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https://www.readbyqxmd.com/read/29217140/inhibition-of-canonical-wnt-signaling-pathway-by-%C3%AE-catenin-cbp-inhibitor-icg-001-ameliorates-liver-fibrosis-in-vivo-through-suppression-of-stromal-cxcl12
#1
Büsra Öztürk Akcora, Gert Storm, Ruchi Bansal
Quiescent hepatic stellate cells (HSCs), in response to liver injury, undergo characteristic morphological transformation into proliferative, contractile and ECM-producing myofibroblasts. In this study, we investigated the implication of canonical Wnt signaling pathway in HSCs and liver fibrogenesis. Canonical Wnt signaling pathway activation and inhibition using β-catenin/CBP inhibitor ICG001 was examined in-vitro in TGFβ-activated 3T3, LX2, primary human HSCs, and in-vivo in CCl4-induced acute liver injury mouse model...
December 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29214019/pkm2-is-not-required-for-colon-cancer-initiated-by-apc-loss
#2
Allison N Lau, William J Israelsen, Jatin Roper, Mark J Sinnamon, Larissa Georgeon, Talya L Dayton, Alissandra L Hillis, Omer H Yilmaz, Dolores Di Vizio, Kenneth E Hung, Matthew G Vander Heiden
Background: Cancer cells express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2). PKM2 expression is not required for some cancers, and PKM2 loss can promote cancer progression; however, PKM2 has been reported to be essential in other tumor contexts, including a proposed non-metabolic role in β-catenin nuclear translocation. PKM2 is expressed in colon cancers where loss of the Apc tumor suppressor results in β-catenin nuclear translocation and aberrant activation of the canonical Wnt signaling pathway...
2017: Cancer & Metabolism
https://www.readbyqxmd.com/read/29212857/mutational-mechanisms-that-activate-wnt-signaling-and-predict-outcomes-in-colorectal-cancer-patients
#3
William C Hankey, Michael A McIlhatton, Kenechi Ebede, Brian Kennedy, Baris Hancioglu, Jie Zhang, Guy N Brock, Kun Huang, Joanna L Groden
APC biallelic loss-of-function mutations are the most prevalent genetic changes in colorectal tumors, but it is unknown whether these mutations phenocopy gain-of-function mutations in the CTNNB1 gene encoding ß-catenin that also activate canonical WNT signaling. Here we demonstrate that these two mutational mechanisms are not equivalent. Further, we show how differences in gene expression produced by these different mechanisms can stratify outcomes in more advanced human colorectal cancers. Gene expression profiling in Apc-mutant and Ctnnb1-mutant mouse colon adenomas identified candidate genes for subsequent evaluation of human TCGA data for colorectal cancer outcomes...
December 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/29212798/the-gsk3-kinase-inhibitor-lithium-produces-unexpected-hyperphosphorylation-of-%C3%AE-catenin-a-gsk3-substrate-in-human-glioblastoma-cells
#4
Ata Ur Rahman Mohammed Abdul, Bhagya De Silva, Ronald K Gary
Lithium salt is a classic glycogen synthase kinase 3 (GSK3) inhibitor. Beryllium is a structurally-related inhibitor that is more potent but relatively uncharacterized. This study examined the effects of these inhibitors on the phosphorylation of endogenous GSK3 substrates. In NIH-3T3 cells, both salts caused a decrease in phosphorylated glycogen synthase, as expected. GSK3 inhibitors produce enhanced phosphorylation of Ser9 of GSK3β via a positive feedback mechanism, and both salts elicited this enhancement...
