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https://www.readbyqxmd.com/read/29343616/rapamycin-activates-tgf-receptor-independently-of-its-ligand-implications-for-endothelial-dysfunction
#1
Ayumi A Miyakawa, Thais Girao-Silva, Jose E Krieger, Elazer R Edelman
Rapamycin, the macrolide immunosuppressant and active pharmaceutic in drug-eluting stents (DES), has a well-recognized anti-proliferative action that involves inhibition of the mTOR pathway after binding to the cytosolic protein FKBP12. TGF receptor-type I (TGFRI) spontaneous activation is inhibited by the association with FKBP12. We hypothesized that rapamycin, in addition to inhibition of mTOR signaling, activates TGFRI independent of TGFb. Human umbilical vein endothelial cells (HUVEC) were treated with rapamycin (10nmoL/L) and/or TGF-b RI kinase inhibitor (TGFRIi, 100nmoL/L) for 24 hours...
January 17, 2018: Clinical Science (1979-)
https://www.readbyqxmd.com/read/29314205/cdc42-is-essential-for-both-articular-cartilage-degeneration-and-subchondral-bone-deterioration-in-experimental-osteoarthritis
#2
Xinhua Hu, Xing Ji, Mengting Yang, Shihao Fan, Jirong Wang, Meiping Lu, Wei Shi, Liu Mei, Chengyun Xu, Xueying Fan, Musaddique Hussain, Jingyu Du, Junsong Wu, Ximei Wu
Cdc42, a member of Rho family small GTPases, is critical for cartilage development. We investigated the roles of Cdc42 in osteoarthritis and explored the potential mechanism underlying Cdc42-mediated articular cartilage degeneration and subchondral bone deterioration. Cdc42 is highly expressed in both articular cartilage and subchondral bone in a mouse osteoarthritis model with surgical destabilisation of the medial meniscus (DMM) in the knee joints. Specifically, genetic disruption of Cdc42, knockdown of Cdc42 expression, or inhibition of Cdc42 activity robustly attenuates the DMM-induced destruction, hypertrophy, high expression of matrix metallopeptidase-13 and collagen X, and activation of Stat3 in articular cartilages...
January 3, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29312637/notch-signaling-negatively-regulates-bmp9-induced-osteogenic-differentiation-of-mesenchymal-progenitor-cells-by-inhibiting-junb-expression
#3
Nan Wang, Wei Liu, Tao Tan, Chao-Qun Dong, Duan-Yang Lin, Jun Zhao, Chang Yu, Xiao-Ji Luo
Although interaction between BMP and Notch signaling has been demonstrated to be crucial for osteogenic differentiation of mesenchymal stem cells (MSCs), the precise molecular mechanism remains unknown. Here, we show that Notch intracellular domain (NICD) overexpression inhibits BMP9-induced C3H10T1/2 cell osteogenesis in vivo and in vitro. Our results show that activated Notch signaling results in down-regulation of Runx2 and early osteogenesis differentiation factors, without affecting p-Smad1/5/8 expression, and that blocking Notch signaling with DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) significantly increases p-Smad1/5/8 expression...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29290366/reduced-calcification-and-osteogenic-features-in-advanced-atherosclerotic-plaques-of-mice-with-macrophage-specific-loss-of-trpc3
#4
Prabhatchandra R Dube, Lakshmikanth L Chikkamenahalli, Lutz Birnbaumer, Guillermo Vazquez
BACKGROUND AND AIMS: Recent in vitro studies have showed that in macrophages, deletion of the non-selective Ca2+-permeable channel TRPC3 impairs expression of the osteogenic protein BMP-2. The pathophysiological relevance of this effect in atherosclerotic plaque calcification remains to be determined. METHODS: We used Ldlr-/- mice with macrophage-specific loss of TRPC3 (MacTrpc3-/-/Ldlr-/-) to examine the effect of macrophage Trpc3 on plaque calcification and osteogenic features in advanced atherosclerosis...
