• Archives of Pharmacal Research
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• v.25 no.3
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• pp.370-374
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• 2002

Administration of dopamine agonist, apomorphine (2 mg/kg, s.c.), produces cage climbing behavior in mice that exhibit typical dopaminergic stimulation. The present study investigated the pCREB expression level in several brain regions following apomorphine treatment in order to determine whether the increased the dopaminergic activation produced by apomorphine accompanies the changes in pCREB immunoreactivity. A mouse brain was removed at 0min, 10 min, 30 min, 1 h, 2 h, 7 h, and 24 h after apomorphine treatment. The brain tissue was fixed by an intracardiac perfusion with ice-cold 4％ paraformaldehyde in PBS. Immunohistochemical study was conducted using the ABC-DAB method. The data showed that the immunoreactivity of pCREB increased in the striatum, nucleus-accumbens, piriform cortex and the dentate gyrus of the hippocampus of a mouse brain 30 min after the apomorphine treatment. Increased immunoreactivity began to diminish 2 h after the apomorphine treatment in all the brain regions measured. The time course for the pCREB immunoreactivity was similar to the behavioral response induced by the apomorphine treatment. These results suggest that activation of the dopamine receptor is accompanied by an increase in pCREB expression in the mouse brain.

• Journal of Pharmacopuncture
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• v.21 no.1
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• pp.35-40
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• 2018

Objective: The role of BDNF (brain-derived neurotrophic factor), CREB (cAMP response element binding) and VGF neuropeptide has been proved in antidepressant activity of long term saffron administration in the rat hippocampus. In this study we evaluated the role of these proteins in antidepressant activity of saffron in long term administration in the rat cerebellum. Methods: Saffron aqueous extract (40 and 80 mg/kg/day) and imipramine (10 mg/kg/day) were administered intraperitoneally for 21 days to rats. At the end of experiment, animals were sacrificed and cerebellums were separated. The protein levels of BDNF, VGF, CREB and P- CREB in the rat cerebellum were evaluated using western blot analysis. Results: Saffron aqueous extract (80mg/kg/day) caused significant increase in protein level of P-CREB in long term treatment in the rat cerebellum. The increases in the protein levels of VGF, CREB and BDNF were not significant. Conclusion: In summary, our results showed that antidepressant effect of saffron in rat cerebellum might be due to the enhanced phosphorylation of CREB.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.4
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• pp.299-305
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• 2001

Activation of D1-like dopamine receptors by psychostimulants, such as amphetamine, upregulates the expression of immediate early gene and opioid peptide gene in the striatum. The genomic changes are regulated by phosphorylated transcription factors via complicated intracellular events. To evaluate temporal expression of the transcription factors by dopaminergic stimulation, the D1-like dopamine agonist, amphetamine or SKF82958, was systematically delivered. As intracellular markers in response to the agonist, phosphorylated cAMP response element-binding protein (pCREB), Fos-related antigens (FRA) and FosB immunoreactivity (IR) was compared at 20 and 120 min time points in the selected areas of the striatum. Semi-quantitative immunocytochemistry showed that amphetamine (5 mg/kg, i.p.) significantly increased pCREB-IR at 20 min, sustained up to 60 min and decreased at 120 min after the infusion. Like amphetamine, the full D1 agonist, SKF82958 (0.5 mg/kg, s.c.), also increased pCREB-IR at 20 min, but not at 120 min after the infusion in the dorsal striatum (caudoputaman, CPu) and shell of ventral striatum (nucleus accumbens, NAc). In contrast, FRA- and FosB-IR induced by SKF82958 was significantly increased at 120 min, but not at 20 min after the administration. These data indicate that SKF82958 mimics induction of CREB phosphorylation by amphetamine and differentially regulates temporal induction of pCREB, and FRA and FosB expression in the striatum.

• Tuberculosis and Respiratory Diseases
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• v.59 no.6
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• pp.631-637
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• 2005

