Biomedical subjects

Jin Tae Hong

Publications and source records attributed to Jin Tae Hong.

36 records · Page 2Linked to original sources

PubMed2005

Effect of sesaminol glucosides on beta-amyloid-induced PC12 cell death through antioxidant mechanisms.

Several lines of evidence support that beta-amyloid (Abeta)-induced neurotoxicity is mediated through the generation of reactive oxygen species (ROS) and elevation of intracellular calcium. In this study, we have investigated protective effects of sesaminol glucosides on Abeta-induced oxidative cell death in cultured rat pheochromocytoma (PC12) cells. Sesaminol glucoside (50-250microg/ml) decreased Abeta(25-35)-induced ROS generation, formation of 8-oxodG, a form of oxidative DNA and elevation of intracellular calcium level concomitant with prevention of apoptotic cell death dose dependently. Sesaminol glucoside (50-250microg/ml) also effectively decreased Abeta1-42 and ADDL form of Abeta1-42 as well as the combination of H2O2 with FeSO4-induced cell damages. In mechanistic study, sesaminol glucosides attenuated Abeta25-35-induced activation of redox transcription factor nuclear factor-kappaB NF-kappaB through inhibition of p50 translocation and IkappaB phosphorylation, and blocked NF-kappaB-dependent luciferase activity in addition to the inhibitory effect on Abeta25-35-induced activation of ERK kinase signal pathway. Consistent with the inhibitory effect on Abeta25-35-induced stress-induced cell death, sesaminol glucosides decreased expression of pro-apoptotic gene p53, and Bax and caspase-3, but enhanced expression of anti-apoptotic Bcl-2. Moreover, the protective effects of sesaminol glucoside on Abeta25-35-induced ROS generation, NF-kappaB activation and cell death were further enhanced with glutathione. This study therefore suggests that sesaminol glucosides have protective effect on Abeta-induced neuronal cell death, and its effect may be through antioxidative property.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

EPO receptor-mediated ERK kinase and NF-kappaB activation in erythropoietin-promoted differentiation of astrocytes.

Erythropoietin (EPO), a hematopoietic factor, is also required for normal brain development, and its receptor is localized in brain. Therefore, it is possible that EPO could act as a neurotropic factor inducing differentiation of neurons. In the present study, we investigated whether EPO can promote differentiation of neuronal stem cells into astrocytes. In primary culture of cortical neuronal stem cells isolated from post neonatal (Day 1) rat brain, EPO dose (0.1-10U/ml) dependently promoted initiation of morphological differentiation of astrocyte and expression of an astrocyte marker protein, glial fibrillary acidic protein (GFAP). Expression of EPO receptor was also increased during morphological differentiation of astrocytes. EPO-induced increased morphological differentiation of astrocytes and GFAP expression were reduced by treatment with anti-EPO and EPO receptor antibodies. Since our previous study showed that activation of MAPK family and transcription factors is differentially involved in neuronal cell differentiation, we further determined the activation of MAP kinase family and NF-kappaB during morphological differentiation of astrocytes. Concomitant with the progression of the morphological differentiation of astrocytes, ERK(2) but not JNK(1) and p38 MAPK as well as NF-kappaB were activated. However, in the presence of PD98,059, an inhibitor of ERK, and salicylic acid, an NF-kappaB inhibitor, the EPO-induced morphological differentiation of astrocytes and expression of FGAP and EPO receptor were reduced. Conversely, treatment with anti-EPO and EPO receptor antibodies also reduced EPO-induced ERK(2) and NF-kappaB activation. These data demonstrate that EPO can promote differentiation of neuronal stem cells into astrocytes in an EPO receptor dependent manner, and this effect may be associated with the activation of ERK kinase and NF-kappaB pathway.

Animals↗

PubMed2004

Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NF-kappaB without affecting IkappaB degradation.