December 22, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/29284776/the-tgf-beta%C3%A2-smad-pathway-is-inactivated-in%C3%A2-cronic%C3%A2-lymphocytic-leukemia-cells
#5
A Matveeva, L Kovalevska, I Kholodnyuk, T Ivanivskaya, E Kashuba
AIM: To study the status of the tumor growth factor beta (TGFB) pathway in chronic lymphocytic leukemia (CLL) cells and to uncover molecular details underlying CLL cell genesis. OBJECTS AND METHODS: The study was conducted on peripheral blood samples of patients with CLL using the following methods: RNA isolation, analysis of expression of transcription factors using RT2 profiler assay, bioinformatics analysis of publicly available data bases on expression. RESULTS: We have shown that the TGFB - SMAD canonical pathway is not active in CLL cells...
December 2017: Experimental Oncology
https://www.readbyqxmd.com/read/29273814/the-crucial-role-of-the-trpm7-kinase-domain-in-the-early-stage-of-amelogenesis
#6
Kayoko Ogata, Tomoyuki Tsumuraya, Kyoko Oka, Masashi Shin, Fujio Okamoto, Hiroshi Kajiya, Chiaki Katagiri, Masao Ozaki, Masayuki Matsushita, Koji Okabe
Transient receptor potential melastatin-7 (TRPM7) is a bi-functional protein containing a kinase domain fused to an ion channel. TRPM7 is highly expressed in ameloblasts during tooth development. Here we show that TRPM7 kinase-inactive knock-in mutant mice (TRPM7 KR mice) exhibited small enamel volume with opaque white-colored incisors. The TRPM7 channel function of ameloblast-lineage cells from TRPM7 KR mice was normal. Interestingly, phosphorylation of intracellular molecules including Smad1/5/9, p38 and cAMP response element binding protein (CREB) was inhibited in ameloblasts from TRPM7 KR mice at the pre-secretory stage...
December 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29249772/inhibition-of-adenosine-monophosphate-activated-protein-kinase-suppresses-bone-morphogenetic-protein-2-induced-mineralization-of-osteoblasts-via-smad-independent-mechanisms
#7
Ayumu Takeno, Ippei Kanazawa, Masakazu Notsu, Ken-Ichiro Tanaka, Toshitsugu Sugimoto
Previous studies showed that adenosine monophosphate-activated protein kinase (AMPK), which plays as an intracellular energy sensor, promotes the differentiation and mineralization of osteoblasts via enhancing expression of bone morphogenetic protein (BMP)-2, which is a potent inducer of osteoblastogenesis. Thus, the aim of this study was to examine the roles of AMPK in BMP-2-induced osteoblastogenesis. We used a murine osteoblastic cell line MC3T3-E1 and a murine marrow stromal cell line ST2. BMP-2 (50 and 100 ng/mL) stimulated alkaline phosphatase (ALP) activity and enhanced mineralization of MC3T3-E1 cells, while the effects of BMP-2 were partly abolished by an inhibitor of AMPK, ara-A (0...
December 16, 2017: Endocrine Journal
https://www.readbyqxmd.com/read/29247325/tgf-%C3%AE-signaling-inhibits-canonical-bmp-signaling-pathway-during-palate-development
#8
Guohua Yuan, Yunyan Zhan, Xiaohui Gou, Yiping Chen, Guobin Yang
During early palate development, gene expression and regulation exhibit heterogeneity along the anterior-posterior axis. Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways play essential roles in secondary palatal formation but the exact relationship between the TGF-β and BMP pathways in palate development remains unknown. Here, we demonstrate that, during early secondary palate development, phospho-(p)Smad1/5/8 is highly expressed in the anterior palate but relatively lowly expressed in the posterior palate...
