24.5 and 12.7% in the first and second trials, respectively (P=0.002 and 0.012). The dual treatment also increased HDL-cholesterol levels in human apolipoprotein A-I transgenic mice by 87.5% (P=0.021). The results show that a combination treatment of fibrate plus 9-cis beta-carotene-rich Dunaliella powder amplifies the effect of the drug on HDL-cholesterol levels.
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Aterosclerosis/tratamiento farmacológico , Chlorophyta , HDL-Colesterol/sangre , Antagonistas Colinérgicos/uso terapéutico , Ácido Clofíbrico/uso terapéutico , Vitaminas/uso terapéutico , beta Caroteno/uso terapéutico , Adulto , Anciano , Animales , Apolipoproteína A-I/sangre , Apolipoproteína A-I/efectos de los fármacos , Aterosclerosis/sangre , HDL-Colesterol/efectos de los fármacos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Polvos , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate lens epithelial cell (LEC) proliferation on the anterior optic of 2 types of hydrophobic intraocular lenses (IOLs). SETTING: Harlan Biotech Israel and Kaplan Medical Center, Rehovot, Israel. DESIGN: Experimental study. METHODS: Ten New Zealand white rabbits had crystalline lens removal and implantation of an Acrysof IOL in 1 eye (Group 1) and a Tecnis IOL in the fellow eye (Group 2). A weekly biomicroscopy examination was performed during the 2-week study duration, after which the rabbits were humanely killed. The eyes were enucleated, and the complexes containing the IOL and the capsular bag were evaluated for the presence of LECs and large cells (macrophages and giant cells) on the IOL anterior optic and for proteinaceous matrix deposits along the capsulorhexis margin. RESULTS: Lens epithelial cell were detected on all of the IOLs in Group 1 and on none in Group 2 (P < .001). Areas of proteinaceous matrix deposits adjacent to the edge of the capsulorhexis were detected on 8 IOLs in Group 1 and on none in Group 2 (P < .001). Large cells were identified on all IOLs in Group 1 and on 9 IOLs in Group 2 (P = 1.0). No difference in the general inflammation markers was found between the 2 IOL types (P = .234). CONCLUSIONS: Lens epithelial cell with corresponding proteinaceous matrix deposits were significantly more abundant on the IOLs in Group 1 than on the IOLs in Group 2. There was no difference in the presence of large cells or in general inflammation markers between the 2 IOL types. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.
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Proliferación Celular , Células Epiteliales/patología , Cristalino/patología , Lentes Intraoculares , Resinas Acrílicas , Animales , Capsulorrexis , Cristalinas/metabolismo , Células Gigantes/patología , Interacciones Hidrofóbicas e Hidrofílicas , Implantación de Lentes Intraoculares , Cristalino/cirugía , Macrófagos/patología , Masculino , Unión Proteica/fisiología , ConejosRESUMEN
Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-ß-carotene (9-cis-ßc) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-ßc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with ßc from the alga Dunaliella led to ßc accumulation in peritoneal macrophages. 9-cis-ßc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from ßc in RAW264.7 macrophages. Furthermore, 9-cis-ßc, as well as all-trans-ßc, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-ßc augmented cholesterol efflux from macrophages ex vivo. 9-cis-ßc increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE) and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-ßc from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of ßc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages.