December 6, 2017: Biology Open
https://www.readbyqxmd.com/read/29212028/non-canonical-hedgehog-signaling-is-a-positive-regulator-of-the-wnt-pathway-and-is-required-for-the-survival-of-colon-cancer-stem-cells
#5
Joseph L Regan, Dirk Schumacher, Stephanie Staudte, Andreas Steffen, Johannes Haybaeck, Ulrich Keilholz, Caroline Schweiger, Nicole Golob-Schwarzl, Dominik Mumberg, David Henderson, Hans Lehrach, Christian R A Regenbrecht, Reinhold Schäfer, Martin Lange
Colon cancer is a heterogeneous tumor driven by a subpopulation of cancer stem cells (CSCs). To study CSCs in colon cancer, we used limiting dilution spheroid and serial xenotransplantation assays to functionally define the frequency of CSCs in a panel of patient-derived cancer organoids. These studies demonstrated cancer organoids to be enriched for CSCs, which varied in frequency between tumors. Whole-transcriptome analysis identified WNT and Hedgehog signaling components to be enhanced in CSC-enriched tumors and in aldehyde dehydrogenase (ALDH)-positive CSCs...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29209231/early-determination-of-the-periodontal-domain-by-the-wnt-antagonist-frzb-sfrp3
#6
Thimios A Mitsiadis, Pierfrancesco Pagella, Claudio Cantù
Odontogenesis results from the continuous and reciprocal interaction between cells of the oral epithelium and cranial neural crest-derived mesenchyme. The canonical Wnt signaling pathway plays a fundamental role in mediating these interactions from the earliest stages of tooth development. Here we analyze by in situ hybridization the expression patterns of the extracellular Wnt antagonist Frzb/Sfrp3. Although Frzb is expressed in dental mesenchymal cells from the earliest stages of odontogenesis, its expression is absent from a tiny population of mesenchymal cells immediately adjacent to the invaginating dental epithelium...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29208525/novel-familial-mutation-of-lrp5-causing-high-bone-mass-genetic-analysis-clinical-presentation-and-characterization-of-bone-matrix-mineralization
#7
K M Roetzer, G Uyanik, A Brehm, J Zwerina, S Zandieh, T Czech, P Roschger, B M Misof, K Klaushofer
The Wnt signalling pathway is a critical regulator of bone mass and quality. Several heterozygous mutations in the LRP5 gene, a Wnt co-receptor, causing high bone mass (LRP5-HBM) have been described to date. The pathogenic mechanism is thought to be a gain-of-function caused by impaired inhibition of the canonical Wnt signalling pathway, thereby leading to increased bone formation. We report the cases of two affected family members, a 53-year-old mother and her 23-year-old daughter, with high bone mass (T-scores mother: lumbar spine 11...
December 5, 2017: Bone
https://www.readbyqxmd.com/read/29208373/roles-of-maternal-wnt8a-transcripts-in-axis-formation-in-zebrafish
#8
Hiromu Hino, Akiko Nakanishi, Ryoko Seki, Tsubasa Aoki, Etsuro Yamaha, Atsuo Kawahara, Takashi Shimizu, Masahiko Hibi
In early zebrafish development, the program for dorsal axis formation begins soon after fertilization. Previous studies suggested that dorsal determinants (DDs) localize to the vegetal pole, and are transported to the dorsal blastomeres in a microtubule-dependent manner. The DDs activate the canonical Wnt pathway and induce dorsal-specific genes that are required for dorsal axis formation. Among wnt-family genes, only the wnt8a mRNA is reported to localize to the vegetal pole in oocytes and to induce the dorsal axis, suggesting that Wnt8a is a candidate DD...
December 2, 2017: Developmental Biology
https://www.readbyqxmd.com/read/29207657/discovery-of-novel-frizzled-7-inhibitors-by-targeting-the-receptor-s-transmembrane-domain
#9
Wei Zhang, Wenyan Lu, Subramaniam Ananthan, Mark J Suto, Yonghe Li
Frizzled (Fzd) proteins are seven transmembrane receptors that belong to a novel and separated family of G-protein-coupled receptors (GPCRs). The Fzd receptors can respond to Wnt proteins to activate the canonical β-catenin pathway which is important for both initiation and progression of cancers. Disruption of the Wnt/β-catenin signal thus represents an opportunity for rational cancer prevention and therapy. Of the 10 members of the Fzd family, Fzd7 is the most important member involved in cancer development and progression...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29206819/mechanisms-of-inactivation-of-the-tumour-suppressor-gene-rhoa-in-colorectal-cancer
#10
Higinio Dopeso, Paulo Rodrigues, Josipa Bilic, Sarah Bazzocco, Fernando Cartón-García, Irati Macaya, Priscila Guimarães de Marcondes, Estefanía Anguita, Marc Masanas, Lizbeth M Jiménez-Flores, Águeda Martínez-Barriocanal, Rocío Nieto, Miguel F Segura, Simo Schwartz, John M Mariadason, Diego Arango
BACKGROUND: Reduced RHOA signalling has been shown to increase the growth/metastatic potential of colorectal tumours. However, the mechanisms of inactivation of RHOA signalling in colon cancer have not been characterised. METHODS: A panel of colorectal cancer cell lines and large cohorts of primary tumours were used to investigate the expression and activity of RHOA, as well as the presence of RHOA mutations/deletions and promoter methylation affecting RHOA. Changes in RHOA expression were assessed by western blotting and qPCR after modulation of microRNAs, SMAD4 and c-MYC...
