• Journal of Integrative Natural Science
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• v.11 no.1
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• pp.19-24
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• 2018

CRFR is involved in the pathophysiology of various disorders including depression, stress, anxiety, post-traumatic stress disorder, and addiction. The discovery of novel and structurally diverse CRF1 receptor inhibitors becomes essential. In this study, we have performed molecular docking of CRF1R with the derivatives of 8-substituted-2-aryl-5-alkylaminoquinolines as CRF1R inhibitors. The antagonist molecules were optimized and docked into the binding site of the receptor. On analysing the docked complexes we have identified that the residues HIS214, THR215, ARG227, ARG1008, LYS1060 and ASP1061 are important in forming hydrogen bond with the inhibitors. Further studies on these residues could reveal important structural features required for the formation of CRF1R-inhibitor complex and thus in the discovery of novel and potent inhibitors.

• BMB Reports
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• v.52 no.1
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• pp.70-85
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• 2019

Reduction of insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) extends the lifespan of various species. So far, several longevity mouse models have been developed containing mutations related to growth signaling deficiency by targeting growth hormone (GH), IGF1, IGF1 receptor, insulin receptor, and insulin receptor substrate. In addition, p70 ribosomal protein S6 kinase 1 (S6K1) knockout leads to lifespan extension. S6K1 encodes an important kinase in the regulation of cell growth. S6K1 is regulated by mechanistic target of rapamycin (mTOR) complex 1. The v-myc myelocytomatosis viral oncogene homolog (MYC)-deficient mice also exhibits a longevity phenotype. The gene expression profiles of these mice models have been measured to identify their longevity mechanisms. Here, we summarize our knowledge of long-lived mouse models related to growth and discuss phenotypic characteristics, including organ-specific gene expression patterns.

• BMB Reports
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• v.54 no.7
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• pp.380-385
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• 2021

Proper targeting of the βPAK-interacting exchange factor (βPIX)/G protein-coupled receptor kinase-interacting target protein (GIT) complex into distinct cellular compartments is essential for its diverse functions including neurite extension and synaptogenesis. However, the mechanism for translocation of this complex is still unknown. In the present study, we reported that the conventional kinesin, called kinesin-1, can transport the βPIX/GIT complex. Additionally, βPIX bind to KIF5A, a neuronal isoform of kinesin-1 heavy chain, but not KIF1 and KIF3. Mapping analysis revealed that the tail of KIF5s and LZ domain of βPIX were the respective binding domains. Silencing KIF5A or the expression of a variety of mutant forms of KIF5A inhibited βPIX targeting the neurite tips in PC12 cells. Furthermore, truncated mutants of βPIX without LZ domain did not interact with KIF5A, and were unable to target the neurite tips in PC12 cells. These results defined kinesin-1 as a motor protein of βPIX, and may provide new insights into βPIX/GIT complex-dependent neuronal pathophysiology.

• YAKHAK HOEJI
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• v.49 no.1
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• pp.44-50
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• 2005

The purpose of this study was to investigate the relationship between Trp64Arg polymorphism in the ${\beta}_3$-adrenergic receptor gene and complex phenotypes such as blood pressure, body compositions and bone parameters in young men about 20 years, and to collect the fundamental data in designing the exercise program. Eighty healthy young men including 41 controls and 39 athletes were recruited, Trp64Arg polymorphism in the ${\beta}_3$-adrenergic receptor gene was genotyped by PCR-RFLP method. By association study, there were no significance in genotype and allele frequencies of Trp64Arg polymorphism in the ${\beta}_3$-adrenergic receptor gene between controls and athletes, respectively (p>0.05). When the relationship between physiological parameters and Trp64Arg polymorphism in the ${\beta}_3$-adrenergic receptor gene was tested, this polymorphism was significantly associated with 3th lumber and left femoral neck Z-score values in controls (p<0.05), but these associations were not detected in athletic groups (p>0.05). It is likely that Trp64Arg polymorphism in the ${\beta}_3$-adrenergic receptor gene is a genetic marker for the bone mineral density index in young men, but environmental factors such as exercise modify the significant effect of this polymorphism. Thus, our results suggest that Trp64Arg polymorphism in the ${\beta}_3$-adrenergic receptor gene may be applicable as a predictive marker for osteoporosis in Korean young men, and regular exercise may prevent the disadventageous effect of this polymorphism for bone mineral density in male athletic group.

• BMB Reports
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• v.49 no.3
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• pp.159-166
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• 2016

Several members of tumor necrosis factor receptor (TNFR) superfamily that these members activate caspase-8 from death-inducing signaling complex (DISC) in TNF ligand-receptor signal transduction have been identified. In the extrinsic pathway, apoptotic signal transduction is induced in death domain (DD) superfamily; it consists of a hexahelical bundle that contains 80 amino acids. The DD superfamily includes about 100 members that belong to four subfamilies: death domain (DD), caspase recruitment domain (CARD), pyrin domain (PYD), and death effector domain (DED). This superfamily contains key building blocks: with these blocks, multimeric complexes are formed through homotypic interactions. Furthermore, each DD-binding event occurs exclusively. The DD superfamily regulates the balance between death and survival of cells. In this study, the structures, functions, and unique features of DD superfamily members are compared with their complexes. By elucidating structural insights of DD superfamily members, we investigate the interaction mechanisms of DD domains; these domains are involved in TNF ligand-receptor signaling. These DD superfamily members play a pivotal role in the development of more specific treatments of cancer.