Asunto(s)
Aterosclerosis/prevención & control , HDL-Colesterol/metabolismo , Suplementos Dietéticos , Reguladores del Metabolismo de Lípidos/uso terapéutico , Macrófagos Peritoneales/metabolismo , Regulación hacia Arriba , beta Caroteno/análogos & derivados , Transportador 1 de Casete de Unión a ATP/agonistas , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/agonistas , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Animales , Apolipoproteínas E/agonistas , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Células Cultivadas , Chlorophyta/química , HDL-Colesterol/sangre , Inducción Enzimática , Reguladores del Metabolismo de Lípidos/metabolismo , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fitoplancton/química , Células RAW 264.7 , Receptores de LDL/genética , Receptores de LDL/metabolismo , Ácido Retinoico 4-Hidroxilasa/química , Ácido Retinoico 4-Hidroxilasa/genética , Ácido Retinoico 4-Hidroxilasa/metabolismo , beta Caroteno/metabolismo , beta Caroteno/uso terapéuticoRESUMEN
Oxygenases are a family of enzymes that dioxygenate unsaturated fatty acids, thus initiating membrane oxidation and signaling molecule synthesis. The lipoxygenases (LOs), a family of lipid-peroxidizing enzymes that induce structural and metabolic changes in the cell in a number of pathophysiological conditions, belong to the oxygenases family. This class of enzymes has several subgroups, named 5-, 8-, 12- and 15-LOs, and these LO-isoforms are capable of oxygenating arachidonic and linoleic acid. 15-LOs were reported to play an inhibitory role in tumor angiogenesis and, consequently, they slow down carcinogenesis. It has been suggested that its anti-carcinogenic effect is conferred by promoting cell differentiation and apoptosis. Using transgenic mice that over-express 15-LO-1 in endothelial cells under the regulation of the murine preproendothelin-1 promoter, we studied its effect on tumor and metastasis growth. We found that 15-LO-1 inhibited tumor and metastasis growth in the transgenic mice in two different models of cancer (mammary gland and Lewis lung carcinoma). This inhibition was concomitant with a higher number of apoptotic cells in the metastases of the transgenic mice and with a complicated network of multiple small blood vessels. This finding targets 15-LO as a new candidate in the treatment of carcinogenesis.
Asunto(s)
Araquidonato 15-Lipooxigenasa/fisiología , Transformación Celular Neoplásica/genética , Endotelina-1/fisiología , Neovascularización Patológica/genética , Animales , Apoptosis/genética , Apoptosis/fisiología , Araquidonato 15-Lipooxigenasa/biosíntesis , Araquidonato 15-Lipooxigenasa/genética , Vasos Sanguíneos , Carcinoma Pulmonar de Lewis/irrigación sanguínea , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/fisiopatología , Regiones Promotoras Genéticas , Regulación hacia ArribaRESUMEN
Atherosclerosis is a major cause of morbidity and mortality in developed societies, and begins when activated endothelial cells recruit monocytes and T-cells from the bloodstream into the arterial wall. Macrophages that accumulate cholesterol and other fatty materials are transformed into foam cells. Several epidemiological studies have demonstrated that a diet rich in carotenoids is associated with a reduced risk of heart disease; while previous work in our laboratory has shown that the 9-cis ß-carotene rich alga Dunaliella inhibits atherogenesis in mice. The effect of 9-cis ß-carotene on macrophage foam cell formation has not yet been investigated. In the present work, we sought to study whether the 9-cis ß-carotene isomer, isolated from the alga Dunaliella, can inhibit macrophage foam cell formation upon its conversion to retinoids. The 9-cis ß-carotene and Dunaliella lipid extract inhibited foam cell formation in the RAW264.7 cell line, similar to 9-cis retinoic acid. Furthermore, dietary enrichment with the algal powder in mice resulted in carotenoid accumulation in the peritoneal macrophages and in the inhibition of foam cell formation ex-vivo and in-vivo. We also found that the ß-carotene cleavage enzyme ß-carotene 15,15'-monooxygenase (BCMO1) is expressed and active in macrophages. Finally, 9-cis ß-carotene, as well as the Dunaliella extract, activated the nuclear receptor RXR in hepa1-6 cells. These results indicate that dietary carotenoids, such as 9-cis ß-carotene, accumulate in macrophages and can be locally cleaved by endogenous BCMO1 to form 9-cis retinoic acid and other retinoids. Subsequently, these retinoids activate the nuclear receptor RXR that, along with additional nuclear receptors, can affect various metabolic pathways, including those involved in foam cell formation and atherosclerosis.
