• Molecules and Cells
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• 제44권1호
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• pp.1-12
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• 2021

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the master transcriptional regulator in adipogenesis. PPARγ forms a heterodimer with another nuclear receptor, retinoid X receptor (RXR), to form an active transcriptional complex, and their transcriptional activity is tightly regulated by the association with either coactivators or corepressors. In this study, we identified T-cell death-associated gene 51 (TDAG51) as a novel corepressor of PPARγ-mediated transcriptional regulation. We showed that TDAG51 expression is abundantly maintained in the early stage of adipogenic differentiation. Forced expression of TDAG51 inhibited adipocyte differentiation in 3T3-L1 cells. We found that TDAG51 physically interacts with PPARγ in a ligand-independent manner. In deletion mutant analyses, large portions of the TDAG51 domains, including the pleckstrin homology-like, glutamine repeat and proline-glutamine repeat domains but not the proline-histidine repeat domain, are involved in the interaction with the region between residues 140 and 506, including the DNA binding domain, hinge, ligand binding domain and activation function-2 domain, in PPARγ. The heterodimer formation of PPARγ-RXRα was competitively inhibited in a ligand-independent manner by TDAG51 binding to PPARγ. Thus, our data suggest that TDAG51, which could determine adipogenic cell fate, acts as a novel negative regulator of PPARγ by blocking RXRα recruitment to the PPARγ-RXRα heterodimer complex in adipogenesis.

• Journal of Periodontal and Implant Science
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• 제41권1호
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• pp.17-22
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• 2011

Purpose: Nitric oxide (NO) has been known as an important regulator of osteoblasts and periodontal ligament cell activity. This study was performed to investigate the relationship between NO-mediated cell death of human periodontal ligament fibroblasts (PDLFs) and N-methyl-D-aspartic acid (NMDA) receptor antagonist (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (MK801). Methods: Human PDLFs were treated with various concentrations (0 to 4 mM) of sodium nitroprusside (SNP) with or without $200\;{\mu}M$ MK801 in culture media for 16 hours and the cell medium was then removed and replaced by fresh medium containing MTS reagent for cell proliferation assay. Western blot analysis was performed to investigate the effects of SNP on the expression of Bax, cytochrome c, and caspase-3 proteins. The differences for each value among the sample groups were compared using analysis of variance with 95% confidence intervals. Results: In the case of SNP treatment, as a NO donor, cell viability was significantly decreased in a concentration-dependent manner. In addition, a synergistic effect was shown when both SNP and NMDA receptor antagonist was added to the medium. SNP treated PDLFs exhibited a round shape in culture conditions and were dramatically reduced in cell number. SNP treatment also increased levels of apoptotic marker protein, such as Bax and cytochrome c, and reduced caspase-3 in PDLFs. Mitogen-activated protein kinase signaling was activated by treatment of SNP and NMDA receptor antagonist. Conclusions: These results suggest that excessive production of NO may induce apoptosis and that NMDA receptor may modulate NO-induced apoptosis in PDLFs.

• BMB Reports
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• 제30권6호
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• pp.415-420
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• 1997

Although $CD4^+$ T cell responses to protein-derived antigen have well been understood, the epitopes recognized by hapten-specific $CD4^+$ T cells have not been fully defined. In this study, we characterized the response of a T cell hybridoma (5Di0.1B8) which is specific for a hapten. N-hydroxysuccinimidyl-4-azidobenzoate (HSAB) restricted by MHC class II $I-A^d$. Using three different antigen presenting cells (APCs) expressing $I-A^d$, the role of class II MHC proteins in haptenic antigen presentation and subsequent activation of 5D10.1B8 has been examined. Activation of 5D10.1B8 T cells by HSAB analogs was also performed. Our results show that each APC activated T cells differentially and that interleukin-2 (IL-2) augmented antigen-presenting ability of all the APCs, suggesting that increased expression of class II MHC protein by IL-2 played an important role in HSAB presentation and T cell activation. Finally, early T cell receptor-dependent signals induced by HSAB or its analogs were examined by phosphotyrosine immunoblot analysis, and showed that tyrosine phosphorylation level of a 18-20 kD protein increased upon stimulation.

