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E1 inhibitor

Joanna Koszela, Nhan T Pham, David Evans, Stefan Mann, Irene Perez-Pi, Steven Shave, Derek F J Ceccarelli, Frank Sicheri, Mike Tyers, Manfred Auer
BACKGROUND: The ubiquitin-proteasome system (UPS) controls the stability, localization and/or activity of the proteome. However, the identification and characterization of complex individual ubiquitination cascades and their modulators remains a challenge. Here, we report a broadly applicable, multiplexed, miniaturized on-bead technique for real-time monitoring of various ubiquitination-related enzymatic activities. The assay, termed UPS-confocal fluorescence nanoscanning (UPS-CONA), employs a substrate of interest immobilized on a micro-bead and a fluorescently labeled ubiquitin which, upon enzymatic conjugation to the substrate, is quantitatively detected on the bead periphery by confocal imaging...
August 10, 2018: BMC Biology
M Haffner-Luntzer, I Lackner, A Liedert, V Fischer, A Ignatius
Clinical and experimental studies demonstrate the potential of low-magnitude high-frequency vibration (LMHFV) to enhance bone formation in the intact skeleton and during fracture healing. Moreover, it was shown that the effects of vibration therapy during fracture healing are highly dependent on the estrogen status of the vibrated individual and that estrogen receptor (ER) α signaling plays a major role in mechanotransduction of LMHFV. Because it is known that LMHFV can directly act on osteogenic cells, we hypothesize that the differential effects of LMHFV in the presence and absence of estrogen are mediated by ERα signaling in osteoblasts...
August 7, 2018: Biochemical and Biophysical Research Communications
Thiago Sardinha de Oliveira, Lais Moraes de Oliveira, Lanussy Porfiro de Oliveira, Rafael Menezes da Costa, Rita de Cassia Tostes, Raphaela de Castro Georg, Elson Alves Costa, Núbia de Souza Lobato, Fernando Paranaiba Filgueira, Paulo César Ghedini
Estrone (E1) produces remarkable vascular effects, including relaxation, modulation of proliferation, apoptosis and cell adhesion. This study investigated the role of estrogen receptors and endothelial signaling pathways in the vascular relaxation promoted by E1. Aortic rings from male Wistar rats (250-300 g) were contracted with phenylephrine and stimulated with graded concentrations of E1. The concentration-dependent relaxation induced by E1 was abolished after removal of the endothelium or incubation with the estrogen receptor antagonist ICI 182,780...
July 31, 2018: Vascular Pharmacology
Kazuhiko Fujita, Takanobu Otsuka, Tetsu Kawabata, Shingo Kainuma, Go Sakai, Rie Matsushima-Nishiwaki, Osamu Kozawa, Haruhiko Tokuda
Heat shock protein 90 (HSP90), expressed abundantly in a variety of cell types, is a molecular chaperone, and has a central role in protein homeostasis under stress conditions. In our previous study, it was shown that thrombin stimulates interleukin‑6 (IL‑6) synthesis via p44/p42 mitogen‑activated protein kinase (MAPK) and p38 MAPK in osteoblast‑like MC3T3‑E1 cells, and that Rho‑kinase acts as a positive regulator at a point upstream of p38 MAPK, but not p44/p42 MAPK. The present study investigated whether or not HSP90 is involved in the thrombin‑stimulated synthesis of IL‑6 and examined the mechanism by which HSP90 is involved in MC3T3‑E1 cells...
July 18, 2018: International Journal of Molecular Medicine
N Zhang, R-F Zhang, A-N Zhang, G-X Dong, N Suo, Z-P Wu, Y-M Liu, L-T Wang
OBJECTIVE: To investigate the effects and related mechanisms of miR-204 on fracture healing. MATERIALS AND METHODS: Mouse osteoblastic cell line MC3T3-E1 was used in our experiment. Three groups were established to investigate the potential function between miR-204 and osteoblastic cells: miR-NC group (negative control), miR-204 mimics group (MC3T3-E1 cells transfected with miR-204 mimics) and miR-204 mimics + inhibitor group (MC3T3-E1 cells transfected with miR-204 mimics and inhibitor)...
