Sickle cell disease （SCD） is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vaso- occlusio...Sickle cell disease （SCD） is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vaso- occlusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived- 2 related factor 2 （Nrf2） controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD.展开更多
We report a fresh and simpler approach to the modelling of the kinetics of the polymerization of Hb SS in sickle cell patients that couples the kinetics and the hydrodynamics of blood flow in mechanistic understanding...We report a fresh and simpler approach to the modelling of the kinetics of the polymerization of Hb SS in sickle cell patients that couples the kinetics and the hydrodynamics of blood flow in mechanistic understanding of the process. The well-known two-step autocatalytic reaction scheme was used for the polymerization reaction with the assumption of simpler first-order reaction scheme for each stage. In addition, the forces acting on a particle in motion were also introduced to account for compelling settling of the red cells that lead to vessel occlusion (vaso-occlusion). A first attempt on the prediction of vessel blockage was made using this novel model. The time for the onset of the polymerization reaction was derived from hydrodynamic considerations and kinetics while the kinetic rate constants were obtained from the autocatalytic nature of the reaction. Experimental data for model validation were obtained from recruited SS patients and in vitro data of Hofrichter. Over 100 volunteers were recruited for participation in this work but less than 40% met the inclusion criteria. Participants were of age range 13 - 43 (with a mean of 26 ± 8 years) for SCD patients and 18 - 43 (with a mean of 28 ± 7 years) for control participants. Blood indices and Transcranial Doppler (TCD) test parameters of all participants were the principal parameters used for model validation. Constant k2/k1 ratios was obtained for individual in vivo/in vitro system. This ratio is unique for any individual, independent on protein sequence and also suggests the degree of expression of the symptoms of Sickle Cell Disease (SCD) with higher values reflecting greater propensity to pain crisis. Delay time, tD, was found to have an inverse relationship with the kinetic constant for the residual reaction, k1. Therefore, long delay times calculated, offer insight on why SCD patients are not in perpetual crises because enough time is provided the cells to escape microcirculation while keeping the residual reaction at the minimum. Sensitivity analys展开更多
文摘Sickle cell disease （SCD） is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vaso- occlusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived- 2 related factor 2 （Nrf2） controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD.
文摘We report a fresh and simpler approach to the modelling of the kinetics of the polymerization of Hb SS in sickle cell patients that couples the kinetics and the hydrodynamics of blood flow in mechanistic understanding of the process. The well-known two-step autocatalytic reaction scheme was used for the polymerization reaction with the assumption of simpler first-order reaction scheme for each stage. In addition, the forces acting on a particle in motion were also introduced to account for compelling settling of the red cells that lead to vessel occlusion (vaso-occlusion). A first attempt on the prediction of vessel blockage was made using this novel model. The time for the onset of the polymerization reaction was derived from hydrodynamic considerations and kinetics while the kinetic rate constants were obtained from the autocatalytic nature of the reaction. Experimental data for model validation were obtained from recruited SS patients and in vitro data of Hofrichter. Over 100 volunteers were recruited for participation in this work but less than 40% met the inclusion criteria. Participants were of age range 13 - 43 (with a mean of 26 ± 8 years) for SCD patients and 18 - 43 (with a mean of 28 ± 7 years) for control participants. Blood indices and Transcranial Doppler (TCD) test parameters of all participants were the principal parameters used for model validation. Constant k2/k1 ratios was obtained for individual in vivo/in vitro system. This ratio is unique for any individual, independent on protein sequence and also suggests the degree of expression of the symptoms of Sickle Cell Disease (SCD) with higher values reflecting greater propensity to pain crisis. Delay time, tD, was found to have an inverse relationship with the kinetic constant for the residual reaction, k1. Therefore, long delay times calculated, offer insight on why SCD patients are not in perpetual crises because enough time is provided the cells to escape microcirculation while keeping the residual reaction at the minimum. Sensitivity analys
