Jae-Sun Choi

AMP-activated protein kinase is activated in Parkinson’s disease models mediated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The selective loss of dopaminergic neurons in the substantia nigra pars compacta is a feature of Parkinsons disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity is the most common experimental model used to investigate the pathogenesis of PD. Administration of MPTP in mice produces neuropathological defects as observed in PD and 1-methyl-4-pyridinium (MPP(+)) induces cell death when neuronal cell cultures are used. AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis. In the present study, we demonstrated that AMPK is activated by MPTP in mice and MPP(+) in SH-SY5Y cells. The inhibition of AMPK by compound C resulted in an increase in MPP(+)-induced cell death. We further showed that overexpression of AMPK increased cell viability after exposure to MPP(+) in SH-SY5Y cells. Based on these results, we suggest that activation of AMPK might prevent neuronal cell death and play a role as a survival factor in PD.

Melatonin suppresses tumor progression by reducing angiogenesis stimulated by HIF-1 in a mouse tumor model

The sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. Hypoxia‐inducible factor‐1 (HIF‐1) plays an essential role in tumor angiogenesis and growth by regulating the transcription of genes in response to hypoxic stress. This study was designed to investigate the effects of melatonin on tumor growth and angiogenesis, as well as the mechanism underlying the antitumor activities of melatonin. In this study, we show that the administration of melatonin inhibits tumor growth and blocks tumor angiogenesis in mice. Moreover, melatonin diminished the expression of the HIF‐1α protein within the tumor mass during tumorigenesis. Our findings suggest that melatonin is a promising anti‐angiogenic therapeutic agent targeting HIF‐1α in cancer. Considering that HIF‐1α is overexpressed in a majority of human cancers, melatonin could offer a potent therapeutic agent for cancer.

Antiangiogenic Effects of P-Coumaric Acid in Human Endothelial Cells

p‐Coumaric acid, a hydroxy derivative of cinnamic acid, has been known to possess antioxidant and anticancer activities. Despite its potential contribution to chemopreventive effects, the mechanism by which p‐coumaric acid exerts its antiangiogenic actions remains elusive. In this study, we revealed that p‐coumaric acid inhibited the sprouting of endothelial cells in rat aortic rings and inhibited the tube formation and migration of endothelial cells. We observed that p‐coumaric acid could downregulate mRNA expression levels of the key angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. Also, we demonstrated that p‐coumaric acid inhibited both the AKT and ERK signaling pathways, which are known to be crucial for angiogenesis. Using a mouse model, we also showed that p‐coumaric acid effectively suppressed tumor growth in vivo by lowering hemoglobin contents. Collectively, these findings indicate that p‐coumaric acid possesses potent anticancer properties due to the inhibition of angiogenesis in vivo. Copyright

The Anti-Angiogenic Activities of Glycyrrhizic Acid in Tumor Progression

Glycyrrhizic acid (GA) is the bioactive compound of licorice and has been used as a herbal medicine because of its anti‐viral, anti‐cancer, and anti‐inflammatory properties. This study was designed to investigate the effects of GA on tumor growth, angiogenesis, and the mechanisms underlying the anti‐angiogenic activities of GA. We observed that GA inhibited tumor growth and angiogenesis in mice. GA decreased angiogenic activities, such as the migration, invasion, and tube formation of endothelial cells. We also demonstrated that GA reduced the production of reactive oxygen species and activation of ERK in endothelial cells. Our findings suggest that GA is a promising anti‐angiogenic therapeutic agent that targets the ERK pathway. Considering that angiogenesis is highly stimulated in the majority of cancers, GA could offer a potent therapeutic agent for cancer. Copyright

Ethyl pyruvate has a neuroprotective effect through activation of extracellular signal-regulated kinase in Parkinson's disease model.

Ethyl pyruvate (EP), a simple derivative of endogenous pyruvate, has an anti-inflammatory function. Recently, the protective neurological effects of EP have been reported in cell culture and animal models of neurological diseases. The present study investigates the protective effects of EP on dopaminergic cell death in Parkinsons disease models. The selective death of dopaminergic neurons in substantia nigra was prevented by EP in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models. EP also suppressed the 1-methyl-4-pyridinium-induced cell death of SH-SY5Y cells and restored the phosphorylation of extracellular signal-regulated kinase. Thus, EP has neuroprotective effects of EP in Parkinsons disease and its related signaling pathways.

Cinnamic aldehyde suppresses hypoxia-induced angiogenesis via inhibition of hypoxia-inducible factor-1α expression during tumor progression.

