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https://www.readbyqxmd.com/read/28928392/mucosa-associated-lymphoid-tissue-lymphoma-translocation-1-as-a-novel-therapeutic-target-for-rheumatoid-arthritis
#1
Chang Hoon Lee, Su Jeong Bae, Miok Kim
Emerging evidence suggests that mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) is a key regulator of inflammatory diseases; however, the pathological role of MALT1 in rheumatoid arthritis (RA) is not well understood. Consequently, this protein has not been therapeutically targeted for the treatment of RA. MALT1 plays a role in the paracaspase pathway, has proteolytic activity and is involved in the regulation of inflammatory responses. In this study, we found that the MALT1-targeting inhibitory small molecule, MALT1 selective inhibitor 2-chloro-N-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1H-1,2,4-triazol-1-yl]phenylacetamide (MI-2) strongly suppresses the differentiation of monocytes into osteoclasts in the absence or presence of the inflammatory cytokine tumour necrosis factor α...
September 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28921505/nfatc1-activation-by-dna-hypomethylation-in-chronic-lymphocytic-leukemia-correlates-with-clinical-staging-and-can-be-inhibited-by-ibrutinib
#2
Christine Wolf, Angela Garding, Katharina Filarsky, Jasmin Bahlo, Sandra Robrecht, Natalia Becker, Manuela Zucknick, Arefeh Rouhi, Anja Weigel, Rainer Claus, Dieter Weichenhan, Barbara Eichhorst, Kirsten Fischer, Michael Hallek, Florian Kuchenbauer, Christoph Plass, Hartmut Döhner, Stephan Stilgenbauer, Peter Lichter, Daniel Mertens
B cell receptor (BCR) signaling is key for survival of chronic lymphocytic leukemia (CLL) cells, and BCR signaling inhibitors are clinically active. However, relapse and resistance to treatment require novel treatment options. In order to detect novel candidate therapeutic targets, we performed a genome-wide DNA methylation screen with custom arrays and identified aberrant promoter DNA methylation in 2192 genes. The transcription factor NFATC1 that is a downstream effector of BCR signaling was among the top hypomethylated genes and was concomitantly transcriptionally upregulated in CLL...
September 18, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28920922/g%C3%AE-13-ablation-reprograms-myofibers-to-oxidative-phenotype-and-enhances-whole-body-metabolism
#3
Ja Hyun Koo, Tae Hyun Kim, Shi-Young Park, Min Sung Joo, Chang Yeob Han, Cheol Soo Choi, Sang Geon Kim
Skeletal muscle is a key organ in energy homeostasis owing to its high requirement for nutrients. Heterotrimeric G proteins converge signals from cell-surface receptors to potentiate or blunt responses against environmental changes. Here, we show that muscle-specific ablation of Gα13 in mice promotes reprogramming of myofibers to the oxidative type, with resultant increases in mitochondrial biogenesis and cellular respiration. Mechanistically, Gα13 and its downstream effector RhoA suppressed nuclear factor of activated T cells 1 (NFATc1), a chief regulator of myofiber conversion, by increasing Rho-associated kinase 2-mediated (Rock2-mediated) phosphorylation at Ser243...
September 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28920919/age-dependent-human-%C3%AE-cell-proliferation-induced-by-glucagon-like-peptide-1-and-calcineurin-signaling
#4
Chunhua Dai, Yan Hang, Alena Shostak, Greg Poffenberger, Nathaniel Hart, Nripesh Prasad, Neil Phillips, Shawn E Levy, Dale L Greiner, Leonard D Shultz, Rita Bottino, Seung K Kim, Alvin C Powers
Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets...
September 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28919027/macrolactin-f-inhibits-rankl-mediated-osteoclastogenesis-by-suppressing-akt-mapk-and-nfatc1-pathways-and-promotes-osteoblastogenesis-through-a-bmp-2-smad-akt-runx2-signaling-pathway
#5
Liang Li, Mahesh Sapkota, Ming Gao, Hyukjae Choi, Yunjo Soh
The balance between bone formation and bone resorption is maintained by osteoblasts and osteoclasts. In the current study, macrolactin F (MF) was investigated for novel biological activity on the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis in primary bone marrow-derived macrophages (BMMs). We found that RANKL-induced osteoclast formation and differentiation from BMMs was significantly inhibited by MF in a dose-dependent manner without cytotoxicity. RANKL-induced F-actin ring formation and bone resorption activity in BMMs which was attenuated by MF...