4-Methyl-N1-(3-phenyl-propyl)-benzene-1,2-diamine (JSH-23) is a novel chemically synthetic compound. The aromatic diamine JSH-23 compound exhibited inhibitory effect with an IC(50) value of 7.1 microM on nuclear factor (NF)-kappaB transcriptional activity in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7, and interfered LPS-induced nuclear translocation of NF-kappaB without affecting IkappaB degradation. This mechanism of action is very rare for controlling NF-kappaB activation. Furthermore, the compound inhibited not only LPS-induced expressions of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and inducible nitric oxide synthase and cyclooxygenase-2 but also LPS-induced apoptosis of the RAW 264.7 cells.

Animals↗

PubMed2004

Neuronal differentiation of embryonic midbrain cells by upregulation of peroxisome proliferator-activated receptor-gamma via the JNK-dependent pathway.

Our previous study showed that the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist 15-deoxy-PGJ(2) has the promoting ability to differentiate neuronal PC12 cells. To expand our study, the effect of 15-deoxy-PGJ(2) on the differentiation of embryonic midbrain cells into dopaminergic neuronal cells was investigated in this study. The relationship between cell differentiation with activation of PPAR-gamma and the possible signal pathway were also investigated. 15-Deoxy-PGJ(2) increased neurite extension, a typical characteristic of the differentiation of embryonic midbrain cells isolated from 12-day rat embryos in a dose-dependent manner. The expression of differentiation markers, neurofilament, tyrosine hydroxylase, and nestin, was also increased by the treatment of 15-deoxy-PGJ(2). Consistent with the increasing effect on cell differentiation, 15-deoxy-PGJ(2) increased the expression and transcriptional activity of PPAR-gamma in cultured embryonic midbrain cells. In addition, the expression of PPAR-gamma and NeuN in the differentiated neuron of fetus (17 days) and adult rat brain was co-localized. Furthermore, treatment of PPAR-gamma antagonist bisphenol A diglycidyl ether blocked 15-deoxy-PGJ(2)-induced neuronal differentiation of embryonic midbrain cells and expression of PPAR-gamma. To elucidate the possible signal pathway, the activation of mitogenic-activated protein (MAP) kinase family was determined. 15-Deoxy-PGJ(2) (0.5 microM) increased activation of Jun N-terminal kinase (JNK) and p38 kinase but not extra-signal response kinase (ERK). In addition, NGF (50 ng/ml) further increased the 15-deoxy-PGJ(2)-induced JNK activation. Moreover, pretreatment of specific inhibitor of JNK SP600125 blocked the 15-deoxy-PGJ(2)-induced JNK activation. This inhibition correlated well with the inhibition of neurite extension and expression of PPAR-gamma induced by 15-deoxy-PGJ(2). The present results therefore indicate that 15-deoxy-PGJ(2) stimulates differentiation of embryonic midbrain cells into dopaminergic neuronal cells, and its effect may be PPAR-gamma and JNK signal pathway dependent.

Animals↗

PubMed2004

Inhibitory effects of ochratoxin A on nerve growth factor-induced neurite extension through downregulation of p38 MAP kinase and AP-1 activation in cultured pheochromocytoma cells.

Ochratoxin A (OTA) induces microcephaly in animals and in vitro cultured whole embryos. Inhibition of neuronal cell differentiation was proposed as underlying mechanisms responsible for OTA-induced microcephaly. Previously it was found that OTA inhibited differentiation of cultured rat embryonic midbrain cells into neurons. In this study, the influence of OTA on differentiation in PC-12 cells, a widely accepted model cells for study of neuronal differentiation was examined. Cell differentiation was assessed by measurement of neurite extension and quantified by the number of neurites extended. OTA decreased serum and nerve growth factor (NGF)-induced neurite extension in a concentration-dependent manner. Since MAP kinase and transcription factors have been implicated in cell differentiation of neuronal cells, and our previous study demonstrated that p38 MAP kinase and AP-1 are activated during PC 12 cell differentiation, the effect of OTA on NGF-induced p38 MAP kinase and transcription factor activation was examined. Co-treatment of OTA with NGF resulted in inhibition of NGF-induced p38 MAP kinase and AP-1 activation. Moreover, SB203580, a specific inhibitor of p38 MAP kinase blocked p38 MAP kinase and AP-1 activation accompanied by further inhibition of neurite extension. The present study shows that OTA inhibited cell differentiation of PC-12 cells, and this inhibitory effect may be related to inhibition of the activation of the p38 MAP kinase in conjunction with transcription factors AP-1. This finding suggests that the inhibitory effect on neuronal cell differentiation by OTA might be a mechanism responsible for OTA-induced microcephaly.

