Joo Yeon Jeong

CHI3L1 (YKL-40) is expressed in human gliomas and regulates the invasion, growth and survival of glioma cells

Chitinase 3‐like 1 (CHI3L1) is a secreted glycoprotein that has pleiotropic activity in aggressive cancers. In our study, we examined the expression and function of CHI3L1 in glioma cells. CHI3L1 was highly expressed in human glioma tissue, whereas its expression in normal brain tissue was very low. CHI3L1 suppression by shRNA reduced glioma cell invasion, anchorage‐independent growth and increased cell death triggered by several anticancer drugs, including cisplatin, etoposide and doxorubicin, whereas CHI3L1 overexpression had the opposite effect in glioma cells. Because the invasive nature of glioma cells plays a critical role in the high morbidity of glioma, we have further defined the role of CHI3L1 in the process of glioma invasion. Downregulation of CHI3L1 results in decreased cell–matrix adhesion and causes a marked increase in stress fiber formation and cell size with fewer cellular processes. Furthermore, the expression and activity of matrix metalloproteinase‐2 was also decreased in glioma cells in which CHI3L1 was knocked down. Taken together, these results suggest that CHI3L1 plays an important role in the regulation of malignant transformation and local invasiveness in gliomas. Thus, targeting the CHI3L1 molecule may be a potential therapeutic molecular target for gliomas.

Ethanol-induced oxidative stress is mediated by p38 MAPK pathway in mouse hippocampal cells

It has been known that ethanol causes neuronal cell death through oxidative stress. Ethanol itself and reactive oxygen species (ROS) produced by ethanol modulate intracellular signaling pathways including mitogen-activated protein kinase (MAPK) cascades. This study was conducted to examine the impact of ethanol on MAPK signaling in HT22 cells. Ethanol (100 and 400mM) caused activation of ERK, p38 MAPK, and JNK. ERK activation occurred in early time and p38 MAPK activation was evident when ERK activation was diminished. Specific inhibitor of p38 MAPK (SB203580) protected HT22 cells against ethanol, which was accompanied by an inhibition of ROS accumulation. However, inhibitors of ERK (U0126) and JNK (SP600125) had no effects on ethanol-induced neuronal cell death when they are treated with ethanol for 24h. These results suggest that p38 MAPK may have important roles in ROS accumulation during ethanol-induced oxidative stress in HT22 cells.

Effects of chronic restraint stress on body weight, food intake, and hypothalamic gene expressions in mice.

Background Stress affects body weight and food intake, but the underlying mechanisms are not well understood. Methods We evaluated the changes in body weight and food intake of ICR male mice subjected to daily 2 hours restraint stress for 15 days. Hypothalamic gene expression profiling was analyzed by cDNA microarray. Results Daily body weight and food intake measurements revealed that both parameters decreased rapidly after initiating daily restraint stress. Body weights of stressed mice then remained significantly lower than the control body weights, even though food intake slowly recovered to 90% of the control intake at the end of the experiment. cDNA microarray analysis revealed that chronic restraint stress affects the expression of hypothalamic genes possibly related to body weight control. Since decreases of daily food intake and body weight were remarkable in days 1 to 4 of restraint, we examined the expression of food intake-related genes in the hypothalamus. During these periods, the expressions of ghrelin and pro-opiomelanocortin mRNA were significantly changed in mice undergoing restraint stress. Moreover, daily serum corticosterone levels gradually increased, while leptin levels significantly decreased. Conclusion The present study demonstrates that restraint stress affects body weight and food intake by initially modifying canonical food intake-related genes and then later modifying other genes involved in energy metabolism. These genetic changes appear to be mediated, at least in part, by corticosterone.