September 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28901449/fk506-suppresses-hypoxia%C3%A2-induced-inflammation-and-protects-tight-junction-function-via-the-can%C3%A2-nfatc1-signaling-pathway-in-retinal-microvascular-epithelial-cells
#6
Yaguang Hu, Boyu Yang, Yue Xu, Li Jiang, Ching-Kit Tsui, Xiaoling Liang
The present study aimed to identify whether FK506 suppresses hypoxia‑induced inflammation and protects tight junction function via the calcineurin‑nuclear factor of activated T‑cells 1 (CaN‑NFATc1) signaling pathway in mouse retinal microvascular endothelial cells (mRMECs). The mRMECs were treated with FK506 at different concentrations following the induction of hypoxia. Trans‑epithelial electrical resistance (TEER) and cell permeability were examined to measure the integrity of the tight junctions...
September 12, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28894104/nfatc1-controls-the-cytotoxicity-of-cd8-t-cells
#7
Stefan Klein-Hessling, Khalid Muhammad, Matthias Klein, Tobias Pusch, Ronald Rudolf, Jessica Flöter, Musga Qureischi, Andreas Beilhack, Martin Vaeth, Carsten Kummerow, Christian Backes, Rouven Schoppmeyer, Ulrike Hahn, Markus Hoth, Tobias Bopp, Friederike Berberich-Siebelt, Amiya Patra, Andris Avots, Nora Müller, Almut Schulze, Edgar Serfling
Cytotoxic T lymphocytes are effector CD8(+) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1 (-/-) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection...
September 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28890387/peptides-derived-from-transcription-factor-eb-bind-to-calcineurin-at-a-similar-region-as-the-nfat-type-motif
#8
Ruiwen Song, Jing Li, Jin Zhang, Lu Wang, Li Tong, Ping Wang, Huan Yang, Qun Wei, Huaibin Cai, Jing Luo
Calcineurin (CN) is involved in many physiological processes and interacts with multiple substrates. Most of the substrates contain similar motifs recognized by CN. Recent studies revealed a new CN substrate, transcription factor EB (TFEB), which is involved in autophagy. We showed that a 15-mer QSYLENPTSYHLQQS peptide from TFEB (TFEB-YLENP) bound to CN. When the TFEB-YLENP peptide was changed to YLAVP, its affinity for CN increased and it had stronger CN inhibitory activity. Molecular dynamics simulations revealed that the TFEB-YLENP peptide has the same docking sites in CN as the 15-mer DQYLAVPQHPYQWAK motif of the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1-YLAVP)...
September 7, 2017: Biochimie
https://www.readbyqxmd.com/read/28886186/the-cardiac-calsequestrin-gene-transcription-is-modulated-at-the-promoter-by-nfat-and-mef-2-transcription-factors
#9
Rafael Estrada-Avilés, Gabriela Rodríguez, Angel Zarain-Herzberg
Calsequestrin-2 (CASQ2) is the main Ca2+-binding protein inside the sarcoplasmic reticulum of cardiomyocytes. Previously, we demonstrated that MEF-2 and SRF binding sites within the human CASQ2 gene (hCASQ2) promoter region are functional in neonatal cardiomyocytes. In this work, we investigated if the calcineurin/NFAT pathway regulates hCASQ2 expression in neonatal cardiomyocytes. The inhibition of NFAT dephosphorylation with CsA or INCA-6, reduced both the luciferase activity of hCASQ2 promoter constructs (-3102/+176 bp and -288/+176 bp) and the CASQ2 mRNA levels in neonatal rat cardiomyocytes...
