A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Comparison between Oligoryzomys nigripes and O. flavescens by RAPD and genetic diversity in O. nigripes (Rodentia, Cricetidae)

The genus of Oligoryzomys includes species of small size, morphologically similar, which may impede taxonomic identification, mainly between O. flavescens (Waterhouse, 1837) and O. nigripes (Olfers, 1818). The main objective of this work was to investigate whether the RAPD markers are capable of genetically differentiating the specimens O. nigripes and O. flavescens, coming from Rio Grande do Sul (RS) and Santa Catarina (SC) states, and also to estimate the genetic variability among populations of O. nigripes, with the Uruguay River as a geographical barrier. For this purpose, samples were collected in fragments of forests situated in the North of RS, at FLONA (Floresta Nacional de Passo Fundo) and in fragments from SC, close to the Uruguay River. The karyotyping of two samples for each species was carried out and compared using the RAPD technique together with non- karyotyped individuals. Samples of O. nigripes presented 2n = 62; NA = 82, with submetacentric arms on the largest chromosomes, while samples of O. flavescens showed 2n = 64; NA = 66, with the largest chromosomes presenting acrocentric morphology, making such a result the main difference between the species. The analysis was able to detect two distinct groups, being the first one with karyotyped O. flavescens and the second with karyotyped O. nigripes. Identification afforded 211 loci, among them 181 (85.78%) polymorphic. The Jaccard similarity coefficient was in the range of 0.45 to 0.87. The UPGMA and Main Coordinate Analysis techniques demonstrated the existence of heterogeneous genetics among populations, but did not separate them completely in terms of geographical standards, and they are not influenced by the Uruguay River, which did not act as an efficient barrier

Comparison between Oligoryzomys nigripes and O. flavescens by RAPD and genetic diversity in O. nigripes (Rodentia, Cricetidae)

The genus of Oligoryzomys includes species of small size, morphologically similar, which may impede taxonomic identification, mainly between O. flavescens (Waterhouse, 1837) and O. nigripes (Olfers, 1818). The main objective of this work was to investigate whether the RAPD markers are capable of genetically differentiating the specimens O. nigripes and O. flavescens, coming from Rio Grande do Sul (RS) and Santa Catarina (SC) states, and also to estimate the genetic variability among populations of O. nigripes, with the Uruguay River as a geographical barrier. For this purpose, samples were collected in fragments of forests situated in the North of RS, at FLONA (Floresta Nacional de Passo Fundo) and in fragments from SC, close to the Uruguay River. The karyotyping of two samples for each species was carried out and compared using the RAPD technique together with non- karyotyped individuals. Samples of O. nigripes presented 2n = 62; NA = 82, with submetacentric arms on the largest chromosomes, while samples of O. flavescens showed 2n = 64; NA = 66, with the largest chromosomes presenting acrocentric morphology, making such a result the main difference between the species. The analysis was able to detect two distinct groups, being the first one with karyotyped O. flavescens and the second with karyotyped O. nigripes. Identification afforded 211 loci, among them 181 (85.78%) polymorphic. The Jaccard similarity coefficient was in the range of 0.45 to 0.87. The UPGMA and Main Coordinate Analysis techniques demonstrated the existence of heterogeneous genetics among populations, but did not separate them completely in terms of geographical standards, and they are not influenced by the Uruguay River, which did not act as an efficient barrier