Animals↗

PubMed2004

Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit.

OBJECTIVE: To investigate the molecular mechanisms of the antiarthritic effects of bee venom (BV) and melittin (a major component of BV) in a murine macrophage cell line (Raw 264.7) and in synoviocytes obtained from patients with rheumatoid arthritis. METHODS: We evaluated the antiarthritic effects of BV in a rat model of carrageenan-induced acute edema in the paw and in a rat model of chronic adjuvant-induced arthritis. The inhibitory effects of BV and melittin on inflammatory gene expression were measured by Western blotting, and the generation of prostaglandin E(2) (PGE(2)) and nitric oxide (NO) and the intracellular calcium level were assayed. NF-kappaB DNA binding and transcriptional activity were determined by gel mobility shift assay or by luciferase assay. Direct binding of BV and melittin to the p50 subunit of NF-kappaB was determined with a surface plasmon resonance analyzer. RESULTS: BV (0.8 and 1.6 mug/kg) reduced the effects of carrageenan- and adjuvant-induced arthritis. This reducing effect was consistent with the inhibitory effects of BV (0.5, 1, and 5 mug/ml) and melittin (5 and 10 mug/ml) on lipopolysaccharide (LPS; 1 mug/ml)-induced expression of cyclooxygenase 2, cytosolic phospholipase A(2), inducible NO synthase, generation of PGE(2) and NO, and the intracellular calcium level. BV and melittin prevented LPS-induced transcriptional and DNA binding activity of NF-kappaB via the inhibition of IkappaB release and p50 translocation. BV (affinity [K(d)] = 4.6 x 10(-6)M) and melittin (K(d) = 1.2 x 10(-8)M) bound directly to p50. CONCLUSION: Target inactivation of NF-kappaB by directly binding to the p50 subunit is an important mechanism of the antiarthritic effects of BV.

Animals↗

PubMed2004

Protective role of Bcl-2 on beta-amyloid-induced cell death of differentiated PC12 cells: reduction of NF-kappaB and p38 MAP kinase activation.

Activation of the apoptosis program by an increased production of beta-amyloid peptides (Abeta) has been implicated in the neuronal cell death of Alzheimer's disease (AD). Bcl-2 is a well-demonstrated anti-apoptotic protein, however, the mechanisms of anti-apoptotic action of Bcl-2 in Abeta-induced neuronal cell death are not fully understood. In the present study, we therefore have investigated the possibility that overexpression of Bcl-2 may prevent Abeta-induced cell death through inhibition of pro-apoptotic activation of p38 MAP kinase and the transcription factor NF-kappaB in nerve growth factor (NGF)-induced differentiated PC12 cells. Treatment of Abeta into differentiated PC12 cells transfected with plasmid alone resulted in increase of cell death determined by measurement of cytotoxicity and apoptosis in a dose dependent manner. Consistent with the increase of cell death, treatment of Abeta resulted in increase of p38 MAP kinase and NF-kappaB activation. However, overexpression of Bcl-2 reduced Abeta-induced apoptosis, and suppressed the activation of p38 MAP kinase and NF-kappaB. In addition, a p38 MAP kinase specific inhibitor SB 203580 attenuated Abeta-induced apoptosis. This inhibitory effect was correlated well with the inhibition of p38 MAP kniase and NF-kappaB activation. Moreover, inhibition of NF-kappaB activation by sodium salicylates reduced Abeta-induced apoptosis and activation of p38 MAP kinase, and up regulated Bcl-2 expression. These results suggest that Bcl-2 overexpression protects against Abeta-induced cell death of differentiated PC12, and its protective effect may be related to the reduction of Abeta-induced activation of p38 MAP kinase and NF-kappaB.