July 2018: European Review for Medical and Pharmacological Sciences
Xuesong Han, Jicheng Zhou, Wei Peng
Dysfunction of osteoblastic bone formation and matrix mineralization plays a key role in the pathological development of osteoporosis. The orexin peptide orexin-A, a highly excitatory neuropeptide hormone, possesses various biological functions by activating its specific G protein-coupled receptors, orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R). Here, we report that OX1R but not OX2R was expressed in MC3T3-E1 cells. Importantly, we found that orexin-A accelerated osteoblast differentiation and matrix mineralization in MC3T3-E1 cells, as manifested by elevation of physiological markers of osteoblastic differentiation [alkaline phosphatase (ALP) and osteogenic genes] and Alizarin Red staining, respectively...
July 2018: IUBMB Life
Haihua Zhang, Weixiao Nan, Shiyong Wang, Xingchao Song, Huazhe Si, Tong Li, Guangyu Li
Background: Hair follicles play an essential role in the growth of hair. Epigallocatechin-3-gallate (EGCG), a catechin polyphenol in green tea, has various bioactivities. The present study aims to evaluate the effect of EGCG on the growth of mink hair follicles and investigate the possible molecular mechanisms. Methods: The length of hair follicles was recorded up to 6 days in presence of 0.1-5 μM EGCG. Primary dermal papilla cells (DPCs) and outer root sheath cells (ORSCs) were treated with 0.25-4 μM EGCG, and their growth was evaluated by MTT assay and cell cycle detection...
2018: Frontiers in Pharmacology
Anika M S Hartz, Yu Zhong, Andrew N Shen, Erin L Abner, Björn Bauer
One characteristic of Alzheimer's disease (AD) is excessive accumulation of amyloid-β (Aβ) in the brain. Aβ brain accumulation is, in part, due to a reduction in Aβ clearance from the brain across the blood-brain barrier. One key element that contributes to Aβ brain clearance is P-glycoprotein (P-gp) that transports Aβ from brain to blood. In AD, P-gp protein expression and transport activity levels are significantly reduced, which impairs Aβ brain clearance. The mechanism responsible for reduced P-gp expression and activity levels is poorly understood...
2018: Frontiers in Aging Neuroscience
Tsui-Ling Chang, Pei-Shin Liou, Pei-Yuan Cheng, Hsiang-Ning Chang, Pei-Jane Tsai
Targeting the two degradation systems, ubiquitin proteasome pathway and ubiquitin signal autophagy lysosome system, plays an important function in cancer prevention. Borneol is called an "upper guiding drug". Luteolin has demonstrated anticancer activity. The fact that borneol regulates luteolin can be sufficient to serve as an alternative strategy. Borneol activates luteolin to inhibit E1 and 20S activity (IC50 = 118.8 ± 15.7 μM) and perturb the 26S proteasome structure in vitro. Borneol regulates luteolin to inhibit 26S activity (IC50 = 157 ± 19 μM), induces apoptosis (LC50 = 134 ± 4 μM), and causes pre-G1 and G0/G1 arrest in HepG2 cells...
July 30, 2018: Journal of Agricultural and Food Chemistry
Yu Lin, Lili Xiao, Yiyuan Zhang, Ping Li, Yinsheng Wu, Yanping Lin
BACKGROUND: Understanding of the molecular mechanisms of miRNAs involved in osteoblast differentiation is important for the treatment of bone-related diseases. METHODS: MC3T3-E1 cells were induced to osteogenic differentiation by culturing with bone morphogenetic protein 2 (BMP2). After transfected with miR-26b-3p mimics or inhibitors, the osteogenic differentiation of MC3T3-E1 cells was detected by ALP and ARS staining. Cell viability was analyzed by MTT. The expressions of miR-26b-3p and osteogenic related markers and signaling were examined by qPCR and western blot...
