Tissue Uptake Mechanisms Involved in the Clearance of Non-Protein Nanoparticles that Mimic LDL Composition: A Study with Knockout and Transgenic Mice.

Lipid core nanoparticles (LDE) resembling LDL behave similarly to native LDL when injected in animals or subjects. In contact with plasma, LDE acquires apolipoproteins (apo) E, A-I and C and bind to LDL receptors. LDE can be used to explore LDL metabolism or as a vehicle of drugs directed against tumoral or atherosclerotic sites. The aim was to investigate in knockout (KO) and transgenic mice the plasma clearance and tissue uptake of LDE labeled with 3H-cholesteryl ether. LDE clearance was lower in LDLR KO and apoE KO mice than in wild type (WT) mice (p < 0.05). However, infusion of human apoE3 into the apoE KO mice increased LDE clearance. LDE clearance was higher in apoA-I KO than in WT. In apoA-I transgenic mice, LDE clearance was lower than in apoA-I KO and than in apoA-I KO infusion with human HDL. Infusion of human HDL into the apoA-I KO mice resulted in higher LDE clearance than in the apoA-I transgenic mice (p < 0.05). In apoA-I KO and apoA-I KO infused human HDL, the liver uptake was greater than in WT animals and apoA-I transgenic animals (p < 0.05). LDE clearance was lower in apoE/A-I KO than in WT. Infusion of human HDL increased LDE clearance in those double KO mice. No difference among the groups in LDE uptake by the tissues occurred. In conclusion, results support LDLR and apoE as the key players for LDE clearance, apoA-I also influences those processes.

Reduction of Atherosclerotic Lesions by the Chemotherapeutic Agent Carmustine Associated to Lipid Nanoparticles.

PURPOSE: After injection in the bloodstream, a lipid nanoparticle (LDE) resembling low-density lipoprotein (LDL) concentrates in atherosclerotic lesions of cholesterol-fed rabbits. Here, rabbits with atherosclerosis were treated with carmustine, an antiproliferative agent used in cancer chemotherapy, associated to LDE to investigate the effects on the lesions. METHODS: Twenty-seven male New Zealand rabbits were fed a 1 % cholesterol diet for 8 weeks. After 4 weeks nine animals were treated with intravenous saline solution, nine with intravenous LDE alone, and nine with intravenous LDE-carmustine (4 mg/kg, weekly for 4 weeks). RESULTS: LDE-carmustine reduced lesion size by 90 % compared to the controls. LDE-carmustine reduced the presence of macrophages, vascular smooth muscle cells, and regulatory T cells in the arterial intima, as well as the presence of matrix metallopeptidase-9, interleukin-1ß and TNF-α and lipoprotein receptors, namely LDL-receptor, LDL-related protein-1, scavenger receptor class B member 1. When injected alone, without association to carmustine, LDE was not different from injected saline solution. CONCLUSIONS: LDE-carmustine treatment resulted in marked reduction of lesion area, of the invasion of the arterial intima by macrophages and vascular smooth muscle cells and pro-inflammatory factors. Therefore, this new formulation shows great potential for therapy of atherosclerotic cardiovascular disease.

Alterações hematológicas em pacientes infectados pelo vírus da imunodeficência humana submetidos à terapia antirretroviral com e sem inibidor de protease / Hematological abnormalities in patients infected with human immunodeficiency virus on antiretroviral therapy with and without protease inhibitors

A anemia é uma anormalidade hematológica comumente encontrada em pacientes infectados pelo vírus da imunodeficiência humana (HIV) e sua prevalência estimada entre 63 por cento a 95 por cento. O objetivo deste estudo foi avaliar as alterações hematológicas e o Índice de Massa Corporal (IMC) de pacientes HIV soropositivos com ou sem uso de terapia antirretroviral com e sem inibidor de protease. Os pacientes HIV soropositivos foram diagnosticados pelo teste de enzimaimunoensaio (ELISA) e confirmados por imunofluorescência. As alterações hematológicas foram determinadas por aparelho de automação Coulter Maxim Autoloader®, contagem de células CD4+ e CD8+ por citometria de fluxo FACSCount® e carga viral por amplificação baseada na sequência do ácido nucleico - Nucleic Acid Sequence Based Amplification (NASBA®). A avaliação dos dados hematológicos demonstrou níveis diminuídos no número de leucócitos e hemoglobina no grupo de estudo que fazia uso de terapia antirretrovial, quando comparado ao grupo controle sem uso desta terapia; resultado semelhante verificou-se também para o IMC dos pacientes HIV soropositivos (p<0,0001, p=0,006 e p<0,0001) respectivamente. Não houve diferença significativa entre os grupos que faziam uso de terapia antirretrovial com e sem inibidores de protease (IP). A avaliação dos dados hematológicos associada à contagem de células CD4+ e quantificação da carga viral pode contribuir para o monitoramento da infecção e auxiliar na tomada de decisão a respeito da intervenção clínica mais adequada nestes pacientes. Rev. Bras. Hematol. Hemoter.

Anemia is the most commonly encountered hematologic abnormality in from 63 percent to 95 percent of human immunodeficiency virus (HIV)-positive patients. This study intends to evaluate hematological alterations and changes in the body mass index of HIV-positive patients on antiretroviral therapy with or without protease inhibitors and those who are not on antiretroviral therapy. The HIV-positive patients were diagnosed by the ELISA test and confirmed by immunofluorescence. The hematological alterations were determined using a Coulter Maxim Autoloader®, CD4+ and CD8+ cell counts by FACSCount® Flux cytometry and viral load by Nucleic Acid Sequence Based Amplification (NASBA®). The evaluation of hematological alterations showed smaller numbers of leukocytes and hemoglobin in the study group who used antiretroviral therapy compared to the control group (not on antiretroviral therapy); similar results were found for the body mass index of HIV-positive patients (p<0.0001, p=0.006 and p<0.0001), respectively. There were no significant differences identified between the groups on antiretroviral therapy with or without protease inhibitors. An evaluation of the hematological alterations associated with CD4+ cell counts and measurement of the viral load may contribute to monitor HIV infection and assist in the decision of the most appropriate clinical intervention in these patients. Rev. Bras. Hematol. Hemoter.

Antihyperlipidemic effect of Casearia sylvestris methanolic extract.

Casearia sylvestris methanolic extract (MCE) was screened at doses of 125-500 mg/kg for its antihyperlipidemic activity. The antihyperlipidemic effect was evaluated in olive oil-loaded mice. Acute treatment caused inhibition in the triglyceride (TG) and serum lipase elevation-induced by 5 ml/kg of olive oil.