• Bulletin of the Korean Chemical Society
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• 제30권8호
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• pp.1827-1831
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• 2009

Ligand molecules that can recognize and interact with cancer cell surface marker proteins with high affinity and specificity should greatly aid the development of novel cancer diagnostics and therapeutics. HER-2/ErbB2/Neu (HER-2), a member of the epidermal growth factor receptor family, is specifically overexpressed on the surface of breast cancer cells and serves as both a useful biomarker and a therapeutic target for breast cancer. In this study, we aimed to isolate RNA aptamers that specifically bind to a HER-2-overexpressing human breast cancer cell line, SK-BR-3, using Cell-SELEX strategy. The selected aptamers showed strong affinity to SK-BR-3, but not to MDAMB- 231, a HER-2-underexpressing breast cancer cell line. In addition, we confirmed the specific targeting of HER-2 receptor by aptamers using an unrelated mouse cell line overexpressing human HER-2 receptor. The HER-2-targeting RNA aptamers could become a useful reagent for the development of breast cancer diagnostics and therapeutics.

• IMMUNE NETWORK
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• 제23권2호
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• pp.12.1-12.17
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• 2023

Ssu72, a dual-specificity protein phosphatase, not only participates in transcription biogenesis, but also affects pathophysiological functions in a tissue-specific manner. Recently, it has been shown that Ssu72 is required for T cell differentiation and function by controlling multiple immune receptor-mediated signals, including TCR and several cytokine receptor signaling pathways. Ssu72 deficiency in T cells is associated with impaired fine-tuning of receptor-mediated signaling and a defect in CD4⁺ T cell homeostasis, resulting in immune-mediated diseases. However, the mechanism by which Ssu72 in T cells integrates the pathophysiology of multiple immune-mediated diseases is still poorly elucidated. In this review, we will focus on the immunoregulatory mechanism of Ssu72 phosphatase in CD4⁺ T cell differentiation, activation, and phenotypic function. We will also discuss the current understanding of the correlation between Ssu72 in T cells and pathological functions which suggests that Ssu72 might be a therapeutic target in autoimmune disorders and other diseases.

• The Korean Journal of Physiology and Pharmacology
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• 제9권5호
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• pp.255-262
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• 2005

Striatum is involved in the control of movement and habitual memory. It receives glutamatergic input from wide area of the cerebral cortex as well as an extensive serotonergic (5-hydroxytryptamine, 5-HT) input from the raphe nuclei. In our study, the effects of 5-HT on synaptic transmission were studied in the rat corticostriatal brain slice using in vitro whole-cell recording technique. 5-HT inhibited the amplitude as well as frequency of spontaneous excitatory postsynaptic currents (sEPSC) significantly, and neither ${\gamma}-aminobutyric$ acid (GABA)A receptor antagonist bicuculline (BIC), nor $N-methyl-_{D}-aspartate$ (NMDA) receptor antagonist, $_{DL}-2-amino-5-phosphonovaleric$ acid (AP-V) could block the effect of 5-HT. In the presence non-NMDA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenxo[f] quinoxaline-7-sulfonamide (NBQX), the inhibitory effect of 5-HT was blocked. We also figured out that 5-HT change the channel kinetics of the sEPSC. There was a significant increase in the rise time during the 5-HT application. Our results suggest that 5-HT has an effect on both pre- and postsynaptic site with decreasing neurotransmitter release probability of glutamate and decreasing the sensitivity to glutamate by increasing the rise time of non-NMDA receptor mediated synaptic transmission in the corticostriatal synapses.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 제2회 추계심포지움
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• pp.93-98
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• 1994

Most drug discovery has focused in recent years on the development of molecules that either interact with or block receptors, proteins that act as on-off switches for genetic activity, on the surfaces of human cells. Now, we have developed a technology that targets “receptors inside the cell” (intracellular receptors), opening a new and compelling avenue for drug discovery. Our receptor-based small molecule drugs can be catagorized in two ways: 1) receptor agonists, or molecules that activate a receptor; and 2) receptor antagonists, or drugs that inactivate a receptor.