Asunto(s)
Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismo , beta Caroteno/farmacología , beta-Caroteno 15,15'-Monooxigenasa/metabolismo , Alimentación Animal , Animales , Línea Celular , Células Cultivadas , Activación Enzimática , Expresión Génica , Masculino , Ratones , Ratones Noqueados , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/metabolismo , Estereoisomerismo , beta Caroteno/química , beta Caroteno/metabolismo , beta-Caroteno 15,15'-Monooxigenasa/genéticaRESUMEN
Vitamin A is involved in regulation of glucose concentrations, lipid metabolism, and inflammation, which are major risk factors for atherogenesis. However, the effect of vitamin A deficiency on atherogenesis has not been investigated. Therefore, the objective of the current study was to examine whether vitamin A deficiency accelerates atherogenesis in apolipoprotein E-deficient mice (apoE(-/-)). ApoE(-/-) mice were allocated into the following groups: control, fed vitamin A-containing chow diet; BC, fed chow diet fortified with Dunaliella powder containing ßc isomers; VAD, fed vitamin A-deficient diet; and VAD-BC group, fed vitamin A-deficient diet fortified with a Dunaliella powder. Following 15 weeks of treatment, liver retinol concentration had decreased significantly in the VAD group to about 30% that of control group. Vitamin A-deficient diet significantly increased both plasma cholesterol concentrations and the atherosclerotic lesion area at the aortic sinus (+61%) compared to the control group. Dietary ßc fortification inhibited the elevation in plasma cholesterol and retarded atherogenesis in mice fed the vitamin A-deficient diet. The results imply that dietary vitamin A deficiency should be examined as a risk factor for atherosclerosis and that dietary ßc, as a sole source of retinoids, can compensate for vitamin A deficiency.
Asunto(s)
Apolipoproteínas E/deficiencia , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/etiología , Suplementos Dietéticos , Deficiencia de Vitamina A/complicaciones , Vitamina A/metabolismo , beta Caroteno/uso terapéutico , Animales , Aterosclerosis/sangre , Aterosclerosis/prevención & control , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Resistencia a la Insulina , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Vitamina A/sangre , Deficiencia de Vitamina A/sangre , Deficiencia de Vitamina A/patologíaRESUMEN
The L1 cell adhesion molecule (L1CAM) is overexpressed in many human cancers and can serve as a biomarker for prognosis in most of these cancers (including type I endometrial carcinomas). Here we provide an optimized immunohistochemical staining procedure for a widely used automated platform (VENTANA™), which has recourse to commercially available primary antibody and detection reagents. In parallel, we optimized the staining on a semi-automated BioGenix (i6000) immunostainer. These protocols yield good stainings and should represent the basis for a reliable and standardized immunohistochemical detection of L1CAM in a variety of malignancies in different laboratories.
Asunto(s)
Molécula L1 de Adhesión de Célula Nerviosa/análisis , Neoplasias Ováricas/química , Femenino , Formaldehído , Humanos , Inmunohistoquímica , Neoplasias Ováricas/patología , Adhesión en Parafina , Fijación del TejidoRESUMEN
IMPORTANCE: Retinitis pigmentosa (RP) is the leading cause of incurable inherited blindness in the developed world, with an estimated prevalence of 1 in 3500 individuals. Therefore, it is important to develop new treatments for this disease. OBJECTIVE: To determine the effect of oral treatment with 9-cis ß-carotene on visual function of patients with RP. DESIGN: Randomized, double-masked, placebo-controlled, crossover clinical trial. SETTING: University tertiary medical facility. PARTICIPANTS: Thirty-four patients with RP who were at least 18 years of age. Twenty-nine patients completed the study and were included in the analysis. INTERVENTIONS: Patients were treated daily for 90 days with capsules containing 300 mg of 9-cis ß-carotene-ich alga Dunaliella bardawil (ß-carotene, approximately 20 mg) or placebo (starch). Following a 90-day washout period, they were treated for 90 days with the other capsules. MAIN OUTCOMES AND MEASURES: The primary outcomewas the change for both eyes from baseline to the end of each treatment in dark-adapted maximal electroretinographic b-wave amplitude. The secondary outcomes were the changes in light-adapted maximal b-wave amplitude, dark- and light-adapted visual field, and best-corrected visual acuity. RESULTS: The mean change in dark-adapted maximal b-wave amplitude relative to initial baseline was +8.4 µV for 9-cis ß-carotene vs −.9 µV for placebo (P = .001). Ten participants (34.5%) had an increase of more than 10 µV for both eyes (range, 11-42 µV) after 9-cis ß-carotene treatment compared with no participants after placebo treatment. The percentage change in light-adapted b-wave response was +17.8%for 9-cis ß-carotene vs −.0% for placebo (P = .01). No significant differences were found between the groups for visual field and best-corrected visual acuity. No adverse effects were observed. CONCLUSIONS AND RELEVANCE: Treatment with 9-cis ß-carotene significantly increased retinal function in patients with RP under the tested conditions. The optimal therapeutic regimen will be determined in future, larger clinical trials. 9-cis ß-Carotene may represent a new therapeutic approach for some patients with RP. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01256697.