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Despite being highly effective for newly diagnosed chronic myeloid leukemia (CML), imatinib not only is inactive against quiescent CML stem cells, but also has limited activity against blast crisis (BC) CML. The relative activity of Bcr-Abl and the expression levels of antiapoptotic proteins in proliferating and quiescent CD34+ BC CML progenitor cells and the effects of targeting antiapoptotic proteins in these cells are unknown. Here we report higher levels of p-CrkL in quiescent than in proliferating CD34+ progenitor cells and comparable expression levels of Bcl-2, Bcl-xL, Mcl-1 and XIAP in the two populations in BC CML. Inhibition of Bcl-2/Bcl-xL by ABT-737 in cells from patients with tyrosine kinase inhibitor (TKI)-resistant BC CML promoted apoptosis in quiescent CD34+ progenitor cells with an efficacy similar to that in proliferating cells. Combination of ABT-737 with imatinib (which decreases Mcl-1 levels) or triptolide (which decreases Mcl-1 and XIAP) synergistically induced death of both proliferating and quiescent CD34+ progenitor cells obtained from TKI-resistant BC CML patients. These results suggest that antiapoptotic proteins are critical targets in BC CML and that activation of apoptosis signaling can eliminate both proliferating and quiescent CD34+ progenitor cells in BC CML, independent of response to TKIs. [ABSTRACT FROM AUTHOR]

In order to investigate the pharmacological basis of 'Yang-invigorating' action, the effect of oral treatment with the methanolic extract of 'Yang-invigorating' herbs on ATP-generation capacity was examined, using heart homogenates prepared from herb-pretreated mice. Tonifying (i.e., health-promoting) herbs of other functional categories were also included for comparison. The results indicated that 'Yang-invigorating' Chinese tonifying herbs could invariably enhance myocardial ATP-generation capacity, with the extent of stimulation varying among the herbs. In contrast, 'Yin-nourishing' herbs either did not stimulate or even decreased myocardial ATP-generation capacity. While 'Qi-invigorating' herbs produced variable effects on myocardial ATP-generation capacity, most of the 'blood-enriching' herbs did not cause any significant changes. The results obtained from studies using myocardial mitochondrial fractions isolated from herb-pretreated mice suggest that 'Yang-invigorating' herbs might speed up ATP generation by increasing mitochondrial electron transport. The ensemble of results has provided evidence for the first time to support the pharmacological basis of 'Yang invigoration' in Chinese medicine.

The effects of short-term (2-week) diabetes on myocardial ischemia-reperfusion (I-R) injury and associated changes in myocardial non-enzymatic antioxidant level were examined. Isolated-perfused hearts prepared from control and diabetic rats were subjected to increasing periods of ischemia and reperfusion, and myocardial I-R injury was assessed by measuring the extent of lactate dehydrogenase (LDH) leakage and contractile force recovery. While a brief period (20 min) of post-ischemic reperfusion caused a smaller extent of LDH leakage, the prolonged period (40 min) of reperfusion produced a greater degree of I-R injury in diabetic hearts, as indicated by the impaired recovery of contractile force. The apparent protection against I-R injury in diabetic hearts during the early phase of post-ischemic reperfusion was associated with increases in myocardial reduced glutathione/ascorbic acid and a-tocopherol levels, with the effect on a-tocopherol being most prominent. Insulin treatment could reverse the diabetes-associated changes in susceptibility to myocardial I-R injury and antioxidant response. The ensemble of results indicates that the myocardium isolated from short-term diabetic rat can produce a beneficial antioxidant response to I-R challenge, which may, in turn, be attributable to the decreased susceptibility to I-R injury observable during the early phase of reperfusion.

Effects of Sheng Mai San (SMS), a traditional Chinese medicine used for the treatment of coronary heart disease, and the lignan-enriched extract of Fructus Schisandrae (FS), an antioxidant component of SMS, were examined in an in vivo model of myocardial infarction and an ex vivo model of myocardial ischemia-reperfusion injury in rats. Pretreatment with SMS (12 g/kg/day × 3, p. o.) or FS extract (0.8 g/kg/day × 3, p. o.) was found to protect against the isoproterenol-induced myocardial injury in rats and the ischemia-reperfusion injury in isolated perfused hearts prepared from the pretreated animals. Pretreatment with α-tocopherol (0.8 g/kg/day × 3, p. o.) produced similar beneficial effect on the myocardium. The myocardial protection afforded by SMS pretreatment is likely, at least in part, mediated by the FS-derived antioxidant activity., (Copyright © 1996 Gustav Fischer Verlag · Stuttgart · Jena · New York. Published by Elsevier GmbH.. All rights reserved.)

Exposure of liver homogenates to an in vitro tert-butyl hydroperoxide challenge can be used as a means for measuring the reduced glutathione regeneration capacity (GRC) of hepatic tissues. Pretreatment of rats with a lignan-enriched extract of Fructus Schisandrae (FS) caused a moderate enhancement of hepatic GRC in control rats, but the GRC enhancing effect of FS pretreatment on hepatic tissues was greatly exaggerated after CCl4 challenge. This in vitro bioassay can be used for investigating the hepatic GRC promoting action of orally active agents.