• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.9
• /
• pp.5017-5021
• /
• 2013

Objective: MicroRNAs (miRNAs) are a small class of non-coding, single-stranded RNAs with a critical role in genesis and maintenance of renal cancer mainly through binding to 3'-untranslated regions (3'UTR) of target mRNAs, which causes a block of translation and/or mRNA degradation. The aim of the present study was to investigate the potential effects of miR-122 in human renal cell carcinomas. Methods: The expression level of miR-122 was quantified by qRT-PCR. MTT, colony formation, invasion and migration assays were used to explore the potential functions of miR-122 in human renal cell carcinoma cells. Results: Cellular growth, invasion and migration in two A498 and 786-O cells were significantly increased after miR-122 transfection. Further experiments demonstrated that overexpression of miR-122 resulted in the increase of phospho-Akt (Ser473) and phospho-mTOR (Ser2448), then activation of mTOR targets, p70S6K and 4E-BP1. Conclusions: The up-regulation of miR-122 may play an important role in the progress of renal cancer through activating PI3K/Akt signal pathway and could be a potential molecular target for anti-cancer therapeutics.

• Korean Journal of Pharmacognosy
• /
• v.27 no.3
• /
• pp.231-237
• /
• 1996

The antitumor components of the protoplast fusants of Lentinula edodes and Ganoderma lucidum were examined for immunological activity to elucidate the mechanism of their antitumor activity. They did not show any direct cytotoxicity against tumor cells. But being examined for immunopotentiation activity, they increased the number of colonies in the bone marrow stem cells to 3.0 times. They also increased the activities of the acid phosphatase in activated macrophages to 2.1 times and the secretion of nitric oxide in RAW 264.7 to 2.2 times, respectively. They activated the components of the alternative complement pathway. In humoral immunity. they increased the activities of the alkaline phosphatase in differentiated B cells to 1.6 times and the number of plaque forming cells to 1.8 times, respectively. In cellular immunity, they restored the depressed response of delayed type hypersensitivity in tumor bearing mice to normal level.

• Molecules and Cells
• /
• v.21 no.3
• /
• pp.337-342
• /
• 2006

Interstitial cells of Cajal (ICCs) are pacemaker cells that activate the periodic spontaneous depolarization (pacemaker potentials) responsible for the production of slow waves in gastrointestinal smooth muscle. The effects of vasoactive intestinal polypeptide (VIP) on the pacemaker potentials in cultured ICCs from murine small intestine were investigated by whole-cell patch-clamp techniques. Addition of VIP (50 nM-$1{\mu}M$) decreased the amplitude of pacemaker potentials and depolarized resting membrane potentials. To examine the type of receptors involved in ICC, we examined the effects of the $VIP_1$ agonist and found that it had no effect on pacemaker potentials. Pretreatment with $VIP_1$ antagonist ($1{\mu}M$) for 10 min also did not block the VIP (50 nM)-induced effects. On the other hand exposure to 1H-(1,2,4)oxadiazolo(4,3-A)quinoxalin-1-one (ODQ, $100{\mu}M$), an inhibitor of guanylate cyclase, prevented VIP inhibition of pacemaker potentials. Similarly KT-5823 ($1{\mu}M$) or RP-8-CPT-cGMPS ($10{\mu}M$), inhibitors of protein kinase G (PKG) blocked the effect of VIP (50 nM) on pacemaker potentials as did N-nitro-L-arginine (L-NA, $100{\mu}M$), a non-selective nitric oxide synthase (NOS) inhibitor. These results imply that the inhibition of pacemaker activity by VIP depends on the NO-cGMP-PKG pathway.

• Molecules and Cells
• /
• v.38 no.5
• /
• pp.396-401
• /
• 2015

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important redox-sensitive transcription factor that regulates the expression of several cytoprotective genes. More recently, genetic analyses of human tumors have indicated that Nrf2 may cause resistance to chemotherapy. In this study, we found that the expression levels of Nrf2 and its target genes GCLC, HO-1, NQO1 were significantly higher in cisplatin-resistant A549 (A549/CDDP) cells than those in A549 cells, and this resistance was partially reversed by Nrf2 siRNA. 3,4,5,5,7-Pentamethoxyflavone (PMF), a natural flavon extracted from Rutaceae plants, sensitized A549/CDDP to CDDP and substantially induced apoptosis compared with that of CDDP alone treated group, and this reversal effect decreased when Nrf2 was downregulated by siRNA. Mechanistically, PMF reduced Nrf2 expression leading to a reduction of Nrf2 downstream genes, and in contrast, this effect was decreased by blocking Nrf2 with siRNA. Taken together, these results demonstrated that PMF could be used as an effective adjuvant sensitizer to increase the efficacy of chemotherapeutic drugs by downregulating Nrf2 signaling pathway.