December 16, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/29245956/combination-therapy-of-exendin-4-and-allogenic-adipose-derived-mesenchymal-stem-cell-preserved-renal-function-in-a-chronic-kidney-disease-and-sepsis-syndrome-setting-in-rats
#9
Chih-Hung Chen, Ben-Chung Cheng, Kuan-Hung Chen, Pei-Lin Shao, Pei-Hsun Sung, Hsin-Ju Chiang, Chih-Chao Yang, Kun-Chen Lin, Cheuk-Kwan Sun, Jiunn-Jye Sheu, Hsueh-Wen Chang, Mel S Lee, Hon-Kan Yip
Combined therapy with exendin-4 (Ex4) and allogenic adipose-derived mesenchymal stem cells (ADMSC) was tested against either therapy alone for protecting kidney function against chronic kidney disease (CKD) complicated by sepsis syndrome (SS) [i.e., by intraperitoneal injection of cecal-derived bacteria (1.0 × 104) cells/milliliter/total 5.0 cc].Adult-male-Sprague Dawley rats (n=36) were equally divided into group 1 (sham-control), group 2 (CKD), group 3 (CKD-SS), group 4 (CKD-SS-Ex4), group 5 (CKD-SS-ADMSC) and group 6 (CKD-SS-Ex4-ADMSC)...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29245051/magnesium-phosphate-ceramics-incorporating-a-novel-indene-compound-promote-osteoblast-differentiation-in%C3%A2-vitro-and-bone-regeneration-in%C3%A2-vivo
#10
Ju Ang Kim, Hui-Suk Yun, Young-Ae Choi, Jung-Eun Kim, So-Young Choi, Tae-Geon Kwon, Young Kyung Kim, Tae-Yub Kwon, Myung Ae Bae, Nak Jeong Kim, Yong Chul Bae, Hong-In Shin, Eui Kyun Park
Incorporating bioactive molecules into synthetic ceramic scaffolds is challenging. In this study, to enhance bone regeneration, a magnesium phosphate (MgP) ceramic scaffold was incorporated with a novel indene compound, KR-34893. KR-34893 induced the deposition of minerals and expression of osteoblast marker genes in primary human bone marrow mesenchymal stem cells (BMSCs) and a mouse osteoblastic MC3T3-E1 cell line. Analysis of the mode of action showed that KR-34893 induced the phosphorylation of MAPK/extracellular signal-regulated kinase and extracellular signal-regulated kinase, and subsequently the expression of bone morphogenetic protein 7, accompanied by SMAD1/5/8 phosphorylation...
December 7, 2017: Biomaterials
https://www.readbyqxmd.com/read/29236309/leptin-induces-mmp1-13-and-adamts-4-expressions-through-bone-morphogenetic-protein-2-autocrine-effect-in-human-chondrocytes
#11
Yu-Ping Su, Cheng-Nan Chen, Kuo-Chin Huang, Hsin-I Chang, Ko-Chao Lee, Chun-Min Lo, Shun-Fu Chang
The induction of bone morphogenetic protein (BMP) 2 in injured and arthritis articular cartilage has been proposed, but the precise mechanism has not been clearly clarified. Our previous study has found that leptin could stimulate the BMP2 autocrine effect to increase the anabolic collagen II expression when it initiates the catabolic response in human chondrocytes. It has been suggested that this BMP2 autocrine effect contributes to a reparative role in leptin-stimulated human chondrocytes. In this study, we further determined whether this BMP2 autocrine effect also affect the expressions of catabolic matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)...
