• Molecules and Cells
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• 제46권7호
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• pp.399-413
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• 2023

cAMP responsive element-binding protein (CREB) is one of the most intensively studied phosphorylation-dependent transcription factors that provide evolutionarily conserved mechanisms of differential gene expression in vertebrates and invertebrates. Many cellular protein kinases that function downstream of distinct cell surface receptors are responsible for the activation of CREB. Upon functional dimerization of the activated CREB to cis-acting cAMP responsive elements within the promoters of target genes, it facilitates signal-dependent gene expression. From the discovery of CREB, which is ubiquitously expressed, it has been proven to be involved in a variety of cellular processes that include cell proliferation, adaptation, survival, differentiation, and physiology, through the control of target gene expression. In this review, we highlight the essential roles of CREB proteins in the nervous system, the immune system, cancer development, hepatic physiology, and cardiovascular function and further discuss a wide range of CREB-associated diseases and molecular mechanisms underlying the pathogenesis of these diseases.

• Toxicological Research
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• 제26권3호
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• pp.177-183
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• 2010

This study was performed to examine whether elevated activity of cAMP responsive element-binding protein (CREB) attenuates the detrimental effects of acute gamma ($\gamma$)-irradiation on hippocampal neurogenesis and related functions. C57BL/6 male mice were treated with rolipram (1.25 mg/kg, i.p., twice a day for 5 consecutive days) to activate the cAMP/CREB pathway against cranial irradiation (2 Gy), and were euthanized at 24 h post-irradiation. Exposure to $\gamma$-rays decreased both CREB phosphorylation and immunohistochemical markers for neurogenesis, including Ki-67 and doublecortin (DCX), in the hippocampal dentate gyrus (DG). However, the rolipram treatment protected from $\gamma$-irradiation-induced decreases of CREB phosphorylation, and Ki-67 and DCX immunoreactivity in the hippocampal DG. In an object recognition memory test, mice trained 24 h after acute $\gamma$-irradiation (2 Gy) showed significant memory impairment, which was attenuated by rolipram treatment. The results suggest that activation of CREB signaling ameliorates the detrimental effects of acute $\gamma$-irradiation on hippocampal neurogenesis and related functions in adult mice.

• Biomolecules & Therapeutics
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• 제20권2호
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• pp.207-213
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• 2012

The present study examined the effects of krill-derived phosphatidylserine (Krill-PS) on the learning and memory function and the neural activity in rats with trimethyltin (TMT)-induced memory deficits. The rats were administered vehicle (medium-chain triglyceride: MCT) or Krill-PS (50, 100 mg/kg, p.o.) daily for 21 days. The cognitive improving efficacy of Krill-PS in TMT-induced amnesic rats was investigated by assessing the Morris water maze test and by performing choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and cAMP responsive element binding protein (CREB) immunohistochemistry. The rats with TMT injection showed impaired learning and memory of the tasks and treatment with Krill-PS produced a significant improvement of the escape latency to find the platform in the Morris water maze at the $2^{nd}$ and $4^{th}$ day compared to that of the MCT group (p<0.05). In the retention test, the Krill-PS+MCT groups showed increased time spent around the platform compared to that of the MCT group. Consistent with the behavioral data, Krill-PS 50+MCT group significantly alleviated the loss of acetylcholinergic neurons in the hippocampus and medial septum compared to that of the MCT group. Treatment with Krill-PS significantly increased the CREB positive neurons in the hippocampal CA1 area as compared to that of the MCT group. These results suggest that Krill-PS may be useful for improving the cognitive function via regulation of cholinergic marker enzyme activity and neural activity.

• Molecules and Cells
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• 제23권1호
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• pp.23-29
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• 2007

Cyclic AMP-responsive element binding protein (CREB) is known to be associated with angiogenesis. In the present study we investigated the possible role of CREB in the expression of vascular endothelial growth factor (VEGF) by mouse macrophages. Over-expression of CREB increased VEGF secretion by cells of the RAW264.7 mouse macrophage cell line. It also increased the promoter activity of a mouse reporter driven by the VEGF promoter, while a dominant negative CREB (DN-CREB) abrogated the activity, suggesting that CREB mediates VEGF transcription. Forskolin, an adenylyl cyclase activator, stimulated VEGF transcription, and the PKA inhibitor H89 abolished this effect. IFN-${\gamma}$, a potent cytokine, stimulated VEGF expression only in part through the PKA-CREB pathway. These results indicate that PKA phosphorylates CREB and so induces VEGF gene expression. An analysis of mutant promoters revealed that one of the putative CREB responsive elements (CREs), at -399 ~ -388 in the promoter, is critical for CREB-mediated VEGF promoter activity, and the significance of this CRE was confirmed by chromatin immunoprecipitation assays.