July 5, 2018: Genomics
Ana V Vujačić Nikezić, Goran V Janjić, Aleksandra M BondŽić, BoŽidarka L Zarić, Dragana D Vasić-Anićijević, Tatjana G Momić, Vesna M Vasić
The present paper deals with investigation of the interaction between selected simple structure Au(iii) ([AuCl4]-, [AuCl2(dmso)2]+, [AuCl2(bipy)]+) and Pt(ii) ([PtCl2(dmso)2]) complexes with Na/K-ATPase as the target enzyme, using an experimental and theoretical approach. Reaction stoichiometries and binding constants for these enzyme/complex systems were determined, while kinetic measurements were used in order to reveal the type of inhibition. Based on the results obtained by quantum mechanical calculations (electrostatic surface potential (ESP), volume and surface of the complexes) the nature of the investigated complexes was characterized...
July 18, 2018: Metallomics: Integrated Biometal Science
Mary Ellen Urick, Daphne W Bell
Serous endometrial cancers (ECs) are clinically aggressive tumors that frequently harbor somatic mutations in FBXW7 (F-box and WD repeat domain-containing 7). The FBXW7 tumor suppressor is part of a SCF (complex of SKP1, Cullin 1, F-box protein) ubiquitin ligase complex which controls the degradation of numerous substrates that, if not properly regulated, can contribute to the initiation or progression of tumorigenesis. Despite reports that up to 30% of serous ECs include somatic mutations in FBXW7, the molecular effects of mutated FBXW7 in ECs have not been determined...
July 2, 2018: Molecular Carcinogenesis
Xiao-Lin Li, Ya-Qiong Yu, Li-Hong Qiu, Jia-Jie Guo, Li-Na Shao, Si-Mo Wang, Di Yang
PURPOSE: To investigate the effects of lipopolysaccharide (LPS) extracted from Porphyromonas endodontalis (P.endodontalis) on expression of monocyte chemotactic protein-1 (MCP-1) mRNA and protein in MC3T3-E1 cells and the role of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kB(NF-kB)in the process. METHODS: MC3T3-E1 cells were treated with different concentrations of P.endodontalis LPS(0-50mg/L) and 20 mg/L P.endodontalis LPS for different hours (0-48 h)...
February 2018: Shanghai Kou Qiang Yi Xue, Shanghai Journal of Stomatology
Weihua Zhou, Jie Xu, Mingjia Tan, Haomin Li, Hua Li, Wenyi Wei, Yi Sun
UBE2M and UBE2F are two family members of neddylation E2 conjugating enzyme that, together with E3s, activate CRLs (Cullin-RING Ligases) by catalyzing cullin neddylation. However, whether and how two E2s cross-talk with each other are largely unknown. Here, we report that UBE2M is a stress-inducible gene subjected to cis-transactivation by HIF-1 and AP1, and MLN4924, a small molecule inhibitor of E1 NEDD8-activating enzyme (NAE), upregulates UBE2M via blocking degradation of HIF-1α and c-JUN. UBE2M is a dual E2 for targeted ubiquitylation and degradation of UBE2F, acting as a neddylation E2 to activate CUL3-Keap1 E3 under physiological conditions but as a ubiquitylation E2 for Parkin-DJ-1 E3 under stressed conditions...
June 21, 2018: Molecular Cell
Fan Bai, Xuewu Chen, Hui Yang, Hong-Guang Xu
Tumor necrosis factor (TNF) -α plays a crucial role in rheumatoid arthritis (RA)-related bone loss disease. The main mechanism of action of RA induced bone loss is the significant inhibitory effect of TNF-α on osteoblast differentiation. TNF-α inhibits osteoblast differentiation mainly by activating nuclear factor (NF) -κB signaling pathway. Owing to the crucial role of TNF-α and NF-κB in the inhibition of osteoblast differentiation, they are considered as targets for the development of therapeutic drugs...