• Molecules and Cells
• /
• v.41 no.10
• /
• pp.909-916
• /
• 2018

In pancreatic ${\beta}$ cells, glucose stimulates the biosynthesis of insulin at transcriptional and post-transcriptional levels. The RNA-binding protein, polypyrimidine tract-binding protein 1 (PTBP1), also named hnRNP I, acts as a critical mediator of insulin biosynthesis through binding to the pyrimidine-rich region in the 3'-untranslated region (UTR) of insulin mRNA. However, the underlying mechanism that regulates its expression in ${\beta}$ cells is unclear. Here, we report that glucose induces the expression of PTBP1 via the insulin receptor (IR) signaling pathway in ${\beta}$ cells. PTBP1 is present in ${\beta}$ cells of both mouse and monkey, where its levels are increased by glucose and insulin, but not by insulin-like growth factor 1. PTBP1 levels in immortalized ${\beta}$ cells established from wild-type (${\beta}IRWT$) mice are higher than levels in ${\beta}$ cells established from IR-null (${\beta}IRKO$) mice, and ectopic re-expression of IR-WT in ${\beta}IRKO$ cells restored PTBP1 levels. However, PTBP1 levels were not altered in ${\beta}IRKO$ cells transfected with IR-3YA, in which the Tyr1158/1162/1163 residues are substituted with Ala. Consistently, treatment with glucose or insulin elevated PTBP1 levels in ${\beta}IRWT$ cells, but not in ${\beta}IRKO$ cells. In addition, silencing Akt significantly lowered PTBP1 levels. Thus, our results identify insulin as a pivotal mediator of glucose-induced PTBP1 expression in pancreatic ${\beta}$ cells.

• Journal of Applied Biological Chemistry
• /
• v.63 no.2
• /
• pp.137-145
• /
• 2020

Oxidative stress is one of the pathogenic mechanisms of various neurodegenerative diseases, such as Alzheimer's disease. Neuroglia, the most abundant cells in the brain, is thought to play an important role in the antioxidant defense system and neuronal metabolic support against neurotoxicity and oxidative stress. We investigated the protective effect of paeoniflorin (PF) against oxidative stress in C6 glial cells. Exposure of C6 glial cells to hydrogen peroxide (H₂O₂, 500 μM) significantly decreased cell viability and increased amounts of lactate dehydrogenase (LDH) release, indicating H₂O₂-induced cellular damage. However, treatment with PF significantly attenuated H₂O₂-induced cell death as shown by increased cell survival and decreased LDH release. The H₂O₂-stimulated reactive oxygen species production was also suppressed, and it may be associated with improvement of superoxide dismutase activity by treatment with PF. In addition, an increase in ratio of Bcl-2/Bax protein expression was observed after treatment with PF. In particular, the down-stream of the apoptotic signaling pathway was inhibited in the presence of PF, mostly by reduction of cleaved-poly ADP ribose polymerase, cleaved caspase-3, and -9 protein expression. Furthermore, H₂O₂-induced phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 was attenuated by treatment with PF. Taken together, neuroprotective effect of PF against oxidative stress probably result from the regulation of apoptotic pathway in C6 glial cells. In conclusion, our findings suggest that PF may be a potent therapeutic agent for neurodegenerative disorders.