• International Journal of Oral Biology
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• v.42 no.2
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• pp.55-61
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• 2017

Recent studies indicate that mitochondria are an important source of reactive oxygen species (ROS) in the spinal dorsal horn. In our previous study, application of malate, a mitochondrial electron transport complex I substrate, induced a membrane depolarization, which was inhibited by pretreatment with ROS scavengers. In the present study, we used patch clamp recording in the substantia geletinosa (SG) neurons of spinal slices, to investigate the cellular mechanism of mitochondrial ROS on neuronal excitability. DNQX (an AMPA receptor antagonist) and AP5 (an NMDA receptor antagonist) decreased the malate-induced depolarization. In an external calcium free solution and addition of tetrodotoxin (TTX) for blockade of synaptic transmission, the malate-induced depolarization remained unchanged. In the presence of DNQX, AP5 and AP3 (a group I metabotropic glutamate receptor (mGluR) antagonist), glutamate depolarized the membrane potential, which was suppressed by PBN. However, oligomycin (a mitochondrial ATP synthase inhibitor) or PPADS (a P2 receptor inhibitor) did not affect the substrates-induced depolarization. These results suggest that mitochondrial substrate-induced ROS in SG neuron directly acts on the postsynaptic neuron, therefore increasing the ion influx via glutamate receptors.

• Development and Reproduction
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• v.10 no.2
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• pp.85-92
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• 2006

Progesterone(P4) is an important intermediate in the synthesis of androgens and estrogens. Furthermore, P4 itself plays a crucial role in ovulation, atresia and luteinization, and is essential for the continuation of early pregnancy in all mammalian species. In spite of the hormone's physiological importance, the exact action mechanism(s) of P4 in mammalian ovary has not been fully understood yet. In this context, a decades-long controversy regarding the identity of receptors that mediate non-genomic, transcription-independent cellular responses to P4 is presently attracting huge scientific interests. P4 may exert its action in mammalian ovary by several ways: 1) the well-documented genomic pathway, involving hormone binding to so-called classic cytosolic receptor(PGR) and subsequent modulation of gene expression by the ligand-receptor complex as transcription factor. 2) pathways are operating that do not act on the genome, therefore refered to as non-genomic actions. The prominent characteristics of the non-genomic P4 actions are: (i) rapid, (ii) insensitive to transcription inhibitors, (iii) transduced by membrane associated molecules. In particular, the non-genomic P4 actions could be mediated by: (a) classic genomic P4 receptor(PGR) that localizes at or near the plasma membrane, (b) a family of membrane progestin receptors(MPR $\alpha$, MPR $\beta$ and MPR $\gamma$), (c) progesterone receptor membrane component I(PGRMC1), and (d) a membrane complex composed of serpine I mRNA binding protein(SERBP1). The present review summarized these rapid signaling pathways of P4 in the mammalian ovary.

• IMMUNE NETWORK
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• v.24 no.3
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• pp.21.1-21.16
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• 2024

IL-1, a pleiotropic cytokine with profound effects on various cell types, particularly immune cells, plays a pivotal role in immune responses. The proinflammatory nature of IL-1 necessitates stringent control mechanisms of IL-1-mediated signaling at multiple levels, encompassing transcriptional and translational regulation, precursor processing, as well as the involvement of a receptor accessory protein, a decoy receptor, and a receptor antagonist. In T-cell immunity, IL-1 signaling is crucial during both the priming and effector phases of immune reactions. The fine-tuning of IL-1 signaling hinges upon two distinct receptor types; the functional IL-1 receptor (IL-1R) 1 and the decoy IL-1R2, accompanied by ancillary molecules such as the IL-1R accessory protein (IL-1R3) and IL-1R antagonist. IL-1R1 signaling by IL-1β is critical for the differentiation, expansion, and survival of Th17 cells, essential for defense against extracellular bacteria or fungi, yet implicated in autoimmune disease pathogenesis. Recent investigations emphasize the physiological importance of IL-1R2 expression, particularly in its capacity to modulate IL-1-dependent responses within Tregs. The precise regulation of IL-1R signaling is indispensable for orchestrating appropriate immune responses, as unchecked IL-1 signaling has been implicated in inflammatory disorders, including Th17-mediated autoimmunity. This review provides a thorough exploration of the IL-1R signaling complex and its pivotal roles in immune regulation. Additionally, it highlights recent advancements elucidating the mechanisms governing the expression of IL-1R1 and IL-1R2, underscoring their contributions to fine-tuning IL-1 signaling. Finally, the review briefly touches upon therapeutic strategies targeting IL-1R signaling, with potential clinical applications.

• Molecules and Cells
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• v.25 no.2
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• pp.289-293
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• 2008

The role of SPOP in the ubiquitination of $ER{\alpha}$ by the Cullin3-based E3 ubiquitin ligase complex was investigated. We showed that the N-terminal region of SPOP containing the MATH domain interacts with the AF-2 domain of $ER{\alpha}$ in cultured human embryonic 293 cells. SPOP was required for coimmunoprecipitation of $ER{\alpha}$ with Cullin3. This is the first report of the essential role of SPOP in $ER{\alpha}$ ubiquitination by the Cullin3-based E3 ubiquitin ligase complex. We also demonstrated repression of the transactivation capability of $ER{\alpha}$ in cultured mammalian cells.

• Proceedings of the Korean Society of Life Science Conference
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• 2006.09a
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• pp.72.1-72.1
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• 2006