Caffeine inhibits cell proliferation and regulates PKA/GSK3β pathways in U87MG human glioma cells

Caffeine is the most commonly ingested methylxanthine and has anti-cancer effects in several types of cancer. In this study, we examined the anti-cancer effects of caffeine on gliomas, both in vitro and in vivo. In vitro, caffeine treatment reduced glioma cell proliferation through G0/G1-phase cell cycle arrest by suppressing Rb phosphorylation. In addition, caffeine induced apoptosis through caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage. Caffeine also phosphorylated serine 9 of glycogen synthase kinase 3 beta (GSK3β). Pretreatment with H89, a pharmacological inhibitor of protein kinase A (PKA), was able to antagonize caffeine-induced GSK3βser9 phosphorylation, suggesting that the mechanism might involve a cAMP-dependent PKA-dependent pathway. In vivo, caffeine-treated tumors exhibited reduced proliferation and increased apoptosis compared with vehicle-treated tumors. These results suggest that caffeine induces cell cycle arrest and caspase-dependent cell death in glioma cells, supporting its potential use in chemotherapeutic options for malignant gliomas.

Suppression of survival kinases and activation of JNK mediate ethanol-induced cell death in the developing rat brain

Administration of ethanol to immature rat pups during the period in which synaptogenesis occurs triggers extensive apoptotic cell death in the brain. This ethanol-induced cell death is known to be mediated by Bax activation, which is caused by mitochondrial dysfunction. However, little data is available regarding the regulation of survival signaling pathways and their downstream events that lead to Bax activation. Thus, in the present study, we aimed to investigate the effect of ethanol on survival signaling pathways and their downstream events that lead to cell death in the rat brain during the brain developmental period. Ethanol (3 g/kg, 20% in saline) was administered subcutaneously to post-natal 7-day-old rat pups twice at 2-h intervals and the pups were sacrificed at 4 h following the first ethanol injection. Ethanol treatment suppressed the activation of survival kinases, particularly Akt, Erk1/2 and PKAalpha, whereas it increased the activation of JNK. Moreover, dissociation of dephosphorylated Bad from 14-3-3 and the interaction of activated JNK with Bcl-2 were elevated by ethanol treatment. The present study demonstrated that ethanol treatment during the brain developmental period induced mitochondrial dysfunction, which led to cell death by the suppression of survival kinases, Bad release from 14-3-3 and inactivation of Bcl-2 by activated JNK.

Resveratrol Induces Glioma Cell Apoptosis through Activation of Tristetraprolin

Tristetraprolin (TTP) is an AU-rich elements (AREs)-binding protein, which regulates the decay of AREs-containing mRNAs such as proto-oncogenes, anti-apoptotic genes and immune regulatory genes. Despite the low expression of TTP in various human cancers, the mechanism involving suppressed expression of TTP is not fully understood. Here, we demonstrate that Resveratrol (3,5,4′-trihydroxystilbene, Res), a naturally occurring compound, induces glioma cell apoptosis through activation of tristetraprolin (TTP). Res increased TTP expression in U87MG human glioma cells. Res-induced TTP destabilized the urokinase plasminogen activator and urokinase plasminogen activator receptor mRNAs by binding to the ARE regions containing the 3′ untranslated regions of their mRNAs. Furthermore, TTP induced by Res suppressed cell growth and induced apoptosis in the human glioma cells. Because of its regulation of TTP expression, these findings suggest that the bioactive dietary compound Res can be used as a novel anti-cancer agent for the treatment of human malignant gliomas.

Resveratrol suppresses vascular endothelial growth factor secretion via inhibition of CXC-chemokine receptor 4 expression in ARPE-19 cells