• 대한치과교정학회지
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• 제30권4호
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• pp.441-452
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• 2000

본 실험은 사람의 치주인대세포에서 에스트로겐과 growth hormone(GH)이 상호 어떠한 작용을 하는지를 규명하는 것이 목적이다. 교정치료를 받고자 내원한 환자중에서 건강한 20대 여자환자들의 상하악 제1소구치를 발거하여 치근의 중간1/3부위에서 긁어모은 치주인대 조직을 배양하여 치주인대세포를 얻었다. 사람의 치주인대세포의 분열증식에 대한 $17{\beta}$-estradiol과 hGH의 효과를 평가하고, 치주인대세포에 $17{\beta}$-estradiol을 전처리한 후 치주인대세포의 분열증식에 미치는 hGH의 효과 변화를 평가하였으며, 치주인대세포에 $17{\beta}$-estradiol을 전처리 하였을 경우 치주인대세포에 서 hGH receptor치 발현 양상의 변화를 평가하여 다음과 같은 결론을 얻었다. 1. $17{\beta}$-estradiol이나 humangrowth hormone의 단독처리는 사람의 치주인대세포의 분열종식에 큰 영향을 주지 않는다. 2. $17{\beta}$-estradiol $10^{-12}M$로 전처리한 후 hGH를 투여한 경우 hGH의 농도에 관계없이 사람의 치주인대세포의 분열증식을 증가시킨다. 3. 사람의 치주인대세포에는 hGH receptor가 없으나, $17{\beta}$-estradiol $10^{-12}M$로 5시간 이상 처리하면 hGH receptor가 발현된다. 4. hGH이 사람의 치주인대세포의 분열증식에 미치는 효과는 hGH receptor의 발현과 관련이 있으며 $17{\beta}$-estradiol의 전처리가 치주인대세포에서의 hGH receptor의 발현에 기여함으로써 hGH이 치주인대세포에 작용할 수 있도륵 해준다.비, 상악의 대구치간 너비, 구개정 높이가 상관관계가 있었다.에서 치 아이동은 정상상태보다 촉진될 가능성이 있음을 시사한다.따라 평균마찰력은 유의하게 증가하였다. 6. 브라켓간 거리의 변화에 대한 마찰력의 차이는 교정선의 재질에 따라 차이가 나며, 스테인레스 스틸 교정선은 브라켓간 거리가 감소할 때 마찰력이 유의하게 변화하지 않았으나, NiTi 교정선의 경우는 유의하게 증가하였다. 7. 브라켓내의 교정선의 이동속도에 따라 마찰력은 유의하게 변화하지 않았다. 이상의 결과로 볼 때 교정 치료동안 적정 교정력을 유지하기 위해 자가결찰브라켓, 스테인레스 스틸 교정선과 탄성모듈결찰법을 사용하는 것이 유리하며, 치료시기에 따라서 요구하는 마찰력이 다르므로 상황에 따라 재료를 선택하는 것이 중요할 것으로 사료된다.$, B군에서 $4.3\%$ 감소하였다. 7. 수술로 인한 얼굴폭의 변화는 무시할만한 것으로 판단되나 수술후 얼굴의 길이가 짧아져 상대적으로 얼굴의 폭이 넓어보일 수 있으므로 수술시 이에 대한 충분한 고려 및 환자에 대한 설명이 있어야 한다.로는 4-6세군 ($27.5\%$), 6-8세군 ($19.6\%$), 2-4세군 ($13.7\%$)이 $60\%$이상을 차지하여 초등학교 취학 전에 구순의 반흔을 제거하려 함을 알 수 있었다. 8. 비변형 교정수술시기로는 0-2세군 ($7.1\%$), 2-4세군 ($14.3\%$), 4-6세군 ($21.4\%$), 6-8세군 ($14.3\%$)으로 초등학교 취학이전이 $57.1\%$로서 최근의 조기 치료경향을 반영하는 것으로 보인다. 9. 인두피판술은 평균 6세에 시행되었으며, 수술 시행 시기별의 차이를 보이지 않고 고른 분포를