2017: PloS One
https://www.readbyqxmd.com/read/28881817/dectin-1-signaling-inhibits-osteoclastogenesis-via-il-33-induced-inhibition-of-nfatc1
#10
Xiaoqing Zhu, Yinghua Zhao, Yuxue Jiang, Tianxue Qin, Jintong Chen, Xiao Chu, Qing Yi, Sujun Gao, Siqing Wang
Abnormal osteoclast activation contributes to osteolytic bone diseases (OBDs). It was reported that curdlan, an agonist of dectin-1, inhibits osteoclastogenesis. However, the underlying mechanisms are not fully elucidated. In this study, we found that curdlan potently inhibited RANKL-induced osteoclast differentiation and the resultant bone resorption. Curdlan inhibited the expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), the key transcriptional factor for osteoclastogenesis. Notably, dectin-1 activation increased the expression of MafB, an inhibitor of NFATc1, and IL-33 in osteoclast precursors...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881766/nfatc3-mediates-the-sensitivity-of-gastric-cancer-cells-to-arsenic-sulfide
#11
Xiuli Zhang, Ting Kang, Lian Zhang, Yingying Tong, Wenping Ding, Siyu Chen
Arsenic sulfide (As4S4) is the main component of Realgar which is widely used in traditional Chinese medicine. Previously we showed that As4S4 inhibited the proliferation of colon cancer cells through regulating nuclear factor of activated T cells (NFAT) pathway. Here we explore the role of NFAT in gastric cancer. We showed that As4S4 inhibited the expression of NFATc1, NFATc3, and NFATc4, and modulated the expression of NFATc2 accompanying with p53. The baseline expression of NFATc3 varied distinctly in gastric cancer cell lines (AGS, MGC803, MKN28, MKN45, and SGC7901) and the sensitivity of these cells to As4S4 was dissimilar, with AGS and MGC803 cells showing higher sensitivity while the SGC7901 cells relatively resistant...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28878266/transglutaminase-2-regulates-osteoclast-differentiation-via-a-blimp1-dependent-pathway
#12
Woo-Shin Kim, Haemin Kim, Eui Man Jeong, Hyung Joon Kim, Zang Hee Lee, In-Gyu Kim, Hong-Hee Kim
Transglutaminase 2 (TG2) performs multiple reactions, including transamidation, and also plays a role in signal transduction as a GTP-binding protein. In this study, we reveal that TG2 controls osteoclast differentiation and bone homeostasis in mice. Osteoclasts specifically expressed the TG2 isoform among eight TG family members. Suppression in TG2 expression with siRNA led to increased osteoclast formation from primary mouse precursor cells in response to receptor activator of nuclear factor kappaB ligand (RANKL)...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28867647/inhibitory-effects-of-melatonin-on-titanium-particle-induced-inflammatory-bone-resorption-and-osteoclastogenesis-via-suppression-of-nf-%C3%AE%C2%BAb-signaling
#13
Zichuan Ping, Zhirong Wang, Jiawei Shi, Liangliang Wang, Xiaobin Guo, Wei Zhou, Xuanyang Hu, Xiexing Wu, Yu Liu, Wen Zhang, Huilin Yang, Yaozeng Xu, Ye Gu, Dechun Geng
Wear debris-induced peri-implant osteolysis challenges the longevity of implants. The host response to wear debris causes chronic inflammation, promotes bone resorption, and impairs bone formation. We previously demonstrated that melatonin enhances bone formation and attenuates wear debris-induced bone loss in vivo. However, whether melatonin inhibits chronic inflammation and bone resorption at sites of wear debris-induced osteolysis remains unclear. In this study, we examined the potential inhibitory effects of melatonin on titanium particle-induced inflammatory osteolysis in a murine calvarial model and on RANKL-induced osteoclastic formation in bone marrow-derived macrophages...
August 31, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28861734/inhibitory-effects-of-sesamin-on-human-osteoclastogenesis
#14
Orawan Wanachewin, Peraphan Pothacharoen, Prachya Kongtawelert, Thanyaluck Phitak
The promotional nature of sesamin on human osteoblast differentiation has been proven. Here, the effect of sesamin on human osteoclasts was investigated in terms of differentiation and function in M-CSF and RANKL induced human PBMCs. Sesamin treatment significantly decreased the number of differentiated osteoclasts observed by TRAP staining; however, sesamin inhibition did not result from the alteration of precursor cell proliferation. Sesamin did not decrease NFATc1 gene expression, which opposed the decreasing trend of CathK and TRAP expression...
August 31, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28834554/naringenin-inhibits-osteoclastogenesis-through-modulation-of-helper-t-cells-secreted-il-4
#15
Wengang Wang, Mingjun Li, Ming Luo, Mingkui Shen, Chen Xu, Genzhong Xu, Yaokun Chen, Lei Xia
Naringenin (NAR) is a natural predominant flavanone and has a wide range of pharmacological activities. The aim of this study was to investigate the protective mechanisms of NAR on RANKL-induced osteoclastogenesis and osteoclast bone resorption. T cells were divided into 4 groups under different concentrations of NAR (0, 25, 50, 100 µM). CD4(+) T cell subsets in different groups were evaluated by flow cytometry. TRAP staining, pit formation assays and F-actin ring immunofluorescent staining were performed...
