Skeletal myogenesis by human embryonic stem cells. (1/115)

We have examined the myogenic potential of human embryonic stem (hES) cells in a xeno-transplantation animal model. Here we show that precursors differentiated from hES cells can undergo myogenesis in an adult environment and give rise to a range of cell types in the myogenic lineage. This study provides direct evidences that hES cells can regenerate both muscle and satellite cells in vivo and are another promising cell type for treating muscle degenerative disorders in addition to other myogenic cell types.  (+info)

Beta-cardiotoxin: a new three-finger toxin from Ophiophagus hannah (king cobra) venom with beta-blocker activity. (2/115)

Snake venoms have provided a number of novel ligands with therapeutic potential. We have constructed a partial cDNA library from the mRNA of Ophiophagus hannah (king cobra) venom gland tissue and identified five new genes encoding proteins belonging to the three-finger toxin family of snake venom proteins. We have isolated and characterized one of these beta-sheet containing proteins with a mass of 7012.43 +/- 0.91 Da from the venom. The protein was nonlethal up to a dose of 10 mg/kg when injected intraperitoneally into Swiss albino mice. However, it induces labored breathing and death at a dose of 100 mg/kg. It does not show any hemolytic or anticoagulant activity. It caused a dose-dependent decrease of heart rate in vivo (anesthetized Sprague-Dawley rats) and also ex vivo (Langendorff isolated rat heart). This is in contrast to classical cardiotoxins from snake venom that increase the heart rate in animals. Radioligand displacement studies showed that this protein targets beta-adrenergic receptors with a binding affinity (Ki) of 5.3 and 2.3 microM toward beta1 and beta2 subtypes, respectively, to bring about its effect, and hence, it was named as beta-cardiotoxin. This is the first report of a natural exogenous beta-blocker.  (+info)

Functional analysis of homeodomain-containing transcription factor Lbx1 in satellite cells of mouse skeletal muscle. (3/115)

Satellite cells are usually mitotically quiescent muscle stem cells, located between the sarcolemma and the basement membrane of muscle fibers. When muscles are damaged, satellite cells become activated, proliferate and differentiate to form multinucleate myofibers. The molecular mechanisms underlying these processes are poorly understood. In the present study, we found that, following treatment with cardiotoxin, homeodomain-containing transcription factor Lbx1 was strongly expressed in the satellite cells of regenerating adult skeletal muscle. Our immunohistochemical and northern blot analyses indicate that Lbx1 is expressed in activated but not quiescent satellite cells. In vitro, this Lbx1 expression was gradually downregulated when satellite cells differentiate into mature myofibers. Transfection and forced expression of Lbx1 in satellite-cell-derived C2C12 myoblast cells resulted in severe depression of myogenic differentiation and incomplete myotube formation, concomitantly with the activation of the paired-box transcription factor Pax7 and depression of the myogenic regulatory factor MyoD. Moreover, knockdown of Lbx1 in in-vitro-cultured satellite cells resulted in downregulation of Pax7. These results suggest that Lbx1 plays important roles in differentiation and maintenance of satellite cells of mature myofibers, probably through the regulation of Pax7.  (+info)

Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. (4/115)

Imatinib, a selective, small-molecule tyrosine kinase inhibitor, has life-saving clinical activity in certain cancers, but questions have been raised about the potential for cardiac toxicity through inhibition of its target, ABL kinase. In this issue of the JCI, Fernandez et al. describe a novel method by which the ABL-inhibitory activity of imatinib was deleted by modifying its chemical structure (see the related article beginning on page 4044). The anticancer activity of the reengineered agent, called WBZ_4, was instead preserved against gastrointestinal stromal tumors in both in vitro and in vivo models via inhibition of KIT tyrosine kinase, and the desired safety was demonstrated with less cardiotoxicity of WBZ_4 compared with imatinib via the inhibition of JNK. The study shows that structural reengineering of a kinase-inhibitory drug to improve tolerability while preserving efficacy is feasible.  (+info)

An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. (5/115)

Targeting kinases is central to drug-based cancer therapy but remains challenging because the drugs often lack specificity, which may cause toxic side effects. Modulating side effects is difficult because kinases are evolutionarily and hence structurally related. The lack of specificity of the anticancer drug imatinib enables it to be used to treat chronic myeloid leukemia, where its target is the Bcr-Abl kinase, as well as a proportion of gastrointestinal stromal tumors (GISTs), where its target is the C-Kit kinase. However, imatinib also has cardiotoxic effects traceable to its impact on the C-Abl kinase. Motivated by this finding, we made a modification to imatinib that hampers Bcr-Abl inhibition; refocuses the impact on the C-Kit kinase; and promotes inhibition of an additional target, JNK, a change that is required to reinforce prevention of cardiotoxicity. We established the molecular blueprint for target discrimination in vitro using spectrophotometric and colorimetric assays and through a phage-displayed kinase screening library. We demonstrated controlled inhibitory impact on C-Kit kinase in human cell lines and established the therapeutic impact of the engineered compound in a novel GIST mouse model, revealing a marked reduction of cardiotoxicity. These findings identify the reengineered imatinib as an agent to treat GISTs with curbed side effects and reveal a bottom-up approach to control drug specificity.  (+info)

Comparative genomics identifies genes mediating cardiotoxicity in the embryonic zebrafish heart. (6/115)

 (+info)

Atrial dysfunction as a marker of iron cardiotoxicity in thalassemia major. (7/115)

 (+info)

Mechanisms responsible for reduced cardiotoxicity of mitoxantrone compared to doxorubicin examined in isolated guinea-pig heart preparations. (8/115)

We reported previously that doxorubicin, an anticancer agent that has an anthracycline structure, alters Ca2+ releasing and uptake mechanisms in the sarcoplasmic reticulum of myocardial cells. These effects of doxorubicin are apparently related to its cardiotoxicity. Mitoxantrone is a similar anticancer agent with an anthracenedion structure that has been shown to be significantly less cardiotoxic. In the present study, the effects of mitoxantrone on the functions of the sarcoplasmic reticulum were examined in isolated muscle preparations obtained from the guinea-pig heart. In electrically-stimulated left atrial muscle preparations, incubation in vitro for 4 hr with 30 or 100 microM mitoxantrone significantly prolonged the time to the peak of twitch tension, markedly increased the developed tension observed at lower stimulation frequencies, thereby attenuating the slope of positive force-frequency relationships, and increased the postrest contraction observed after a 60-sec quiescent period. In myocytes isolated from ventricular muscles, 30 microM mitoxantrone increased the peak and the size of intracellular Ca2+ concentrations ([Ca2+] i), and prolonged the time to peak [Ca2+]i. In skinned muscle fiber preparations obtained from the left ventricular muscle, 30 muM mitoxantrone significantly increased the caffeine-induced contraction without affecting the Ca2+ sensitivity of contractile proteins. These results suggest that mitoxantrone enhances Ca2+ release from the sarcoplasmic reticulum in isolated atrial muscle preparations obtained from the guinea-pig heart. Apparent enhancement of the sarcoplasmic reticulum functions, in contrast to anthracyclines that has been shown to suppress these functions, seems to explain the relative lack of marked cardiotoxicity of mitoxantrone.  (+info)

• 1
• 2
• 3
• 4
• 5
• 6
• 7
• 8
• 9
• 10