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Molecular Medicine Volume 10

Articles from this Volume

Rajesh Aneja, Paul W Hake, Timothy J Burroughs, Alvin G Denenberg, Hector R Wong, and Basilia Zingarelli 

Epigallocatechin-3-gallate (EGCG) is the most prominent catechin in green tea. EGCG has been shown to modulate numerous molecular targets in the setting of inflammation and cancer. These molecular targets have also been demonstrated to be important participants in reperfusion injury, hence this study examines the effects of EGCG in myocardial reperfusion injury. Male Wistar rats were subjected to myocardial ischemia (30 min) and reperfusion (up to 2 h). Rats were treated with EGCG (10 mg/kg intravenously) or with vehicle at the end of the ischemia period followed by a continuous infusion (EGCG 10 mg/kg/h) during the reperfusion period. In vehicle-treated rats, extensive myocardial injury was associated with tissue neutrophil infiltration as evaluated by myeloperoxidase activity, and elevated levels of plasma creatine phosphokinase. Vehicle-treated rats also demonstrated increased plasma levels of interleukin-6. These events were associated with cytosol degradation of inhibitor κB-α, activation of IκB kinase, phosphorylation of c-Jun, and subsequent activation of nuclear factor-κB and activator protein-1 in the infarcted heart. In vivo treatment with EGCG reduced myocardial damage and myeloperoxidase activity. Plasma IL-6 and creatine phosphokinase levels were decreased after EGCG administration. This beneficial effect of EGCG was associated with reduction of nuclear factor-κB and activator protein-1 DNA binding. The results of this study suggest that EGCG is beneficial for the treatment of reperfusion-induced myocardial damage by inhibition of the NF-κB and AP-1 pathway. 

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Posted by MolMed Editor on Jun 3, 2004 12:00 AM CDT
Christopher C Keller, James B Hittner, Benjamin K Nti, J Brice Weinberg, Peter G Kremsner, and Douglas J Perkins

Molecular immunologic determinants of disease severity during Plasmodium falciparum malaria are largely undetermined. Our recent investigations showed that peripheral blood mononuclear cell (PBMC) cyclooxygenase-2 (COX-2) gene expression and plasma prostaglandin E2 (PGE2) production are suppressed in children with falciparum malaria relative to healthy, malaria-exposed children with partial immunity. Furthermore, decreased COX-2/PGE2 levels were significantly associated with increased plasma interleukin-10 (IL-10), an anti-inflammatory cytokine that inhibits the expression of COX-2 gene products. To determine the mechanism(s) responsible for COX-2–derived PGE2 suppression, PBMCs were cultured from children with falciparum malaria. PGE2 production was suppressed under baseline and COX-2–promoting conditions (stimulation with lipopolysaccharide [LPS] and interferon [IFN]-γ) over prolonged periods, suggesting that an in vivo–derived product(s) was responsible for reduced PGE2 biosynthesis. Ingestion of hemozoin (malarial pigment) by PBMC was investigated as a source of COX-2/PGE2 suppression in PBMCs from healthy, malaria-naive adults. In addition, synthetically prepared hemozoin, β-hematin, was used to investigate the effects of the core iron component of hemozoin, ferriprotoporphyrin-IX (FPIX). Physiologic concentrations of hemozoin or β-hematin suppressed LPS- and IFN-γ–induced COX-2 mRNA in a time- and dosedependent manner, resulting in decreased COX-2 protein and PGE2 production. Suppression of COX-2/PGE2 by hemozoin was not due to decreased cell viability as evidenced by examination of mitochondrial bioactivity. These data illustrate that ingestion of FPIX by blood mononuclear cells is responsible for suppression of COX-2/PGE2. Although hemozoin induced overproduction of IL-10, neutralizing IL-10 antibodies failed to restore PGE2 production. Thus, acquisition of hemozoin by blood mononuclear cells is responsible for suppression of PGE2 in malaria through inhibition of de novo COX-2 transcripts via molecular mechanisms independent of increased IL-10 production. 