December 5, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29202785/anti-aggregant-tau-mutant-promotes-neurogenesis
#11
Maria Joseph, Marta Anglada-Huguet, Katharina Paesler, Eckhard Mandelkow, Eva-Maria Mandelkow
BACKGROUND: The microtubule-associated protein Tau plays a role in neurodegeneration as well as neurogenesis. Previous work has shown that the expression of the pro-aggregant mutant Tau repeat domain causes strong aggregation and pronounced neuronal loss in the hippocampus whereas the anti-aggregant form has no deleterious effects. These two proteins differ mainly in their propensity to form ß structure and hence to aggregate. METHODS: To elucidate the basis of these contrasting effects, we analyzed organotypic hippocampal slice cultures (OHSCs) from transgenic mice expressing the repeat domain (RD) of Tau with the anti-aggregant mutation (TauRDΔKPP) and compared them with slices containing pro-aggregant TauRDΔK...
December 4, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29198828/altered-differentiation-potential-of-gaucher-s-disease-ipsc-neuronal-progenitors-due-to-wnt-%C3%AE-catenin-downregulation
#12
Ola Awad, Leelamma M Panicker, Rania M Deranieh, Manasa P Srikanth, Robert A Brown, Antanina Voit, Tejasvi Peesay, Tea Soon Park, Elias T Zambidis, Ricardo A Feldman
Gaucher's disease (GD) is an autosomal recessive disorder caused by mutations in the GBA1 gene, which encodes acid β-glucocerebrosidase (GCase). Severe GBA1 mutations cause neuropathology that manifests soon after birth, suggesting that GCase deficiency interferes with neuronal development. We found that neuronopathic GD induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs) exhibit developmental defects due to downregulation of canonical Wnt/β-catenin signaling and that GD iPSCs' ability to differentiate to dopaminergic (DA) neurons was strikingly reduced due to early loss of DA progenitors...
November 27, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29192455/-molecular-mechanism-of-total-flavonoids-in-isodon-amethystoides-on-adjuvant-arthritis-in-rats
#13
Cheng-Gui Miao, Wei-Jing Shi, Wei Wei, Mei-Song Qin, Hao Chen, Bing Zhang
Our preliminary study showed that the total flavonoids in Isodon amethystoides(TFIA), a local medicinal herb in Suzhou, had a certain therapeutic effect on adjuvant arthritis, and this therapeutic effect may be achieved through the up-regulation of miR-152 expression. In this paper, the molecular mechanism of TFIA on the pathogenesis of adjuvant arthritis(AA) rats was further studied. AA rats were prepared with complete Freund's adjuvant, and then treated with TFIA by intragastric administration. Real-time qPCR was used to detect the effects of TFIA on the negative regulatory loop of miR-152, methylase DNMT1 and methyl-CpG binding protein MeCP2 in fibroblast like synoviocytes(FLS) of AA rats, as well as the effects of TFIA on the classic Wnt signaling pathway and the expression of fibronectin gene in AA rats...
September 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29192250/coupling-optogenetics-and-light-sheet-microscopy-a-method-to-study-wnt-signaling-during-embryogenesis
#14
Prameet Kaur, Timothy E Saunders, Nicholas S Tolwinski
Optogenetics allows precise, fast and reversible intervention in biological processes. Light-sheet microscopy allows observation of the full course of Drosophila embryonic development from egg to larva. Bringing the two approaches together allows unparalleled precision into the temporal regulation of signaling pathways and cellular processes in vivo. To develop this method, we investigated the regulation of canonical Wnt signaling during anterior-posterior patterning of the Drosophila embryonic epidermis. Cryptochrome 2 (CRY2) from Arabidopsis Thaliana was fused to mCherry fluorescent protein and Drosophila β-catenin to form an easy to visualize optogenetic switch...
November 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29188452/bisphosphonates-hinder-osteoblastic-osteoclastic-differentiation-in-the-maxillary-sinus-mucosa-derived-stem-cells
#15
Jun Zhang, Jaesuh Park, Jung-Woo Lee, Yong-Dae Kwon, Eun-Cheol Kim
OBJECTIVES: Although bisphosphonates (BPs) are known to be associated with osteonecrosis of the maxilla, the precise effects of BPs on bone metabolism in human maxillary sinus mucosal cells (HMSMCs) are not yet known. The purposes of this study were to examine the effects of the BPs zoledronate (ZOL) and alendronate (ALN) on osteoblastic and osteoclastic differentiation in HMSMCs and to investigate the signaling pathways involved. MATERIALS AND METHODS: The effects of ZOL and ALN were assessed for osteoblast differentiation by alkaline phosphatase (ALP) activity, alizarin red staining, and RT-PCR for genes encoding Runx2 and osterix...
