Synthesis and pharmacological evaluation of pomalidomide derivatives useful for sickle cell disease treatment.

Fetal hemoglobin (HbF) induction constitutes a valuable and validated approach to treat the symptoms of sickle cell disease (SCD). Here, we synthesized pomalidomide-nitric oxide (NO) donor derivatives (3a-f) and evaluated their suitability as novel HbF inducers. All compounds demonstrated different capacities of releasing NO, ranging 0.3-30.3%. Compound 3d was the most effective HbF inducer for CD34+ cells, exhibiting an effect similar to that of hydroxyurea. We investigated the mode of action of compound 3d for HbF induction by studying the in vitro alterations in the levels of transcription factors (BCL11A, IKAROS, and LRF), inhibition of histone deacetylase enzymes (HDAC-1 and HDAC-2), and measurement of cGMP levels. Additionally, compound 3d exhibited a potent anti-inflammatory effect similar to that of pomalidomide by reducing the TNF-α levels in human mononuclear cells treated with lipopolysaccharides up to 58.6%. Chemical hydrolysis studies revealed that compound 3d was stable at pH 7.4 up to 24 h. These results suggest that compound 3d is a novel HbF inducer prototype with the potential to treat SCD symptoms.

Impact of Regular Physical Activity on Adipocytokines and Cardiovascular Characteristics in Spinal Cord-Injured Subjects.

OBJECTIVE: To investigate the relationship of carotid artery intima-media thickness (IMT) and cardiac structure and function with adipocytokines in sedentary (S-SCI) and physically active (PA-SCI) subjects with spinal cord injury (SCI). DESIGN: Cross-sectional observational study. SETTING: Academic medical center. PARTICIPANTS: Men with chronic (>1y) SCI (N=41; 16 S-SCI, 25 PA-SCI) were evaluated. S-SCI subjects did not perform labor that required physical effort, recreational physical activity, or sports, while PA-SCI subjects included competing athletes who were regularly performing adapted sports. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Clinical, laboratory, carotid ultrasonography, and echocardiography analysis. Plasma leptin, adiponectin, and plasminogen activating inhibitor-1 (PAI-1) levels were determined. RESULTS: PA-SCI subjects had similar levels of adipocytokines, but lower carotid IMT and carotid IMT/diameter, and better left ventricular diastolic function than S-SCI participants. Bivariate analysis showed that adiponectin was inversely correlated with triglycerides (r=-.85, P<.001), low-density lipoprotein cholesterol (r=-.57, P<.05), and carotid IMT/diameter (r=-.56, P<.05) in S-SCI but not in PA-SCI participants. Additionally, the leptin-adiponectin ratio showed a direct correlation with triglycerides (r=.84, P<.001) and low-density lipoprotein cholesterol (r=.53, P<.05) in S-SCI but not in PA-SCI individuals. By contrast, the studied adipocytokines did not correlate with cardiac structure and function in PA-SCI and S-SCI participants. CONCLUSIONS: Lower adiponectin levels and higher leptin-adiponectin ratio are related to adverse vascular and/or metabolic characteristics in individuals with SCI. This relationship, however, appears to be mitigated by regular physical activity.

Matrix metalloproteinases and left ventricular function and structure in spinal cord injured subjects.

Subjects with spinal cord injury (SCI) exhibit impaired left ventricular (LV) diastolic function, which has been reported to be attenuated by regular physical activity. This study investigated the relationship between circulating matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) and echocardiographic parameters in SCI subjects and the role of physical activity in this regard. Forty-two men with SCI [19 sedentary (S-SCI) and 23 physically-active (PA-SCI)] were evaluated by clinical, anthropometric, laboratory, and echocardiographic analysis. Plasmatic pro-MMP-2, MMP-2, MMP-8, pro-MMP-9, MMP-9, TIMP-1 and TIMP-2 levels were determined by enzyme-linked immunosorbent assay and zymography. PA-SCI subjects presented lower pro-MMP-2 and pro-MMP-2/TIMP-2 levels and improved markers of LV diastolic function (lower E/Em and higher Em and E/A values) than S-SCI ones. Bivariate analysis showed that pro-MMP-2 correlated inversely with Em and directly with E/Em, while MMP-9 correlated directly with LV mass index and LV end-diastolic diameter in the whole sample. Following multiple regression analysis, pro-MMP-2, but not physical activity, remained associated with Em, while MMP-9 was associated with LV mass index in the whole sample. These findings suggest differing roles for MMPs in LV structure and function regulation and an interaction among pro-MMP-2, diastolic function and physical activity in SCI subjects.