Amyloid beta-Peptides↗

PubMed2004

Altered de novo sphingolipid biosynthesis is involved in the serum deprivation-induced cell death in LLC-PK1 cells.

Fumonisin B1, a specific inhibitor of ceramide synthase, and ISPI (Myriocin), a serine palmitoyltransferase inhibitor, modulate the de novo sphingolipid biosynthesis pathway. This study was conducted to determine whether serum deprivation-induced cell death is regulated by de novo sphingolipid biosynthesis in pig kidney LLC-PK1 cells. Serum withdrawal from the culture medium produced cell death in LLC-PK1 cells. Fumonisin B1 at concentrations ranging from 5 M to 30 M delayed until 48 h this cell death resulting from the absence of fetal bovine serum (FBS) in cell culture. Pretreatment of cultured cells with fumonisin B1 in the presence of serum for 24 h increased by approximately 70% this cytoprotective activity of fumonisin B1 against serum deprivation-induced cell death. Serum deprivation increased sphingolipid biosynthesis threefold compared to 5% serum-enriched culture. Fumonisin B1 at 5-30 M lowered the content of total complex sphingolipids to levels of 50% and 77% of the content in serum-enriched culture, although the concentration of intracellular free sphinganine was elevated. ISP1 alone at greater than 1 nM concentration reduced total complex sphingolipid content to values in LLC-PK1 cells grown in the presence of 5% FBS. The results suggest that the de novo complex sphingolipid biosynthesis modulated by either fumonisin B1 or ISP1 may regulate serum deprivation-induced cell death in LLC-PK1 cells.

Animals↗

PubMed2004

Reproductive disorders in pubertal and adult phase of the male rats exposed to vinclozolin during puberty.

Vinclozolin (VCZ) is a systemic dicarboximide fungicide with antiandrogenic activity. Reproductive toxicity of VCZ was investigated in male rats exposed to VCZ during puberty. Sprague-Dawley male rats aged with 35 days were assigned to six different groups; negative control, positive control receiving flutamide (100 mg/kg), VCZ (100, 200 and 400 mg/kg), and a combination of VCZ (200 mg/kg) + methyltestosterone (100 mg/kg). The animals were treated with test compounds by oral gavage daily during 35 to 44 days of age. In pubertal rats sacrificed on the next day after final treatment, VCZ or flutamide-treated group showed a decrease in weights of prostate, epididymis, and seminal vesicle, hypertrophy of Leydig cells in the testis, detached debris and sloughed cells in the tubules of the caput epididymis, and an increase in serum testosterone levels. On the other hand, combined treatment of VCZ + methyltestosterone decreased testicular weight, increased seminal vesicle weight, and induced degeneration of spermatocytes. In adult rats sacrificed at five weeks after final treatment, flutamide decreased testicular sperm counts, and VCZ, flutamide and VCZ + methyltestosterone also decreased epididymal sperm counts. In addition, treatment of VCZ (400 mg) or VCZ + methyltestosterone decreased some motion kinematic parameters of sperms including curvilinear velocity, mean angular displacement and lateral head displacement. Flutamide treatment also decreased lateral head displacement. These results indicate that VCZ exposure during pubertal period in male rats causes reproductive disorders in puberty and adulthood.

Administration, Oral↗

PubMed2003

Aggravation of L-DOPA-induced neurotoxicity by tetrahydropapaveroline in PC12 cells.