November 30, 2017: Clinical Oral Investigations
https://www.readbyqxmd.com/read/29186898/thermodynamic-aspects-and-reprogramming-cellular-energy-metabolism-during-the-fibrosis-process
#16
REVIEW
Alexandre Vallée, Yves Lecarpentier, Jean-Noël Vallée
Fibrosis is characterized by fibroblast proliferation and fibroblast differentiation into myofibroblasts, which generate a relaxation-free contraction mechanism associated with excessive collagen synthesis in the extracellular matrix, which promotes irreversible tissue retraction evolving towards fibrosis. From a thermodynamic point of view, the mechanisms leading to fibrosis are irreversible processes that can occur through changing the entropy production rate. The thermodynamic behaviors of metabolic enzymes involved in fibrosis are modified by the dysregulation of both transforming growth factor β (TGF-β) signaling and the canonical WNT/β-catenin pathway, leading to aerobic glycolysis, called the Warburg effect...
November 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29183322/extracts-of-zuo-jin-wan-a-traditional-chinese-medicine-phenocopies-5-htr1d-antagonist-in-attenuating-wnt-%C3%AE-catenin-signaling-in-colorectal-cancer-cells
#17
Jielu Pan, Yangxian Xu, Haiyan Song, Xiqiu Zhou, Zemin Yao, Guang Ji
BACKGROUND: In vitro and in vivo studies have shown that Zuo Jin Wan (ZJW), a herbal formula of traditional Chinese medicine (TCM), possessed anticancer properties. However, the underlying mechanism for the action of ZJW remains unclear. Various subtypes of 5-Hydroxytryptamine receptor (5-HTR) have been shown to play a role in carcinogenesis and cancer metastasis. 5-HTR1D, among the subtypes, is highly expressed in colorectal cancer (CRC) cell lines and tissues. The present study aimed at investigating effect of ZJW extracts on the biological function of CRC cells, the expression of 5-HTR1D, and molecules of Wnt/β-catenin signaling pathway...
November 28, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/29176883/wnt-co-receptors-lrp5-and-lrp6-differentially-mediate-wnt3a-signaling-in-osteoblasts
#18
Aimy Sebastian, Nicholas R Hum, Deepa K Murugesh, Sarah Hatsell, Aris N Economides, Gabriela G Loots
Wnt3a is a major regulator of bone metabolism however, very few of its target genes are known in bone. Wnt3a preferentially signals through transmembrane receptors Frizzled and co-receptors Lrp5/6 to activate the canonical signaling pathway. Previous studies have shown that the canonical Wnt co-receptors Lrp5 and Lrp6 also play an essential role in normal postnatal bone homeostasis, yet, very little is known about specific contributions by these co-receptors in Wnt3a-dependent signaling. We used high-throughput sequencing technology to identify target genes regulated by Wnt3a in osteoblasts and to elucidate the role of Lrp5 and Lrp6 in mediating Wnt3a signaling...
2017: PloS One
https://www.readbyqxmd.com/read/29175269/sclerostin-deficiency-modifies-the-development-of-ckd-mbd-in-mice
#19
Nadine Kaesler, Anja Verhulst, Annelies De Maré, Annika Deck, Geert J Behets, Ayshe Hyusein, Pieter Evenepoel, Jürgen Floege, Nikolaus Marx, Anne Babler, Ina Kramer, Michaela Kneissel, Rafael Kramann, Daniel Weis, Patrick C D'Haese, Vincent M Brandenburg
Sclerostin is a soluble antagonist of canonical Wnt signaling and a strong inhibitor of bone formation. We present experimental data on the role of sclerostin in chronic kidney disease - bone mineral disorder (CKD-MBD). METHODS: We performed 5/6 nephrectomies in 36-week-old sclerostin-deficient (SOST-/-) B6-mice and in C57BL/6J wildtype (WT) mice. Animals received a high phosphate diet for 11weeks. The bones were analyzed by high-resolution micro-computed tomography (μCT) and quantitative bone histomorphometry...
November 21, 2017: Bone
https://www.readbyqxmd.com/read/29175155/neuroanatomical-distribution-of-dek-protein-in-corticolimbic-circuits-associated-with-learning-and-memory-in-adult-male-and-female-mice
#20
Valentina Ghisays, Elizabeth T Nguyen, Joshua Streicher, Nicholas A Pease, Maureen Fitzgerald, Christina M Estrada, Ana Franco-Villanueva, Lisa Privette Vinnedge, Matia B Solomon
DEK, a chromatin-remodeling gene expressed in most human tissues, is known for its role in cancer biology and autoimmune diseases. DEK depletion in vitro reduces cellular proliferation, induces DNA damage subsequently leading to apoptosis, and down-regulates canonical Wnt/β-catenin signaling, a molecular pathway essential for learning and memory. Despite a recognized role in cancer (non-neuronal) cells, DEK expression and function is not well characterized in the central nervous system. We conducted a gene ontology analysis (ToppGene), using a cancer database to identify genes associated with DEK deficiency, which pinpointed several genes associated with cognitive-related diseases (i...
November 23, 2017: Neuroscience
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