• BMB Reports
• /
• v.51 no.4
• /
• pp.165-166
• /
• 2018

Osteoarthritis (OA) is the most common form of arthritis and is a leading cause of disability with a large socioeconomic cost. OA is a whole-joint disease characterized by cartilage destruction, synovial inflammation, osteophyte formation, and subchondral bone sclerosis. To date, however, no effective disease-modifying therapies for OA have been developed. The estrogen-related receptors (ERRs), a family of orphan nuclear receptor transcription factors, are composed of $ERR{\alpha}$, $ERR{\beta}$, and $ERR{\gamma}$, which play diverse biological functions such as cellular energy metabolism. However, the role of ERRs in OA pathogenesis has not been studied yet. Among the ERR family members, $ERR{\gamma}$ is markedly upregulated in human and various models of mouse OA cartilage. Adenovirus-mediated overexpression of $ERR{\gamma}$ in the mouse knee joint tissue caused OA pathogenesis. Additionally, cartilage-specific $ERR{\gamma}$ transgenic (Tg) mice exhibited enhanced experimental OA. Consistently, $ERR{\gamma}$ in articular chondrocytes directly caused expression of matrix metalloproteinase (MMP) 3 and MMP13, which play a crucial role in cartilage destruction. In contrast, genetic ablation of Esrrg or shRNA-mediated Esrrg silencing in the joint tissues abrogated experimental OA in mice. These results collectively indicated that $ERR{\gamma}$ is a novel catabolic regulator of OA pathogenesis and can be used as a therapeutic target for OA.

• Development and Reproduction
• /
• v.13 no.4
• /
• pp.249-256
• /
• 2009

The estrogen receptor-related receptors (ERRs) are a group of nuclear receptor superfamily of transcription factors. ERRs and estrogen receptors (ERs) have overlapping affinities for coactivators and DNA binding sites, but differ markedly in ligand binding and activation. The three mammalian ERR genes have been implicated in diverse physiological processes ranging from placental development to maintenance of bone density, whereas the molecular diversity, function, and regulation of ERRs in non-mammalian species are not well understood. In the present study, to investigate the involvement of ERR in transcription and embryogenesis in marine invertebrates, a cDNA encoding ERR (SnERR) was cloned from the gonad in Strongylocentrotus nudus, by polymerase chain reaction (PCR). The amino acid sequence of SnERR showed high homology with that of S. purpuratus (91%). A phylogenetic tree clearly showed that SnERR is a member of the ERR family and clustered in echinodermata group as supported by a high bootstrap value. We examined gene expression of SnERR during embryonic development of S. nudus using real-time PCR. During the embryonic development, the mRNA of ERR was significantly high levels in early development stages (4~64 cell) and larval stages. The SnERR slightly activated transcription through the classical estrogen response elements (EREs) in the presence of genistein. In addition, peroxisome proliferator-activated receptor $\gamma$ coactivator (PGC)-$1\alpha$ knwon as a coactivator of ERR enhanced the snERR-mediated transactivation, suggesting that the PGC-$1\alpha$ is a coactivator of SnERR.

• The Korea Journal of Herbology
• /
• v.28 no.3
• /
• pp.95-106
• /
• 2013

Objectives : The researcher investigated the anti-obesity effect of Alismatis Orientale Rhizoma(AP) water extract in mice fed a high fat diet and focused on the analysis of local area adipose tissue. Methods : Male ICR mice were divided into three groups, which were fed either a normal AIN diet, a 45% high fat diet (CT group), or a high fat diet and orally administration with a concentrations of 100 mg/kg (AP100 group) and 300 mg/kg body weight (AP300 group) for eight weeks. Results : As compared with CT group, AP100 group showed significant reductions in absolute weight of liver. As compared with CT group, AP100 group and AP300 group showed significant reductions in weight gain and relative weight of total fat. AST, triglyceride, total-cholesterol levels from the AP 100 group and 300 group were significantly lower than those of the CT, and ALT, LDL-cholesterol levels from the AP 100 group was significantly lower than those of the CT. But serum HDL-cholesterol levels from the AP 100 group and 300 group were significantly higher than those of the CT. And serum adiponectin levels from the AP 100 group was significantly higher than those of the CT. In result of real time PCR, all mRNA expression(PEPCK, G6Pase, PGC-$1{\alpha}$ and $ERR{\gamma}$) of two experimental groups were significantly decreased compared to those of CT group. The treatment with AP on local abdominal area made a fat cell size lessen on the fat tissue in the abdominal cavity and subcutaneous area. Conclusions : These results suggest that AP has an anti-obesity effect and the effect is mediated by inhibition of fat gain.

