Natural estrogens enhance the engraftment of human hematopoietic stem and progenitor cells in immunodeficient mice

Hematopoietic Stem and Progenitor Cells are crucial in the maintenance of lifelong production of all blood cells. These Stem Cells are highly regulated to maintain homeostasis through a delicate balance between quiescence, self-renewal and differentiation. However, this balance is altered during the hematopoietic recovery after Hematopoietic Stem and Progenitor Cell Transplantation. Transplantation efficacy can be limited by inadequate Hematopoietic Stem Cells number, poor homing, low level of engraftment, or limited self-renewal. As recent evidences indicate that estrogens are involved in regulating the hematopoiesis, we sought to examine whether natural estrogens (estrone or E1, estradiol or E2, estriol or E3 and estetrol or E4) modulate human Hematopoietic Stem and Progenitor Cells. Our results show that human Hematopoietic Stem and Progenitor Cell subsets express estrogen receptors, and whose signaling is activated by E2 and E4 on these cells. Additionally, these natural estrogens cause different effects on human Progenitors in vitro. We found that both E2 and E4 expand human Hematopoietic Stem and Progenitor Cells. However, E4 was the best tolerated estrogen and promoted cell cycle of human Hematopoietic Progenitors. Furthermore, we identified that E2 and, more significantly, E4 doubled human hematopoietic engraftment in immunodeficient mice without altering other Hematopoietic Stem and Progenitor Cells properties. Finally, the impact of E4 on promoting human hematopoietic engraftment in immunodeficient mice might be mediated through the regulation of mesenchymal stromal cells in the bone marrow niche. Together, our data demonstrate that E4 is well tolerated and enhances human reconstitution in immunodeficient mice, directly by modulating human Hematopoietic Progenitor properties and indirectly by interacting with the bone marrow niche. This application might have particular relevance to ameliorate the hematopoietic recovery 3 after myeloablative conditioning, especially when limiting numbers of Hematopoietic Stem and Progenitor Cells are available

Efecto de la administracion de escualeno sobre el desarrollo aterosclerotico asociado con el contenido hepatico de lipidos dependiente del sexo

Trabajo presentado en el XXXI Congreso Sociedad Española de Bioquímica y Biología Molecular SEBBM, celebrado en Bilbao (España) el 10 de septiembre de 2008.[Objective]: To investigate the effect of this isoprenoid on the development of atherosclerosis.[Methods and Results]: Two groups of apoE-knockout mice, separated according to sex, were fed on standard chow diet: the control group receiving only vehicle and the second group an aqueous solution of squalene to provide a dose of 1 g/kg/day for 10 weeks. At the end of this period, plasma lipid parameters, oxidative stress markers and hepatic fat were measured as well as cross-sectional lesion area of aortic root in both groups. Data showed that in males squalene feeding reduced atherosclerotic lesion area independently of plasma lipids and activation of circulating monocytes. In contrast, squalene intake did not decrease lesion area in females, despite reducing plasma cholesterol and triglycerides, isoprostane and percentage of Mac-1 expressing white cells. In males, atherosclerotic lesion area was positively and signifi cantly associated with hepatic fat content and the plasma triglycerides were also strongly associated with liver weight.[Conclusions]: These results indicate that administration of squalene modulate lesion development in a gender specifi c manner, and that accumulation of hepatic fat by liver

Olive oil preparation determines the atherosclerotic protection in apolipoprotein E knockout mice

Oils enriched in monounsaturated fatty acids do not seem to behave similarly in protecting against the development of atherosclerosis in animal models, which has been attributed to the presence of soluble phenolic compounds. To test the relevance of other components of oils in the prevention of atherosclerosis, two olive oils from the same cultivar devoid of soluble phenolic compounds were prepared using different procedures (pressure or centrifugation), characterized and fed to apolipoprotein E-deficient mice as 10% (w/w) of their diet. The 2 olive oils had similar levels of monounsaturated fatty acids and squalene, but they differed in their content of linoleic, phytosterols, tocopherols, triterpenes and waxes, which were particularly enriched in the test olive oil obtained by centrifugation. In mice that received a diet enriched in the olive oil derived through centrifugation, the progression of atherosclerosis was delayed compared to the mice that received standard olive oil. That effect was associated with decreases in plasma triglycerides, total and non-high-density lipoprotein cholesterol and isoprostane 8-iso-prostaglandin F2α. Our results clearly indicate that the preparation of olive oil is crucial in determining its antiatherosclerotic effect, which extends beyond the presence of phenolic compounds. The test olive oil exerted its antiatherosclerotic effects by modifying plasma lipids and oxidative stress, and it might be a good candidate to replace other fats in functional foods.This research was supported by grants FEGA-FEOGA (CAO99-014), CICYT (SAF2004-08173-C03-02 and AGL2002-00495), Junta de Andalucía (CAO01-002), FISS 01/0202, Redes DGA (A-26) and FISS de investigación cooperativa C03-01 and G03-140 and by Fundación Española del Corazón.Peer reviewe

