Elevated vascular γ-butyrobetaine levels attenuate the development of high glucose-induced endothelial dysfunction

The aim of the present study was to investigate the effects of vascular tissue levels of l-carnitine and its precursor, γ-butyrobetaine (GBB), on the development of endothelial dysfunction induced by 5 μmol/L lysophosphatidylcholine (LPC), 10 mmol/L triglycerides (TG) or a high glucose concentration (44 mmol/L). Changes in vascular tissue levels of l-carnitine and GBB were induced by administration of l-carnitine (100 mg/kg), mildronate (100 mg/kg; an inhibitor of l-carnitine synthesis) or their combination to male Wistar rats for 2 weeks. Treatment with l-carnitine elevated vascular tissue levels of l-carnitine, whereas administration of mildronate reduced l-carnitine levels and increased GBB levels. Experimental animals that received the combination of both drugs showed elevated tissue levels of GBB. The results from organ bath experiments demonstrated that increased GBB levels with preserved l-carnitine content in vascular tissues attenuated the development of endothelial dysfunction induced by high glucose. However, changes in vascular tissue l-carnitine and GBB levels had no impact on endothelial dysfunction induced by TG or LPC. The results demonstrate that increased levels of GBB with preserved l-carnitine content in vascular tissue attenuate the development of endothelial dysfunction induced by high glucose concentrations.publishersversionPeer reviewe

High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection

The only cure of HIV has been achieved in a small number of people who received a hematopoietic stem cell transplant (HSCT) comprising allogeneic cells carrying a rare, naturally occurring, homozygous deletion in the CCR5 gene. The rarity of the mutation and the significant morbidity and mortality of such allogeneic transplants precludes widespread adoption of this HIV cure. Here, we show the application of CRISPR/Cas9 to achieve >90% CCR5 editing in human, mobilized hematopoietic stem progenitor cells (HSPC), resulting in a transplant that undergoes normal hematopoiesis, produces CCR5 null T cells, and renders xenograft mice refractory to HIV infection. Titration studies transplanting decreasing frequencies of CCR5 edited HSPCs demonstrate that <90% CCR5 editing confers decreasing protective benefit that becomes negligible between 54% and 26%. Our study demonstrates the feasibility of using CRISPR/Cas9/RNP to produce an HSPC transplant with high frequency CCR5 editing that is refractory to HIV replication. These results raise the potential of using CRISPR/Cas9 to produce a curative autologous HSCT and bring us closer to the development of a cure for HIV infection

Mildronate treatment alters γ-butyrobetaine and l -carnitine concentrations in healthy volunteers

Objectives In this study, we aimed to investigate the effects of long-term administration of the cardioprotective drug mildronate on the concentrations of l-carnitine and γ-butyrobetaine in healthy volunteers. Methods Mildronate was administered perorally, at a dosage of 500 mg, twice daily. Plasma and urine samples were collected weekly. Daily meat consumption within an average, non-vegetarian diet was monitored. l-Carnitine, γ-butyrobetaine and mildronate concentrations were measured using the UPLC/MS/MS method. Key findings After 4 weeks, the average concentrations of l-carnitine in plasma significantly decreased by 18%. The plasma concentrations of γ-butyrobetaine increased about two-fold, and this effect was statistically significant in both the male and female groups. In urine samples, a significant increase in l-carnitine and γ-butyrobetaine levels was observed, which provides evidence for increased excretion of both substances during the mildronate treatment. At the end of the treatment period, the plasma concentration of mildronate was 20 μm on average. There were no significant differences between the effects observed in female and male volunteers. Meat consumption partially reduced the l-carnitine-lowering effects induced by mildronate. Conclusions Long-term administration of mildronate significantly lowers l-carnitine plasma concentrations in non-vegetarian, healthy volunteers.publishersversionPeer reviewe

A Systematic Review of Occupational Exposure to Particulate Matter and Cardiovascular Disease

Exposure to ambient particulate air pollution is a recognized risk factor for cardiovascular disease; however the link between occupational particulate exposures and adverse cardiovascular events is less clear. We conducted a systematic review, including meta-analysis where appropriate, of the epidemiologic association between occupational exposure to particulate matter and cardiovascular disease. Out of 697 articles meeting our initial criteria, 37 articles published from January 1990 to April 2009 (12 mortality; 5 morbidity; and 20 intermediate cardiovascular endpoints) were included. Results suggest a possible association between occupational particulate exposures and ischemic heart disease (IHD) mortality as well as non-fatal myocardial infarction (MI), and stronger evidence of associations with heart rate variability and systemic inflammation, potential intermediates between occupational PM exposure and IHD. In meta-analysis of mortality studies, a significant increase in IHD was observed (meta-IRR = 1.16; 95% CI: 1.06–1.26), however these data were limited by lack of adequate control for smoking and other potential confounders. Further research is needed to better clarify the magnitude of the potential risk of the development and aggravation of IHD associated with short and long-term occupational particulate exposures and to clarify the clinical significance of acute and chronic changes in intermediate cardiovascular outcomes