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Inhibition of nuclear translocation of NF-kappaB by IkappaBalpha phosphorylation blockade could provide an effective approach to attenuation of ischemia/reperfusion injury. The cardioprotective effects of IMD-0354 include not only reduction of harmful neutrophil accumulation in myocardium but also inhibition of harmful cytokine and chemokine production by cardiomyocytes.

IntroductionGain-of-function mutations in the c-kit receptor induce factorindependent proliferation of mast cells, thereby resulting in neoplastic transformation. 1 Various c-kit receptor mutations have been identified in different mast cell lines that have an ability to proliferate in the absence of any growth factor. 2-6 HMC-1 cells, which were derived from human mast cell leukemia, have 2 point mutations in the intracellular juxtamembrane domain (Val560Gly) and in the catalytic domain (Asp816Val) of the c-kit receptor. 2,6 The former mutation was also found in the c-kit receptor in cells from gastrointestinal stromal tumor (GIST), and the latter is known to exist most commonly in cells from human mastocytosis. 7,8 Because of these mutations, the tyrosine kinase of the c-kit receptor is automatically phosphorylated, and the related growth signal is activated. Several signaling molecules have been identified as candidates for transducing c-kit receptor signals, including mitogenactivated protein (MAP) kinase, phosphatidylinositol 3 (PI3) kinase, protein kinase C (PKC), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. [9][10][11] Recently available tyrosine kinase inhibitors have been applied to c-kit-dependent diseases, including GIST and mastocytosis; however, therapeutic effects have been limited in the treatment of mastocytosis in contrast to the great success in the treatment of GIST. [12][13][14] Mutational analysis has revealed some variants of the c-kit gene in patients with mastocytosis. Imatinib mesylate (STI571) was shown to be effective against mast cell diseases involving wild-type c-kit and mutants with Val560Gly or Phe522Cys substitutions. 14,15 However, STI571 was not effective against aggressive systemic mastocytosis involving an Asp816Val mutation in the c-kit receptor. 15 Homeostatic or nonhomeostatic cell renewal is controlled through cell cycle progression. Entry into the S phase normally relies on mitogenic stimulation, involving growth factors, and is regulated by cell cycle regulatory molecules, such as cyclins, cyclin-dependent kinases (CDKs), and a retinoblastoma protein (pRb). 16,17 D-type cyclins, namely cyclin D 1 , D 2 , and D 3 , are growth factor sensitive, and their expression is facilitated in response to growth factor stimulation. Byl binding with CDK4 and CDK6, D-type cyclins control a kinase activity of CDK and phosphorylate substrates that are required for G 1 progression and S phase entry. [18][19][20] One of their important targets is pRb. [18][19][20] We have already reported that the expression of cyclin D 3 and the phosphorylation of pRb are accelerated in mouse bone marrow-derived cultured mast cells (BMCMCs) incubated with stem cell factor (SCF), indicating that these regulatory molecules are essential for cell cycle progression in mast cell proliferation. 21 NF-B, a dimeric transcription factor of the rel family, exists as an inactive form in the cytoplasm by binding its endogenous Materials and methods Cell cultureHMC-1 cel...

Further development of the potent carborane-containing estrogenic agonists described here, having a new skeletal structure and unique characteristics, should yield novel therapeutic agents, especially selective estrogen receptor modulators. Furthermore, the suitability of the spherical carborane cage for binding to the cavity of the estrogen receptor-alpha ligand-binding domain should provide a basis for a similar approach to developing novel ligands for other steroid receptors.

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August 18, 2006; doi:10.1152/ajpheart.00549.2006.-Several studies have demonstrated that NF-B is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-B is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of I B that acts via inhibition of IKK-␤, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group (P Ͻ 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV enddiastolic area: vehicle, 74.13 Ϯ 3.57 mm 2 ; IMD-0354, 55.00 Ϯ 3.73 mm 2 ; P Ͻ 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 Ϯ 0.26; IMD-0354, 2.61 Ϯ 0.24; P Ͻ 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 Ϯ 14.87 pg/ml; IMD-0354, 110.75 Ϯ 6.41 pg/ml; P Ͻ 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-␤1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-B activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI. experimental heart failure; nuclear factor-b; matrix metalloproteinase; echocardiography MYOCARDIAL INFARCTION (MI) frequently leads to left ventricular (LV) dilatation and associated interstitial fibrosis in the noninfarcted myocardium. This adverse LV remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after MI (20). One of the recent conceptual advances in our understanding of the pathogenesis of LV remodeling is that this process is driven by the overexpression of various factors, including proinflammatory cytokines, angiotensin II, and norepinephrine, which have direct pathophysiological effects on cardiac myocytes, noncardiac myocytes, and the extracellular matrix (20). Although the expression of proinflammatory cytokines may be involved in wound healing after MI, it is believed that the overexpression of cytokines damages cardiac tissue and evokes excess deposition of fibrotic components, even in the noninfarcted myocardium.Several recent studies reported that nuclear factor-B (NF-B) is involved in the pathogenesis of heart failure (7, 35). Activation of NF-B induces activation of genetic programs that lead to transactivation of cytokines, chemokines, and matrix metalloproteinases (MMPs), promoting inflammatory and fibrotic responses that participate in the progre...