Background : Transcriptional factors of the CREB(cAMP Response Element Binding Protein) are involved in the regulation of gene expression in response to a variety of signaling pathways. Proteins produced by the CREB genes play key roles in many physiological processes, including memory and long-term potentiation. The retinoic acid receptor (RAR) axis mediates epithelial cell differentiation and proliferation in many tissues including the lung. Material and method : The RAR and CREB expression levels were examined in 60 adenocarcinomas and 60 squamous cell carcinomas of the lung using immunohistochemical staining. Results : 1) RAR protein expression was found in 58.3%(35/60) of adenocarcinomas and 36.7%(22/60) of squamous cell carcinomas(P<0.05). 2) RAR protein expression was found in 80%(16/20) of well differentiated adenocarcinomas, 60%(12/20) of moderately differentiated adenocarcinomas, and 35%(7/20) of poorly differentiated adenocarcinomas (P<0.01). 3) RAR protein expression was found in 45%(9/20) of well differentiated squamous cell carcinomas, 35%(7/20) of moderately differentiated squamous cell carcinomas, and 30%(6/20) of poorly differentiated squamous cell carcinomas (P>0.05). 4) CREB expression was found in 61.7%(37/60) of adenocarcinomas and 40%(24/60) of squamous cell carcinomas( P<0.05). 5) CREB expression was found in 85%(17/20) of well differentiated adenocarcinomas, 60%(12/20) of moderately differentiated adenocarcinomas, and 40%(8/20) of poorly differentiated adenocarcinomas (P<0.01). 6) CREB expression was found in 45%(9/20) of well differentiated squamous cell carcinomas, 35%(7/20) of moderately differentiated squamous cell carcinomas, and 35%(8/20) of poorly differentiated squamous cell carcinomas(P>0.05). 7) RAR and CREB expression was found in 68.5% of lung cancers, and there was a significant correlation between them(P<0.05). Conclusion : RAR and CREB expression can be used to indirectly determine the malignant potentiality of a cell.

• Journal of Gastric Cancer
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• v.8 no.4
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• pp.182-188
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• 2008

Purpose: Transcriptional factors of CREB (cAMP response element binding protein) are involved in regulating the gene expression in response to a variety of signaling pathways. The proteins produced by the CREB genes play key roles in many physiological processes, including memory and long-term potentiation. The retinoic acid receptor (RAR) axis mediates epithelial cell differentiation and proliferation in many tissues. This study examined the expressions of RAR and CREB and their relationship with the clinicopathologic factors and their significance. Materials and Methods: The levels of the RAR and CREB expressions were measured in 150 gastric adenocarcinomas by performing immunohistochemical staining. Results: 1. An RAR protein expression was found in 63.3% of the adenocarcinomas (95/150) and a CREB expression was found in 60.7% (91/150) of the adenocarcinomas. 2. An RAR protein expression was found in 72.2% (78/108) of the intestinal type adenocarcinomas and in 40.5% (17/42) of the diffuse type adenocarcinomas (P<0.05). Based on the depth of invasion, an RAR protein expression was found in 58.3% (14/24) of the T1 adenocarcinomas, in 61.9% (13/21) of the T2 adenocarcinomas, in 63.5% (61/96) of the T3 adenocarcinomas, in 77.8% (7/9) of the T4 adenocarcinomas and in 74.7% (62/83) of the adenocarcinomas with lymph node metastasis and in 49.2% (33/67) of the adenocarcinomas without lymph node metastasis (P<0.01). 3. A CREB expression was found in 69.4% (75/108) of the intestinal type and in 38.1% (16/42) of the diffuse type (P>0.05). Based on the depth of invasion, a CREB expression was found in 50% (12/24) of the T1 adenocarcinomas, in 52.4% (11/21) of the T2 adenocarcinomas, in 64.6% (62/96) of the T3 adenocarcinomas, in 66.6% (6/9) of the T4 adenocarcinomas, in 71.1% (59/83) of the adenocarcinomas with lymph node metastasis and in 47.8% (32/67) of the adenocarcinomas without lymph node metastasis (P<0.01). 4. The RAR protein and CREB expressions coincided in 71.4% of the gastric adenocarcinomas and a significant correlation between them was found (P<0.05). Conclusion: We found a significant relationship between the expression of RAR and CREB and the histology and lymph node metastasis of gastric cancer. Further studies are needed to confirm their biologic meaning in gastric carcinogenesis.

• Journal of Acupuncture Research
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• v.21 no.3
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• pp.61-81
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• 2004

Background and Objective : The aim of this study was to investigate the effects of acupuncture and electroacupuncture on the DCX, PSA-NCAM, and pCREB expression in the brain of spontaneously hypertensive rats(SHR). Materials and Methods : SHR were divided into five groups: control group, acupuncture group, 2Hz electroacupuncture(EA) group and 100Hz EA group. We evaluated the changes of the DCX, PSA-NCAM, and pCREB positive cells using immunohistochemical method. In the olfactory bulb, we investigate the optical densities of the immunoactive cells. In the dentate gyrus and the piriform cortex, we count the immunoactive cells under the $100{\times}$ visual field optical microscope. Results : 1. The optical densities of DCX-positive cells in the subependymal zone were significantly decreased in all groups, compared to the control group. 2. The counts of DCX-positive cells in the dentate gyrus were significantly increased in all groups, compared to the control group. The counts of DCX-positive cells in the piriform cortex were significantly increased in the acupuncture and 100Hz EA group, compared to the control group. 3. The optical densities of PSA-NCAM-positive cells in the subependymal zone were significantly decreased in the acupuncture and 2Hz EA group, compared to the control group. 4. The counts of PSA-NCAM-positive cells in the dentate gyrus and the piriform cortex were significantly increased in all group, compared to the control group. 5. The counts of pCREB-positive cells in the dentate gyrus were significantly increased in all groups, compared to the control group. The counts of pCREB-positive cells in the piriform cortex were significantly increased in the acupuncture and 100Hz EA group, compared to the control group. Conclusion : We conclude that acupuncture and EA may affect neuronal cell proliferation, differentiation and plasticity in the brain.