• The Korean Journal of Physiology and Pharmacology
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• 제22권5호
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• pp.585-595
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• 2018

Amitriptyline, a tricyclic antidepressant, is commonly used to treat depression and neuropathic pain, but its mechanism is still unclear. We tested the effect of amitriptyline on 5-hydroxytryptamine 3 ($5-HT_3$) receptor currents and studied its blocking mechanism because the clinical applications of amitriptyline overlapped with $5-HT_3$ receptor therapeutic potentials. Using a whole-cell voltage clamp method, we recorded the currents of the $5-HT_3$ receptor when 5-HT was applied alone or co-applied with amitriptyline in cultured NCB-20 neuroblastoma cells known to express $5-HT_3$ receptors. To elucidate the mechanism of amitriptyline, we simulated the $5-HT_3$ receptor currents using Berkeley $Madonna^{(R)}$ software and calculated the rate constants of the agonist binding and receptor transition steps. The $5-HT_3$ receptor currents were inhibited by amitriptyline in a concentration-dependent, voltage-independent manner, and a competitive mode. Amitriptyline accelerated the desensitization of the $5-HT_3$ receptor. When amitriptyline was applied before 5-HT treatment, the currents rose slowly until the end of 5-HT treatment. When amitriptyline was co-applied with 5-HT, currents rose and decayed rapidly. Peak current amplitudes were decreased in both applications. All macroscopic currents recorded in whole cell voltage clamping experiments were reproduced by simulation and the changes of rate constants by amitriptyline were correlated with macroscopic current recording data. These results suggest that amitriptyline blocks the $5-HT_3$ receptor by close and open state blocking mechanisms, in a competitive manner. We could expand an understanding of pharmacological mechanisms of amitriptyline related to the modulation of a $5-HT_3$ receptor, a potential target of neurologic and psychiatric diseases through this study.

• BMB Reports
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• 제54권5호
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• pp.266-271
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• 2021

Estrogen-related receptor γ (ERRγ), a member of the orphan nuclear receptor family, is a key mediator in cellular metabolic processes and energy homeostasis. Therefore, ERRγ has become an attractive target for treating diverse metabolic disorders. We recently reported that ERRγ acts as a negative regulator of osteoclastogenesis induced by receptor activator of nuclear factor-κB ligand (RANKL). In the present study, we explored the effects of an ERRγ-specific modulator, GSK5182, on ERRγ-regulated osteoclast differentiation and survival. Interestingly, GSK5182 increased ERRγ protein levels much as does GSK4716, which is an ERRγ agonist. GSK5182 inhibited osteoclast generation from bone-marrow-derived macrophages without affecting cytotoxicity. GSK5182 also attenuated RANKL-mediated expression of cFos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), pivotal transcription factors for osteoclastogenesis. Arrested osteoclast differentiation was associated with reduced RANK expression, but not with the M-CSF receptor, c-Fms. GSK5182 strongly blocked the phosphorylation of IκBα, c-Jun N-terminal kinase, and extracellular signal-regulated kinase in response to RANKL. GSK5182 also suppressed NF-κB promoter activity in a dose-dependent manner. In addition to osteoclastogenesis, GSK5182 accelerated osteoclast apoptosis by caspase-3 activation. Together, these results suggest that GSK5182, a synthetic ERRγ modulator, may have potential in treating disorders related to bone resorption.