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Hypoxia-induced up-regulation of vascular endothelial growth factor (VEGF) expression is a critical event leading to tumor neovascularization. Hypoxia stimulates hypoxia-inducible factor-1α (HIF-1α), a transcriptional activator of VEGF. Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, is also induced by hypoxia. We reported previously that COX-2 inhibition prevents hypoxic up-regulation of VEGF in human prostate cancer cells and that prostaglandin E2(PGE2) restores hypoxic effects on VEGF. We hypothesized that PGE2mediates hypoxic effects on VEGF by modulating HIF-1α expression. Addition of PGE2to PC-3ML human prostate cancer cells had no effect on HIF-1α mRNA levels. However, PGE2significantly increased HIF-1α protein levels, particularly in the nucleus. This effect of PGE2largely results from the promotion of HIF-1α translocation from the cytosol to the nucleus. PGE2addition to PC-3 ML cells transfected with a GFP-HIF-1α vector induced a time-dependent nuclear accumulation of the HIF-1α protein. Two selective COX-2 inhibitors, meloxicam and NS398, decreased HIF-1α levels and nuclear localization, under both normoxic and hypoxic conditions. Of several prostaglandins tested, only PGE2reversed the effects of a COX-2 inhibitor in hypoxic cells. Finally, PGE2effects on HIF-1α were specifically inhibited by PD98059 (a MAPK inhibitor). These data demonstrate that PGE2production via COX-2-catalyzed pathway plays a critical role in HIF-1α regulation by hypoxia and imply that COX-2 inhibitors can prevent hypoxic induction of HIF-mediated gene transcription in cancer cells.

Significance: Hydrogen sulfide (H 2 S) has traditionally been considered a toxic environmental pollutant. In the late 1990s, the presumed solely harmful role of H 2 S has been challenged because H 2 S may also be involved in the maintenance and preservation of cardiovascular homeostasis. Recent Advances: The production of endogenous H 2 S has been attributed to three key enzymes, cystathionine c-lyase (CSE), cystathionine b-synthase, and 3-mercaptopyruvate sulfurtransferase. The recognition of H 2 S as the third gaseous signaling molecule has stimulated research on a multitude of pathophysiologic events in the cardiovascular system. In particular, important roles in cardiovascular disorder processes are ascribed to the CSE/H 2 S pathway, such as atherosclerosis, myocardial infarction, hypertension, and shock. Critical Issues: Many biological activities and molecular mechanisms of H 2 S in the cardiovascular system have been demonstrated in studies using different tools, such as the genetic overexpression of CSE, the direct administration of H 2 S donors, or the use of H 2 S-releasing prodrugs. Unfortunately, the role of the CSE/H 2 S pathway in cardiovascular disease remains controversial in numerous areas, and many questions regarding the gaseous molecule still remain unanswered. Future Directions: Advances in basic research indicate that the CSE/H 2 S pathway may provide potential therapeutic targets for treating cardiovascular disorders. But the molecular targets of H 2 S still need to be identified. Antioxid. Redox Signal. 17, 106-118.

Epidemiologic evidence suggests that a diet rich in fruits and vegetables is associated with a reduced risk of prostate cancer (PCa) development. Although several dietary compounds have been tested in preclinical PCa prevention models, no agents have been identified that either prevent the progression of premalignant lesions or treat advanced disease. Momordica charantia, known as bitter melon in English, is a plant that grows in tropical areas worldwide and is both eaten as a vegetable and used for medicinal purposes. We have isolated a protein, designated as MCP30, from bitter melon seeds. The purified fraction was verified by SDS-PAGE and mass spectrometry to contain only 2 highly related single chain Type I ribosome-inactivating proteins (RIPs), α-momorcharin and β-momorcharin. MCP30 induces apoptosis in PIN and PCa cell lines in vitro and suppresses PC-3 growth in vivo with no effect on normal prostate cells. Mechanistically, MCP30 inhibits histone deacetylase-1 (HDAC-1) activity and promotes histone-3 and -4 protein acetylation. Treatment with MCP30 induces PTEN expression in a prostatic intraepithelial neoplasia (PIN) and PCa cell lines resulting in inhibition of Akt phosphorylation. In addition, MCP30 inhibits Wnt signaling activity through reduction of nuclear accumulation of β-catenin and decreased levels of c-Myc and Cyclin-D1. Our data indicate that MCP30 selectively induces PIN and PCa apoptosis and inhibits HDAC-1 activity. These results suggest that Type I RIPs derived from plants are HDAC inhibitors that can be utilized in the prevention and treatment of prostate cancer.

Background and Purpose-Oxidative stress is known to be involved in ischemic stroke. Intense interest is drawn to the therapeutic potential of Chinese herbs on ischemic stroke because many of them contain antioxidant properties. Leonurine, 1 of the active compounds from purified Herba Leonuri, was studied to evaluate its possible therapeutic effects on ischemic stroke. Method-Middle cerebral artery occlusion was selected as our model of study. The animals were pretreated with Leonurine orally for 7 days and the surgery was done. One day after surgery, 2,3,5-triphenyltetrazolium chloride staining and neurological deficit score were carried out to evaluate the functional outcome of animals, whereas levels of superoxide dismutase, glutathione peroxidase, and malondialdehyde were analyzed for oxidative stress analysis. For mitochondrial studies, 3 hours after surgery, mitochondria were isolated for analysis of reactive oxygen species production, adenosine triphosphate biosynthesis, oxygen consumption, and respiratory control ratio value. Result-In in vivo experiments, Leonurine pretreatment reduced infarct volume, improved neurological deficit in stroke groups, increased activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase, and decreased levels from the lipid peroxidation marker malondialdehyde. In terms of mitochondrial modulation, Leonurine inhibited mitochondrial reactive oxygen species production and adenosine triphosphate biosynthesis. Animal studies also demonstrated that the mitochondrial function and redox state were restored by Leonurine treatment. Conclusions-Leonurine has neuroprotective effects and carries a therapeutic potential of stroke prevention. (Stroke.

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