December 13, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29234012/structural-basis-for-genome-wide-recognition-of-5-bp-gc-motifs-by-smad-transcription-factors
#12
Pau Martin-Malpartida, Marta Batet, Zuzanna Kaczmarska, Regina Freier, Tiago Gomes, Eric Aragón, Yilong Zou, Qiong Wang, Qiaoran Xi, Lidia Ruiz, Angela Vea, José A Márquez, Joan Massagué, Maria J Macias
Smad transcription factors activated by TGF-β or by BMP receptors form trimeric complexes with Smad4 to target specific genes for cell fate regulation. The CAGAC motif has been considered as the main binding element for Smad2/3/4, whereas Smad1/5/8 have been thought to preferentially bind GC-rich elements. However, chromatin immunoprecipitation analysis in embryonic stem cells showed extensive binding of Smad2/3/4 to GC-rich cis-regulatory elements. Here, we present the structural basis for specific binding of Smad3 and Smad4 to GC-rich motifs in the goosecoid promoter, a nodal-regulated differentiation gene...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29232368/ascorbic-acid-promotes-cardiomyogenesis-through-smad1-signaling-in-differentiating-mouse-embryonic-stem-cells
#13
Maria Grazia Perino, Satoshi Yamanaka, Daniel R Riordon, Yelena Tarasova, Kenneth R Boheler
Numerous groups have documented that Ascorbic Acid (AA) promotes cardiomyocyte differentiation from both mouse and human ESCs and iPSCs. AA is now considered indispensable for the routine production of hPSC-cardiomyocytes (CMs) using defined media; however, the mechanisms involved with the inductive process are poorly understood. Using a genetically modified mouse embryonic stem cell (mESC) line containing a dsRED transgene driven by the cardiac-restricted portion of the ncx1 promoter, we show that AA promoted differentiation of mESCs to CMs in a dose- and time-dependent manner...
2017: PloS One
https://www.readbyqxmd.com/read/29231215/involvement-of-fak-mediated-bmp-2-smad-pathway-in-mediating-osteoblast-adhesion-and-differentiation-on-nano-ha-chitosan-composite-coated-titanium-implant-under-diabetic-conditions
#14
Xiang-Yu Ma, Ya-Fei Feng, Tian-Sheng Wang, Wei Lei, Xiang Li, Da-Peng Zhou, Xin-Xin Wen, Hai-Long Yu, Liang-Bi Xiang, Lin Wang
Chitosan (CS)-based hydroxyapatite (HA) composites have emerged as a novel strategy for promoting bone regeneration. Here nanophase HA/CS composite coated porous titanium implants (nCT) were fabricated and their biological behavior under diabetic conditions was investigated. We proposed that the focal adhesion kinase (FAK)-mediated BMP-2/Smad pathway played a role in mediating the promotive effect of nCTs on osteoblast adhesion and differentiation under diabetes-induced high reactive oxygen species (ROS) condition...
December 12, 2017: Biomaterials Science
https://www.readbyqxmd.com/read/29219668/multispectral-imaging-reveals-hyper-active-tgf-%C3%AE-signaling-in-colorectal-cancer
#15
Lei Yang, Zheng Liu, Jinjing Tan, Hongwei Dong, Xiaojing Zhang
Advances in multiplex immunohistochemistry (IHC) techniques and digital pathology platforms allow quantification of multiple proteins at same tissue section and produce continuous data. TGF-β signaling plays crucial and complex roles in colorectal cancer (CRC). We here aimed to investigate clinical pathological relevant of proteins involved in TGF-β signaling at CRC tissues. Multiplex fluorescent IHC was used to quantitative analysis. The levels of eight proteins (TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD2/3, p-SMAD2/3, SMAD1/5/9, and p-SMAD1/5/9) were determined in TMA sections...