• Clinical and Experimental Reproductive Medicine
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• v.25 no.3
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• pp.305-313
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• 1998

Steroid hormone is known to cause the dynamic changes of mammalian uterus during reproductive cycle. However there is little information about the effect of estrogen (E) and progesterone (P) on the expression of various transcription factors involved in gene expression. Thus the present study was designed to demonstrate E and/or P-induced expression of c-Fos, CREB, ATF and HSP70 in rat uterus. Rats, ovariectomized (OVX) for two weeks, were divided into 6 experimental groups, 1) OVX, 2) OVX+V, 3) OVX+E, 4) OVX+P, 5) OVX+E+V, 6) OVX+E+P, and western blotting assay for nuclear extract and immunohistochemical staining were carried out for each experimental group. Treatment of E $(10{\mu}g)$ showed to increase the expression of c-Fos, CREB, ATF, and HSP70, and maximal expression was occured at $3\sim6$ hr after E administration. P (1mg) also increased, but much less than E, the expression of c-Fos, ATF, and HSP70. However, P did not reveal any effect on the expression CREE. P treatment 4 hr after E injection decreased c-Fos, CREB, and ATF expression, but did not show any change in the E-induced HSP70 expression. In immunohistochemical study c-Fos-, CREB-, and ATF-immunoreactivities were confined to the cells of luminal epithelium of uterine endometrium. These results suggest that proliferation and differentiation of rat uterus during reproductive cycle may mediated via expression of transcription factors, such as c-Fos, CREB, ATF, and HSP70.

• Biomolecules & Therapeutics
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• v.16 no.2
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• pp.113-117
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• 2008

Morphine is a potent analgesic with significant abuse potential, because of drug craving and psychological dependence. It is reported that repeated treatment of morphine can produce conditioned place preference (CPP) showing a reinforcing effect in mice. Previously, we have reported the inhibitory effect of the methanolic extract of Coptis japonica (MCJ) on morphine-induced CPP in mice. The present study was employed whether p-CREB expression is involved in the inhibitory effect of MCJ on the morphine-induced CPP in the mouse hippocampus. Repeated administration of MCJ 100 mg/kg inhibited morphine-induced CPP. Expression of p-CREB was increased in the dentate gyrus of the hippocampus that had undergone morphineinduced CPP. This increase of expression was significantly inhibited by administration of MCJ 100 mg/kg, compared to the morphine control group. Taken together, these results suggest that MCJ inhibits morphine-induced CPP through the regulation of p-CREB expression in the mouse dentate gyrus of the hippocampus.

• BMB Reports
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• v.41 no.3
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• pp.242-247
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• 2008

MSS, a comprising mixture of maesil (Prunus mume Sieb. et Zucc) concentrate, disodium succinate and Span80 (3.6 : 4.6 : 1 ratio) showed a significant improvement of memory when daily administered (460 mg/kg day, p.o.) into the normal rats for 3 weeks. During the spatial learning of 4 days in Morris water maze test, both working memory and short-term working memory index were significantly increased when compared to untreated controls. We investigated a molecular signal transduction mechanism of MSS on the behaviors of spatial learning and memory. MSS treatment increased hippocampal mRNA levels of NR2B and TrkB without changes of NR1, NR2A, ERK1, ERK2 and CREB. However, the protein levels of pERK/ERK and pCREB/CREB were all significantly increased to $1.5{\pm}0.17$ times. These results suggest that the improving effect of spatial memory for MSS is linked to MAPK/ERK signaling pathway that ends up in the phosphorylation of CREB through TrkB and/or NR2B of NMDA receptor.

• BMB Reports
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• v.42 no.3
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• pp.142-147
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• 2009

Small-molecule inhibitors of protein kinases have contributed immensely to our understanding of biological signaling path-ways and have been exploited therapeutically for the treatment of cancers and other disease states. The pyridinyl imidazole compounds SB 203580 and SB 202190 were identified as ATP competitive antagonists of the p38 stress-activated protein kinases and have been widely used to elucidate p38-dependent cellular processes. Here, we identify SB 203580 and SB 202190 as potent inhibitors of stress-induced CREB phosphorylation on Serine 111 (Ser-111) in intact cells. Unexpectedly, we found that the inhibitory activity of SB 203580 and SB 202190 on CREB phosphorylation was independent of p38, but instead correlated with inhibition of casein kinase 1 (CK1) in vitro. The inhibition of CK1-mediated CREB phosphorylation by concentrations of pyridinyl imidazoles commonly employed to suppress p38, suggests that in some cases conclusions of p38-dependence derived solely from the use of these inhibitors may be invalid.