The present study characterizes the effects of resveratrol (Res) on vascular endothelial growth factor (VEGF) secretion in retinal pigment epithelial (RPE) cells. ARPE-19 cells were treated with CoCl2, a hypoxia mimetic agent. CoCl2 treatment increased protein levels of hypoxia inducible factor-1α (HIF-1α) and CXC-chemokine receptor 4 (CXCR4), and secretion of VEGF. To confirm the effects of Res on VEGF secretion, the human umbilical vein endothelial cell tube formation assay was performed with conditioned medium from Res-treated ARPE-19 cells. The well-known antioxidant Res effectively blocked these effects and reduced phosphorylation of nuclear factor (NF)-κB, an upstream activator of CXCR4. Furthermore, Res also suppressed VEGF secretion induced by SDF-1, a ligand of CXCR4. Conditioned medium from Res-treated ARPE-19 cells clearly suppressed tube formation compared with hypoxia-treated conditioned medium. The results demonstrated that Res inhibited the hypoxia mimetic CoCl2-induced expression of VEGF in ARPE-19 cells. Res suppressed CXCR4 expression through decreased phosphorylation of NF-κB, resulting in downregulation of VEGF secretion.

Effects of postnatal alcohol exposure on hippocampal gene expression and learning in adult mice

Fetal alcohol syndrome (FAS) is a condition resulting from excessive drinking by pregnant women. Symptoms of FAS include abnormal facial features, stunted growth, intellectual deficits and attentional dysfunction. Many studies have investigated FAS, but its underlying mechanisms remain unknown. This study evaluated the relationship between alcohol exposure during the synaptogenesis period in postnatal mice and subsequent cognitive function in adult mice. We delivered two injections, separated by 2 h, of ethanol (3 g/kg, ethanol/saline, 20% v/v) to ICR mice on postnatal day 7. After 10 weeks, we conducted a behavioral test, sacrificed the animals, harvested brain tissue and analyzed hippocampal gene expression using a microarray. In ethanol-treated mice, there was a reduction in brain size and decreased neuronal cell number in the cortex, and also cognitive impairment. cDNA microarray results indicated that 1,548 genes showed a > 2-fold decrease in expression relative to control, whereas 974 genes showed a > 2-fold increase in expression relative to control. Many of these genes were related to signal transduction, synaptogenesis and cell membrane formation, which are highlighted in our findings.

Fermented soy-powder milk with Lactobacillus plantarum P1201 protects against high-fat diet-induced obesity

Summary Fermented soy-powder milk (FSPM) with Lactobacillus plantarum P1201 contains more conjugated linoleic acid (CLA) and isoflavone aglycones compared with unfermented soy-powder milk (UFSPM). In this study, the antiobesity effect of FSPM was investigated in a high-fat diet (HFD)-induced obesity model. Results showed that FSPM reduced the weight of body, body weight gain, liver and mesenteric white adipose tissue by 10.7%, 17.7%, 32.8% and 24.1%, respectively, compared with the HFD group. Meanwhile, FSPM suppressed the HFD-induced increase of serum parameters such as total and low-density lipoprotein, cholesterol, alanine transaminase, glucose and c-peptide. To investigate how FSPM ameliorated obesity, several lipid metabolism and inflammation-related genes in liver were analysed. FSPM significantly ameliorated HFD-induced hepatic steatosis by down-regulating peroxisome proliferator-activated receptor gamma, lipoprotein lipase, fatty acid synthase, acetyl CoA carboxylase, adipocyte fatty acid-binding protein, tumour necrosis factor alpha and interleukin 1 beta. Our results showed FSPM can protect against HFD-induced obesity.

Anti-diabetic Effects of Ethanol Extract from Bitter Melon in Mice Fed a High-fat Diet

ABSTRACT Present study aimed to determine the effect of ‘bitter melon’, a popularly used fruit in Bangladesh and several other Asian countries, on high-fat-diet-induced type 2 diabetes. To investigate the effect, ethanol extract from bitter melon (BME) as a dietary supplement with mouse chow was used. BME was found to significantly attenuate the high-fat diet (HFD) -induced body weight and total fat mass. BME also effectively reduced the insulin resistance induced by the HFD. Furthermore, dietary supplementation of BME was highly effective in increasing insulin sensitivity and reducing hepatic fat and obesity. These results indicate that BME could be effective in attenuating type 2 diabetes and could therefore be a preventive measure against type 2 diabetes.