Tetrahydropapaveroline (THP) is formed in Parkinsonian patients receiving L-DOPA therapy and is detected in the plasma and urine of these patients. In this study, we have investigated the effects of THP on L-DOPA-induced neurotoxicity in cultured rat adrenal pheochromocytoma, PC12 cells. Exposure of PC12 cells up to 10 microM THP or 20 microM L-DOPA after 24 or 48 hr, neither affected the cell viability determined by MTT assay, nor induced apoptosis by flow cytometry and TUNEL staining. However, at concentrations higher than 15 microM, THP showed cytotoxicity through an apoptotic process. In addition, THP at 5-15 microM for both incubation time points significantly enhanced L-DOPA-induced neurotoxicity (L-DOPA concentration, 50 microM). Exposure of PC12 cells to THP, L-DOPA and THP plus L-DOPA for 48 hr resulted in a marked increase in the cell loss and percentage of apoptotic cells compared with exposure for 24hr. The enhancing effects of THP on L-DOPA-induced neurotoxicity were concentration- and treated-time-dependent. THP, L-DOPA and THP plus L-DOPA produced a significant increase in intracellular reactive oxygen species generation and decrease in ATP levels, supporting the involvement of oxidative stress in THP- and L-DOPA-induced apoptosis. The antioxidant N-acetyl-L-cysteine strongly inhibited changes in apoptosis, decreases in cell viability and ROS generation induced by THP associated with L-DOPA. These results suggest that THP aggravates L-DOPA-induced oxidative neurotoxic and apoptotic effects in PC12 cells. Therefore, Parkinsonian patients treated with L-DOPA for long-term need to be monitored for the relationship between plasma concentration of THP and the symptoms of neurotoxicity.

Acetylcysteine↗

PubMed2003

Peroxisome proliferator-activated receptor-gamma activator 15-deoxy-Delta12,14-prostaglandin J2 inhibits neuroblastoma cell growth through induction of apoptosis: association with extracellular signal-regulated kinase signal pathway.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been demonstrated to inhibit growth of several cancer cells. Here, we investigated whether one of the PPAR-gamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15-deoxy-PGJ2) inhibits cell growth of two human neuroblastoma cells (SK-N-SH and SK-N-MC) in a PPAR-gamma-dependent manner. PPAR-gamma was expressed in these cells, and 15-deoxy-PGJ2 increased expression, DNA binding activity, and transcriptional activity of PPAR-gamma. 15-Deoxy-PGJ2 also inhibited cell growth in time- and dose-dependent manners in both cells. Cells were arrested in G2/M phase after 15-deoxy-PGJ2 treatment with concomitant increase in the expression of G2/M phase regulatory protein cyclin B1 but decrease in the expression of cdk2, cdk4, cyclin A, cyclin D1, cyclin E, and cdc25C. Conversely, related to the growth inhibitory effect, 15-deoxy-PGJ2 increased the induction of apoptosis in a dose-dependent manner. Consistent with the induction of apoptosis, 15-deoxy-PGJ2 increased the expression of proapoptotic proteins caspase 3, caspase 9, and Bax but down-regulated antiapoptotic protein Bcl-2. 15-Deoxy-PGJ2 also activated extracellular signal-regulated kinase (ERK) 2. In addition, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor PD98059 (2'-amino-3'-methoxyflavone) decreased 15-deoxy-PGJ2-induced ERK2 activation, and expression of PPAR-gamma, capase-3, and cyclin B1. Moreover, MEK1/2 inhibitor PD98059 significantly prevented against the 15-deoxy-PGJ2-induced cell growth inhibition. We also found that PPAR-gamma antagonist GW9662 (2-chloro-5-nitro-N-phenylbenzamide) reversed the 15-deoxy-PGJ2-induced cell growth inhibition, PPAR-gamma expression, and activation of ERK2. These results demonstrate that 15-deoxy-PGJ2 inhibits growth of human neuroblastoma cells via the induction of apoptosis in a PPAR-gamma-dependent manner through activation of ERK pathway and suggest that 15-deoxy-PGJ2 may have promising application as a therapeutic agent for neuroblastoma.