• 동의생리병리학회지
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• 제28권3호
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• pp.337-345
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• 2014

The present study examined the effects of soybean-derived phosphatidylserine (SB-PS) on the learning and memory function and the neural activity in rats with trimethyltin (TMT)-induced memory deficits. The cognitive improving efficacy of SB-PS on the amnesic rats, which was induced by TMT, was investigated by assessing the Morris water maze test and by performing cholineacetyl transferase (ChAT), acetylcholinesterase (AChE) and cAMP responsive element binding protein (CREB) immunohistochemistry. A positron emission tomography (PET) scanning the rat brain was by performed administer 18F-Fluorodeoxy-glucose (18F-FDG). The rats with TMT injection showed impaired learning and memory of the tasks and treatment with SB-PS produced a significant improvement of the escape latency to find the platform in the Morris water maze at the 2nd day compared to that of the MCT group. In the retention test, the SB-PS group showed increased time spent around the platform compared to that of the MCT group. Consistent with the behavioral data, SB-PS 50 group significantly alleviated the loss of acetyl cholinergic neurons in the hippocampus compared to that of the MCT group. Treatment with SB-PS significantly increased the CREB positive neurons in the hippocampus as compared to that of the MCT group. In addition, SB-PS groups increased the glucose uptake in the hippocampus and SB-PS 50 group increased the glucose uptake in the frontal lobe, as compared to that of the MCT group. These results suggest that SB-PS may be useful for improving the cognitive function via regulation of cholinergic marker enzyme activity and neural activity.

• 생명과학회지
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• 제32권5호
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• pp.355-361
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• 2022

멜라닌 색소는 피부색의 주요 원인이다. 멜라닌 색소는 멜라닌 세포에서 생성된 다음 각질 세포로 전달되어 결국 피부 표면에 다양한 색상을 부여한다. 많은 탈색제 및 피부 미백제가 개발되었지만, 색소 침착을 감소시키기 위한 재료에 대한 수요는 여전히 증가하고 있다. 본 연구에서 천연 화합물을 사용하여 탈색 및 피부 미백에 대한 재료를 찾으려고 시도한 결과 겨우살이(Viscum album var. coloratum) 추출물이 색소 침착을 억제할 수 있음을 발견하였다. 인간 멜라닌 세포에 겨우살이 추출물(mistletoe extracts, ME)을 처리했을 때 색소 침착이 극적으로 감소하였다. 프로모터 리포터 분석은 ME 처리가 HM3KO 흑색종 세포에서 microphthalmia-associated transcription factor (MITF), melanophilin (MLPH), tyrosinase related protein 2 (TRP-2), and tyrosinase (TYR) 유전자의 전사를 억제한다는 것을 보여주었다. 일관되게 ME는 MITF, TRP-1 및 TYR과 같은 색소 침착 관련 분자의 단백질 수준을 감소시켰다. 또한 ME는 cAMP Responsive Element Binding Protein (CREB), AKT 및 ERK의 인산화를 감소시켰다. 이러한 결과는 ME가 색소 침착과 관련된 세포 내 신호 전달의 조절을 통해 멜라닌 생성을 억제한다는 것을 시사한다. 끝으로 ME는 색소 침착에 대한 생체 내 평가 모델인 제브라피쉬 배아의 멜라닌 생성을 현저하게 억제하였다.

• 한국약용작물학회지
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• 제19권6호
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• pp.456-463
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• 2011

The present study examined the effects of Korean white ginseng (WG, Panax ginseng C. A. Meyer) on the learning and memory function and the neural activity in rats with trimethyltin (TMT)-induced memory deficits. The rats were administered with saline or WG (WG 100 or 300 mg/kg, p.o.) daily for 21 days. The cognitive improving efficacy of WG on the amnesic rats, which was induced by TMT, was investigated by assessing the Morris water maze test and by performing immunohistochemistries on choline acetyltransferase (ChAT), acetylcholinesterase (AchE), cAMP responsive element binding protein (CREB) and brain derived neurotrophic factor (BDNF). The rats treated with TMT injection (control group) showed impaired learning and memory of the tasks, but the rats treated with TMT injection and WG administration produced significant improvement of the escape latency to find the platform in the Morris water maze at the 2nd and 4th days compared to that of the control group. In the retention test, the WG 100 and WG 300 groups showed significantly increased crossing number around the platform compared to that of the control group (p < 0.001). Consistently with the behavioral data, result of immunohistochemistry analysis showed that WG 100 mg/kg significantly alleviated the loss of BDNF-ir neurons in the hippocampus compared to that of the control group (p < 0.01). Also, treatment with WG has a trend to be increased the cholinergic neurons in the hippocampal CA1 and CA3 areas as compared to that of the control group. These results suggest that WG may be useful for improving the cognitive function via regulation of neurotrophic activity.