Squalene in a sex-dependent manner modulates atherosclerotic lesion which correlates with hepatic fat content in apoE-knockout male mice

BACKGROUND: Squalene is an intermediate of cholesterol biosynthesis which can be obtained from the diet where it is abundant, for example, in olive oil. The effect of this isoprenoid on the development of atherosclerosis was investigated on apoE-knockout mice. METHODS AND RESULTS: Two groups of animals, separated according to sex, were fed on standard chow diet: the control group receiving only vehicle and the second group an aqueous solution of squalene to provide a dose of 1g/kg/day in male and female mice. This treatment was maintained for 10 weeks. At the end of this period, plasma lipid parameters, oxidative stress markers and hepatic fat were measured as well as cross-sectional lesion area of aortic root in both groups. Data showed that in males squalene feeding reduced atherosclerotic lesion area independently of plasma lipids and activation of circulating monocytes. In contrast, squalene intake did not decrease lesion area in females, despite reducing plasma cholesterol and triglycerides, isoprostane and percentage of Mac-1 expressing white cells. In males, atherosclerotic lesion area was positively and significantly associated with hepatic fat content and the plasma triglycerides were also strongly associated with liver weight. CONCLUSIONS: These results indicate that administration of squalene modulates lesion development in a gender specific manner, and that accumulation of hepatic fat by liver is highly correlated with lesion progression in males. Hence, squalene administration could be used as a safe alternative to correct hepatic steatosis and atherosclerosis particularly in males.Peer reviewe

Hydroxytyrosol administration enhances atherosclerotic lesion development in apo E deficient mice

Hydroxytyrosol is a phenol found in olive oil. To verify the effect of hydroxytyrosol on the development of atherosclerosis, two groups of apo E deficient male mice on a standard chow diet were used: the control group receiving only water, and the second group an aqueous solution of hydroxytyrosol in order to provide a dose of 10 mg/kg/day to each mouse. This treatment was maintained for 10 weeks. At the moment of sacrifice, blood was drawn and heart removed. Plasma lipids, apolipoproteins and monocyte Mac-1 expression were assayed as well as aortic atherosclerotic areas in both groups. Data showed no significant changes in HDL cholesterol, paraoxonase, apolipoprotein B or triglyceride levels. However, hydroxytyrosol administration decreased apolipoprotein A-I and increased total cholesterol, atherosclerotic lesion areas and circulating monocytes expressing Mac-1. The latter was highly correlated with lesion areas (r = 0.65, P < 0.01). These results indicate that administration of hydroxytyrosol in low cholesterol diets increases atherosclerotic lesion associated with the degree of monocyte activation and remodelling of plasma lipoproteins. Our data supports the concept that phenolic-enriched products, out of the original matrix, could be not only non useful but also harmful. Our results suggest that the formulation of possible functional foods should approximate as much as possible the natural environment in which active molecules are found.This research was supported by grants FEGA-FEOGA (CAO99-0014), CICYT (SAF2004-08173-C03-02 and AGL2002-00495), Junta de Andalucía (CAO01-002), FISS 01/0202, Redes DGA (A-26) and FISS de investigación cooperativa C03-01 and G03-140 and by Fundación Española del Corazón.This research was supported by grants FEGA-FEOGA (CAO99-0014), CICYT (SAF2004-08173-C03-02 and AGL2002-00495), Junta de Andalucía (CAO01-002), FISS 01/0202, Redes DGA (A-26) and FISS de investigación cooperativa C03-01 and G03-140 and by Fundación Española del Corazón. R.C., S.A., M.A.N. and N.G. were recipient of DGA, FEGA-FEOGA and Fundación Cuenca Villoro fellowships.Peer reviewe