Anilides↗

PubMed2003

A simple ELISA for screening ligands of peroxisome proliferator-activated receptor-gamma.

Peroxisome proliferator-activated receptors (PPARs) are orphan nuclear hormone receptors that are known to control the expression of genes that are involved in lipid homeostasis and energy balance. PPARs activate gene transcription in response to a variety of compounds, including hypolipidemic drugs. Most of these compounds have high affinity to the ligand-binding domain (LBD) of PPARs and cause a conformational change within PPARs. As a result, the receptor is converted to an activated mode that promotes the recruitment of co-activators such as the steroid receptor co-activator-1 (SRC-1). Based on the activation mechanism of PPARs (the ligand binding to PPAR gamma induces interactions of the receptor with transcriptional co-activators), we performed Western blot and ELISA. These showed that the indomethacin, a PPAR gamma ligand, increased the binding between PPAR gamma and SRC-1 in a ligand dose-dependent manner. These results suggested that the in vitro conformational change of PPAR gamma by ligands was also induced, and increased the levels of the ligand-dependent interaction with SRC-1. Collectively, we developed a novel and useful ELISA system for the mass screening of PPAR gamma ligands. This screening system (based on the interaction between PPAR gamma and SRC-1) may be a promising system in the development of drugs for metabolic disorders.

Animals↗

PubMed2003

Reduction of serotonin content by tetrahydropapaveroline in murine mastocytoma P815 cells.

The inhibitory effects of tetrahydropapaveroline on serotonin biosynthesis in serotonin-producing murine mastocytoma P815 cells were investigated. Tetrahydropapaveroline decreased serotonin content in a concentration-dependent manner in P815 cells and showed 44.9% reduction of serotonin content at a concentration of 5.0 microM for 24 h. The value of 50% inhibitory concentration, IC(50), of tetrahydropapaveroline was 7.5 microM. Under these conditions, tryptophan hydroxylase (EC 1.14.16.4, TPH) was inhibited for 24-36 h after treatment with tetrahydropapaveroline in P815 cells (46.6% inhibition at 7.5 microM). In addition, tetrahydropapaveroline inhibited the activity of TPH, prepared from the P815 cells (P815-TPH), with the IC(50) value of 8.4 microM. Inhibition of P815-TPH by tetrahydropapaveroline was found to be non-competitive both with the substrate L-tryptophan and with the cofactor DL-6-methyl-5,6,7,8-tetrahydropterine. The K(i) value of tetrahydropapaveroline with L-tryptophan was 9.29 microM. These data indicate that tetrahydropapaveroline leads to a decrease in serotonin content by inhibiting TPH activity in P815 cells.

Animals↗

PubMed2003

Inhibitory effects of glycine on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice.

The effects of glycine on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice was examined. A single administration of morphine (10 mg/kg, s.c.) induced hyperactivity as measured in mice. The morphine-induced hyperactivity was inhibited by pretreatment with glycine (100, 200 and 400 mg/kg, i.p.). In addition, it was found repeated administration of morphine (10 mg/kg, s.c.) to mice daily for 6 days caused an increase in motor activity which could be induced by a subsequent morphine dose, an effect known as reverse tolerance or sensitization. Glycine (100, 200 and 400 mg/kg, i.p.) also inhibited morphine-induced reverse tolerance. Mice that had received 7 daily repeated administrations of morphine also developed postsynaptic dopamine receptor supersensitivity, as shown by enhanced ambulatory activity after administration of apomorphine (2 mg/kg, s.c.). Glycine inhibited the development of postsynaptic dopamine receptor supersensitivity induced by repeated administration of morphine. It is suggested that the inhibitory effects of glycine might be mediated by dopaminergic (DAergic) transmission. Accordingly, the inhibition by glycine of the morphine-induced hyperactivity, reverse tolerance and dopamine receptor supersensitivity suggests that glycine might be useful for the treatment of morphine addiction.