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Posted by MolMed Editor on Jun 2, 2004 12:00 AM CDT
Nelson Ruiz-Opazo, Kenneth S Kosik, Lyle V Lopez, Pia Bagamasbad, Lorenz Rb Ponce, and Victoria Lm Herrera

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Posted by MolMed Editor on Jun 1, 2004 12:00 AM CDT
Csaba Szabó, Pál Pacher, Zsuzsanna Zsengellér, Anne Vaslin, Katalin Komjáti, Rita Benkö, Min Chen, Jon G Mabley, and Márk Kollai

Angiotensin II (AII) contributes to the pathogenesis of many cardiovascular disorders. Oxidant-mediated activation of poly(adenosine diphosphate–ribose) polymerase (PARP) plays a role in the development of endothelial dysfunction and the pathogenesis of various cardiovascular diseases. We have investigated whether activation of the nuclear enzyme PARP contributes to the development of AII-induced endothelial dysfunction. AII in cultured endothelial cells induced DNA single-strand breakage and dose-dependently activated PARP, which was inhibited by the AII subtype 1 receptor antagonist, losartan; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin; and the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester. Infusion of sub-pressor doses of AII to rats for 7 to 14 d induced the development of endothelial dysfunction ex vivo. The PARP inhibitors PJ34 or INO-1001 prevented the development of the endothelial dysfunction and restored normal endothelial function. Similarly, PARP-deficient mice infused with AII for 7 d were found resistant to the AIIinduced development of endothelial dysfunction, as opposed to the wild-type controls. In spontaneously hypertensive rats there was marked PARP activation in the aorta, heart, and kidney. The endothelial dysfunction, the cardiovascular alterations and the activation of PARP were prevented by the angiotensin-converting enzyme inhibitor enalapril. We conclude that AII, via AII receptor subtype 1 activation and reactive oxygen and nitrogen species generation, triggers DNA breakage, which activates PARP in the vascular endothelium, leading to the development of endothelial dysfunction in hypertension. 

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Posted by MolMed Editor on May 1, 2004 12:00 AM CDT
Yong Woo Lee, Sung Yong Eum, Kuey Chu Chen, Bernhard Hennig, and Michal Toborek

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Posted by MolMed Editor on Apr 1, 2004 12:00 AM CST
Jikui Shen, Rebecca Samul, Joelle Zimmer, Hansheng Liu, Xiaoling Liang, Sean Hackett, and Peter A Campochiaro

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Posted by MolMed Editor on Mar 1, 2004 12:00 AM CST
Henri H Versteeg, C Arnold Spek, Maikel P Peppelenbosch, and Dick J Richel 

Tissue factor (TF) initiates the coagulation cascade but also plays a role in cancer and metastasis. This transmembrane protein is frequently upregulated on tumor cells and cells that show metastatic behavior. Furthermore, it is a significant risk factor for hepatic metastasis in patients suffering from colon cancer. Recently, it has been shown that TF, together with its natural ligand factor VIIa, induces intracellular changes, such as signal transduction cascades, gene transcription, and protein synthesis. Moreover, TF:factor VIIa interaction leads to survival of cells that have been stimulated to undergo apoptosis. Together with TF-dependent processes such as angiogenesis, these intracellular phenomena form a plausible explanation for the influence of TF on metastasis. In this review, we will discuss these phenomena in more detail and hypothesize on their role in TF-driven metastasis. 

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Posted by MolMed Editor on Feb 1, 2004 12:00 AM CST
Michael Bukrinsky 

As a member of the Retrovirus family, human immunodeficiency virus (HIV), a causative agent of AIDS, replicates by integrating its genome into the host cell’s nuclear DNA. However, in contrast to most retroviruses that depend on mitotic dissolution of the nuclear envelope to gain access to the host cell’s genome, the HIV pre-integration complex can enter the nucleus of the target cell during the interphase. Such capacity greatly enhances HIV replication and allows the virus to productively infect terminally differentiated nonproliferating cells, such as macrophages. Infection of macrophages is a critical factor in the pathogenesis of diseases caused by HIV-1 and other lentiviruses. The mechanisms responsible for this unusual feature of HIV have enticed researchers since the early 90s, when the first characterization of the HIV-1 pre-integration complex was reported. Several viral factors, including matrix protein, integrase, viral protein R, and central DNA flap, have been proposed as regulators of HIV-1 nuclear import, only to be later shown as nonessential for this process. As a result, after more than a decade of intense research, there is still no consensus on which HIV-1 and cellular proteins control this critical step in HIV-1 replication. In this review, we will discuss recent advances and suggest possible solutions to the controversial issue of HIV-1 nuclear import. 

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Posted by MolMed Editor on Jan 1, 2004 12:00 AM CST