• Proceedings of the Korean Society of Machine Tool Engineers Conference
• /
• 1996.10a
• /
• pp.167-172
• /
• 1996

A Dual Mass Flywheel system is a evolution to the reduction of torsional vibration and impact noise occuring in powertrain when a vehicle is eit-her moving or idling. The name already explains what it is : The mass of the conventional single mass flywheel is divided. One section continues to belong to the mass moment of inertia of the engine-side. The ot-her section increass the mass moment of inertia of the transmission-side. The two masses are connected via a spring /damping system. This reduces the speed at which the dreaded resonance occurs to below idle speed. Since 1984 Dual Mass Flywheel has been de-veloped again and again. But the prosidures of de-velopment of D.M.F system didn't have had differe-nce from conventional clutch system's trial and err-or This paper presents the method for systematical design of D.M.F system with demensionless design variables of D.M.F system mass ratio between two flywheels λ. natual frequency rate of two flywheel s, ${\gamma}$and viscosity coefficient ζ. And experimental re-sults are used to prove these theoretical results.

• Molecules and Cells
• /
• v.24 no.3
• /
• pp.372-377
• /
• 2007

The orphan nuclear receptor, SF-1, plays a pivotal role in the development and differentiation of the endocrine and reproductive systems, and also regulates the transcription of a host of genes, including those encoding several steroidogenic enzymes and gonadotropins. We found that a previously unidentified repressor, EID-1, is an SF-1-interacting protein that inhibits the transactivation of SF-1. A transient transfection assay revealed that EID-1 inhibits SF-1, but not LRH-1, $ERR{\gamma}$, or mCAR. Using the yeast two hybrid and GST pull-down assays, we determined that EID-1 interacted strongly with SF-1. In addition, it colocalized with SF-1 in mammalian cells and interacted specifically with the AF-2 domain of SF-1, competing with SRC-1 to inhibit SF-1 transactivation. EID-1 is expressed in the mouse testis, and its expression decreases during testis development. The results of the present study suggest that EID-1 can act as a repressor, regulating the function of SF-1.

• BMB Reports
• /
• v.55 no.11
• /
• pp.547-552
• /
• 2022

Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.44 no.3
• /
• pp.324-330
• /
• 2015

In this study, the anti-diabetic activity of a cold water extract of Korean mistletoe (KME) was investigated in C57BL/6J Lep ob (ob/ob) mice. Oral administration of KME (50 or 100 mg/kg/d) significantly inhibited the level of blood glucose of ob/ob mice after 5 days from the beginning of KME treatment. And the anti-diabetic effect of KME was stabilized 10 days after oral administration, showing a substantial reduction of blood glucose levels by more than 20% as compared with control mice. The results of oral glucose tolerance test (OGTT) revealed that oral administration of KME gave rise to a remarkable improvement in overall glucose response. Oral administration of KME in ob/ob diabetic mice also significantly reduced blood total cholesterol (TCHO) and triglyceride (TG) levels compared with the diabetic control mice. Moreover, in an in vitro experiment using C2C12 myotubes, treatment of KME prominently increased glucose uptake. Interestingly, KME significantly increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-${\alpha}$ ($PGC-1{\alpha}$), a head regulator of mitochondrial biogenesis and oxidative metabolism, and $PGC-1{\alpha}$-associated genes such as glucose transporter type 4 (GLUT4), estrogen-related receptor-${\alpha}$ ($ERR-{\alpha}$), nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TmfA) in C2C12 cells. These results suggest that KME has potential as a novel therapeutic agent for diabetes, and its anti-diabetic activity may be related to the regulation of mitochondrial biogenesis.

• BMB Reports
• /
• v.54 no.5
• /
• pp.266-271
• /
• 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.