[Show abstract][Hide abstract] ABSTRACT: Previous studies have demonstrated that a natural coumarin compound esculetin (Esc) possesses antioxidant, anti-tumor, and anti-inflammation activities and rescues cultured primary neurons from NMDA toxicity. In this study, we investigated the neuroprotective effects of Esc on cerebral ischemia/reperfusion (I/R) injury in a middle cerebral artery occlusion model in mice. Esc (20 μg) was administered intracerebroventricularly at 30 min before ischemia. We found that Esc significantly reduced infarct volume and decreased neurological deficit scores after 75 min of ischemia and 24 h of reperfusion. Post-treatment of Esc still provided neuroprotection even when Esc was administered after 4 h of reperfusion. Our data also indicated that intraperitoneal administration of Esc showed protective effects on cerebral I/R injury in a dose-dependent manner. We further explored the protective mechanisms of Esc on cerebral I/R injury and found that Esc decreased cleaved caspase 3 level, a marker of apoptosis. Finally, our data demonstrated that Esc exerted its anti-apoptotic activity by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax, two apoptosis-related proteins. Because of its clinical use as an anticoagulant and its safety profile, Esc may have a therapeutic potential for the treatment of stroke in the future clinical trials.
Journal of Neurochemistry 03/2012; 121(6):1007-13. DOI:10.1111/j.1471-4159.2012.07744.x · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: Despite extensive research, cancer continues to be a leading cause of death worldwide and is expected to continue to rise as a result of an aging population. Therefore, new therapies are constantly being developed. Par-4 is a naturally occurring tumor suppressor protein that is capable of inducing apoptosis in cancer, but not normal cells. For this reason, Par-4 offers an attractive target for development of cancer therapy, particularly of difficult to treat cancers. Areas covered: The mechanisms by which Par-4 induces cell death are summarized. The ways that Par-4 is controlled in cancer cells are discussed. We discuss how different research groups have developed ways to overexpress and/or activate Par-4 in vitro and in vivo. The studies described demonstrate that when Par-4 levels and/or activity are increased, susceptibility to apoptosis is enhanced and tumor growth is inhibited. Expert opinion: Par-4 is a promising therapeutic protein that can be overexpressed and/or activated to induce apoptosis in a cancer-selective manner. This cancer selectivity is important given that the side-effects of chemotherapeutics can be as debilitating as cancer itself. However, there are key issues that need to be addressed to optimize the effects of Par-4 in patients.
[Show abstract][Hide abstract] ABSTRACT: Par-4 is a pro-apoptotic, tumor suppressor protein that induces apoptosis selectively in cancer cells. Endoplasmic reticulum-stress and higher levels of protein kinase A in tumor cells confer the coveted feature of cancer selective response to extracellular and intracellular Par-4, respectively. Recent studies have shown that systemic Par-4 confers resistance to tumor growth in mice, and that tumor-resistance is transferable by bone-marrow transplantation. Moreover, recombinant Par-4 inhibits the growth of tumors in mice. As systemic Par-4 induces apoptosis via cell surface GRP78, strategies that promote GRP78 trafficking to the cell surface are expected sensitize cancer cells to circulating levels of Par-4. This review illustrates the domains and mechanisms by which Par-4 orchestrates the apoptotic process in both cell culture models and in physiological settings.
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