• KSBB Journal
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• 제28권2호
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• pp.137-145
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• 2013

In order to develop new skin whitening agents, we prepared the $CH_2Cl_2$ layer (NGC) and BuOH layer (NGB) of 75% EtOH extract of the Nelumbinis nucifera Gaertner. We measured their tyrosinase inhibitory activity in vitro and melanin synthesis inhibitory activity in B16-F1 melanoma cells. They did not show inhibitory activity against mushroom tyrosinase but showed melanin synthesis inhibitory activity in a dose-dependent manner. In a melanin synthesis inhibition assay, NGC and NGB suppressed melanin production up to 52% and 46% at a concentration of $100{\mu}g/mL$, respectively. To elucidate the mechanism of the inhibitory effects of NGC and NGB on melanogenesis, we measured the expression of melanogenesis-related proteins by western blot assay. As a result, NGC suppressed the expression of tyrosinase, tyrosinase related protein 1 (TRP-1), tyrosinase related protein 2 (TRP-2), phosphorylated cAMP responsive element binding (p-CREB) protein, and microphthalmia associated transcription factor (MITF). And NGB inhibited the protein expression of tyrosinase and MITF, but had no significant effect on TRP-1, TRP-2, and p-CREB expression. Moreover, NGB increased the expression of phosphorylated extracellular signal-regulated kinase (p-ERK). In addition, we examined the inhibitory effect on the glycosylation of tyrosinase. As a result, NGC and NGB inhibited the activity of ${\alpha}$-glucosidase in vitro and the glycosylation of tyrosinase in B16-F1 melanoma cells. From these results, we concluded that NGC and NGB could be used as active ingredients for skin whitening.

• Tuberculosis and Respiratory Diseases
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• 제63권2호
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• pp.165-172
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• 2007

폐암의 발생은 여러 많은 유전자의 변화가 축적되어 나타나는 일련의 과정에 의한다. 세포 내 전사 조절 인자의 하나인 CBP는 폐를 포함한 인체 내 여러 조직에서 상피세포의 분화 및 증식에 중요한 역할을 담당하며, 유전자들에서 전사조절인자로서 세포의 성장에 관여하며 발암 과정에서도 중요할 것으로 기대된다. 이에 아직까지 폐암에서 CBP에 대한 연구가 확정된 바가 없어, 폐의 전암성 병변(상피 화생 20예, 이형성증 40예) 및 편평상피세포폐암 60예를 대상으로 하여 CBP의 발현정도를 면역화학적 방법으로 비교 분석하여 다음과 같은 결과를 얻었다. 1) 화생성 병변(7예; 35%)에 비해 이형성 병변(26례; 65%)이나 편평세포암종(42례; 70%)에서 CBP의 발현이 유의하게 높았다(p<0.05). 2) 이형성 병변의 경우, 경도의 이형성 병변(20예 중 10예; 50%)보다 고도의 이형성 병변(20예 중 16예; 80%)에서 높은 CBP의 발현율을 보였다(p<0.01). 3) 편평세포암의 분화도별로 살펴보았을 때, 고분화암에서 95%(20예 중 19예), 중등도 분화암에서 85%(20예 중 17예), 저분화 암에서는 30%(20예 중 6예)의 발현율을 보였다(p<0.05). 이상과 같은 결과를 볼 때, CBP는 폐 조직에서 정상 기관지 상피 세포가 전암성 병변으로 변하거나 전암성 병변이 암으로 진행하는 과정에서 중요한 역할을 하는 것으로 보이며, 세포가 암으로의 발전할 수 있는 잠재성을 가늠하는 표지자가 될 수 있을 것으로 보인다.

• BMB Reports
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• 제53권3호
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• pp.154-159
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• 2020

We investigated the effects of physalin A, B, D, and F on osteoclastogenesis induced by receptor activator of nuclear factor κB ligand (RANKL). The biological functions of different physalins were first predicted using an in silico bioinformatic tool (BATMAN-TCM). Afterwards, we tested cell viability and cell apoptosis rate to analyze the cytotoxicity of different physalins. We analyzed the inhibitory effects of physalins on RANKL-induced osteoclastogenesis from mouse bone-marrow macrophages (BMMs) using a tartrate-resistant acid phosphatase (TRAP) stain. We found that physalin D has the best selectivity index (SI) among all analyzed physalins. We then confirmed the inhibitory effects of physalin D on osteoclast maturation and function by immunostaining of F-actin and a pit-formation assay. On the molecular level, physalin D attenuated RANKL-evoked intracellular calcium ([Ca(2+)](i)) oscillation by inhibiting phosphorylation of phospholipase Cγ2 (PLCγ2) and thus blocked the downstream activation of Ca2+/calmodulin-dependent protein kinases (CaMK)IV and cAMP-responsive element-binding protein (CREB). An animal study showed that physalin D treatment rescues bone microarchitecture, prevents bone loss, and restores bone strength in a model of rapid bone loss induced by soluble RANKL. Taken together, these results suggest that physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via suppressing the PLCγ2-CaMK-CREB pathway.