June 20, 2018: Journal of Craniofacial Surgery
Yu Wu, Miaomiao Wang, Kefan Zhang, Yingjiang Li, Manlin Xu, Shaidi Tang, Xiuxia Qu, Chunping Li
Osteoblast uses aerobic glycolysis to meet the metabolic needs in differentiation process. Lactate, the end product of glycolysis, presents in the environment with elevated PTH and osteoblast differentiation. Although previous findings showed that lactate promoted osteoblast differentiation, whether lactate affects PTH-mediated osteoblast differentiation is unclear. To investigate this, pre-osteoblast cell line MC3T3-E1 was treated PTH with or without physiological dose of lactate. Lactate increases ALP positive cell formation, increases ALP activity and expression of differentiation related markers, enriches the CREB transcriptional factor target genes in PTH treated cells...
June 21, 2018: Biochemical and Biophysical Research Communications
Shuyuan Liu, Jinhua Wan, Yunyuan Kong, Yonglu Zhang, Lagen Wan, Zhanglin Zhang
The cullin-RING ligase (CRL)-NEDD8 pathway maintains essential cellular processes, including cell cycle progression, apoptosis, autophagy, DNA repair, antigen processing and signal transduction. Growing evidence demonstrates that the alteration of the CRL-NEDD8 pathway in some cancers constitutes an attractive target for therapeutic intervention, but the roles of CRL-NEDD8 pathway in acute promyelocytic leukemia (APL) is still unclear. In the present study, we found that ATRA could decrease the expression of NEDD8-activating enzyme E1 (NAE1) and inhibit the neddylation of cullin1 and cullin3 in the APL cell line NB4...
2018: International Journal of Medical Sciences
Zengfa Huang, Cheng Cheng, Jing Wang, Xianzhe Liu, Hui Wei, Yu Han, Shuhua Yang, Xiang Wang
Osteoporosis has become one of the most serious public health problems. Icariin, miR-153 and Runt-related transcription factor 2 (Runx2) have been demonstrated to regulate cell proliferation and differentiation in multiple cells. The aim of the present experiments was to investigate the potential mechanism underlying osteoblast differentiation and cell proliferation of MC3T3-E1 cells treated with icariin. Cell Counting kit-8, alkaline phosphatase (ALP) activity and alizarin red S assays, as well as reverse transcription-quantitative polymerase chain reaction and western blot analysis, were performed to examine whether icariin promoted osteoblast differentiation and cell proliferation in MC3T3-E1 cells...
June 2018: Experimental and Therapeutic Medicine
Juergen Koessler, Valerie-Noelle Trulley, Andrea Bosch, Katja Weber, Angela Koessler, Markus Boeck, Anna Kobsar
INTRODUCTION: Adenosine diphosphate (ADP) as physiological activator of human platelets mediates its effects via three purinergic receptors: P2Y1, P2Y12 and P2X1. The inhibition of P2Y12 is used pharmacologically to suppress aggregation underlining the physiological significance of this receptor. Since the regulation of purinergic receptor expression has not thoroughly been investigated yet, this study analyzed the content of purinergic receptors on the platelet surface membrane upon activation and inhibition...
June 5, 2018: Thrombosis Research
Tine Peeters, Silvia Monteagudo, Przemko Tylzanowski, Frank P Luyten, Rik Lories, Frédéric Cailotto
Tissue calcification is an important physiological process required for the normal structure and function of bone. However, ectopic or excessive calcification contributes to diseases such as chondrocalcinosis, to calcium deposits in the skin or to vascular calcification. SMOC2 is a member of the BM-40/osteonectin family of calcium-binding secreted matricellular proteins. Using osteoprogenitor MC3T3-E1 cells stably overexpressing SMOC2, we show that SMOC2 inhibits osteogenic differentiation and extracellular matrix mineralization...
2018: PloS One
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