During tumor progression, hypoxia-inducible factor 1 (HIF-1) plays a critical role in tumor angiogenesis and tumor growth by regulating the transcription of several genes in response to a hypoxic environment and changes in growth factors. This study was designed to investigate the effects of cinnamic aldehyde (CA) on tumor growth and angiogenesis and the mechanisms underlying CAs anti-angiogenic activities. We found that CA administration inhibits tumor growth and blocks tumor angiogenesis in BALB/c mice. In addition, CA treatment decreased HIF-1α protein expression and vascular endothelial growth factor (VEGF) expression in mouse tumors and Renca cells exposed to hypoxia in vitro. Interestingly, CA treatment did not affect the stability of von Hippel-Lindau protein (pVHL)-associated HIF-1α and CA attenuated the activation of mammalian target of rapamycin (mTOR) pathway. Collectively, these findings strongly indicate that the anti-angiogenic activity of CA is, at least in part, regulated by the mTOR pathway-mediated suppression of HIF-1α protein expression and these findings suggest that CA may be a potential drug for human cancer therapy.

Salicin, an Extract from White Willow Bark, Inhibits Angiogenesis by Blocking the ROS‐ERK Pathways

Salicin has been studied as a potent antiinflammatory agent. Angiogenesis is an essential process for tumor progression, and negative regulation of angiogenesis provides a good strategy for antitumor therapy. However, the potential medicinal value of salicin on antitumorigenic and antiangiogenic effects remain unexplored. In this study, we examined the antitumorigenic and antiangiogenic activity of salicin and its underlying mechanism of action. Salicin suppressed the angiogenic activity of endothelial cells, such as migration, tube formation, and sprouting from an aorta. Moreover, salicin reduced reactive oxygen species production and activation of the extracellular signal‐regulated kinase pathway. The expression of vascular endothelial growth factor was also decreased by salicin in endothelial cells. When the salicin was administered to mice, salicin inhibited tumor growth and angiogenesis in a mouse tumor model. Taken together, salicin targets the signaling pathways mediated by reactive oxygen species and extracellular signal‐regulated kinase, providing new perspectives into a potent therapeutic agent for hypervascularized tumors. Copyright

Zingerone suppresses angiogenesis via inhibition of matrix metalloproteinases during tumor development

Angiogenesis is an essential step for tumor survival and progression, and the inhibition of angiogenesis is a good strategy for tumor therapeutics. In this study, we investigated the therapeutic effect of zingerone in a mouse tumor model. Zingerone suppressed tumor progression and tumor angiogenesis. Moreover, we found that zingerone inhibited the angiogenic activities of endothelial cells by both direct and indirect means. A mechanistic study showed that the activities of MMP-2 and MMP-9 in tumor cells were decreased by treatment with zingerone. Interestingly, zingerone-mediated inhibition of MMP-2 and MMP-9 was involved in the JNK pathway. In conclusion, zingerone showed strong anti-angiogenic activity via the inhibition of MMP-2 and MMP-9 during tumor progression, suggesting that zingerone may be a potential therapeutic drug for human cancers.

Ethyl pyruvate stabilizes hypoxia-inducible factor 1 alpha via stimulation of the TCA cycle

Ethyl pyruvate is a simple derivative of the endogenous metabolite pyruvate. Pyruvate is the starting substrate for the tricarboxylic acid (TCA) cycle and plays a central role in intermediary metabolism. The present study was to determine whether ethyl pyruvate affects the expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and to explore the mechanism of HIF-1alpha regulation. We found that ethyl pyruvate increased HIF-1alpha stability via inhibition of pVHL-mediated degradation. Furthermore, ethyl pyruvate enhanced the reactive oxygen species (ROS) generated through the TCA cycle in mitochondria. Taken together, our results support a novel role for ethyl pyruvate in HIF-1alpha stabilization by which high rates of the TCA cycle can promote ROS production.

Coenzyme Q10 decreases basic fibroblast growth factor (bFGF)-induced angiogenesis by blocking ERK activation.

Coenzyme Q10 (CoQ10) is an essential factor of the mitochondrial respiratory chain and has effective antioxidant properties. Therefore, CoQ10 has been used in a variety of clinical applications and used as a nutritional supplement to treat several human diseases. Here, we tested the effects of CoQ10 on angiogenesis stimulated by basic fibroblast growth factor (bFGF). CoQ10 significantly inhibited bFGF-induced angiogenesis in a mouse Matrigel plug and the sprouting of endothelial cells in rat aortic rings. In addition, CoQ10 decreased the ability of tube formation, migration, and invasion in endothelial cells. When CoQ10 was used to inhibit angiogenesis in endothelial cells, the expression of vascular endothelial growth factor (VEGF) and the phosphorylation of ERK were decreased. Taken together, these results indicate that CoQ10 is able to act as an antiangiogenic regulator, and its inhibitory activity is mediated by blocking an ERK-dependent pathway. This study suggests that CoQ10 may be used a therapeutic agent to decrease neovascularization in several diseases, including solid tumors.