• Molecular & Cellular Toxicology
• /
• v.3 no.2
• /
• pp.137-144
• /
• 2007

The mechanism of cytotoxicity of doxifluridine, a prodrug fluorouracil (5-FU), has been ascribed to the misincorporation of fluoropyrimidine into RNA and DNA and to the inhibition of the nucleotide synthetic enzyme thymidylate synthase. Increased understanding of the mechanism of 5-FU has led to the development of strategies that increases its anticancer activity or predicts its sensitivity to patients. Using GeneChip?? Rhesus Macaque Genome arrays, we analyzed gene expression profiles of doxifluridine after two weeks repeated administration in cynomolgus monkey. Kegg pathway analysis suggested that cytoskeletal rearrangement and cell adhesion remodeling were commonly occurred in colon, jejunum, and liver. However, expression of genes encoding extracellular matrix was distinguished colon from others. In colon, COL6A2, COL18A1, ELN, and LAMA5 were over-expressed. In contrast, genes included in same category were down-regulated in jejunum and liver. Interestingly, MMP7 and TIMP1, the key enzymes responsible for ECM regulation, were overexpressed in colon. Several studies were reported that both gene reduced cell sensitivity to chemotherapy-induced apoptosis. Therefore, we suggest they have potential as target for modulation of 5-FU action. In addition, the expression of genes which have been previously known to involve in 5-FU pathway, were examined in three organs. Particularly, there were more remarkable changes in colon than in others. In colon, ECGF1, DYPD, TYMS, DHFR, FPGS, DUT, BCL2, BAX, and BAK1 except CAD were expressed in the direction that was good response to doxifluridine. These results may provide that colon is a prominent target of doxifluridine and transcriptional profiling is useful to find new targets affecting the response to the drug.

• Journal of Embryo Transfer
• /
• v.24 no.1
• /
• pp.1-14
• /
• 2009

Ovarian cancer is a significant cause of cancer-related death in women, but the main biological causes remain open questions. Hormonal factors have been considered to be an important determinant causing ovarian cancer. Recent studies have shown that gonadotropin-releasing hormone (GnRH)-I and its analogs have clinically therapeutic value in the treatment of ovarian cancer. In addition, numerous studies have shown that the potential of GnRH-II in normal reproductive system or reproductive disorder. GnRH-I receptors have been detected in approximately 80% of ovarian cancer biopsy specimens as well as normal ovarian epithelial cells and immortalized ovarian surface epithelium cells. GnRH-II receptors have also been found to be more widely expressed than GnRH-I receptors in mammals, suggesting that GnRH receptors may have additional functions in reproductive system including ovarian cancer. The signal transduction pathway following the binding of GnRH to GnRH receptor has been extensively studied. The activation of protein kinase A/C (PKA/PKC) pathway is involved in the GnRH-I induced anti-proliferative effect in ovarian cancer cells. In addition, GnRH-I induced mitogen-activated protein kinase (MAPK) activation plays a role in anti-proliferative effect and apoptosis in ovarian cancer cells and the activation of transcriptional factors related to cellular responses. However, the role of GnRH-I and II receptors, there are discrepancies between previous reports. In this review, the role of GnRH in ovarian cancer and the mechanisms to induce anti-proliferation were evaluated.

• Journal of Life Science
• /
• v.24 no.7
• /
• pp.762-768
• /
• 2014

Diet exerts a major stress on the body and may affect gene expression and physiological functions. Understanding of cellular responses during starvation is necessary in developing strategies to reduce damage caused by diet. In this study, we isolated 10 genes (Comt, RGN, Scd1, Temt, Idi1, Fabp5, Car3, Cyp2c70, Pinx1, and Poldip3) that are down-regulated in starvation and are closely related to liver metabolism. Water supply during starvation had no effect on the induction of apoptosis, autophagy, and ERQC. The genes down-regulated by starvation were associated with many related pathways rather than limited to the liver homeostasis pathway. Water supply during starvation is important. However, maintaining NaCl homeostasis is more important. The results are thought to be closely related to gender-specific metabolism in starvation and NaCl.

• Molecules and Cells
• /
• v.19 no.1
• /
• pp.60-66
• /
• 2005

Low density lipoproteins (LDL) play important roles in the pathogenesis of atherosclerosis. Diabetes is associated with accelerated atherosclerosis leading to cardiovascular disease in diabetic patients. Although LDL stimulates the proliferation of arterial smooth muscle cells (SMC), the mechanisms are not fully understood. We examined the effects of native LDL and glycated LDL on the extracellular signal-regulated kinase (ERK) pathway. Addition of native and glycated LDL to rat aorta SMCs (RASMCs) stimulated ERK phosphorylation. ERK phosphorylation was not affected by exposure to the $Ca^{2+}$ chelator BAPTA-AM but inhibition of protein kinase C (PKC) with GF109203X, inhibition of Src kinase with PP1 ($5{\mu}M$) and inhibition of phospholipase C (PLC) with U73122/U73343 ($5{\mu}M$) all reduced ERK phosphorylation in response to glycated LDL. In addition, pretreatment of the RASMCs with a cell-permeable mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059, $5{\mu}M$) markedly decreased ERK phosphorylation in response to native and glycated LDL. These findings indicate that ERK phosphorylation in response to glycated LDL involves the activation of PKC, PLC, and MEK, but is independent of intracellular $Ca^{2+}$.