Animals↗

PubMed2003

Activation of p38 mitogen-activated protein kinase and activator protein-1 during the promotion of neurite extension of PC-12 cells by 15-deoxy-delta12,14-prostaglandin J2.

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15-deoxy-PGJ(2)), a naturally occurring ligand, activates the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma has been found to induce cell differentiation in such cells as adipose cells and macrophages. Herein, we investigated whether 15-deoxy-PGJ(2) has neuronal cell differentiation and possible underlying molecular mechanisms. Dopaminergic differentiating PC-12 cells treated with 15-deoxy-PGJ(2) (0.2 to 1.6 microM) alone showed measurable neurite extension and expression of neurofilament, a marker of cell differentiation. However, a much greater extent of neurite extension and expression of neurofilament was observed in the presence of NGF (50 ng/ml). In parallel with its increasing effect on the neurite extension and expression of neurofilament, 15-deoxy-PGJ(2) enhanced NGF-induced p38 MAP kinase expression and its phosphorylation in addition to the activation of transcription factor AP-1 in a dose-dependent manner. Moreover, pretreatment of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), a specific inhibitor of p38 MAP kinase, inhibited the promoting effect of 15-deoxy-PGJ(2) (0.8 microM) on NGF-induced neurite extension. This inhibition correlated well with the ability of SB203580 to inhibit the enhancing effect of 15-deoxy-PGJ(2) on the expression of p38 MAP kinase and activation of AP-1. The promoting ability of 15-deoxy-PGJ(2) did not occur through PPAR-gamma because synthetic PPAR-gamma agonist and antagonist did not change the neurite-promoting effect of 15-deoxy-PGJ(2). In addition, contrast to other cells (embryonic midbrain and neuroblastoma SK-N-MC cells), PPAR-gamma was not expressed in PC-12 cells. Other structure-related prostaglandins (PGD(2) and PGE(2)) acting via a cell surface G-protein-coupled receptor (GPCR) did not increase basal or NGF-induced neurite extension. Moreover, GPCR (PGE(2) and PGD(2) receptors) antagonists did not alter the promoting effect of 15-deoxy-PGJ(2) on neurite extension and activation of p38 MAP kinase, suggesting that the promoting effect of 15-deoxy-PGJ(2) may not be mediated by GPCR either. These data demonstrate that activation of p38 MAP kinase in conjunction with AP-1 signal pathway may be important in the promoting activity of 15-deoxy-PGJ(2) on the differentiation of PC-12 cells.

Animals↗

PubMed2002

Inhibitory effect of glycolic acid on ultraviolet B-induced c-fos expression, AP-1 activation and p53-p21 response in a human keratinocyte cell line.

Glycolic acid, an alpha-hydroxy acid derived from fruit and milk sugars, has been commonly used as a cosmetic ingredient since it was known to have photo-protective and anti-inflammatory effects, and anti-oxidant effect in UV-irradiated skin. However, little has been known about the functional role of glycolic acid on UV-induced skin tumorigenesis. We previously found that glycolic acid inhibited UV-induced skin tumor development in hairless mouse. In this study we investigated anti-tumor promoting mechanism of glycolic acid on the UV-induced skin tumor development. The ability of glycolic acid to inhibit the UVB-induced cytotoxicity, apoptosis and expression of apoptosis-regulatory genes (p53 and p21) was examined. We also investigated whether glycolic acid could inhibit UVB-induced alternation of cell cycle, c-fos expression and activation of transcription factor AP-1 in cultured immortalized human keratinocyte HaCaT cells. Glycolic acid treatment attenuated the UVB-induced cell cytotoxicity as well as apoptosis. Glycolic acid also inhibited the UVB-induced expression of c-fos and the activation of transcription factor AP-1, and inhibited mRNA levels of apoptosis-regulatory gene (p53 and p21). These results suggest that glycolic acid may exert the inhibitory effect on the UVB-induced skin tumor development by blocking the UVB-induced of apoptosis and cytotoxicity through inhibition of c-fos expression and activation of AP-1 in addition to the inhibition of p53-p2l response pathway.