December 8, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29218106/extracorporeal-shock-wave-therapy-effectively-protects-brain-against-chronic-cerebral-hypo-perfusion-induced-neuropathological-changes
#16
Han-Tan Chai, Kuan-Hung Chen, Christopher Glenn Wallace, Chih-Hung Chen, Pei-Hsun Sung, Yung-Lung Chen, Chun-Man Yuen, Pei-Lin Shao, Cheuk-Kwan Sun, Hsueh-Wen Chang, Ching-Jen Wang, Mel S Lee, Hon-Kan Yip, Sheung-Fat Ko
This study tested the hypothesis that extracorporeal shock wave (ECSW) therapy could protect mouse brain from chronic cerebral hypoperfusion (CHP)-induced neuropathological changes in a bilateral carotid arterial stenosis (CAS) model. Adult-male C57BL/6 (B6) mice (n=36) were randomized into group 1 (sham-control), group 2 (CHP) and group 3 [CHP+ECSW (100 impulses at 0.15 mJ/mm2) on day 5, 10 and 15 after CHP induction]. By day 60 after CHP induction, the white matter lesion, protein expressions of inflammatory (TNF-α/NF-κB/iNOS), oxidative-stress (NOX-1/NOX-2/NOX-4/nitrotyrosine), angiogenesis (eNOS/CD31), apoptotic (Bax/caspase-3/PARP), fibrotic (Smad3/TGF-ß) and mitochondrial-damaged (cytosolic cytochrome-C) biomarkers were significantly higher in group 2 than in groups 1 and 3, and significantly higher in group 3 than in group 1, whereas the protein expressions of anti-apoptotic (Bcl-2), anti-fibrotic (BMP-2/Smad1/5), and mitochondrial-integrity (mitochondrial cytochrome-C) biomarkers showed an opposite pattern to inflammation among the three groups (all P<0...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/29212066/fstl1-promotes-glioma-growth-through-the-bmp4-smad1-5-8-signaling-pathway
#17
Xin Jin, Er Nie, Xu Zhou, Ailiang Zeng, Tianfu Yu, Tongle Zhi, Kuan Jiang, Yingyi Wang, Junxia Zhang, Yongping You
BACKGROUND: Gliomas result in the highest morbidity and mortality rates of intracranial primary central nervous system tumors because of their aggressive growth characteristics and high postoperative recurrence. They are characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior in patients. Proliferation is a key aspect of the clinical progression of malignant gliomas, complicating complete surgical resection and enabling tumor regrowth and further proliferation of the surviving tumor cells...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29202447/bone-forming-peptide-3-induces-osteogenic-differentiation-of-bone-marrow-stromal-cells-via-regulation-of-the-erk1-2-and-smad1-5-8-pathways
#18
Jun Sik Lee, Mi Eun Kim, Jong Keun Seon, Ju Yeon Kang, Taek Rim Yoon, Yong-Duk Park, Hyung Keun Kim
A bone-remodeling imbalance induced by increased bone resorption and osteoclast formation causes skeletal diseases such as osteoporosis. Induction of osteogenic differentiation of bone marrow stromal cells (BMSCs) leads to bone regeneration. Many researchers have tried to develop new adjuvants as specific stimulators of bone regeneration for therapeutic use in patients with bone resorption. We tried to develop a new adjuvant that has stronger osteogenic differentiation-promoting activity than bone morphogenetic proteins (BMPs)...
November 22, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29196107/distribution-of-smad-mrna-and-proteins-in-the-rat-brain
#19
Takayuki Nakajima, Ryusuke Hata, Yuji Kunieda, Tomohiro Kondo
Smad proteins are known to transduce the action of TGF-β superfamily proteins including TGF-βs, activins, and bone morphogenetic proteins (BMPs). In this study, we examined the expression of Smad1, -2, -3, -4, -5, and -8 mRNA in the rat brain by means of RT-PCR and in situ hybridization (ISH). In addition, we examined the nuclear accumulation of Smad1, -2, -3, -5, and -8 proteins after intracerebroventricular injection of TGF-β1, activin A, or BMP6 with immunohistochemistry to investigate whether TGF-β, activin, and/or BMP activate Smads in the rat brain...
November 28, 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/29180690/fad104-a-regulator-of-adipogenesis-is-a-novel-suppressor-of-tgf-%C3%AE-mediated-emt-in-cervical-cancer-cells
#20
Motoharu Goto, Shigehiro Osada, Masayoshi Imagawa, Makoto Nishizuka
Epithelial-to-mesenchymal transition (EMT) is a biological process in which epithelial cells translate into a mesenchymal phenotype with invasive capacities, contributing to tumour progression, metastasis, and the acquisition of chemotherapy resistance. To identify new therapeutic targets for cancers, it is important to clarify the molecular mechanism of induction of EMT. We have previously reported that fad104, a positive regulator of adipocyte differentiation, suppressed the invasion and metastasis of melanoma and breast cancer cells...
November 27, 2017: Scientific Reports
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