August 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28829497/correlation-between-nfatc1-gene-polymorphisms-and-congenital-heart-disease-in-children
#16
C-L Li, L Niu, M-Y Fu, J Tian, Q-W Wang, X-J An
OBJECTIVE: To analyze the links between NFATC1 gene polymorphism and congenital heart disease in children. PATIENTS AND METHODS: In the present study, we selected 85 children patients with congenital heart disease who were hospitalized from February 2013 to February 2015 as research subjects (observation group), and 92 healthy subjects as control group. Restriction fragment length polymorphism (RFLP) was used for analysis of NFATC1 gene in samples from each group...
August 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28807800/the-synergistic-effects-of-sr-and-si-bioactive-ions-on-osteogenesis-osteoclastogenesis-and-angiogenesis-for-osteoporotic-bone-regeneration
#17
Lixia Mao, Lunguo Xia, Jiang Chang, Jiaqiang Liu, Lingyong Jiang, Chengtie Wu, Bing Fang
Bioactive ions released from bioceramics play important roles in bone regeneration; however, it is unclear how each ionic composition in complex bioceramics exerts its specific effect on bone regeneration. The aim of this study is to elucidate the functional effects of Sr and Si ions in bioceramics on the regeneration of osteoporotic bone. A model bioceramic with Sr- and Si-containing components (SMS) was successfully fabricated and the effects of ionic products from SMS bioceramics on the osteogenic, osteoclastic and angiogenic differentiation of rBMSCs-OVX and RANKL-induced osteoclasts were investigated...
August 12, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28793932/hydroxychloroquine-inhibits-cd154-expression-in-cd4-t-lymphocytes-of-systemic-lupus-erythematosus-through-nfat-but-not-stat5-signaling
#18
Shu-Fen Wu, Chia-Bin Chang, Jui-Mei Hsu, Ming-Chi Lu, Ning-Sheng Lai, Chin Li, Chien-Hsueh Tung
BACKGROUND: Overexpression of membranous CD154 in T lymphocytes has been found previously in systemic lupus erythematosus (SLE). Because hydroxychloroquine (HCQ) has been used frequently in the treatment of lupus, we sought to identify the effects of HCQ on CD154 and a possibly regulatory mechanism. METHODS: CD4(+) T cells were isolated from the blood of lupus patients. After stimulation with ionomycin or IL-15 and various concentrations of HCQ, expression of membranous CD154 and NFAT and STAT5 signaling were assessed...
August 9, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28791728/smoking-is-associated-with-hypermethylation-of-the-apc-1a-promoter-in-colorectal-cancer-the-colocare-study
#19
Timothy M Barrow, Hagen Klett, Reka Toth, Jürgen Böhm, Biljana Gigic, Nina Habermann, Dominique Scherer, Petra Schrotz-King, Stephanie Skender, Clare Abbenhardt-Martin, Lin Zielske, Martin Schneider, Alexis Ulrich, Peter Schirmacher, Esther Herpel, Hermann Brenner, Hauke Busch, Melanie Boerries, Cornelia M Ulrich, Karin B Michels
Smoking tobacco is a known risk factor for the development of colorectal cancer, and for mortality associated with the disease. Smoking has been reported to be associated with changes in DNA methylation in blood and in lung tumour tissues, although there has been scant investigation of how epigenetic factors may be implicated in the increased risk of developing colorectal cancer. To identify epigenetic changes associated with smoking behaviours, we performed epigenome-wide analysis of DNA methylation in colorectal tumours from 36 never smokers, 47 former smokers and 13 active smokers, and adjacent mucosa from 49 never smokers, 64 former smokers and 18 active smokers...
August 9, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28791425/rab44-a-novel-large-rab-gtpase-negatively-regulates-osteoclast-differentiation-by-modulating-intracellular-calcium-levels-followed-by-nfatc1-activation
#20
Yu Yamaguchi, Eiko Sakai, Kuniaki Okamoto, Hiroshi Kajiya, Koji Okabe, Mariko Naito, Tomoko Kadowaki, Takayuki Tsukuba
Rab44 is an atypical Rab GTPase that contains some additional domains such as the EF-hand and coiled-coil domains as well as Rab-GTPase domain. Although Rab44 genes have been found in mammalian genomes, no studies concerning Rab44 have been reported yet. Here, we identified Rab44 as an upregulated protein during osteoclast differentiation. Knockdown of Rab44 by small interfering RNA promotes RANKL-induced osteoclast differentiation of the murine monocytic cell line, RAW-D or of bone marrow-derived macrophages (BMMs)...
August 8, 2017: Cellular and Molecular Life Sciences: CMLS
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