Apoptosis↗

PubMed2002

Inhibitory effect of peroxisome proliferator-activated receptor gamma agonist on ochratoxin A-induced cytotoxicity and activation of transcription factors in cultured rat embryonic midbrain cells.

The effects of 15-deoxy-delta12,14-prostaglandin J2 (15-deoxy PGJ2) on ochratoxin A (OTA)-induced neurotoxicity and on the activation of transcription factors activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB) were investigated in cultured rat embryonic midbrain cells. Twelve-day rat embryo midbrain cells were cultured for 48 h. OTA (0.5 or 1 microg/ml) and/or 1.5-deoxy PGJ2 (0.5 microM) were then added for 48 h. Cell number and neurite outgrowth were determined to assess the neurotoxicity of OTA. AP-1 and NF-kappaB activation was determined by gel mobility shift assay after 3 h of exposure to OTA and/or 15-deoxy PGI2. OTA caused concentration-dependent reductions in neurite outgrowth and cell number, and induced AP-1 and NF-kappaB activation. Cotreatment with 15-deoxy PGJ2 (0..5 microM) blocked OTA-induced decrease in neurite outgrowth and cell number and inhibited AP-1 and NF-kappaB activation. 15-Deoxy PGJ2 (0.5 microM) caused the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in the cells. Results show that 1.5-deoxy PGJ2 blocked OTA-induced neurotoxicity by inhibiting AP-1 and NF-kappaB activation in cultured rat embryonic midbrain cells.

Animals↗

PubMedDate not supplied

Chemoprevention of colon cancer by Korean food plant components.

Inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS/NOS-2) play pivotal roles as mediators of inflammation involved in early steps of carcinogenesis in certain organs. Therefore, chemoprevention is theoretically possible through inhibition of COX-2 and/or iNOS. In the present study, we examined the chemopreventive effects of indole-3-carbinol (I3C), a constituent of cruciferous vegetables (the family of Cruciferae) such as cabbages, cauliflowers and broccoli on the multiple intestinal neoplasia (Min) genetic mouse model, and on mouse colon carcinogenesis induced by azoxymethane (AOM). The consumption of cruciferous vegetables such as cabbage, broccoli, and Brussels sprouts has been shown to have cancer chemopreventive effects in humans and experimental animals. I3C has been shown to exert a cancer chemopreventive influence in liver, colon, and mammary tissue when given before or concurrent with exposure to a carcinogen. Powdered AIN-76A diets (Harlan Teklad Research Diet, Madison, USA) containing 100 or 300 ppm I3C (group 1 or 2) or the same pellet diets without supplement (group 3) were fed to 6-week-old male C57BL/6J-Apc(Min)(/+) (Min/+) mice (The Jackson Laboratory, Bar Harbor, ME, USA) for 10 weeks. In addition the same diets were given to wild-type normal C57BL/6J-Apc(Min)(/+) littermates after AOM initiation (groups 4-7: 10 mice in each group) for 32 weeks from week 4. At 16 weeks of age, all Min/+ mice (groups 1-3) were sacrificed for assessment of intestinal polyp development. The incidences of the colonic adenomatous polyps in the groups 1-3 were 60% (12/20), 60% (15/25) and 84% (21/25), respectively. A decreasing tendency in multiplicities of the colonic adenomatous polyps in group 1 (I3C 100 ppm; 0.85 +/- 0.22; 61%) and group 2 (I3C 300 ppm; 1.32 +/- 0.28; 94%) was observed when compared with group 3 (control; 1.40 +/- 0.21; 100%). Total number of aberrant crypt foci (ACF)/colon or aberrant crypts (AC)/colon in wild-type mice of group 4 or 5 were decreased significantly compared with those of the AOM alone group (group 6) (P < 0.01). These results suggest that I3C may be a potential chemopreventive agent for colon cancer.

Animals↗