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

Whole genomic comparative analysis of Streptococcus pneumoniae serotype 1 isolates causing invasive and non-invasive infections among children under 5 years in Casablanca, Morocco. [Open Access].

AbstractBackground: Streptococcus pneumoniae serotype 1 remains a leading cause of invasive pneumococcal diseases, even in countries with PCV-10/PCV-13 vaccine implementation. The main objective of this study, which is part of the Pneumococcal African Genome project (PAGe), was to determine the phylogenetic relationships of serotype 1 isolates recovered from children patients in Casablanca (Morocco), compared to these from other African countries; and to investigate the contribution of accessory genes and recombination events to the genetic diversity of this serotype.Results: The genome average size of the six-pneumococcus serotype 1 from Casablanca was 2,227,119 bp, and the average content of coding sequences was 2113, ranging from 2041 to 2161. Pangenome analysis of the 80 genomes used in this study revealed 1685 core genes and 1805 accessory genes. The phylogenetic tree based on core genes and the hierarchical bayesian clustering analysis revealed five sublineages with a phylogeographic structure by country. The Moroccan strains cluster in two different lineages, the five invasive strains clusters altogether in a divergent clade distantly related to the non-invasive strain, that cluster with all the serotype 1 genomes from Africa.Conclusions: The whole genome sequencing provides increased resolution analysis of the highly virulent serotype 1 in Casablanca, Morocco. Our results are concordant with previous works, showing that the phylogeography of S. pneumoniae serotype 1 is structured by country, and despite the small size (six isolates) of the Moroccan sample, our analysis shows the genetic cohesion of the Moroccan invasive isolates

ANODAL TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) APPLIED TO THE MOTOR CORTEX AMELIORATES FREEZING OF GAIT IN PATIENTS AFFECTED BY PARKINSON’S DISEASE

Background: Progression of Parkinson’s disease (PD) is frequently characterized by the occurrence of freezing of gait (FOG), which generally does not improve with dopaminergic therapy and with current available surgical therapies. Recent evidences show that motor symptoms may be ameliorated by means of non-invasive brain stimulation techiniques in PD (transcranial current direct stimulation, TDCS; repetitive transcranial magnetic stimulation, RTMS). Objective: To investigate the efficacy of anodal TDCS in the treatment of FOG in PD. Excitatory anodal tDCS was applied unilaterally to the motor and premotor cortices controlateral to the most affected leg. Methods: randomized, double-blind, sham-controlled study. TDCS was applied consecutively for 5 days to 8 patients who were randomly assigned to anodal or sham TDCS. Efficacy of the interventions was investigated after the 1st, the 5th stimulation, 1 week, 2 weeks and 1 month after the start of the trial. Clinical assessment was performed by Stand Walk Sit test (SWS), UPDRS, Freezing of Gait Questionnaire (FOG-Q), Gait and Falls Questionnaire (GFQ), and the Parkinson's Disease Questionnaire (PDQ-39). 5 patients also underwent gait analysis. All patients received stimulation when “on” medication. Results: anodal TDCS compared to the sham significantly improved gait and FOG starting from the first stimulation. The effect was evident up to 1 month from the first treatment. Conclusion: Anodal TDCS of the motor and premotor cortex is safe and it may have therapeutic potential for FOG in patients with PD. TDCS might determine release of dopamine in the caudate and putamen. Alternatively excitation of the less active motor cortex may restore an inter-hemispheric balance, as it has been recently hypothesized as possible mechanism at the origin of FOG

ANODAL TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) APPLIED TO THE MOTOR CORTEX AMELIORATES FREEZING OF GAIT IN PATIENTS AFFECTED BY PARKINSON’S DISEASE

Background: Progression of Parkinson’s disease (PD) is frequently characterized by the occurrence of freezing of gait (FOG), which generally does not improve with dopaminergic therapy and with current available surgical therapies. Recent evidences show that motor symptoms may be ameliorated by means of non-invasive brain stimulation techiniques in PD (transcranial current direct stimulation, TDCS; repetitive transcranial magnetic stimulation, RTMS). Objective: To investigate the efficacy of anodal TDCS in the treatment of FOG in PD. Excitatory anodal tDCS was applied unilaterally to the motor and premotor cortices controlateral to the most affected leg. Methods: randomized, double-blind, sham-controlled study. TDCS was applied consecutively for 5 days to 8 patients who were randomly assigned to anodal or sham TDCS. Efficacy of the interventions was investigated after the 1st, the 5th stimulation, 1 week, 2 weeks and 1 month after the start of the trial. Clinical assessment was performed by Stand Walk Sit test (SWS), UPDRS, Freezing of Gait Questionnaire (FOG-Q), Gait and Falls Questionnaire (GFQ), and the Parkinson's Disease Questionnaire (PDQ-39). 5 patients also underwent gait analysis. All patients received stimulation when “on” medication. Results: anodal TDCS compared to the sham significantly improved gait and FOG starting from the first stimulation. The effect was evident up to 1 month from the first treatment. Conclusion: Anodal TDCS of the motor and premotor cortex is safe and it may have therapeutic potential for FOG in patients with PD. TDCS might determine release of dopamine in the caudate and putamen. Alternatively excitation of the less active motor cortex may restore an inter-hemispheric balance, as it has been recently hypothesized as possible mechanism at the origin of FOG